Abiraterone prodrugs

Abstract

Provided are methods for administering to a disease or condition afflicted with sex hormone dependence or androgen receptor actuation, sustained release abiraterone prodrug formulations, methods, and kits for parenteral administration in human subjects, such as sex hormone dependent benign or malignant conditions such as prostate cancer, androgen receptor driven cancer, and / or syndromes caused by hyperandrogen.

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 315,240, filed on March 1, 2022, and U.S. Provisional Application No. 63 / 425,839, filed on November 16, 2022, the contents of each of which are incorporated herein by reference in their entirety.

[0002] The present disclosure generally relates to novel abiraterone prodrugs and long-acting, depot-based parenteral formulations of abiraterone prodrugs. The present disclosure is subject to a wide range of applications, such as for intramuscular (IM) injection to patients with sex hormone-dependent or androgen receptor-driven diseases or conditions, such as androgen- or estrogen-dependent benign or malignant conditions or androgen receptor-driven cancers, including various cancers (such as prostate cancer, bladder cancer, hepatocellular carcinoma, lung cancer, breast cancer and ovarian cancer, etc.), and for the treatment of non-neoplastic syndromes caused by excessive production of androgens (including classic and non-classical congenital adrenal hyperplasia, endometriosis, polycystic ovary syndrome, precocious puberty, hirsutism, etc.). Background Art

[0003] Abiraterone ((3β)-17-(pyridin-3-yl)androsta-5,16-dien-3-ol; CAS No.: 154229-19-3); Formula: C 24 H 31 NO; molar weight: 349.5 g / mol) is an inhibitor of CYP17A1 (CYP17A1 is a member of the cytochrome P450 enzyme superfamily that catalyzes the synthesis of cholesterol, steroids and other lipids and is involved in drug metabolism). CYP17A1 has both 17α-hydroxylase activity and 17,20-lyase activity. Abiraterone effectively and selectively inhibits both CYP17A1 17α-hydroxylase and 17,20-lyase activities, which may be referred to as CYP17A1 hydroxylase activity and CYP17A1 lyase activity, or simply hydroxylase or lyase activity, respectively, hereinafter. The 17α-hydroxylase activity of CYP17A1 is required for the production of glucocorticoids such as cortisol. However, the hydroxylase and 17,20-lyase activities of CYP17A1 are required for the production of androgenic steroids (e.g., androstenedione, testosterone, and dihydrotestosterone) and estrogenic steroids (estrone, estradiol, estriol) by converting 17α-hydroxypregnenolone to the sex steroid precursor dehydroepiandrosterone, see Figure 1 Thus, abiraterone interferes with the synthesis of androgens and estrogens both in the gonads (primarily in the testes and ovaries) and outside the gonads (e.g., in the adrenal glands and in the tumor itself).

[0004] Although abiraterone itself is poorly absorbed, it can be administered orally as an abiraterone acetate prodrug. Abiraterone acetate is also poorly absorbed but can be converted to abiraterone in the intestines, and after cleavage of the acetate prodrug, abiraterone is poorly absorbed into the bloodstream. Abiraterone acetate ((3β)-17-(3-pyridyl)androsten-5-acetate; CAS No. 154229-18-2) is available in the United States for The brand name is approved for the treatment of castration-resistant or castration-sensitive prostate cancer. Abiraterone acetate is also now available worldwide.

[0005] It is known that the orally administered abiraterone acetate prodrug is not significantly absorbed by the gastrointestinal tract (and the prodrug is barely detectable in plasma). In contrast, it has been demonstrated that abiraterone acetate is hydrolyzed to abiraterone in the intraluminal environment, resulting in abiraterone supersaturation, which is responsible for the strong driving force for abiraterone absorption (Stappaerts et al., Eur. J. Pharmaceutics Biopharmaceutics 90: 1, 2015).

[0006] Because abiraterone blocks the normal physiological production of steroids by the adrenal glands, its prodrug formulations are often prescribed with low-dose steroids to prevent adrenal insufficiency. (250 mg tablets) is approved in the United States only for use in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC) and metastatic castration-sensitive prostate cancer (CSPC). The prescribing information provided recommends 1,000 mg (4 x 250 mg tablets) taken orally once daily in combination with prednisone (5 mg) taken orally twice daily for CRPC patients or once daily for CSPC patients. Approved only for use in combination with prednisone or prednisolone.

[0007] Because administration of abiraterone acetate with food increases the absorption of abiraterone acetate and, therefore, may result in increased and highly variable exposures, which could potentially lead to a variety of side effects, including cardiovascular side effects and / or hepatotoxicity, the prodrug should be taken on an empty stomach at least one hour before or two hours after a meal. The prescribing information for states that it must be taken on an empty stomach and that food should not be consumed for at least two hours before and at least one hour after oral administration.

[0008] The prescribing information explains that for patients with metastatic CRPC, a daily oral dose of 1,000 mg Abiraterone steady state C maxThe value was 226±178 ng / mL (mean±SD) and its area under the curve (AUC) value was 1173±690 ng.hr / mL (mean±SD). A single-dose (1,000 mg) crossover study found that when Systemic exposure of abiraterone is increased when administered with food. When administered with a low-fat meal (7% fat, 300 calories), the C max The value and AUC value were approximately 7 times and 5 times higher, respectively, while when When administered with a high-fat meal (57% fat, 825 calories), the levels were approximately 17-fold and 10-fold higher, respectively.

[0009] The currently approved solid oral dosage form of the prodrug abiraterone acetate has several disadvantages. For example, it has very low bioavailability, requiring patients to take a large pill burden per day (4 x 250 mg tablets once daily). In addition, due to the combination of low bioavailability and a large food effect, it can result in highly variable blood levels in patients. Furthermore, because abiraterone is rapidly cleared, this approved dosing regimen results in a daily C of abiraterone. min , which is believed to be associated with a loss of therapeutic effect in patients with metastatic CRPC. In addition, it is known that abiraterone acetate is a non-selective CYP17A1 inhibitor and inhibits both hydroxylase activity and lyase activity, resulting in an undesirable increase in steroids upstream of the hydroxylase. For example, it is known that oral administration of abiraterone acetate can lead to elevated progesterone levels, which can activate certain progesterone-activated mutant androgen receptors and lead to resistance to CYP17A1 inhibition. See, for example, Chen, EJ et al. Clin. Cancer. Res. 21(6): 1273-1280 (2014).

[0010] Non-oral modes of administration (eg, parenteral routes) have been explored for other classes of drugs. However, to date, there are no commercially available sustained-release injectable prodrug formulations of abiraterone. Summary of the invention

[0011] The present disclosure generally relates to novel abiraterone prodrugs, long-acting abiraterone prodrug formulations and methods of use thereof, for example, for treating human subjects suffering from sex hormone-dependent or androgen receptor-driven diseases or conditions, such as sex hormone-dependent benign or malignant conditions, androgen receptor-driven cancers and / or syndromes caused by androgen excess, see also U.S. Patent No. 10,792,292B2 issued to Propella Therapeutics, Inc. on October 6, 2020; PCT application No. PCT / US2021 / 048607 filed on September 1, 2021 and PCT application No. PCT / US2022 / 016278 filed on February 14, 2022, the contents of each of which are incorporated herein by reference in their entirety.

[0012] The novel abiraterone prodrug can generally be a fatty acid ester of abiraterone, which releases abiraterone and a safe and degradable fatty acid component after cleavage. Compared with oral abiraterone acetate preparations, the novel abiraterone prodrug and preparations herein are a breakthrough because they provide increased bioavailability, eliminate food effects, reduce pill burden, lower dosing frequency, and sustained effective abiraterone plasma levels, for example, for at least one week after administration of the abiraterone prodrug preparation, typically for at least two weeks and up to ten weeks or longer. In addition, pharmacokinetic and pharmacodynamic studies of representative abiraterone prodrugs have demonstrated that the novel abiraterone prodrug and preparation are suitable for once a week, once a month, once every two months, once every three months, or even less frequent administration for the treatment of diseases or conditions that are sex hormone-dependent or androgen receptor-driven, such as sex hormone-dependent benign or malignant conditions, androgen receptor-driven cancers, and / or syndromes caused by androgen excess in human subjects. This feature alone represents a significant improvement over currently marketed abiraterone prodrugs. This is a significant improvement over the FDA-approved tablets, which require patients to carry a large daily pill burden (4 x 250 mg tablets once daily).

[0013] As described in detail herein, the present disclosure demonstrates that administration of abiraterone prodrugs, particularly abiraterone decanoate, can selectively inhibit CYP17A1 lyase activity over CYP17A1 hydroxylase activity in human subjects, providing new treatment options where lyase selectivity is desired or considered beneficial. In particular, as shown in the Examples section and Figures herein, human subjects treated with one or more intramuscular injections of abiraterone decanoate can achieve lyase selectivity without significant increases in steroid levels that may occur due to inhibition of CYP17A1 hydroxylase activity. In addition, the clinical results herein demonstrate that human subjects treated with abiraterone decanoate do not experience mineralocorticoid toxicity, which is a result of administering abiraterone decanoate to human subjects. Tablets are common side effects. See, e.g., McKay, RR et al. Cancer 125(4):524-532 (2019). The selectivity of the cleavage enzyme found in humans after administration of abiraterone decanoate was unexpected; by administering to human subjects The same selectivity is not observed with tablets. For example, oral administration of abiraterone acetate is known to result in an 80-fold increase in mineralocorticoid concentrations, which can lead to significant side effects, with 30% of men receiving abiraterone acetate having signs and symptoms of mineralocorticoid excess - hypertension, hypokalemia, and edema, and may develop resistance to the regimen because the 40-fold increase in progesterone and pregnenolone produced by the oral abiraterone acetate regimen can stimulate androgen receptors, progesterone receptors, etc. See, for example, Wright, C. et al. Eur, J. Endocrinol. 182(4):413-421(2020) and Prescribing Information (2011). On the other hand, FIG. 11 shows that the fold changes from baseline for corticosterone and progesterone observed in groups 3, 4, and 5 were significantly reduced compared to those changes reported in the literature for Zytiga at day 28. In addition, the present disclosure shows that administration of abiraterone prodrugs, particularly abiraterone decanoate, is effective in reducing or eliminating cancer metastases to one or more lymph nodes. Without wishing to be bound by theory, it is believed that the efficacy observed in treating cancer metastases to lymph nodes is due in part to lymphatic delivery of agents (e.g., lipophilic prodrugs, such as abiraterone decanoate), which results in higher concentrations of active drug within the lymphatic system.

[0014] The present disclosure also demonstrates that administration of abiraterone prodrugs, particularly abiraterone decanoate, can reduce PSA levels in patients continuously throughout the treatment period (see, e.g. Figure 7 ). In addition, the response rates (in terms of reduction in PSA levels) observed in CRPC patients in the studies described herein are also much higher than the response rates reported in the literature for abiraterone acetate and enzalutamide, see e.g. Fig.9A and 9B .

[0015] The present disclosure also demonstrates that certain pharmaceutically acceptable antioxidants are beneficial in stabilizing abiraterone prodrugs, particularly abiraterone decanoate formulations for storage at room temperature.

[0016] In addition, the present disclosure shows that the administration of abiraterone prodrugs, particularly abiraterone decanoate, can effectively treat patients whose disease (cancer) has progressed after androgen receptor antagonist-based treatment, particularly enzalutamide treatment. In some embodiments, the abiraterone prodrugs herein can also be used in combination with androgen receptor antagonists (such as enzalutamide) to achieve a synergistic effect in inhibiting cancer growth.

[0017] The present disclosure also shows that administration of abiraterone decanoate to human subjects is generally well tolerated. This is consistent with earlier observations in animal studies, where no hepatotoxicity was observed with intramuscular administration of abiraterone decanoate at the doses tested.

[0018] Thus, the compositions and methods described herein provide for the administration of oral administration of drugs in human subjects that are not available through commercially available oral formulations. New therapeutic options enabled by tablets. In addition, the compositions and methods described herein meet a long-standing unmet need by providing an alternative to oral formulations that suffer from the following problems: (1) poor bioavailability, (2) interactions with ingested food, (3) delivery of highly variable blood levels of the parent drug with the potential for reduced efficacy and increased side effects, (4) requirement for daily dosing and high pill burden, (5) requirement for castration, (6) poor patient compliance due to the need to fast within hours of administration, high pill burden, and conflicting dosing schedules when supplemented with daily administration of prednisone or prednisolone and taken with food, and (7) undesirable excess of mineralocorticoids, particularly progesterone.

[0019] In some embodiments, the present disclosure provides the following embodiments in enumerated paragraphs [1]-

[109] :

[0020] [1] A method for treating a disease or condition in a human subject in need thereof, the method comprising administering, preferably parenterally, to the human subject a therapeutically effective amount of a pharmaceutical composition comprising an abiraterone prodrug (e.g., an abiraterone lipophilic ester), wherein the disease or condition is sex hormone-dependent or androgen receptor-driven, such as a sex hormone-dependent benign or malignant condition or a syndrome caused by androgen excess.

[0021] [2] The method of [1], wherein the abiraterone prodrug is abiraterone decanoate or a pharmaceutically acceptable salt thereof,

[0022]

[0023] Abiraterone decanoate.

[0024] [3] The method of [1] or [2], wherein the method selectively inhibits CYP17A1 lyase activity compared to CYP17A1 hydroxylase activity in the human subject.

[0025] [4] The method of any one of [1]-[3], wherein the disease or condition is polycystic ovary syndrome (PCOS), congenital adrenal hyperplasia (CAH), or endometriosis.

[0026] [5] The method of any one of [1]-[3], wherein the disease or condition is cancer, wherein the cancer is sex hormone-dependent or androgen receptor-driven cancer.

[0027] [6] The method of [5], wherein the cancer is prostate cancer, endometrial cancer, or ovarian cancer.

[0028] [7] The method of [5], wherein the cancer is prostate cancer.

[0029] [8] The method of any one of [5]-[7], wherein the cancer has metastasized to one or more lymph nodes, and the administration of the pharmaceutical composition effectively inhibits the growth of the cancer in the one or more lymph nodes.

[0030] [9] The method of any one of [5]-[8], wherein the cancer is prostate cancer characterized by a Gleason score ≤6.

[0031]

[10] The method of any one of [5]-[9], wherein the human subject has measurable prostate-specific antigen.

[0032]

[11] The method of any one of [5]-[7], wherein the cancer is localized prostate cancer, such as high-risk localized prostate cancer.

[0033]

[12] The method of any one of [5]-[7], wherein the cancer is metastatic castration-sensitive prostate cancer, non-metastatic castration-sensitive prostate cancer, non-metastatic castration-resistant prostate cancer, or metastatic castration-resistant prostate cancer.

[0034]

[13] The method of any one of [5]-[7], wherein the cancer is newly diagnosed high-risk metastatic hormone-sensitive prostate cancer.

[0035]

[14] The method of any one of [5]-[7], wherein the cancer is metastatic CRPC (mCRPC), wherein the human subject is asymptomatic or has mild symptoms after failure of androgen deprivation therapy, and wherein chemotherapy is not clinically indicated.

[0036]

[15] The method of any one of [5]-[7], wherein the cancer is metastatic CRPC (mCRPC), wherein the human subject's disease progresses during or after a taxane-based chemotherapy regimen, such as a docetaxel-based or cabazitaxel-based chemotherapy regimen.

[0037]

[16] The method of any one of [5]-[7], wherein the cancer is refractory prostate cancer.

[0038]

[17] The method of any one of [5]-

[16] , wherein (i) the human subject's disease progresses during or after an androgen receptor antagonist-based treatment, such as enzalutamide-based treatment; and / or (ii) the human subject has developed resistance to the combination treatment with abiraterone acetate and prednisone, including resistance due to elevated progesterone levels.

[0039]

[18] The method of any one of [1] to

[17] , wherein the pharmaceutical composition comprises abiraterone decanoate in its basic form and a pharmaceutically acceptable carrier.

[0040]

[19] The method of

[18] , wherein the pharmaceutically acceptable carrier comprises a pharmaceutically acceptable oil and optionally another pharmaceutically acceptable solvent.

[0041]

[20] The method of

[19] , wherein the pharmaceutically acceptable oil comprises a triglyceride (e.g., long chain and / or medium chain triglycerides), and the other pharmaceutically acceptable solvent, if present, comprises an alcohol, ester and / or acid solvent.

[0042]

[21] The method of

[19] or

[20] , wherein the pharmaceutically acceptable oil is selected from vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil and soybean oil, and the other pharmaceutically acceptable solvent, if present, comprises benzyl alcohol, benzyl benzoate or a combination thereof.

[0043]

[22] The method of any one of

[18] -

[21] , wherein the pharmaceutically acceptable carrier comprises corn oil, benzyl alcohol and benzyl benzoate.

[0044]

[23] The method of any one of [1]-

[22] , wherein the pharmaceutical composition comprises, per milliliter, (a) abiraterone decanoate in its base form in an amount of about 100 mg to about 300 mg (e.g., about 100 mg, about 120 mg, about 150 mg, about 180 mg, about 200 mg, or about 250 mg); (b) benzyl alcohol in an amount of about 50 mg to about 150 mg (e.g., about 75 mg, about 100 mg, or about 125 mg); (c) benzyl benzoate in an amount of about 100 mg to about 300 mg (e.g., about 100 mg, about 150 mg, about 200 mg, or about 250 mg); and (d) corn oil in an amount up to 1 milliliter.

[0045]

[24] The method of any one of [1]-

[22] , wherein the pharmaceutical composition comprises, per milliliter, (a) about 180 mg of abiraterone decanoate in its base form; (b) about 50 mg to about 150 mg (e.g., about 75 mg, about 100 mg, or about 125 mg) of benzyl alcohol; (c) about 100 mg to about 300 mg (e.g., about 100 mg, about 150 mg, about 200 mg, or about 250 mg) of benzyl benzoate; and (d) corn oil, q.s. up to 1 milliliter.

[0046]

[25] The method of any one of

[18] -

[24] , wherein the weight ratio of benzyl alcohol to benzyl benzoate in the pharmaceutical composition ranges from about 2:1 to about 1:5 (e.g., about 1:1 to 1:3, such as about 1:2).

[0047]

[26] The method of any one of [1]-

[25] , wherein the abiraterone prodrug is abiraterone decanoate and the abiraterone decanoate is substantially pure, for example characterized as having a purity of at least 95%, preferably at least 98%, such as about 98.5%, about 99%, about 99.5% or more by weight.

[0048]

[27] The method of any one of [1]-

[26] , wherein the pharmaceutical composition is characterized as having a viscosity of less than 0.1 Pa*s, such as about 0.05 Pa*s or less.

[0049]

[28] The method of any of [1]-

[27] , wherein the pharmaceutical composition is characterized as having a glide force of about 1-10 N when measured using a 21G, 1.5 inch needle, and / or having a glide force of about 2-15 N when measured using a 23G, 1.5 inch needle, and / or having a glide force of about 30-150 N when measured using a 27G, 1.5 inch needle.

[0050]

[29] The method of any one of [1]-

[28] , wherein the pharmaceutical composition is characterized as being <788> and / or <789> When measured, it has no more than 1000 particles with a size of 10 μm or more, and no more than 300 particles with a size of 25 μm or more.

[0051]

[30] The method of any one of [1]-

[29] , wherein the pharmaceutical composition is characterized as having a <85> Bacterial endotoxins measured at less than 100 EU / ml, such as less than 25 EU / ml.

[0052]

[31] The method of any one of [1]-

[30] , wherein the human subject is not castrated.

[0053]

[32] The method of any one of [1]-

[30] , wherein the human subject is castrated.

[0054]

[33] The method of any one of claims [1]-

[30] and

[32] , wherein the human subject is treated with a gonadotropin-releasing hormone agonist and / or antagonist.

[0055]

[34] The method of any one of claims [1]-

[33] , wherein the pharmaceutical composition is administered to the human subject by intramuscular injection.

[0056]

[35] The method of any one of [1]-

[34] , wherein the pharmaceutical composition is administered to the human subject once every 1-3 months, such as once every three months.

[0057]

[36] The method of any one of [1]-

[35] , wherein each administration of the pharmaceutical composition comprises administering to the human subject about 50 mg to about 2000 mg of abiraterone decanoate, such as about 180 mg, about 360 mg, about 720 mg, about 1260 mg, about 1800 mg, or any range between the recited values, preferably, the pharmaceutical composition is administered to the human subject once every three months, and each administration of the pharmaceutical composition comprises administering to the human subject about 1260 mg of abiraterone decanoate.

[0058]

[37] The method as described in any one of [1]-

[36] , further comprising administering to the subject a first-generation androgen receptor antagonist, such as paxlovid, bicalutamide, flutamide, nilutamide, or topirutamide.

[0059]

[38] The method of any one of [1]-

[37] , further comprising administering a second generation androgen receptor antagonist (e.g., apalutamide, darolutamide, or enzalutamide) to the human subject.

[0060]

[39] The method of

[38] , wherein the second generation androgen receptor antagonist is enzalutamide.

[0061]

[40] The method as described in any one of [1]-

[39] , further comprising administering to the human subject a third generation androgen receptor antagonist (such as an N-terminal domain inhibitor) or an androgen receptor degrader molecule, alone or in combination with one or more first or second generation androgen receptor antagonists.

[0062]

[41] The method of any one of [1]-

[40] , further comprising administering to the human subject one or more agents selected from the group consisting of hydrocortisone, prednisone, prednisolone, methylprednisolone and dexamethasone, preferably dexamethasone.

[0063]

[42] The method of any one of [1]-

[41] , further comprising administering to the human subject a poly (ADP ribose) polymerase (PARP) inhibitor, such as niraparib, rucaparib, olaparib, talazoparib, veliparib, and fluzoparib.

[0064]

[43] The method as described in any one of [1]-

[42] , further comprising administering a chemotherapeutic agent to the human subject, such as a taxane-based chemotherapeutic agent (e.g., docetaxel, cabazitaxel, paclitaxel, etc.) or a platinum-based chemotherapeutic agent (e.g., cisplatin, carboplatin, oxaliplatin, etc.).

[0065]

[44] A method as described in any one of [1]-

[43] , further comprising administering to the human subject an immunotherapy, such as Sipuleucel-T, an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as pembrolizumab or nivolumab, or an anti-PD-L1 antibody such as avelumab or atezolizumab), or an anti-CTLA-4 antibody (e.g., ipilimumab), etc.

[0066]

[45] The method of any one of [1]-

[44] , further comprising administering a bispecific T cell engager (BiTE) therapy, such as blinatumomab or solitonumab, to the human subject.

[0067]

[46] The method of any one of [1]-

[45] , further comprising administering to the human subject a kinase inhibitor, such as sunitinib, dasatinib, cabozantinib, erdafitinib, dovitinib, capasitinib, onvansetinib, iparectinib, afrottinib, asetinib, abotinib, opanib, etc.

[0068]

[47] The method of any one of [1]-

[46] , further comprising administering a bone protective agent (e.g., denosumab, zoledronic acid) to the human subject, and wherein the human subject is characterized as having prostate cancer (e.g., CRPC) with bone metastases.

[0069]

[48] ​​The method as described in any of [1]-

[47] , further comprising administering to the human subject a therapeutic agent selected from the following: 1) an anti-IL23 targeted monoclonal antibody, such as tetropezumab; 2) selenium, such as sodium selenite; 3) an EZH2 inhibitor, such as CPI-1205, GSK2816126 or tazemetostat; 4) a CDK4 / 6 inhibitor, such as palbociclib, ribociclib, abemaciclib; 6) a bromodomain and extra-terminal domain (BET) inhibitor, such as CCS1477, INCB057643, alobrexib, ZEN-3694 or molibuxib (GSK525762); 7) an anti-CD105 antibody, such as TRC105 or carlotuximab; 8) ) niclosamide; 9) an A2A receptor antagonist such as AZD4635; 10) a PI3K inhibitor such as AZD-8186, buparib, or datolicoxib; 11) another nonsteroidal CYP17A1 inhibitor such as sevitronel; 12) an antiprogestin such as onapristone; 13) navitoclax; 14) an HSP90 inhibitor such as orecoxib (AT13387); 15) an HSP27 inhibitor such as OGX-427; 16) a 5-α-reductase inhibitor such as dutasteride; 17) metformin; 18) AMG-386; 19) dextromethorphan; 20) theophylline; 21) hydroxychloroquine; and 22) lenalidomide.

[0070]

[49] A method as described in any of [1]-

[48] , wherein the method further comprises administering to the human subject one or more kinase modulators selected from the following: FLT-3 (FMS-like tyrosine kinase) inhibitors, AXL (anexelekto) inhibitors (e.g., gilteritinib), CDK (cyclin-dependent kinase) inhibitors (such as CDK1, 2, 4, 5, 6, 7 or 9 inhibitors), retinoblastoma (Rb) inhibitors, protein kinase B (AKT) inhibitors, SRC inhibitors, IκB kinase 1 (IKK1) inhibitors, PIM-1 modulators, Lemur tyrosine kinase 2 (LMTK2) modulators, Lyn inhibitors, Aurora A inhibitors, ANPK (alpha nuclear protein kinase) inhibitors, extracellular signal-regulated kinase (ERK) modulators, c-jun N-terminal kinase (JNK) modulators, large MAP kinase (BMK) modulators, p38 mitogen-activated protein kinase (MAPK) modulators, and combinations thereof.

[0071]

[50] A method as described in any of [1]-

[49] , wherein (i) the human subject has not received chemotherapy or hormone therapy prior to administration of the pharmaceutical composition, such as an mCRPC patient who has not received chemotherapy; and / or (ii) the human subject has liver impairment, such as moderate to severe liver impairment (Child-Pugh B or C) prior to administration of the pharmaceutical composition.

[0072]

[51] The method of any one of [1]-

[50] , wherein (i) the human subject has prostate cancer and the method does not increase progesterone levels in the human subject to a level associated with adverse clinical outcomes and drug resistance, such as a serum or plasma progesterone level greater than about 3 nM when measured 4 weeks, 6 weeks or 12 weeks after the first administration of the pharmaceutical composition; and / or (ii) the human subject has prostate cancer and the human subject is characterized as having a serum or plasma progesterone level greater than about 3 nM after three months of treatment with abiraterone, such as Zytiga (oral abiraterone acetate and prednisone), prior to the first administration of the pharmaceutical composition.

[0073]

[52] The method of any one of [1]-

[51] , wherein the human subject suffers from one or more side effects associated with inhibition of CYP17A1 hydroxylase activity, or the human subject is susceptible to one or more side effects associated with inhibition of CYP17A1 hydroxylase activity, such as mineralocorticoid toxicity.

[0074]

[53] The method of any one of [1] to

[52] , wherein the abiraterone prodrug is abiraterone decanoate, and at least a portion of the administered abiraterone decanoate is absorbed through the lymphatic system.

[0075]

[54] The method of any one of [1]-

[53] , wherein the administration of the pharmaceutical composition is effective to achieve a sustained reduction in serum testosterone levels in the human subject to 50% or less below baseline within 15 days after the first administration of the pharmaceutical composition.

[0076]

[55] The method of

[54] , wherein the sustained reduction in serum testosterone levels is characterized in that once the serum testosterone levels in the human subject are reduced to 50% or less below baseline, the serum testosterone levels are maintained at 50% or less below baseline for up to 8 weeks or longer after the first administration of the pharmaceutical composition.

[0077]

[56] The method of any one of [1]-

[55] , wherein the administration of the pharmaceutical composition does not increase the serum progesterone level in the human subject by (i) more than 40% above baseline 4 weeks after the first administration of the pharmaceutical composition; and / or (ii) more than 40% above baseline 2 weeks to 12 weeks after the second administration of the pharmaceutical composition.

[0078]

[57] A method as described in any of [1]-

[55] , wherein the administration of the pharmaceutical composition does not increase the serum progesterone level in the human subject by (i) more than 20% above baseline 4 weeks after the first administration of the pharmaceutical composition; (ii) more than 20% above baseline 6 weeks, 8 weeks, 10 weeks and / or 12 weeks after the first administration of the pharmaceutical composition; and / or (iii) more than 20% above baseline 2 weeks to 12 weeks after the second administration of the pharmaceutical composition.

[0079]

[58] A method as described in any of [1]-

[57] , wherein, where applicable, the administration of the pharmaceutical composition reduces the prostate specific antigen level in the human subject, preferably, at least at one time point after the first administration of the pharmaceutical composition and / or after one or more subsequent administrations of the pharmaceutical composition, the prostate specific antigen level is reduced to 50% or less, preferably 90% or less, compared to the baseline PSA level.

[0080]

[59] A method for reducing serum testosterone levels in a human subject in need thereof, the method comprising parenterally administering to the human subject an effective amount of a pharmaceutical composition comprising an abiraterone prodrug (e.g., an abiraterone lipophilic ester), wherein the pharmaceutical composition is administered in an amount effective to achieve a sustained reduction in serum testosterone levels in the human subject to 50% or less below baseline within 15 days after the first administration of the pharmaceutical composition, wherein the administration of the pharmaceutical composition does not cause the serum progesterone level in the human subject to (i) increase by 50% or less within 4 weeks after the first administration of the pharmaceutical composition. and / or (ii) increases by more than 40% over baseline 2 weeks to 12 weeks after the second administration of the pharmaceutical composition, preferably, does not increase serum progesterone levels in the human subject (i) by more than 20% over baseline 4 weeks after the first administration of the pharmaceutical composition; (ii) by more than 20% over baseline 6 weeks, 8 weeks, 10 weeks and / or 12 weeks after the first administration of the pharmaceutical composition; and / or (iii) by more than 20% over baseline 2 weeks to 12 weeks after the second administration of the pharmaceutical composition.

[0081]

[60] The method of

[59] , wherein the abiraterone prodrug is abiraterone decanoate or a pharmaceutically acceptable salt thereof,

[0082]

[0083] Abiraterone decanoate.

[0084]

[61] The method of

[59] or

[60] , wherein the human subject suffers from a disease or condition that is sex hormone-dependent or androgen receptor-driven, such as a sex hormone-dependent benign or malignant condition or a syndrome caused by androgen excess.

[0085]

[62] The method of

[61] , wherein the disease or condition is any one of those described in [4]-

[17] .

[0086]

[63] The method of any one of

[59] -

[62] , wherein the sustained reduction in serum testosterone levels is characterized in that once the serum testosterone levels in the human subject are reduced to 50% or less below baseline, the serum testosterone levels remain below 50% or less of baseline for up to 8 weeks or longer after the first administration of the pharmaceutical composition.

[0087]

[64] The method of

[59] -

[63] , wherein the human subject suffers from one or more side effects associated with inhibition of CYP17A1 hydroxylase activity, or the human subject is susceptible to one or more side effects associated with inhibition of CYP17A1 hydroxylase activity, such as mineralocorticoid toxicity.

[0088]

[65] A method for treating cancer in a human subject in need thereof, wherein the cancer is a sex hormone-dependent or androgen receptor-driven cancer and the cancer has metastasized to one or more lymph nodes, the method comprising parenterally administering to the human subject a therapeutically effective amount of a pharmaceutical composition comprising an abiraterone prodrug (e.g., an abiraterone lipophilic ester).

[0089]

[66] The method of

[65] , wherein the abiraterone prodrug is abiraterone decanoate or a pharmaceutically acceptable salt thereof,

[0090]

[0091] Abiraterone decanoate.

[0092]

[67] The method of

[65] or

[66] , wherein the administration of the pharmaceutical composition effectively inhibits the growth of the cancer in the one or more lymph nodes.

[0093]

[68] The method of any one of

[65] -

[67] , wherein the cancer is prostate cancer, such as any of those described in [8]-

[17] as applicable.

[0094]

[69] A method of treating cancer in a human subject in need thereof, wherein the cancer is a sex hormone-dependent or androgen receptor-driven cancer, wherein the human subject's disease progresses during or after androgen receptor antagonist-based therapy, such as enzalutamide-based therapy, the method comprising parenterally administering to the human subject a therapeutically effective amount of a pharmaceutical composition comprising an abiraterone prodrug (e.g., an abiraterone lipophilic ester).

[0095]

[70] The method of

[69] , wherein the abiraterone prodrug is abiraterone decanoate or a pharmaceutically acceptable salt thereof,

[0096]

[0097] Abiraterone decanoate.

[0098]

[71] The method of any one of

[69] or

[70] , wherein the cancer is prostate cancer, such as any of those described in [8]-

[17] as applicable.

[0099]

[72] A method of treating cancer in a human subject in need thereof, wherein the cancer is a sex hormone-dependent or androgen receptor-driven cancer, the method comprising parenterally administering to the human subject a therapeutically effective amount of a pharmaceutical composition comprising an abiraterone prodrug (e.g., an abiraterone lipophilic ester), wherein the human subject is further treated with an androgen receptor antagonist, such as enzalutamide, prior to, simultaneously with, or after the first parenteral administration of the pharmaceutical composition.

[0100]

[73] The method of

[72] , wherein the abiraterone prodrug is abiraterone decanoate or a pharmaceutically acceptable salt thereof,

[0101]

[0102] Abiraterone decanoate.

[0103]

[74] The method of any one of

[72] or

[73] , wherein the cancer is prostate cancer, such as any of those described in [8]-

[17] as applicable.

[0104]

[75] The method of any one of

[59] -

[74] , wherein the pharmaceutical composition is as described in any one of

[18] -

[30] .

[0105]

[76] The method of any one of

[59] -

[75] , wherein the pharmaceutical composition is administered to the human subject by intramuscular injection.

[0106]

[77] The method of any one of

[59] -

[76] , wherein the pharmaceutical composition is administered to the human subject once every 1-3 months, such as once every three months.

[0107]

[78] A method as described in any of

[59] -

[77] , wherein each administration of the pharmaceutical composition comprises administering to the human subject about 50 mg to about 2000 mg of abiraterone decanoate, such as about 180 mg, about 360 mg, about 720 mg, about 1260 mg, about 1800 mg, or any range between the recited values, preferably, the pharmaceutical composition is administered to the human subject once every three months, and each administration of the pharmaceutical composition comprises administering to the human subject about 1260 mg of abiraterone decanoate.

[0108]

[79] The method of any one of

[59] -

[78] , wherein the human subject is castrated.

[0109]

[80] The method of any one of

[59] -

[79] , wherein the human subject is treated with a gonadotropin-releasing hormone agonist and / or antagonist.

[0110]

[81] The method of any one of

[59] -

[78] , wherein the human subject is not castrated.

[0111]

[82] A method as described in any of

[59] -

[81] , wherein (i) the human subject has not received chemotherapy or hormone therapy prior to administration of the pharmaceutical composition, such as an mCRPC patient who has not received chemotherapy; and / or (ii) the human subject has liver impairment, such as moderate to severe liver impairment (Child-Pugh B or C) prior to administration of the pharmaceutical composition.

[0112]

[83] The method of any one of

[59] -

[82] , wherein (i) the human subject has prostate cancer and the method does not increase progesterone levels in the human subject to a level associated with adverse clinical outcomes and drug resistance, such as a serum or plasma progesterone level greater than about 3 nM when measured 4 weeks, 6 weeks or 12 weeks after the first administration of the pharmaceutical composition; and / or (ii) the human subject has prostate cancer and the human subject is characterized as having a serum or plasma progesterone level greater than about 3 nM after three months of treatment with abiraterone, such as Zytiga (oral abiraterone acetate and prednisone), prior to the first administration of the pharmaceutical composition.

[0113]

[84] The method of any one of

[65] -

[83] , wherein the human subject suffers from one or more side effects associated with inhibition of CYP17A1 hydroxylase activity, or the human subject is susceptible to one or more side effects associated with inhibition of CYP17A1 hydroxylase activity, such as mineralocorticoid toxicity.

[0114]

[85] The method of any one of

[59] -

[84] , wherein the abiraterone prodrug is abiraterone decanoate, and at least a portion of the administered abiraterone decanoate is absorbed through the lymphatic system.

[0115]

[86] A method as described in any of

[59] -

[85] , further comprising administering to the human subject one or more additional therapies according to any of

[37] -

[49] .

[0116]

[87] The method of any one of [1]-

[86] , wherein the abiraterone prodrug is administered in an effective amount to reduce the serum testosterone level in the human subject to 80% or less below baseline, such as 85% or less below baseline or 90% or less below baseline, when measured 24 weeks after the first administration of the abiraterone prodrug.

[0117]

[88] The method of any one of [1]-

[87] , wherein the abiraterone prodrug is administered in an effective amount to reduce the serum testosterone level in the human subject to about 50 ng / dL or less (e.g., about 40 ng / dL or less, about 30 ng / dL or less, about 20 ng / dL or less, about 10 ng / dL or less, etc.) when the human subject is a non-castrated human subject, or to about 1 ng / dL or less when the human subject is a castrated human subject.

[0118]

[89] The method of any one of [1]-

[88] , wherein the human subject will benefit from selective inhibition of CYP17A1 lyase activity over CYP17A1 hydroxylase activity.

[0119]

[90] The method of any one of [1]-

[40] and

[42] -

[89] , where applicable, wherein the administration of the pharmaceutical composition does not cause mineralocorticoid toxicity in the human subject.

[0120]

[91] The method of any one of [1]-

[40] and

[42] -

[90] , where applicable, wherein the human subject is not treated with an agent effective for treating mineralocorticoid toxicity.

[0121]

[92] The method of any one of [1]-

[40] and

[42] -

[90] , where applicable, wherein the human subject is not treated with an agent that is a glucocorticoid or mineralocorticoid receptor antagonist.

[0122]

[93] A pharmaceutical composition comprising an abiraterone decanoate solution, wherein each milliliter of the abiraterone decanoate solution comprises: (a) abiraterone decanoate in its alkaline form in an amount of about 100 mg to about 300 mg (e.g., about 100 mg, about 120 mg, about 150 mg, about 180 mg, about 200 mg, or about 250 mg); and (b) benzyl alcohol in an amount of about 50 mg to about 150 mg (e.g., about 75 mg, about 1 00mg or about 125mg); (c) benzyl benzoate in an amount of about 100mg to about 300mg (e.g., about 100mg, about 150mg, about 200mg or about 250mg); (d) 3-mercapto-1,2-propanediol in an amount of about 0.5mg to about 20mg (e.g., about 0.5mg, about 1mg, about 2mg or about 5mg); and (e) corn oil, q.s. to 1 ml, wherein the abiraterone decanoate has the following structure:

[0123]

[0124] Abiraterone decanoate.

[0125]

[94] The pharmaceutical composition of

[93] , wherein each milliliter of the abiraterone decanoate solution comprises: (a) about 180 mg of abiraterone decanoate in its alkaline form; (b) about 50 mg to about 150 mg (e.g., about 75 mg, about 100 mg, or about 125 mg) of benzyl alcohol; (c) about 100 mg to about 300 mg (e.g., about 100 mg, about 150 mg, about 200 mg, or about 250 mg) of benzyl benzoate; (d) about 0.5 mg to about 2 mg of 3-mercapto-1,2-propanediol (e.g., about 0.5 mg, about 1 mg, or about 2 mg); and (e) corn oil, q.s. to 1 milliliter.

[0126]

[95] A pharmaceutical composition as described in

[93] or

[94] , wherein the weight ratio of benzyl alcohol to benzyl benzoate in the pharmaceutical composition ranges from about 2:1 to about 1:5 (e.g., about 1:1 to 1:3, such as about 1:2).

[0127]

[96] A pharmaceutical composition as described in any of

[93] -

[95] , wherein the abiraterone decanoate is substantially pure, for example characterized as having a purity of at least 95%, preferably at least 98%, such as about 98.5%, about 99%, about 99.5% or more by weight.

[0128]

[97] A pharmaceutical composition as described in any of

[93] -

[96] , wherein the abiraterone decanoate solution is contained in a container with a head space, such as a vial, an ampoule, a bottle, etc., wherein the head space is filled with an inert gas, such as nitrogen.

[0129]

[98] The pharmaceutical composition of any one of

[93] -

[96] , wherein the abiraterone decanoate solution is contained in a syringe.

[0130]

[99] The pharmaceutical composition of any one of

[93] -

[98] , which is storage-stable at room temperature for 1 month or longer, preferably for 2 months or 3 months or longer.

[0131]

[100] A pharmaceutical composition as described in any of

[93] -

[99] , wherein the abiraterone decanoate solution is characterized as having a viscosity of less than 0.1 Pa*s, such as about 0.05 Pa*s or less.

[0132]

[101] A pharmaceutical composition as described in any of

[93] -

[100] , wherein the abiraterone decanoate solution is characterized as having a glide force of about 1-10 N when measured using a 21G, 1.5-inch needle, and / or having a glide force of about 2-15 N when measured using a 23G, 1.5-inch needle, and / or having a glide force of about 30-150 N when measured using a 27G, 1.5-inch needle.

[0133]

[102] The pharmaceutical composition of any one of

[93] -

[101] , wherein the abiraterone decanoate solution is characterized as <788> and / or <789> When measured, it has no more than 1000 particles with a size of 10 μm or more, and no more than 300 particles with a size of 25 μm or more.

[0134]

[103] The pharmaceutical composition of any one of

[93] -

[102] , wherein the abiraterone decanoate solution is characterized as having a <85> Bacterial endotoxins measured at less than 100 EU / ml, such as less than 25 EU / ml.

[0135]

[104] A pharmaceutical composition as described in any of

[93] -

[103] , wherein the pharmaceutical composition is in the form of a unit dosage form, wherein the unit dosage form contains about 1 ml to about 20 ml of the abiraterone decanoate solution.

[0136]

[105] The pharmaceutical composition of any one of

[93] -

[103] , wherein the pharmaceutical composition is in the form of a unit dosage form, wherein the unit dosage form contains about 1 or 2 ml of the abiraterone decanoate solution.

[0137]

[106] The pharmaceutical composition of any one of

[93] -

[103] , wherein the pharmaceutical composition is in the form of a unit dosage form, wherein the unit dosage form contains about 3 ml of the abiraterone decanoate solution.

[0138]

[107] A pharmaceutical composition as described in any of

[93] -

[103] , wherein the pharmaceutical composition is in the form of a unit dosage form, wherein the unit dosage form contains about 4 ml to about 10 ml (e.g., about 4, 5, 6, 7, 8, 9 or 10 mL) of the abiraterone decanoate solution, preferably, about 7 mL of the abiraterone decanoate solution.

[0139]

[108] The method of any one of [1]-

[92] , wherein the pharmaceutical composition is any one of those according to

[93] -

[107] , where applicable.

[0140]

[109] The method of any one of [1]-

[90] and

[108] , comprising administering to the human subject (i) intramuscularly administering abiraterone decanoate once every one to three months, preferably once every three months, preferably about 1260 mg of abiraterone decanoate intramuscularly once every three months; and (ii) orally administering dexamethasone once daily, preferably at a daily dose of about 0.5 mg / day.

[0141] Embodiments of the present disclosure can meet the long-term needs of the treatment of sex hormone-dependent diseases and oncology fields, including sex hormone-dependent or androgen receptor-driven cancers such as prostate cancer. Embodiments of the present disclosure can also meet the long-term needs of the treatment of syndrome fields caused by androgen excess syndrome. Embodiments of the present disclosure can overcome the major shortcomings and deficiencies of prior art preparations of abiraterone acetate (including commercially available oral dosage forms) by providing a long-acting, sustained-release reservoir-based parenteral preparation of abiraterone prodrug, a method for producing the preparation, a method for treating the preparation, and a kit for conveniently applying the preparation to a subject of various diseases including prostate cancer who needs to treat.

[0142] Thus, features have been summarized rather broadly so that the detailed description that follows may be better understood and the contribution of the present invention to the art may be better appreciated. Of course, there are additional features that will be further described below. Indeed, it should be understood that both the foregoing summary and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the present disclosure.

[0143] In this regard, before explaining in detail at least one embodiment of the present invention, it is to be understood that the application of the present invention is not limited to the details of component construction and arrangement set forth in the following description or shown in the accompanying drawings. The present invention can have other embodiments and can be implemented and executed in various ways. In addition, it is to be understood that the terms and terminology employed herein are for descriptive purposes and should not be considered limiting.

[0144] Therefore, those skilled in the art will recognize that the concepts upon which the present disclosure is based can be easily used as the basis for designing other formulations, methods, systems, kits and compositions to achieve the several objects of the present disclosure. Therefore, it is important that equivalent constructions are included in the present disclosure without departing from the spirit and scope of the present disclosure.

[0145] The accompanying drawings are included to provide a further understanding and are incorporated in and constitute a part of this specification, illustrate several embodiments, and together with the description, explain principles. BRIEF DESCRIPTION OF THE DRAWINGS

[0146] Figure 1Biochemical pathways showing the effects of CYP17A1 inhibition on the synthesis of androgens, estrogens, glucocorticoids, progesterone, and mineralocorticoids are presented.

[0147] Figure 2 A representative analysis of a batch of high purity abiraterone decanoate is shown.

[0148] Figure 3A The results of the change in serum testosterone levels relative to baseline (cycle 1, day 1 value or C1D1 value) after intramuscular injection of 180 mg, 360 mg, 720 mg, 1260 mg or 1800 mg of abiraterone decanoate to patients in groups 1, 2, 3, 4 and 5, respectively, are shown. Groups 1 and 2 were also orally administered prednisone, 5 mg once a day or twice a day; Groups 3, 4 and 5 were orally administered dexamethasone, 0.5 mg once a day; Groups 1, 2, 3, 4 and 5 in the other figures were treated with the same glucocorticoid regimen, respectively.

[0149] Figure 3B Results are shown for the change in serum dehydroepiandrosterone sulfate (DHEA-S) levels relative to baseline (Cycle 1, Day 1 values) following intramuscular injection of 180 mg, 360 mg, 720 mg, 1260 mg, or 1800 mg abiraterone decanoate to patients in Cohorts 1, 2, 3, 4, and 5, respectively.

[0150] Figure 3C Results are shown for the change in serum dehydroepiandrosterone (DHEA) levels relative to baseline (Cycle 1, Day 1 values) following intramuscular injection of 180 mg, 360 mg, 720 mg, 1260 mg or 1800 mg abiraterone decanoate to patients in Cohorts 1, 2, 3, 4 and 5, respectively.

[0151] Figure 3D Results are shown for the change in serum androstenedione levels relative to baseline (Cycle 1, Day 1 values) following intramuscular injection of 180 mg, 360 mg, 720 mg, 1260 mg or 1800 mg abiraterone decanoate to patients in Cohorts 1, 2, 3, 4 and 5, respectively.

[0152] Figure 3E Results are shown for the change in serum progesterone levels relative to baseline (Cycle 1, Day 1 values) following intramuscular injection of 180 mg, 360 mg, 720 mg, 1260 mg or 1800 mg abiraterone decanoate to patients in Cohorts 1, 2, 3, 4 and 5, respectively.

[0153] Figure 3F Results are shown for the change in serum 11-deoxycorticosterone levels relative to baseline (Cycle 1, Day 1 values) following intramuscular injection of 720 mg, 1260 mg, or 1800 mg abiraterone decanoate to patients in Cohorts 3, 4, and 5, respectively.

[0154] Figure 3G Results are shown for the change in serum corticosterone levels from baseline (Cycle 1, Day 1 values) following intramuscular injection of 720 mg, 1260 mg or 1800 mg abiraterone decanoate to patients in Cohorts 3, 4 and 5, respectively.

[0155] Figure 4A Shown are the plasma abiraterone decanoate concentration versus time curves following intramuscular injection of 180 mg, 360 mg, 720 mg, 1260 mg or 1800 mg abiraterone decanoate to patients in Cohorts 1, 2, 3, 4 and 5, respectively.

[0156] Figure 4B Shown are the plasma abiraterone concentration versus time curves following intramuscular injection of 180 mg, 360 mg, 720 mg, 1260 mg or 1800 mg abiraterone decanoate to patients in Cohorts 1, 2, 3, 4 and 5, respectively.

[0157] Figure 4C Shown are the plasma abiraterone sulfate concentration versus time curves following intramuscular injection of 180 mg, 360 mg, 720 mg, 1260 mg, or 1800 mg abiraterone decanoate to patients in Cohorts 1, 2, 3, 4, and 5, respectively.

[0158] Figure 4D Shown are the plasma abiraterone N-oxide concentration versus time curves following intramuscular injection of 180 mg, 360 mg, 720 mg, 1260 mg or 1800 mg abiraterone decanoate to patients in Cohorts 1, 2, 3, 4 and 5, respectively.

[0159] Figure 4E Shown are plasma abiraterone N-oxide sulfate concentration versus time profiles following intramuscular injection of 180 mg, 360 mg, 720 mg, 1260 mg, or 1800 mg abiraterone decanoate to patients in Cohorts 1, 2, 3, 4, and 5, respectively.

[0160] Figure 5 Shown is the change in serum steroid levels following intramuscular injection of 180 mg abiraterone decanoate to Patient 1 compared to baseline.

[0161] Figure 6 Shown is the change in serum steroid levels compared to baseline following intramuscular injection of 360 mg abiraterone decanoate to Patient 2.

[0162] Figure 7 Shown are patient swim graphs for prostate specific antigen (PSA) responses (% change from baseline) for Cohorts 3, 4, and 5 during the study period.

[0163] Fig. 8AThe best PSA response (% change from baseline) during the study period is shown for all patients in Cohorts 3, 4, and 5.

[0164] Figure 8B Shown are the best PSA responses (% change from baseline) for chemotherapy-previously CRPC patients in Cohorts 3, 4, and 5 during the study period.

[0165] Fig.9A The percentage of patients achieving a ≥50% decline in PSA from baseline at any time point in the study in chemotherapy-naive CRPC patients from Cohorts 3, 4, and 5 is shown compared to literature reported values ​​obtained with abiraterone acetate (AA) / prednisone or enzalutamide (Enza). Outcomes in chemotherapy-naive CRPC patients. PRL-02 stands for intramuscular abiraterone decanoate treatment.

[0166] Fig. 9B The percentage of patients achieving a ≥90% decline in PSA from baseline at any time point in the study for chemotherapy-naive CRPC patients from Cohorts 3, 4, and 5 is shown compared to literature reported values ​​obtained with abiraterone acetate (AA) or enzalutamide (Enza). Outcomes for CRPC patients prior to chemotherapy.

[0167] Fig.10 Graph showing the percent change in PSA from baseline during the study for all patients studied with CRPC.

[0168] Fig.11A Shown is a bar graph comparing the mean mineralocorticoid fold increase from baseline in Cohorts 3, 4, or 5 versus Zytiga / prednisone.

[0169] Fig. 11B Serum progesterone levels versus time are shown for patients in cohorts 4 and 5, with an LLOQ of 1.59 nM. The maximum individual progesterone level for cohorts 1-3 was 2.5 nM.

[0170] Fig.12 A representative flow chart is shown illustrating the steps typically performed during the manufacture of abiraterone decanoate solution. DETAILED DESCRIPTION

[0171] Broadly speaking, the present disclosure relates to novel methods for treating or preventing diseases or conditions associated with sex hormones. Some embodiments of the present disclosure are based in part on the following unexpected discovery: abiraterone prodrugs can be administered to human subjects to selectively inhibit CYP17A1 lyase activity compared to hydroxylase activity. Some embodiments of the present disclosure are also based in part on the following unexpected discovery: administration of abiraterone prodrugs to human subjects can reduce or eliminate cancer metastases to one or more lymph nodes. Some embodiments of the present disclosure are based in part on the following unexpected discovery: administration of abiraterone prodrugs can effectively treat human subjects who progress during or after androgen receptor antagonist-based treatment (such as enzalutamide-based treatment). The data shown in the present disclosure further indicate that the abiraterone prodrugs herein can achieve synergy when used in combination with androgen receptor antagonists (such as enzalutamide). Some embodiments of the present disclosure are based in part on the following discovery of the applicant: the inclusion of a pharmaceutically acceptable antioxidant, particularly monothioglycerol, in abiraterone decanoate formulation can produce a formulation that is stable at room temperature for storage for 9 months or more.

[0172] As described in detail herein and in part in U.S. Patent No. 10,792,292B2 and PCT Application Nos. PCT / US2021 / 048607 and PCT / US2022 / 016278, the methods herein can have advantages over existing methods in many aspects, including, but not limited to, rapid and sustained reduction of serum testosterone, no need for castration, reduced or no liver toxicity compared to methods using oral abiraterone acetate formulations, improved bioavailability, elimination of food effects associated with oral abiraterone acetate formulations, reduced pill burden, better patient compliance, reduced dosing frequency, sustained and stable blood levels of active drug, lower C max , thereby reducing related side effects, etc.

[0173] Without wishing to be bound by theory, it is also believed that the formulations and methods of using abiraterone decanoate herein provide significant advantages over oral abiraterone acetate regimens in that 1) abiraterone decanoate is actively absorbed or has high permeability to cells and tissues, thereby delivering higher concentrations of abiraterone equivalents to tissues; 2) abiraterone decanoate efficacy is therefore independent of plasma levels, and in fact, abiraterone decanoate may be initially delivered to tissues, while plasma concentrations may be secondary and due to elimination from tissues; 3) the long pharmacological half-life of abiraterone decanoate may be due to the slow conversion of abiraterone decanoate to abiraterone in tissues; and 4) the high tissue concentrations of abiraterone observed from intramuscular administration of abiraterone decanoate cannot be produced by an oral regimen because abiraterone released in the intestine has low solubility and permeability (i.e., high plasma concentrations are required to increase concentrations in cells and tissues).

[0174] Thus, in various embodiments, the present disclosure provides novel methods for modulating serum steroid hormone levels (such as for reducing testosterone levels), novel methods for treating or preventing diseases or disorders mediated by or associated with such steroids, such as sex hormone-dependent or androgen receptor-driven cancers, and / or abiraterone prodrugs and formulations useful in such methods.

[0175] Treatment

[0176] In some embodiments, the disclosure provides a method for treating a disease or condition described herein in a human subject in need thereof. The method generally comprises administering to a human subject a pharmaceutical composition comprising abiraterone prodrug (e.g., abiraterone lipophilic ester) in a therapeutically effective amount parenterally. The disease or condition is typically sex hormone-dependent or androgen receptor-driven, such as sex hormone-dependent benign or malignant conditions or syndromes caused by androgen excess.

[0177] Typically, the abiraterone prodrug is abiraterone decanoate or a pharmaceutically acceptable salt thereof,

[0178]

[0179] Abiraterone decanoate.

[0180] As used herein, the term "abiraterone decanoate" in its basic form is to be understood as having the structure shown above. Unless explicitly mentioned as being in salt form or clearly contrary to the context, "abiraterone decanoate" as used herein is to be understood as being in its basic form.

[0181] In some embodiments, the method is characterized in that administration of the abiraterone prodrug can selectively inhibit CYP17A1 lyase activity compared to CYP17A1 hydroxylase activity in a human subject. See, for example, any of the methods described in [3] and [4]-

[58] and

[108] -

[109] (where applicable) in the Summary of the Invention section. As shown in Example 3 herein, the inventors unexpectedly discovered that intramuscular administration of abiraterone decanoate to a human subject achieved lyase selectivity that was superior to oral administration of abiraterone acetate ( Tablets) treatment. Serum steroid levels showed that although abiraterone decanoate administration significantly reduced the levels of androgens such as testosterone, steroids upstream of the hydroxylase enzyme were not significantly reduced and returned to baseline levels within about 4 weeks. See, for example, Figure 3E .like Figure 3EAs shown, even at the highest dose, progesterone levels returned to baseline within about 6 weeks, and progesterone levels did not increase significantly during the second cycle (i.e., after the second administration of abiraterone decanoate on day 84). Therefore, the methods herein can be advantageously used to treat diseases or conditions in human subjects in which cleavage enzyme selectivity is desired or considered to be beneficial, such as endometrial cancer, endometriosis, ovarian cancer, and prostate cancer (such as localized prostate cancer, etc.). In some embodiments, the methods herein can be particularly suitable for treating human subjects suffering from one or more side effects associated with hydroxylase inhibition (such as caused by oral abiraterone acetate treatment) or susceptible to one or more side effects. In some embodiments, the methods herein can be particularly suitable for treating human subjects who are intolerant or otherwise sensitive to increased and / or decreased steroid levels (such as increased progesterone levels) due to hydroxylase inhibition. In any of the embodiments described herein, the methods herein can also be particularly suitable for treating human subjects who will benefit from selective inhibition of CYP17A1 cleavage enzyme activity compared to CYP17A1 hydroxylase activity. For example, an increase in progesterone (such as when plasma progesterone levels are greater than 3 nM) has also been shown to be associated with adverse clinical outcomes, as progesterone has been shown to act as a carcinogenic hormone in prostate cancer. Hou et al. Cell Reports Medicine, 3: 100561 (2022). In addition, patients who respond to abiraterone treatment (e.g., Zytiga) typically relapse within 1 to 2 years. Chen et al. show that one mechanism of this drug resistance may be associated with elevated progesterone levels, which may lead to the selection and / or activation of tumor cells expressing certain mutant androgen receptors. See, for example, Chen, EJ et al. Clin. Cancer. Res. 21 (6): 1273-1280 (2014). Therefore, such as prostate cancer patients who have elevated progesterone levels after oral abiraterone acetate treatment and / or are susceptible to one or more side effects such as mineralocorticoid toxicity or drug resistance due to elevated progesterone levels will be beneficially treated with the methods herein. In some embodiments, the methods herein may be particularly useful for treating human subjects who have developed resistance to oral abiraterone acetate combined with prednisone, including resistance due to elevated progesterone levels. In some embodiments, the methods herein are used to treat human subjects with prostate cancer, and the methods do not increase progesterone levels in the human subjects to levels associated with adverse clinical outcomes and resistance. In some embodiments, because the methods herein do not result in significantly elevated progesterone levels, a separate drug that reduces progesterone levels is not required in such patients to control one or more side effects and / or resistance associated with elevated progesterone levels.

[0182] In some embodiments, the method herein is characterized in that it is used to treat cancer in a human subject in need, wherein the cancer is a sex hormone-dependent or androgen receptor-driven cancer that has metastasized to one or more lymph nodes. See, for example, any of the methods described in

[65] -

[68] and

[75] -

[92] and

[108] -

[109] (where applicable) of the Summary of the Invention section. In some embodiments, administration of the pharmaceutical composition is effective in inhibiting the growth of cancer in one or more lymph nodes. As shown in Example 3 herein, at least in Patient 1, administration of abiraterone decanoate completely regressed cancer that metastasized to one or more lymph nodes. Without wishing to be bound by theory, it is believed that the efficacy observed in treating cancer that metastasizes to lymph nodes is partially attributed to lymphatic delivery of an agent (e.g., a lipophilic prodrug, such as abiraterone decanoate), which results in higher concentrations of active drugs within the lymphatic system. It is expected that the observed efficacy is not limited to prostate cancer as shown in the examples herein. In some embodiments, the cancer that metastasizes to one or more lymph nodes can be prostate cancer (e.g., as described herein).

[0183] In some embodiments, the method is characterized in that it is used to treat cancer in a human subject in need thereof, wherein the cancer is a sex hormone-dependent or androgen receptor-driven cancer, wherein the disease in the human subject progresses during or after an androgen receptor antagonist-based treatment (such as an enzalutamide-based treatment). See, for example, any of the methods described in

[69] -

[71] and

[75] -

[92] and

[108] -

[109] (where applicable) of the Summary of the Invention section. In some embodiments, the cancer is prostate cancer (e.g., as described herein). As also shown in Example 3 herein, administration of abiraterone decanoate was also found to be effective in at least patient 2 whose disease (prostate cancer) progressed after enzalutamide treatment. This result and other results herein indicate that the abiraterone prodrugs herein, particularly abiraterone decanoate, can achieve synergistic effects when used in combination with androgen receptor antagonists (such as enzalutamide).

[0184] In some embodiments, the method is characterized in that it is used to treat cancer in a human subject in need, wherein the cancer is a sex hormone-dependent or androgen receptor-driven cancer, wherein the human subject is further treated with an androgen receptor antagonist (such as enzalutamide) before, simultaneously with, or after parenteral administration of the pharmaceutical composition. See, for example, any of the methods described in

[72] -

[74] and

[75] -

[92] and

[108] -

[109] (where applicable) of the Summary of the Invention. For example, in some embodiments, an androgen receptor antagonist, such as enzalutamide, is administered after the first parenteral administration of the pharmaceutical composition. In some embodiments, an androgen receptor antagonist, such as enzalutamide, is administered before the first parenteral administration of the pharmaceutical composition. Since androgen receptor antagonists such as enzalutamide (Xtandi) are typically administered orally at different dosing frequencies, there is no particular limitation on the dosing regimen for treating human subjects in combination with parenteral administration and one or more androgen receptor antagonists. For example, in some embodiments, one or more androgen receptor antagonists can be administered to human subjects by oral administration (or another route of administration) with a typical dosing regimen of one or more androgen receptor antagonists, such as a dosing regimen approved by the U.S. Food and Drug Administration for one or more corresponding androgen receptor antagonists. For example, in some embodiments, one or more androgen receptor antagonists are enzalutamide, and enzalutamide can be orally administered to human subjects once a day at a daily dose of about 160 mg. In some embodiments, enzalutamide treatment can be started at least one day before the first parenteral administration of the pharmaceutical composition. In some embodiments, enzalutamide treatment can be started on the same day as the first parenteral administration of the pharmaceutical composition. In some embodiments, enzalutamide treatment can be started at least one day after the first parenteral administration of the pharmaceutical composition. In some embodiments, one or more androgen receptor antagonists can be administered to human subjects in combination with the parenteral administration of the pharmaceutical composition to achieve a synergistic effect on cancer treatment.

[0185] There is no particular limitation on the human subjects suitable for treatment with the methods herein, including those human subjects in various stages of disease or treatment and other characteristics. For example, in some embodiments, the human subject may be a non-castrated human subject. As described in detail in PCT / US2022 / 016278, it is found that the administration of abiraterone prodrugs can result in a continuous decrease in testosterone in the subject within a few days after the first administration of the prodrug, without the need for castration or another drug that effectively reduces testosterone levels. However, in some embodiments, the human subject may also be castrated. For example, in some embodiments, chemical castration may be performed on the human subject, such as treatment with a gonadotropin-releasing hormone agonist and / or antagonist. As used herein, the terms "castration", "castration (of)", etc. should be understood to cover all forms of castration, including surgical castration and chemical castration. In some embodiments, the method herein may also administer a pharmaceutical composition comprising abiraterone prodrugs to the human subject, without considering whether the human subject is castrated. In some embodiments, the human subject has not yet undergone prostatectomy. In some embodiments, the human subject may be characterized as having liver impairment prior to administration of the abiraterone prodrug, such as moderate to severe liver impairment (Child-Pugh B or C class). In some embodiments, the human subject has prostate cancer, and the methods herein do not increase progesterone levels in the human subject to levels associated with adverse clinical outcomes and drug resistance, such as serum or plasma progesterone levels greater than about 3 nM when measured 4 weeks, 6 weeks, or 12 weeks after the first administration of the pharmaceutical composition. In some embodiments, the human subject has prostate cancer, and the human subject is characterized as having serum or plasma progesterone levels greater than about 3 nM after three months of abiraterone treatment, such as Zytiga (oral abiraterone acetate and prednisone) treatment, prior to the first administration of the pharmaceutical composition. For example, prostate cancer patients who experience elevated serum or plasma progesterone levels after abiraterone acetate treatment, such as Zytiga (oral abiraterone acetate and prednisone) treatment, particularly those whose progesterone levels rise to greater than about 3nM after 3 months of treatment, can be advantageously treated by converting abiraterone acetate treatment using the methods described herein. In some embodiments, unless contrary to the context, "3nM" progesterone levels herein may refer to plasma progesterone levels. In some embodiments, unless contrary to the context, "3nM" progesterone levels herein may refer to serum progesterone levels. In some embodiments, human subjects may be characterized as being sensitive or otherwise intolerant to gonadotropin-releasing hormone antagonists and / or agonists. In some embodiments, human subjects may be characterized as not having received chemotherapy or not having received hormone therapy before administering the pharmaceutical composition herein. However, in some embodiments, human subjects may also be treated with chemotherapy or hormone therapy before administering the pharmaceutical composition herein.For example, in some embodiments, the human subject may suffer from a disease or condition (e.g., prostate cancer) that progresses during or after chemotherapy and / or hormone therapy, such as a taxane-based chemotherapy regimen, such as docetaxel-based or cabazitaxel-based chemotherapy. In some embodiments, the disease of the human subject progresses during or after treatment based on an androgen receptor antagonist (such as enzalutamide-based treatment). In some embodiments, the disease of the human subject progresses during or after treatment based on oral abiraterone acetate (such as treatment based on oral abiraterone acetate and prednisone). For example, in some embodiments, the human subject develops resistance to the combination treatment of abiraterone acetate and prednisone, including resistance due to increased progesterone levels. As discussed above, a human subject suffering from one or more side effects associated with inhibiting CYP17A1 hydroxylase activity or susceptible to one or more side effects can also be advantageously treated with the methods herein, which selectively inhibit lyase activity compared to hydroxylase activity. In some embodiments, the methods herein may further comprise the steps of identifying and / or selecting a human subject having any one or more of the characteristics described herein, and administering the pharmaceutical composition herein to the human subject identified and / or selected as having one or more of the characteristics described herein, such as a human subject having any of those characteristics described in [4]-

[17] ,

[31] -

[33] ,

[61] -

[62] ,

[64] ,

[65] ,

[69] ,

[79] -

[84] and

[89] of the Summary of the Invention. In some embodiments, the methods herein may further include the steps of determining whether a human subject has one or more of the characteristics described herein, and administering the pharmaceutical composition herein to a human subject determined to have one or more of the characteristics described herein, such as a human subject having any of the characteristics described in [4]-

[17] ,

[31] -

[33] ,

[61] -

[62] ,

[64] ,

[65] ,

[69] ,

[79] -

[84] and

[89] of the Summary of the Invention.

[0186] In the methods herein, where the human subject is not castrated and / or does not wish to become castrated, another drug that is effective in reducing serum and / or gonadal testosterone levels is not administered to the human subject at the same time as the administration of the abiraterone prodrug, is not administered to the human subject during treatment with the abiraterone prodrug, or does not otherwise interfere with the treatment using the abiraterone prodrug. For example, in some embodiments, the human subject is not treated with a gonadal testosterone suppression drug (except the abiraterone prodrug administered) in an amount that is effective in reducing the serum testosterone level in the human subject. In some embodiments, the human subject is not treated with a gonadotropin-releasing hormone antagonist and / or agonist that is effective in reducing the serum testosterone level in the human subject. In some embodiments, the human subject is not treated with any gonadal testosterone suppression drug other than the abiraterone prodrug administered. In some embodiments, the human subject is not treated with any gonadotropin-releasing hormone antagonist and / or agonist. In some embodiments, the human subject is not treated with a drug selected from buserelin, leuprolide, deserelin, futirelin, histrelin, gonadorelin, lanreotide, goserelin, nafarelin, perforelin, and triptorelin. In some embodiments, the human subject is not treated with a drug selected from abarelix, cetrorelix, degarelix, ganirelix, elagrolide, linzagollik, and regliox. In some embodiments, the human subject may be sensitive to or otherwise intolerant of gonadotropin-releasing hormone antagonists and / or agonists.

[0187] Various diseases or conditions are suitable for treatment with the methods herein. For example, in some embodiments, the disease or condition can be a sex hormone-dependent benign or malignant condition, an androgen receptor-driven cancer, or a syndrome caused by androgen excess. In some embodiments, hormone-dependent benign or malignant conditions can be androgen-dependent conditions and estrogen-dependent conditions, such as androgen or estrogen-dependent cancers. In some embodiments, sex hormone-dependent benign or malignant conditions can be prostate cancer or breast cancer. In some embodiments, sex hormone-dependent benign or malignant conditions are CRPC or CSPC. In some embodiments, sex hormone-dependent benign or malignant conditions can be metastatic CRPC or metastatic CSPC. In some embodiments, sex hormone-dependent benign or malignant conditions can also be ovarian cancer, bladder cancer, hepatocellular carcinoma, or lung cancer. Various non-tumor syndromes caused by androgen excess can also be treated with the methods herein, for example, syndromes caused by androgen excess such as endometriosis, polycystic ovary syndrome, classic or non-classical congenital adrenal hyperplasia, precocious puberty, hirsutism, etc.

[0188] In some embodiments, the methods herein are used to treat polycystic ovary syndrome (PCOS), congenital adrenal hyperplasia (CAH), or endometriosis.

[0189] In some specific embodiments, the methods herein are used to treat sex hormone-dependent or androgen receptor-driven cancers. In some embodiments, sex hormone-dependent or androgen receptor-driven cancers have metastasized to one or more lymph nodes, and the administration of the pharmaceutical composition effectively inhibits the growth of cancer in the one or more lymph nodes. In some embodiments, sex hormone-dependent or androgen receptor-driven cancers are prostate cancers that have metastasized to one or more lymph nodes, and the administration of the pharmaceutical composition effectively inhibits the growth of cancer in the one or more lymph nodes.

[0190] In some embodiments, the sex hormone-dependent or androgen receptor-driven cancer may be androgen receptor-positive salivary duct carcinoma, or androgen receptor-positive glioblastoma multiforme.

[0191] In some embodiments, the methods herein are used to treat prostate cancer, endometrial cancer, or ovarian cancer.

[0192] In some embodiments, the methods herein are used to treat prostate cancer (eg, any of those described herein).

[0193] Suitable for the prostate cancer treated with the method herein is not particularly limited, and includes but is not limited to abiraterone or its derivatives (particularly abiraterone acetate) have been approved for listing (for example, in the U.S. or Europe) or abiraterone or its derivatives (for example, abiraterone acetate) are in or have been in clinical trials, such as any of those prostate cancers in those trials registered on the website clinicaltrials.gov as of the submission date of the present application. For example, in some embodiments, prostate cancer can be primary / localized prostate cancer (new diagnosis or early stage), advanced prostate cancer (for example, recurrent prostate cancer after castration, locally advanced prostate cancer, etc.), recurrent prostate cancer (for example, prostate cancer unresponsive to primary therapy), non-metastatic castration-resistant prostate cancer, metastatic prostate cancer, metastatic castration-resistant prostate cancer (CRPC) or hormone-sensitive prostate cancer. In some embodiments, prostate cancer is localized prostate cancer, such as high-risk localized prostate cancer. In some embodiments, human subjects suffering from prostate cancer are characterized as having an elevated amount of prostate-specific antigen, for example, after radical prostatectomy. In some embodiments, prostate cancer is metastatic castration-sensitive prostate cancer, non-metastatic castration-sensitive prostate cancer, non-metastatic castration-resistant prostate cancer, or metastatic castration-resistant prostate cancer. In some embodiments, prostate cancer is a newly diagnosed high-risk metastatic hormone-sensitive prostate cancer. In some embodiments, prostate cancer is CRPC, and in some embodiments, patients with CRPC have not received chemotherapy. In some embodiments, prostate cancer is metastatic CRPC (mCRPC), and in some embodiments, patients with mCRPC have not received chemotherapy. In some embodiments, prostate cancer is metastatic CRPC (mCRPC), wherein human subjects are asymptomatic or have mild symptoms after failure of androgen deprivation therapy, wherein chemotherapy has no clinical indications. In some embodiments, prostate cancer is metastatic CRPC (mCRPC), wherein the disease of human subjects progresses during or after a taxane-based chemotherapy regimen, such as a docetaxel-based or cabazitaxel-based chemotherapy regimen. In some embodiments, prostate cancer is refractory prostate cancer. As used herein and unless otherwise specified, the phrase "refractory prostate cancer" means a prostate cancer that is unresponsive to anticancer treatment or a prostate cancer that is not adequately responsive to anticancer treatment. Refractory prostate cancer can also include recurrent (recurring) or relapsing (relapsing) prostate cancer. As used herein and unless otherwise specified, the phrase "relapsing prostate cancer" means a prostate cancer that was once responsive to anticancer treatment but has become no longer responsive to such treatment or no longer adequately responsive to such treatment.As used herein and unless otherwise indicated, the phrase "recurrent (or recurrent) prostate cancer" means prostate cancer that returns after a patient has been diagnosed with prostate cancer at an earlier stage, received treatment, or was previously diagnosed as cancer-free.

[0194] Prostate cancer can be characterized by certain Gleason scores. Typically, a pathologist observes the arrangement of cancer cells in the prostate and assigns scores on a scale of 3 to 5 from 2 different locations (the area where the cancer is most obvious and another area of ​​growth). Cancer cells that look similar to healthy cells have lower scores. Cancer cells that don't look like healthy cells or that look more aggressive have higher scores. The scores from the two areas are added together to get a total score between 6 and 10.

[0195] The methods herein are not particularly limited to prostate cancers having a particular Gleason score. For example, in some embodiments, prostate cancer can be characterized as having a Gleason score of ≤6. In some embodiments, prostate cancer can be characterized as having a Gleason score of ≤7. In some embodiments, prostate cancer can be characterized as having a Gleason score of ≤8. In some embodiments, prostate cancer can be characterized as having a Gleason score of ≤9. In some embodiments, prostate cancer can be characterized as having a Gleason score of ≤10.

[0196] Prostate cancer can be characterized by a certain level of prostate-specific antigen (PSA). For example, in combination with other indicators, PSA levels less than 10ng / ml, Gleason score ≤6, and clinical stage ≤T2a can be considered as having or developing metastatic disease or dying from prostate cancer. The risk is low; PSA levels between 10-20ng / ml, Gleason score 7 or clinical stage T2b / c can be considered as medium risk; and PSA levels greater than 20ng / ml, Gleason score ≥8 or clinical stage ≥T3 can be considered as high risk. In addition, in some cases, prostate cancer patients may not be able to detect PSA for a period of time after receiving treatment. In some cases, PSA levels subsequently rise, such as higher than the lowest point ≥0.2ng / ml, ≥2.0ng / ml, etc., which can indicate recurrent prostate cancer. The method herein is not particularly limited to treating human subjects with any specific PSA level. In some embodiments, human subjects can be characterized as PSA increases ≥2.0ng / ml relative to the lowest point.

[0197] In some embodiments, the methods herein are used to treat newly diagnosed high-risk metastatic hormone-sensitive prostate cancer.

[0198] In some embodiments, the methods herein can also be used to treat breast cancer. Breast cancer suitable for treatment with the methods herein is not particularly limited. For example, in some embodiments, breast cancer can be molecular apocrine HER2-negative breast cancer, metastatic breast cancer, such as ER+ metastatic breast cancer, ER+ and HER2-negative breast cancer, AR+ triple-negative breast cancer, etc.

[0199] In some embodiments, diseases or conditions associated with 21-hydroxylase deficiency can also be treated using the methods herein.

[0200] In some embodiments, the methods herein can be used to treat a human subject having a cancer such as prostate cancer, breast cancer, adrenal cancer, leukemia, lymphoma, myeloma, Waldenstrom's macroglobulinemia, monoclonal gammopathy, benign monoclonal gammopathy, heavy chain disease, bone and connective tissue sarcomas, brain tumors, thyroid cancer, pancreatic cancer, pituitary cancer, eye cancer, vaginal cancer, vulvar cancer, cervical cancer, uterine cancer, ovarian cancer, esophageal cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, gallbladder cancer, bile duct cancer, lung cancer, testicular cancer, pelvic cancer, oral cancer, skin cancer, kidney cancer, Wilms' tumor, and / or bladder cancer.

[0201] In some embodiments, the methods herein may include treating the human subject with one or more additional therapies. For example, in some embodiments, the human subject is further treated with radiation therapy. In some embodiments, the human subject is further treated with surgery. In some embodiments, the methods are used to treat prostate cancer and include a combination therapy that further includes administering one or more additional therapies to the human subject, for example, as described herein under the section entitled Combined Therapy for Prostate Cancer as described herein below. Non-limiting examples of useful additional therapies also include any of those therapies described in

[37] -

[49] in the Summary of the Invention section herein.

[0202] In some embodiments according to the method herein, abiraterone prodrug (particularly abiraterone decanoate) is administered to a human subject in combination with dexamethasone. For example, in any method described herein, unless otherwise specified or contrary to the context, the method may include administering abiraterone decanoate and dexamethasone to a human subject. In some embodiments, the method is used to treat prostate cancer, such as for treating a CRPC patient who has not received chemotherapy, including a human subject of mCRPC patients who have not received chemotherapy. In some embodiments, the method may include administering abiraterone decanoate intramuscularly to a human subject (i) once every one to three months, preferably, administering about 1260 mg abiraterone decanoate intramuscularly once every three months; and (ii) oral administration of dexamethasone once daily. In some embodiments, dexamethasone is orally administered to a human subject at a dose of about 0.1 to 1 mg / day (such as about 0.5 mg / day). Additional therapies may also be used in conjunction with abiraterone decanoate and dexamethasone treatment, including but not limited to any of such other therapies described herein, such as any of those applicable therapies described in

[37] -

[49] in the Summary of the Invention section herein.

[0203] It is believed that the combined treatment of dexamethasone and abiraterone prodrug (preferably, abiraterone decanoate) is advantageous compared to the combination with another glucocorticoid (such as prednisone or prednisolone).Under the background of oral abiraterone acetate, it is shown that compared with prednisone, dexamethasone can be advantageously used to provide better upstream steroid level control, better ACTH level control, better effect of treating prostate cancer and better and more lasting PSA reaction and progression-free survival (PFS), lower glucocorticoid receptor agonist activity (it is the drug resistance mechanism to abiraterone acetate and prednisone treatment) and longer half-life etc..Not wishing to be bound by theory, it is believed that longer half-life is a reason that dexamethasone is a better glucocorticoid used in combination with long-acting abiraterone prodrug, particularly abiraterone decanoate herein.In addition, it is known that in the patient who progresses in abiraterone acetate and prednisone treatment, the glucocorticoid partner of abiraterone acetate is converted to dexamethasone from prednisone and can cause the elimination of clinical drug resistance of prostate cancer. See, e.g., JAMA Oncology, 5(8), 1159–1167 (2019); British Journal of Cancer, 111(12), 2248–2253 (2014); The Oncologist, 19(12), 1231–1240 (2014); The Oncologist, 20(5), e13–e13 (2015); British Journal of Cancer, 119(9), 1052–1059 (2018); and European Urology, 67(4), 673–679 (2015).

[0204] In some embodiments according to the method herein, glucocorticoid replacement therapy (for example, glucocorticoids are used, such as hydrocortisone, prednisone, prednisolone, methylprednisolone or dexamethasone) is not needed. For example, for human subjects who may suffer from potential illness (such as diabetes), glucocorticoids may be contraindicated. In some embodiments, the feature of the method can also be that human subjects are not treated with glucocorticoid replacement therapy. In some embodiments, human subjects are not treated with an agent selected from hydrocortisone, prednisone, prednisolone, methylprednisolone and dexamethasone. In some embodiments, the method herein can include applying a mineralocorticoid receptor antagonist to human subjects, such as eplerenone. For example, in any embodiment herein, when glucocorticoid replacement therapy is not needed and / or not used, the method can include applying a mineralocorticoid receptor antagonist to human subjects, such as eplerenone.

[0205] In some embodiments according to the method herein, it is not necessary and not to apply to human subjects an agent for treating mineralocorticoid toxicity. As discussed herein, in some embodiments, applying abiraterone prodrugs (such as intramuscular administration of abiraterone decanoate) to human subjects can achieve lyase selectivity and will not cause a significant increase in mineralocorticoid levels and / or will not cause the toxicity caused by excessive mineralocorticoids. Therefore, in some embodiments, human subjects are not treated with an agent that effectively treats mineralocorticoid toxicity. In particular, in some embodiments, human subjects are not treated with an agent as a glucocorticoid or mineralocorticoid receptor antagonist.

[0206] Suitable pharmaceutical compositions and abiraterone prodrugs for the methods herein are not particularly limited, and include any of those described herein, such as any of the abiraterone decanoate preparations described herein, for example, any of those described in the Summary of the Invention section (such as any of those described in

[18] -

[30] or

[93] -

[107] of the Summary of the Invention section herein), any of those described in the Examples section, and any of the abiraterone prodrugs and abiraterone prodrugs described in U.S. Patent No. 10,792,292B2 and PCT Application Nos. PCT / US2021 / 048607 and PCT / US2022 / 016278. Typically, a pharmaceutical composition suitable for the methods herein is a long-acting parenteral preparation comprising an abiraterone prodrug. In some embodiments, the long-acting parenteral formulation can be formulated to deliver therapeutically effective plasma levels of abiraterone in a human subject over an extended period of time (e.g., at least 1 week, e.g., at least two weeks, at least 3 weeks, at least 4 weeks, and up to six weeks or eight weeks or longer, etc.) after a single administration. In some embodiments, the therapeutically effective plasma concentration of abiraterone can be at least 1 ng / ml, e.g., a concentration of at least 2 ng / ml, at least 4 ng / ml, at least 8 ng / ml. In some embodiments, the therapeutically effective plasma concentration of abiraterone can also be about 0.5 ng / ml or higher. In some embodiments, the therapeutically effective plasma concentration of abiraterone can also be about 0.1 ng / ml or higher. In some embodiments, the pharmaceutical composition can be formulated for administration to a human subject to provide the PK characteristics described herein, such as (a) a plasma concentration of abiraterone above 0.5 ng / ml for a period of at least two weeks from a single dose; (b) a single dose or steady-state C of abiraterone between about 1 ng / ml and about 300 ng / ml, such as between about 1 ng / ml and about 10 ng / ml. max ; or (c) both (a) and (b).

[0207] The route of administration and dosing regimen of the methods herein are also not particularly limited, and include any of those described herein. Typically, the pharmaceutical composition can be administered to a human subject by intramuscular injection, intradermal injection, or subcutaneous injection. For example, in some specific embodiments, the pharmaceutical composition is administered to a human subject by intramuscular injection. In some embodiments, parenteral administration herein may be advantageous. For example, in some embodiments, parenteral administration can be performed without regard to whether the human subject is eating, and therefore, in some embodiments, the abiraterone prodrug or abiraterone prodrug formulation of the present disclosure can be administered to a human subject with or without eating. In other words, the fed or fasted state of the human subject is not important. This eliminates the need for currently commercially available Formulation-related restrictions that state that the drug "must be taken on an empty stomach with water at least 1 hour before or 2 hours after a meal." Thus, among other advantages, the methods herein can improve patient compliance.

[0208] The dosage and frequency of the method herein are also not particularly limited, and include any of those described herein. Typically, the pharmaceutical composition is administered to a human subject once a week or more than once a week. For example, in some embodiments, the method herein includes administering the abiraterone prodrug or abiraterone prodrug formulation herein with a dosing frequency ranging from once a week to once every few months. In some embodiments, the pharmaceutical composition is administered to a human subject once a month or more than once a month, such as once every two months or once every three months.

[0209] In some specific embodiments, the method herein may include administering the abiraterone prodrug or abiraterone prodrug formulation herein with a dosing frequency within the range of once a month to once every several months, such as once a month, once every two months, once every three months, or even less frequent administration. The dosage of the abiraterone prodrug (e.g., abiraterone decanoate) administered each time herein may vary, typically ranging from 0.5 mg / kg to 200 mg / kg, such as about 0.5 mg / kg to about 200 mg / kg (e.g., about 0.5 mg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 20 mg / kg, about 30 mg / kg, about 50 mg / kg, about 90 mg / kg, about 100 mg / kg, about 200 mg / kg, or any range between the numerical values) subject body weight. In some embodiments, administration can provide any of the pharmacokinetic characteristics described herein, such as (a) an abiraterone plasma concentration of greater than 0.5 ng / ml for a period of at least two weeks (e.g., up to 10 weeks or longer) from a single dose; (b) an abiraterone single dose or steady state C of between about 1 ng / ml and about 300 ng / ml, such as between about 1 ng / ml and about 10 ng / ml.max ; Or (c) (a) and (b) both. In some embodiments, administration can also provide abiraterone concentration in a tissue of a human subject that is at least 10 times higher than the abiraterone plasma concentration 7 days after administration (i.e., 168 hours from the time of administration), wherein the tissue is selected from the group consisting of liver, lung, testis, inguinal lymph, iliac lymph, adrenal gland and prostate.

[0210] Typically, the amount of the abiraterone prodrug (e.g., abiraterone decanoate) administered can be adjusted to effectively achieve a continuous reduction in serum testosterone levels in human subjects within 15 days after the first administration of the pharmaceutical composition to 50% or less below the baseline, such as about 60% or less below the baseline, about 70% or less below the baseline, about 80% or less below the baseline, or about 90% or less below the baseline, about 95% or less below the baseline. In some embodiments, the continued reduction in serum testosterone levels is characterized in that once the serum testosterone levels in human subjects are reduced to 50% or less below the baseline, the serum testosterone levels remain below the baseline 50% or less for 8 weeks or more after the first administration of the pharmaceutical composition. In some embodiments, abiraterone prodrugs (e.g., abiraterone decanoate) are administered in an effective amount to reduce serum testosterone levels in human subjects to 80% or less below the baseline when measured 24 weeks after the first administration of the abiraterone prodrug. In some embodiments, abiraterone prodrug (e.g., abiraterone decanoate) is administered in an effective amount to reduce serum testosterone levels in human subjects to 85% or less below the baseline when measured 24 weeks after the first administration of the abiraterone prodrug. In some embodiments, abiraterone prodrug (e.g., abiraterone decanoate) is administered in an effective amount to reduce serum testosterone levels in human subjects to 90% or less below the baseline when measured 24 weeks after the first administration of the abiraterone prodrug. In some embodiments, abiraterone prodrug (e.g., abiraterone decanoate) is administered in an effective amount to reduce serum testosterone levels in human subjects to about 50 ng / dL or less (e.g., about 40 ng / dL or less, about 30 ng / dL or less, about 20 ng / dL or less, about 10 ng / dL or less, etc.) when the human subject is a castrated human subject, or when the human subject is a castrated human subject, serum testosterone levels are reduced to about 1 ng / dL or less. As exemplified herein, abiraterone prodrugs (e.g., abiraterone decanoate) can be administered to human subjects without significantly increasing the level of mineralocorticoids, and any such increase returns to baseline levels within 4-6 weeks after the first administration of abiraterone prodrug. In some preferred embodiments, the administration of abiraterone prodrugs (e.g., abiraterone decanoate) will not increase the serum progesterone level in human subjects by more than 40% in 4 weeks after the first administration of abiraterone prodrug. In some embodiments, the administration of abiraterone prodrugs (e.g., abiraterone decanoate) will not increase the serum progesterone level in human subjects by more than 40% in 2 weeks to 12 weeks after the second administration of abiraterone prodrug.In some embodiments, administration of the pharmaceutical composition does not increase serum progesterone levels in a human subject by more than (i) 20% over baseline at 4 weeks after the first administration of the pharmaceutical composition; (ii) 20% over baseline at 6 weeks, 8 weeks, 10 weeks, and / or 12 weeks after the first administration of the pharmaceutical composition; and / or (iii) 20% over baseline at 2 weeks to 12 weeks after the second administration of the pharmaceutical composition.

[0211] In some embodiments, particularly in the methods of treating prostate cancer herein, the amount and frequency of administration of the abiraterone prodrug herein (e.g., abiraterone decanoate) can be adjusted so that administration provides an effective amount of abiraterone to reduce serum testosterone levels in non-castrated human subjects to about 50 ng / dL or less (e.g., about 40 ng / dL or less, about 30 ng / dL or less, about 20 ng / dL or less, about 10 ng / dL or less, etc.) within 15 days (e.g., within 7 days, within 7-15 days, etc.) after the first administration of the abiraterone prodrug, or to reduce serum testosterone levels in castrated human subjects (e.g., human subjects chemically castrated with a GnRH agonist and / or antagonist) to about 1 ng / dL or less. For example, in some embodiments, administration provides an effective amount of abiraterone to reduce serum testosterone levels in non-castrated human subjects to about 50 ng / dL or less (e.g., about 40 ng / dL or less, about 30 ng / dL or less, about 20 ng / dL or less, about 10 ng / dL or less, etc.) when measured on day 15 after the first administration of the abiraterone prodrug, or to reduce serum testosterone levels in castrated human subjects to about 1 ng / dL or less. In some embodiments, administration provides an effective amount of abiraterone to achieve a sustained reduction in serum testosterone levels, such as within 15 days (e.g., within 7 days, within 7-15 days, etc.) after the first administration of abiraterone prodrug, achieving and maintaining serum testosterone levels in non-castrated human subjects at about 50 ng / dL or less (e.g., about 40 ng / dL or less, about 30 ng / dL or less, about 20 ng / dL or less, about 10 ng / dL or less, etc.), or achieving and maintaining serum testosterone levels in castrated human subjects at about 1 ng / dL or less. In some embodiments, the dosage and frequency of the abiraterone prodrug (e.g., abiraterone decanoate) herein can be adjusted so that administration provides an effective amount of abiraterone to reduce serum testosterone levels from baseline by 50% or more, preferably 75% or more within 15 days (e.g., within 7 days, between 7-15 days, etc.) after the first administration of abiraterone prodrug. For example, in some embodiments, administration provides an effective amount of abiraterone to reduce serum testosterone levels from baseline by 50% or more, preferably 75% or more, when measured on the 15th day after the first administration of abiraterone prodrug. In some embodiments, administration provides an effective amount of abiraterone to achieve a sustained reduction in serum testosterone levels, such as within 15 days (e.g., within 7 days, between 7-15 days, etc.) after the first administration of abiraterone prodrug. Reduced from baseline by 50% or more, 75% or more.For clarity, the phrase "sustained reduction in serum testosterone levels" should be understood to mean that serum testosterone levels remain at reduced levels, such as at about 50 ng / dL or below in non-castrated human subjects, or at about 1 ng / dL or below in castrated human subjects, or 50% or less compared to baseline, for a sustained period of time, which can be 1 day or more, 3 days or more, 7 days or more, and up to one or more months. As exemplified herein, serum testosterone levels can be reduced in a dose-dependent manner for an extended period of time.

[0212] In some embodiments, the method of the present invention may be characterized in that the administration of the pharmaceutical composition reduces the level of prostate-specific antigen in a human subject. For example, in some preferred embodiments, at least after the first administration of the pharmaceutical composition and / or at one time point after one or more subsequent administrations of the pharmaceutical composition, the level of prostate-specific antigen can be reduced to 50% or less, preferably 90% or less, compared to the baseline PSA level. In some preferred embodiments, the level of prostate-specific antigen can be reduced to below the lower limit of quantification (LLOQ) at at least one time point during treatment.

[0213] In some embodiments, the methods herein may be characterized as achieving any one or more of the following outcomes: (a) objective response according to RECIST v1.1, with a minimum interval of 4 weeks between confirmed CR and PR; (b) a decrease in PSA of ≥50% from baseline, confirmed by a second consecutive PSA assessment at least 3 weeks later; (c) conversion of circulating tumor cell count (CTC) to a nadir of <5 cells / 7.5 mL of blood, confirmed by an additional assessment at least 3 weeks later (for subjects with CTC counts ≥5 cells / 7.5 mL of blood at baseline); and (4) radiographic progression-free survival (rPFS). In some embodiments, the methods herein may be characterized as being superior to oral administration of The corresponding treatment with the tablets better achieved any one or more of the following outcomes: (1) overall survival, defined as the time from the first dose of study drug to the date of death due to any cause; (2) best overall response (BOR) according to RECIST v1.1, defined as the best radiographic response among responses at all time points; and (3) DOR (defined as the length of time from the date of first documented confirmed response until the date of documented progression or death from any cause using CTC and / or PSA and / or RECIST v1.1 and PCWG3).

[0214] In any embodiment herein, unless indicated or obviously contrary to the context, the method herein may include administering Abiraterone Decanoate intramuscularly to a human subject at a dosing frequency of once every 1-3 months (such as once every three months), wherein each administration includes administering about 50mg to about 2000mg of Abiraterone Decanoate to a human subject, such as about 180mg, about 360mg, about 720mg, about 1260mg, about 1800mg or any range between the values ​​listed. In some preferred embodiments, the method herein may include administering Abiraterone Decanoate intramuscularly to a human subject at a dosing frequency of once every three months, wherein each administration includes administering about 1260mg of Abiraterone Decanoate to a human subject. In some preferred embodiments, the method herein may include administering Abiraterone Decanoate intramuscularly to a human subject at a dosing frequency of once every three months, wherein each administration includes administering about 1260mg of Abiraterone Decanoate to a human subject, and orally administering dexamethasone to a human subject at a daily dose of about 0.5mg / day.

[0215] Ways to lower steroid hormone levels

[0216] Some embodiments of the present disclosure are directed to methods of reducing serum steroid hormone levels in a human subject in need thereof, particularly by selectively inhibiting CYP17A1 lyase activity over hydroxylase activity.

[0217] In some embodiments, the present disclosure provides a method of reducing serum testosterone levels in a human subject in need thereof, the method comprising parenterally administering to the human subject an effective amount of a pharmaceutical composition comprising an abiraterone prodrug (e.g., abiraterone lipophilic ester), wherein the pharmaceutical composition is administered in an effective amount to achieve a sustained reduction in serum testosterone levels in the human subject to 50% or less below baseline within 15 days after the first administration of the pharmaceutical composition, wherein the administration of the pharmaceutical composition does not cause a decrease in serum progesterone levels in the human subject (i) within 15 days after the first administration of the pharmaceutical composition; The amount of abiraterone prodrug (e.g., abiraterone decanoate) administered can be adjusted to effectively achieve a sustained decrease in serum testosterone levels in human subjects to 50% or less below baseline within 15 days after the first administration of the pharmaceutical composition, such as about 60% or less below baseline, about 70% or less below baseline, about 80% or less below baseline, or about 90% or less below baseline, about 95% or less below baseline. In some embodiments, the sustained reduction in serum testosterone levels is characterized in that once the serum testosterone levels in a human subject are reduced to 50% or less below the baseline, the serum testosterone levels remain below 50% or less than the baseline for up to 8 weeks or more after the first administration of the pharmaceutical composition. In some embodiments, the abiraterone prodrug (e.g., abiraterone decanoate) is administered in an effective amount to reduce the serum testosterone levels in a human subject to 80% or less below the baseline, such as 85% or less below the baseline or 90% or less below the baseline, when measured 24 weeks after the first administration of the abiraterone prodrug. In some embodiments, the abiraterone prodrug (e.g., abiraterone decanoate) is administered in an effective amount to reduce serum testosterone levels to about 50 ng / dL or less (e.g., about 40 ng / dL or less, about 30 ng / dL or less, about 20 ng / dL or less, about 10 ng / dL or less, etc.) when the human subject is a non-castrated human subject, or to about 1 ng / dL or less when the human subject is a castrated human subject, when measured 24 weeks after the first administration of the abiraterone prodrug.

[0218] In some specific embodiments, the present disclosure provides a method of reducing serum testosterone levels in a human subject in need thereof, the method comprising parenterally administering to the human subject a pharmaceutical composition comprising an abiraterone prodrug (e.g., abiraterone lipophilic ester), wherein the administration of the pharmaceutical composition does not increase serum progesterone levels in the human subject by more than (i) 40% above baseline after a first administration of the pharmaceutical composition; and / or (ii) by more than 40% above baseline 2 weeks to 12 weeks after a second administration of the pharmaceutical composition, preferably, does not increase serum progesterone levels in the human subject by more than (i) 20% above baseline 4 weeks after the first administration of the pharmaceutical composition; (ii) by more than 20% above baseline 6 weeks, 8 weeks, 10 weeks and / or 12 weeks after the first administration of the pharmaceutical composition; and / or (iii) by more than 20% above baseline 2 weeks to 12 weeks after the second administration of the pharmaceutical composition. Typically, particularly when the human subject is characterized as having prostate cancer, administration provides an effective amount of abiraterone to reduce serum testosterone levels in non-castrated human subjects to about 50 ng / dL or less (e.g., about 40 ng / dL or less, about 30 ng / dL or less, about 20 ng / dL or less, about 10 ng / dL or less, etc.) within 15 days (e.g., within 7 days, within 7-15 days, etc.) after the first administration of the abiraterone prodrug, or to reduce serum testosterone levels in castrated human subjects to about 1 ng / dL or less. For example, in some embodiments, administration provides an effective amount of abiraterone to reduce serum testosterone levels in non-castrated human subjects to about 50 ng / dL or less (e.g., about 40 ng / dL or less, about 30 ng / dL or less, about 20 ng / dL or less, about 10 ng / dL or less, etc.) when measured on day 15 after the first administration of the abiraterone prodrug, or to reduce serum testosterone levels in castrated human subjects to about 1 ng / dL or less. In some embodiments, administration provides an effective amount of abiraterone to achieve a sustained reduction in serum testosterone levels, such as within 15 days (e.g., within 7 days, within 7-15 days, etc.) after the first administration of abiraterone prodrug, to achieve and maintain serum testosterone levels in non-castrated human subjects at about 50 ng / dL or less (e.g., about 40 ng / dL or less, about 30 ng / dL or less, about 20 ng / dL or less, about 10 ng / dL or less, etc.), or to achieve and maintain serum testosterone levels in castrated human subjects at about 1 ng / dL or less. Typically, administration provides an effective amount of abiraterone to reduce serum testosterone levels from baseline by 50% or more, preferably 75% or more within 15 days (e.g., within 7 days, between 7-15 days, etc.) after the first administration of abiraterone prodrug.For example, in some embodiments, the administration provides an effective amount of abiraterone to reduce serum testosterone levels from baseline by 50% or more, preferably 75% or more, when measured on the 15th day after the first administration of abiraterone prodrug. In some embodiments, the administration provides an effective amount of abiraterone to achieve a sustained reduction in serum testosterone levels, such as within 15 days (e.g., within 7 days, between 7-15 days, etc.) after the first administration of abiraterone prodrug. Reduced from baseline by 50% or more, 75% or more. In some embodiments, the sustained reduction in serum testosterone levels is characterized in that, once the serum testosterone levels in human subjects are reduced to 50% or less below the baseline, the serum testosterone levels remain below the baseline 50% or less for 8 weeks or more after the first administration of the pharmaceutical composition. In some embodiments, the sustained reduction in serum testosterone levels is characterized in that once the serum testosterone level in a human subject is reduced to about 50 ng / dL or less (e.g., about 40 ng / dL or less, about 30 ng / dL or less, about 20 ng / dL or less, about 10 ng / dL or less, etc.) in a non-castrated human subject or to 1 ng / dL or less in a castrated human subject, the serum testosterone level is maintained at about 50 ng / dL or less in a non-castrated human subject or at about 1 ng / dL or less in a castrated human subject for up to 8 weeks or more after the first administration of the pharmaceutical composition.

[0219] Suitable for treating with the methods herein to reduce serum testosterone levels in human subjects are not particularly limited and include any human subject in those human subjects described herein. In some embodiments, the human subject can be a non-castrated human subject. In some embodiments, the human subject can also be castrated. For example, in some embodiments, chemical castration can be performed on the human subject, such as with a gonadotropin-releasing hormone agonist and / or antagonist treatment. In some embodiments, the human subject can be characterized as suffering from liver damage before administering abiraterone prodrug, such as moderate to severe liver damage (Child-Pugh B or C class). In some embodiments, the human subject suffers from prostate cancer, and the methods herein will not increase the progesterone level in the human subject to a level associated with adverse clinical outcomes and drug resistance, such as serum or plasma progesterone levels greater than about 3nM when measured at 4 weeks, 6 weeks or 12 weeks after the first administration of the pharmaceutical composition. In some embodiments, the human subject suffers from prostate cancer, and the human subject is characterized as having a serum or plasma progesterone level greater than about 3nM after abiraterone treatment, such as Zytiga (oral abiraterone acetate and prednisone) treatment for three months before the first administration of the pharmaceutical composition herein. In some embodiments, the human subject may be characterized as being sensitive or otherwise intolerant to gonadotropin-releasing hormone antagonists and / or agonists. In some embodiments, the human subject may be characterized as not having received chemotherapy or hormone therapy before administering the pharmaceutical composition herein. However, in some embodiments, the human subject may also be treated with chemotherapy or hormone therapy before administering the pharmaceutical composition herein. For example, in some embodiments, the human subject may suffer from a disease or condition (e.g., prostate cancer) that progresses during or after chemotherapy and / or hormone therapy, such as a chemotherapy regimen based on taxanes, such as docetaxel-based or cabazitaxel-based chemotherapy. In some embodiments, the disease of the human subject progresses during or after an androgen receptor antagonist-based treatment (such as enzalutamide-based treatment). In some embodiments, the human subject's disease progresses during or after an oral abiraterone acetate-based therapy, such as an oral abiraterone acetate and prednisone-based therapy. For example, in some embodiments, the human subject develops resistance to the combination therapy of abiraterone acetate and prednisone, including resistance due to elevated progesterone levels. As discussed above, human subjects who suffer from or are susceptible to one or more side effects associated with inhibition of CYP17A1 hydroxylase activity can also be advantageously treated with the methods herein that selectively inhibit lyase activity over hydroxylase activity.

[0220] Human subjects who need to reduce testosterone usually suffer from one or more androgen-mediated or androgen-related diseases or conditions. For example, in some embodiments, the human subject suffers from a disease or condition that is sex hormone-dependent or androgen receptor-driven, such as sex hormone-dependent benign or malignant conditions or syndromes caused by androgen excess. Suitable diseases or conditions include any of those described herein, such as any of those described in [4]-

[17] of the Summary of the Invention. In some embodiments, the human subject is characterized as suffering from sex hormone-dependent cancer or androgen receptor-driven cancer, such as any of those described herein. In some embodiments, sex hormone-dependent or androgen receptor-driven cancer has metastasized to one or more lymph nodes. In some embodiments, administration of a pharmaceutical composition can effectively inhibit the growth of cancer in one or more lymph nodes. In some embodiments, the human subject is characterized as suffering from androgen receptor-positive salivary duct carcinoma or androgen receptor-positive glioblastoma multiforme. In some embodiments, the human subject is characterized as suffering from prostate cancer (e.g., any of those described herein). For example, in some embodiments, prostate cancer can be primary / localized prostate cancer (newly diagnosed or early), advanced prostate cancer (e.g., recurrent prostate cancer after castration, locally advanced prostate cancer, etc.), recurrent prostate cancer (e.g., prostate cancer that does not respond to primary therapy), non-metastatic castration-resistant prostate cancer, metastatic prostate cancer, metastatic castration-resistant prostate cancer (CRPC), or hormone-sensitive prostate cancer. In some embodiments, prostate cancer is CRPC, and in some embodiments, patients with CRPC have not received chemotherapy. In some embodiments, prostate cancer is metastatic CRPC (mCRPC), and in some embodiments, patients with mCRPC have not received chemotherapy. In some embodiments, human subjects suffer from endometrial cancer or ovarian cancer. In some embodiments, human subjects suffer from polycystic ovary syndrome (PCOS), congenital adrenal hyperplasia (CAH), or endometriosis. In some embodiments, human subjects suffer from newly diagnosed high-risk metastatic hormone-sensitive prostate cancer. In some embodiments, human subjects have not yet received prostatectomy. In some embodiments, human subjects are further treated with radiotherapy.

[0221] Suitable pharmaceutical compositions and abiraterone prodrugs for the methods of reducing serum testosterone levels herein are not particularly limited, and include any of those described herein, such as any of the abiraterone decanoate preparations described herein, for example, any of those described in the Summary of the Invention section (such as any of those described in

[18] -

[30] or

[93] -

[107] of the Summary of the Invention section herein), any of those described in the Examples section, and any of the abiraterone prodrugs and abiraterone prodrugs described in U.S. Patent No. 10,792,292B2 and PCT Application No. PCT / US2021 / 048607 and No. PCT / US2022 / 016278. Typically, the pharmaceutical composition is a long-acting parenteral preparation comprising an abiraterone prodrug. In some embodiments, the long-acting parenteral formulation can be formulated to deliver effective plasma levels of abiraterone in a human subject over an extended period of time (e.g., at least 1 week, e.g., at least two weeks, at least 3 weeks, at least 4 weeks, and up to six weeks or eight weeks or longer, etc.) after a single administration to reduce serum testosterone levels (e.g., to about 50 ng / dL or less in a non-castrated human subject, or to about 1 ng / dL or less in a castrated human subject, or to 50% or more compared to a baseline). In some embodiments, the effective plasma concentration of abiraterone can be at least 1 ng / ml, e.g., a concentration of at least 2 ng / ml, at least 4 ng / ml, at least 8 ng / ml. In some embodiments, the effective plasma concentration of abiraterone can also be about 0.5 ng / ml or higher. In some embodiments, the effective plasma concentration of abiraterone can also be about 0.1 ng / ml or higher. In some embodiments, the pharmaceutical composition can be formulated for administration to a human subject to provide (a) a plasma concentration of abiraterone above 0.5 ng / ml for a period of at least two weeks from a single dose; (b) a single dose or steady-state C of abiraterone between about 1 ng / ml and about 300 ng / ml, such as between about 1 ng / ml and about 10 ng / ml. max ; or (c) both (a) and (b).

[0222] The route of administration and dosage regimen of the method for reducing serum testosterone levels herein are also not particularly limited, and include any of those described herein. Typically, the pharmaceutical composition can be administered to a human subject by intramuscular injection, intradermal injection, or subcutaneous injection. For example, in some specific embodiments, the pharmaceutical composition is administered to a human subject by intramuscular injection. Typically, the pharmaceutical composition is administered to a human subject once a week or more than once a week. For example, in some embodiments, the pharmaceutical composition is administered to a human subject once a month or more than once a month, such as once every two months or once every three months.

[0223] In some embodiments, the present disclosure provides a method for reducing the level of androgen (e.g., testosterone and / or dihydrotestosterone) and / or estrogen in a human subject in need, the method comprising administering any of the abiraterone prodrugs or abiraterone prodrug preparations disclosed herein to the human subject. In some embodiments, the human subject suffers from cancer driven by androgen receptors. In some embodiments, the human subject suffers from syndromes caused by excessive androgen, such as congenital adrenal hyperplasia (e.g., classic and non-classical congenital adrenal hyperplasia), endometriosis, polycystic ovary syndrome, precocious puberty, hirsutism, etc. In some embodiments, the human subject suffers from androgen and / or estrogen related cancers, such as prostate cancer or breast cancer. In some embodiments, the human subject suffers from sex hormone dependent cancers as described herein. Suitable pharmaceutical compositions, subjects, dosing regimens, and routes of administration for the method include any of those described herein in any combination, such as any of those described in conjunction with the method shown in the Summary of the Invention section herein.

[0224] Abiraterone prodrugs and formulations

[0225] Various abiraterone prodrugs and abiraterone prodrug preparations are also provided herein, which can be used for methods herein.For example, in some embodiments, abiraterone drugs can be abiraterone lipophilic esters, such as acetate, propionate, butyrate, (valeric acid ester) valerate, isocaproate, butanecarboxylate, cyclohexanecarboxylate, phenylpropionate, caproate (caproate) (hexanoate (hexanoate)), enanthate (enanthate) (heptanoate (heptanoate)), cyclopentanepropionate, octanoate, nonanoate, decanoate, undecanoate, dodecanoate, tridecanoate, tetradecanoate, pentadecanoate or hexadecanoate.Other suitable abiraterone prodrugs include any of those described in U.S. Patent No. 10,792,292B2 and PCT Application No. PCT / US2021 / 048607 and PCT / US2022 / 016278, and their respective contents are incorporated herein by reference in their entirety. Any of the abiraterone decanoate formulations described in U.S. Provisional Application No. 63,425,839 can be used in the methods herein.

[0226] In any of the embodiments described herein, unless stated or otherwise contradicted by context, the abiraterone prodrug may be abiraterone decanoate or a pharmaceutically acceptable salt thereof,

[0227]

[0228] Abiraterone decanoate.

[0229] Typically, the pharmaceutical composition comprising the abiraterone prodrug (or alternatively referred to herein as the abiraterone prodrug formulation) is formulated for parenteral administration. For example, in some embodiments, the pharmaceutical composition may be formulated for intramuscular injection, intradermal injection, or subcutaneous injection.

[0230] In some embodiments, the pharmaceutical composition comprises abiraterone decanoate solution, the solution comprising abiraterone decanoate dissolved in a pharmaceutically acceptable carrier and a pharmaceutically acceptable antioxidant. For the purposes herein, if the amount of abiraterone decanoate in a liquid mixture of abiraterone decanoate, a pharmaceutically acceptable carrier, a pharmaceutically acceptable antioxidant, and optional other ingredients is below its saturation point (i.e., the maximum solubility of abiraterone decanoate) in a pharmaceutically acceptable carrier at 25°C, the liquid mixture can be characterized as abiraterone decanoate solution, taking into account any effect on the solubility of abiraterone decanoate in a pharmaceutically acceptable carrier caused by the antioxidant and optional other ingredients.

[0231] Pharmaceutical compositions are generally non-aqueous preparations, such as oil-based preparations, and include non-aqueous pharmaceutically acceptable carriers (e.g., as described herein). Pharmaceutical compositions generally include abiraterone prodrugs and pharmaceutically acceptable carriers. Pharmaceutically acceptable carriers are not particularly limited. For example, in some embodiments, pharmaceutically acceptable carriers include pharmaceutically acceptable oils, such as pharmaceutically acceptable oils for injection, including oils of plant origin or synthetic fatty acid monoglycerides or diglycerides. In some embodiments, pharmaceutically acceptable oils can be natural oils, synthetic oils or semi-synthetic oils, such as fractionated coconut oil and medium-chain triglycerides, such as those sold under the trademark Miglyol. In some embodiments, pharmaceutically acceptable carriers include triglycerides derived from fatty acids. In some embodiments, pharmaceutically acceptable carriers include derived from long-chain and / or medium-chain fatty acids, which can be independently polyunsaturated, monounsaturated or saturated triglycerides. As understood by those skilled in the art, medium-chain fatty acids generally include 6-12 carbons, such as caproic acid, caprylic acid, capric acid, lauric acid, etc.; short-chain fatty acids generally have less than 6 carbons; and long-chain fatty acids generally include 13-21 carbons. In some embodiments, a pharmaceutically acceptable carrier includes a pharmaceutically acceptable oil, which can be selected from vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil (peanut oil), poppy seed oil, tea seed oil and soybean oil. In some specific embodiments, a pharmaceutically acceptable carrier may include corn oil, which includes triglycerides, wherein the fatty acid constituents are mainly linoleic acid, oleic acid, palmitic acid and stearic acid.

[0232] In some embodiments, in addition to pharmaceutically acceptable oil, pharmaceutically acceptable carriers may also include pharmaceutically acceptable solvents (or co-solvents, if oil is counted as solvent), such as alcohols, esters, acids, etc. In some embodiments, pharmaceutically acceptable solvents may include benzyl alcohol, benzyl benzoate, ethanol, glycerol, polyethylene glycol, polysorbate 80, acetic acid and / or ethyl acetate. In some embodiments, pharmaceutically acceptable solvents may be benzyl alcohol and / or benzyl benzoate. In some embodiments, pharmaceutically acceptable solvents may be benzyl alcohol. In some embodiments, pharmaceutically acceptable solvents may be a combination of benzyl alcohol and benzyl benzoate. The combination of benzyl alcohol and benzyl benzoate can significantly improve the solubility of abiraterone prodrugs (such as abiraterone decanoate) in pharmaceutically acceptable oils.

[0233] In some embodiments, the pharmaceutically acceptable carrier may include a pharmaceutically acceptable oil and another pharmaceutically acceptable solvent, wherein the pharmaceutically acceptable oil is selected from vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil and soybean oil, and another pharmaceutically acceptable solvent includes benzyl alcohol, benzyl benzoate or a combination thereof. In some embodiments, the pharmaceutically acceptable carrier includes corn oil, benzyl alcohol and benzyl benzoate. In some embodiments, benzyl alcohol is present in an amount of about 5% by volume to 10% by volume, benzyl benzoate is present in an amount of about 10% by volume to 20% by volume, and corn oil is present in an amount of about 70% by volume to 85% by volume, wherein the combined volume of benzyl alcohol, benzyl benzoate and corn oil is 100%.

[0234] There is no particular limitation on the pharmaceutically acceptable antioxidants suitable for use in the pharmaceutical compositions herein. For example, in some embodiments, the pharmaceutical compositions herein may include a sulfur-containing antioxidant, such as 3-mercapto-1,2-propanediol, alternatively known as monothioglycerol, which has the chemical structure In some embodiments, the pharmaceutical compositions herein may include a tocopherol-type antioxidant, such as alpha-tocopherol.

[0235] Exemplary Formulations Containing Abiraterone Decanoate

[0236] In some embodiments, the pharmaceutical composition comprises abiraterone decanoate having the formula:

[0237]

[0238] Or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier. Decanoic acid abiraterone is usually present in the pharmaceutical composition in its alkaline form, and unless the context is obviously contrary, it should be understood as such. In some embodiments, decanoic acid abiraterone can also be in a substantially pure form as described herein. For example, a pharmaceutical composition can be prepared by mixing substantially pure decanoic acid abiraterone with a pharmaceutically acceptable carrier and optional other ingredients. In some specific embodiments, substantially pure decanoic acid abiraterone is in a crystalline form as described herein, preferably crystalline form A, and a pharmaceutical composition can be prepared by mixing the crystalline form with a pharmaceutically acceptable carrier and optional other ingredients (e.g., dissolving, suspending or otherwise forming a mixture).

[0239] In some embodiments, the pharmaceutical composition comprises (1) abiraterone decanoate; (2) a pharmaceutically acceptable oil (e.g., as described herein); (3) a pharmaceutically acceptable solvent (e.g., as described herein); and (4) 3-mercapto-1,2-propanediol.

[0240] In some embodiments, the pharmaceutical composition comprises (1) abiraterone decanoate; (2) benzyl alcohol; (3) benzyl benzoate; (4) corn oil; and (5) 3-mercapto-1,2-propanediol.

[0241] Abiraterone decanoate is usually prepared in high purity form, for example, suitable for pharmaceutical use. In some embodiments, the disclosure provides the Abiraterone decanoate in substantially pure form, such as by weight, by HPLC area or both with greater than 80%, preferably greater than 90% (e.g., greater than 95%, greater than 97%, greater than 98%, greater than 99%, greater than 99.5%) purity. In some embodiments, the Abiraterone decanoate may be characterized by a purity of about 95%, about 97%, about 99%, about 99.5%, about 99.9% or any range between specified values ​​by weight and / or by HPLC area. For example, in some embodiments, the Abiraterone decanoate may be characterized by a purity of about 95%, about 97%, about 99%, about 99.5%, about 99.9% or any range between specified values ​​by weight. In some embodiments, abiraterone decanoate can also be characterized as having a low palladium content, such as less than 150ppm, less than 100ppm, less than 50ppm or less than 10ppm. In some embodiments, abiraterone decanoate meets the specifications shown in Table D herein (see Example 1B). An exemplary procedure for preparing substantially pure abiraterone decanoate is shown in the Examples section. An HPLC method suitable for measuring the purity of abiraterone decanoate is also described in the Examples section. Substantially pure abiraterone decanoate can be in solid form (e.g., a crystalline form (preferred form A), amorphous form, or a combination thereof as described herein) or in a solution, suspension, or another form. For the avoidance of doubt, the abiraterone prodrug preparation comprising substantially pure abiraterone decanoate and one or more other ingredients herein should be understood as a mixture of substantially pure abiraterone decanoate and one or more other ingredients herein, for example, such preparations can be obtained directly or indirectly by mixing substantially pure abiraterone decanoate with one or more other ingredients, such as pharmaceutically acceptable oils, solvents, etc. (e.g., dissolving, suspending, or otherwise forming a mixture).

[0242] In some specific embodiments, the pharmaceutical composition comprises abiraterone decanoate, a pharmaceutically acceptable oil (e.g., as described herein), benzyl alcohol and benzyl benzoate. In some embodiments, the pharmaceutically acceptable oil is corn oil. In some embodiments, benzyl alcohol is present in an amount of about 5% by volume to 10% by volume, benzyl benzoate is present in an amount of about 10% by volume to 20% by volume, and corn oil is present in an amount of about 70% by volume to 85% by volume, wherein the combined volume of benzyl alcohol, benzyl benzoate and corn oil is 100%.

[0243] Pharmaceutical composition generally comprises the decanoic acid abiraterone of about 25mg / ml to about 500mg / ml in concentration. In some embodiments, decanoic acid abiraterone can exist in the concentration of any scope between about 50mg / ml, about 100mg / ml, about 150mg / ml, about 200mg / ml, about 250mg / ml, about 300mg / ml, about 350mg / ml, about 400mg / ml, about 500mg / ml or the listed values. In some embodiments, decanoic acid abiraterone can exist in the concentration of about 100mg / ml to about 300mg / ml, such as about 150mg / ml to about 250mg / ml, about 200mg / ml to about 300mg / ml etc.

[0244] In some embodiments, the pharmaceutical composition may include abiraterone decanoate in its alkaline form, corn oil, benzyl alcohol, and benzyl benzoate. In some embodiments, abiraterone decanoate is present in the pharmaceutical composition in an amount of about 50-300 mg / mL. In some embodiments, the amount of benzyl alcohol is about 50-150 mg / mL. In some embodiments, the amount of benzyl benzoate is about 100-300 mg / mL. In some embodiments, the pharmaceutical composition may include (a) abiraterone decanoate in its alkaline form in an amount of about 100 mg to about 300 mg (e.g., about 100 mg, about 120 mg, about 150 mg, about 180 mg, about 200 mg, or about 250 mg) per milliliter; (b) benzyl alcohol in an amount of about 50 mg to about 150 mg (e.g., about 75 mg, about 100 mg, or about 125 mg); (c) benzyl benzoate in an amount of about 100 mg to about 300 mg (e.g., about 100 mg, about 150 mg, about 200 mg, or about 250 mg); and (d) corn oil, q.s. to 1 milliliter. In some embodiments, the weight ratio of benzyl alcohol to benzyl benzoate in the pharmaceutical composition ranges from about 2:1 to about 1:5 (e.g., about 1:1 to 1:3, such as about 1:2).

[0245] In some embodiments, the pharmaceutical composition comprises an abiraterone decanoate solution, wherein each milliliter of the abiraterone decanoate solution comprises, consists essentially of, or consists of: (a) abiraterone decanoate in its basic form in an amount of about 100 mg to about 300 mg (e.g., about 100 mg, about 120 mg, about 150 mg, about 180 mg, about 200 mg, or about 250 mg); (b) benzyl alcohol in an amount of about 50 mg to about 150 mg (e.g., about 7 5mg, about 100mg or about 125mg); (c) benzyl benzoate in an amount of about 100mg to about 300mg (e.g., about 100mg, about 150mg, about 200mg or about 250mg); (d) 3-mercapto-1,2-propanediol in an amount of about 0.5mg to about 20mg (e.g., about 0.5mg, about 1mg, about 2mg or about 5mg); and (e) corn oil, q.s. to 1 ml, wherein the abiraterone decanoate has the following structure:

[0246]

[0247] Abiraterone decanoate.

[0248] In some embodiments, each milliliter of abiraterone decanoate solution herein comprises, consists essentially of, or consists of: (a) abiraterone decanoate in its basic form in an amount of about 180 mg; (b) benzyl alcohol in an amount of about 50 mg to about 150 mg (e.g., about 75 mg, about 100 mg, or about 125 mg); (c) benzyl benzoate in an amount of about 100 mg to about 300 mg (e.g., about 100 mg, about 150 mg, about 200 mg, or about 250 mg); (d) 3-mercapto-1,2-propanediol in an amount of about 0.5 mg to about 2 mg (e.g., about 0.5 mg, about 1 mg, or about 2 mg); and (e) corn oil, q.s. to 1 milliliter.

[0249] The weight ratio of benzyl alcohol to benzyl benzoate in the abiraterone decanoate solution is typically in the range of about 2:1 to about 1:5 (eg, about 1:1 to 1:3, such as about 1:2).

[0250] In some specific embodiments, each milliliter of the abiraterone decanoate solution herein comprises, consists essentially of, or consists of: (a) abiraterone decanoate in its basic form in an amount of about 180 mg; (b) benzyl alcohol in an amount of about 100 mg; (c) benzyl benzoate in an amount of about 200 mg; (d) 3-mercapto-1,2-propanediol in an amount of about 0.5 mg to about 2 mg (e.g., about 0.5 mg, about 1 mg, or about 2 mg); and (e) corn oil, q.s. to 1 milliliter.

[0251] In some embodiments, the pharmaceutical composition can be prepared by mixing (e.g., dissolving) abiraterone decanoate, such as substantially pure abiraterone decanoate, with a pharmaceutically acceptable carrier and a pharmaceutically acceptable antioxidant. For example, in some embodiments, the pharmaceutical composition can be prepared by mixing (e.g., dissolving) substantially pure abiraterone decanoate in its alkaline form with corn oil, benzyl alcohol, benzyl benzoate, and 3-mercapto-1,2-propanediol, wherein the amount of each ingredient can be any of those described herein.

[0252] The abiraterone decanoate solution can generally be included in a container with a headspace, such as a vial, an ampoule, a bottle, etc. In a preferred embodiment, the headspace of the container is filled with an inert gas, such as nitrogen.

[0253] In some embodiments, abiraterone decanoate solution may also be included in the syringe.

[0254] Exemplary Formulations Comprising Substantially Pure Abiraterone Decanoate

[0255] In some embodiments, the pharmaceutical composition comprises substantially pure abiraterone decanoate having the formula:

[0256]

[0257] Or its pharmaceutically acceptable salt, which is dispersed or dissolved in a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises substantially pure decanoic acid abiraterone in alkaline form, which is dispersed or dissolved in a pharmaceutically acceptable carrier. In some embodiments, substantially pure decanoic acid abiraterone has a purity of at least 95% by weight, preferably at least 98%, such as about 98.5%, about 99%, about 99.5% or higher. In some embodiments, substantially pure decanoic acid abiraterone may be characterized by a purity of about 95%, about 97%, about 99%, about 99.5%, about 99.9% or any range between specified values ​​by weight and / or by HPLC area. In some embodiments, substantially pure decanoic acid abiraterone may be characterized by a purity of about 95%, about 97%, about 99%, about 99.5%, about 99.9% or any range between specified values ​​by weight. In some embodiments, substantially pure abiraterone decanoate may also be characterized as having a low palladium content, such as less than 150ppm, less than 100ppm, less than 50ppm or less than 10ppm. Abiraterone is generally synthesized by a palladium-catalyzed cross-coupling reaction. Therefore, available abiraterone generally has an undesirable level of palladium residues, which may be carried into the crude abiraterone decanoate product. As described herein, the present disclosure shows that by using a recrystallization process using acetone and water as a solvent and activated carbon, it is possible to reduce the palladium content in abiraterone decanoate to less than 5ppm, particularly to 3.7ppm in Example 1B. In some embodiments, substantially pure abiraterone decanoate meets the specifications shown in Table D herein (see Example 1B). In some embodiments, substantially pure abiraterone decanoate includes impurities derived from ethylprasterone. For example, in some embodiments, substantially pure abiraterone decanoate includes ethylprasterone decanoate with the following formula:

[0258]

[0259] Typically, when present, substantially pure abiraterone decanoate comprises ethylprasterone decanoate in an amount of less than 2% by weight, such as less than 1% by weight, less than 0.5% by weight, such as less than 0.3% by weight, less than 0.2% by weight, or less than 0.1% by weight. The amount of ethylprasterone decanoate can be easily determined by HPLC methods, such as those described herein. In some embodiments, substantially pure abiraterone decanoate may also be free of detectable amounts of ethylprasterone decanoate. Abiraterone raw materials can be easily obtained from commercial sources in high purity. From using cross-coupling reactions The abiraterone raw material obtained by the method of introducing a 3-pyridyl group into abiraterone may contain a small amount of impurities, which may eventually be converted into ethyl prasterone. In some embodiments, substantially pure abiraterone decanoate can be prepared from an abiraterone raw material that does not have a detectable amount of ethyl prasterone, for example, from abiraterone raw material that does not include Those obtained by the cross-coupling method. Substantially pure abiraterone decanoate may be in solid form, such as a crystalline form as described herein. For example, in some embodiments, substantially pure abiraterone decanoate may be in crystalline form A, which may be characterized by having one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) of the following peaks X-ray powder diffraction (XRPD) spectrum: 4.6, 6.9, 8.7, 17.5, 18.3, 18.6, 19.1, 19.6 and 20.8, 2θ degrees, ± 0.2°; differential scanning calorimetry (DSC) diagram having an endothermic peak with an onset temperature of about 69.0°C; or a combination thereof. An exemplary procedure is also shown in Example 1A.

[0260] In some embodiments, the pharmaceutical composition comprises substantially pure abiraterone decanoate in its alkaline form, which is dispersed or dissolved in a pharmaceutically acceptable carrier, and the pharmaceutically acceptable carrier comprises a pharmaceutically acceptable oil (e.g., described herein) and optionally another pharmaceutically acceptable solvent (e.g., described herein). In some embodiments, the pharmaceutically acceptable oil includes triglycerides (e.g., long-chain and / or medium-chain triglycerides), and another pharmaceutically acceptable solvent, if present, includes alcohol, ester and / or acid solvent. In some embodiments, the pharmaceutically acceptable oil is selected from vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil and soybean oil, and another pharmaceutically acceptable solvent, if present, includes benzyl alcohol, benzyl benzoate or a combination thereof. In some embodiments, the pharmaceutically acceptable carrier includes corn oil, benzyl alcohol and benzyl benzoate.

[0261] In some specific embodiments, the pharmaceutical composition comprises substantially pure abiraterone decanoate in its basic form dissolved in a pharmaceutically acceptable oil (e.g., as described herein), benzyl alcohol, and benzyl benzoate. In some embodiments, the pharmaceutical composition comprises substantially pure abiraterone decanoate in its basic form dissolved in corn oil, benzyl alcohol, and benzyl benzoate. In some embodiments, the pharmaceutical composition comprises: (a) substantially pure abiraterone decanoate in its basic form at a concentration of about 25 mg / ml to about 500 mg / ml (e.g., about 25 mg / ml, about 50 mg / ml, about 100 mg / ml, about 120 mg / ml, about 150 mg / ml, about 180 mg / ml, about 200 mg / ml, about 250 mg / ml, about 300 mg / ml, about 400 mg / ml, about 500 mg / ml, or any range between the recited values, such as about 100 mg / ml to about 300 mg / ml); (b) benzyl alcohol in an amount of about 50 mg to about 150 mg / mL; (c) benzyl benzoate in an amount of about 100 mg to about 300 mg / mL; (d) a pharmaceutically acceptable oil (e.g., as described herein), such as corn oil, for example, in an amount suitable for the volume of the pharmaceutical composition. In some specific embodiments, the pharmaceutical composition comprises per milliliter (a) substantially pure abiraterone decanoate in its base form in an amount of about 100 mg to about 300 mg (e.g., about 100 mg, about 120 mg / ml, about 150 mg, about 180 mg / ml, about 200 mg, or about 250 mg, or any range between the recited values); (b) benzyl alcohol in an amount of about 50 mg to about 150 mg (e.g., about 75 mg, about 100 mg, or about 125 mg, or any range between the recited values); (c) benzyl benzoate in an amount of about 100 mg to about 300 mg (e.g., about 100 mg, about 150 mg, about 200 mg, or about 250 mg, or any range between the recited values); and (d) corn oil, q.s. to 1 milliliter. In some embodiments, the weight ratio of benzyl alcohol to benzyl benzoate in the pharmaceutical composition ranges from about 2:1 to about 1:5 (e.g., about 1:1 to 1:3, such as about 1:2). In some embodiments, the pharmaceutical composition can be prepared by mixing (e.g., dissolving) substantially pure abiraterone decanoate with a pharmaceutically acceptable carrier. For example, in some embodiments, the pharmaceutical composition can be prepared by mixing (e.g., dissolving) substantially pure abiraterone decanoate in its basic form with corn oil, benzyl alcohol, and benzyl benzoate.

[0262] In some embodiments, the pharmaceutical composition comprises substantially pure abiraterone decanoate in its basic form, dissolved in a pharmaceutically acceptable oil (e.g., as described herein), benzyl alcohol and benzyl benzoate, and a pharmaceutically acceptable antioxidant. In some embodiments, the pharmaceutical composition comprises substantially pure abiraterone decanoate in its basic form, dissolved in corn oil, benzyl alcohol and benzyl benzoate, and 3-mercapto-1,2-propanediol. In some embodiments, the pharmaceutical composition comprises abiraterone decanoate solution, wherein each milliliter of the abiraterone decanoate solution comprises, consists essentially of, or consists of: (a) substantially pure abiraterone decanoate in its basic form in an amount of about 100 mg to about 300 mg (e.g., about 100 mg, about 120 mg, about 150 mg, about 180 mg, about 200 mg, or about 250 mg); (b) benzyl alcohol in an amount of about 50 mg to about 150 mg (e.g. , about 75 mg, about 100 mg or about 125 mg); (c) benzyl benzoate in an amount of about 100 mg to about 300 mg (e.g., about 100 mg, about 150 mg, about 200 mg or about 250 mg); (d) 3-mercapto-1,2-propanediol in an amount of about 0.5 mg to about 20 mg (e.g., about 0.5 mg, about 1 mg, about 2 mg or about 5 mg); and (e) corn oil, q.s. to 1 ml, wherein the abiraterone decanoate has the following structure:

[0263]

[0264] Abiraterone decanoate.

[0265] In some embodiments, each milliliter of abiraterone decanoate solution herein comprises, consists essentially of, or consists of: (a) substantially pure abiraterone decanoate in its basic form in an amount of about 180 mg; (b) benzyl alcohol in an amount of about 50 mg to about 150 mg (e.g., about 75 mg, about 100 mg, or about 125 mg); (c) benzyl benzoate in an amount of about 100 mg to about 300 mg (e.g., about 100 mg, about 150 mg, about 200 mg, or about 250 mg); (d) 3-mercapto-1,2-propanediol in an amount of about 0.5 mg to about 2 mg (e.g., about 0.5 mg, about 1 mg, or about 2 mg); and (e) corn oil, q.s. to 1 milliliter. The weight ratio of benzyl alcohol to benzyl benzoate in the abiraterone decanoate solution is typically in the range of about 2:1 to about 1:5 (eg, about 1:1 to 1:3, such as about 1:2).

[0266] Pharmaceutical compositions comprising substantially pure abiraterone decanoate are typically formulated for parenteral administration. For example, in some embodiments, the pharmaceutical composition is formulated for intramuscular, intradermal, or subcutaneous injection, for example, with a desired viscosity, glide force, particle count, endotoxin, etc. In some embodiments, the pharmaceutical composition is characterized as having (1) a viscosity of less than 0.1 Pa*s, such as about 0.05 Pa*s or less; (2) a glide force of about 1-10 N when measured using a 21G, 1.5-inch needle, and / or a glide force of about 2-15 N when measured using a 23-gauge (or 23G), 1.5-inch needle, and / or a glide force of about 30-150 N when measured using a 27G, 1.5-inch needle; (3) a glide force of about 10 N when measured according to USP. <788> and / or <789> When measured, no more than 1000 particles are 10 μm or larger in size and no more than 300 particles are 25 μm or larger in size; and / or (4) less than 100 EU / ml, such as according to USP <85> The measured bacterial endotoxin was less than 25 EU / ml. Methods for measuring viscosity and sliding force are known in the art and are also illustrated in Example 2 herein. The sliding force measurement can be performed using a 5 mL fill volume (for a 5 mL syringe) or a 2 mL fill volume (for a 3 mL syringe). The USP method cited herein is <788> , <789> and <85> It is to be understood that the current versions of such methods are also known to those skilled in the art.

[0267] In any of the embodiments described herein, unless otherwise indicated or contradicted by context, the pharmaceutical composition comprising abiraterone decanoate (which may alternatively be referred to as an abiraterone prodrug formulation) may be any pharmaceutical composition comprising substantially pure abiraterone decanoate as described herein.

[0268] Abiraterone decanoate in the pharmaceutical composition is generally included in a therapeutically effective amount for treating a disease or condition described herein, such as prostate cancer. In some embodiments, abiraterone decanoate may be present in a pharmaceutical composition in an amount sufficient to provide a therapeutically effective abiraterone plasma concentration after a single administration to a human subject suffering from a sex hormone-dependent or androgen receptor-driven disease or condition, such as a sex hormone-dependent benign or malignant condition, androgen receptor-driven cancer, and / or a syndrome caused by androgen excess, for at least one week, e.g., at least two weeks, at least four weeks, and up to six weeks or eight weeks or longer, such as up to ten weeks or longer. In some embodiments, abiraterone decanoate can be present in a pharmaceutical composition in an amount sufficient to provide a therapeutically effective abiraterone plasma concentration of about 1 ng / ml or more, such as about 2 ng / ml or more, about 4 ng / ml or more, about 5 ng / ml or more, about 8 ng / ml or more, etc., for a period of at least one week, for example, at least two weeks, at least four weeks, and up to six weeks or eight weeks or more, such as up to ten weeks or more, following a single administration to a human subject suffering from a sex hormone-dependent or androgen receptor-driven disease or condition, such as a sex hormone-dependent benign or malignant condition, an androgen receptor-driven cancer, and / or a syndrome caused by androgen excess. In some embodiments, abiraterone decanoate may be present in a pharmaceutical composition in an amount sufficient to provide a therapeutically effective abiraterone plasma concentration of about 0.5 ng / ml or more after a single administration to a human subject suffering from a sex hormone-dependent or androgen receptor-driven disease or condition, such as a sex hormone-dependent benign or malignant condition, androgen receptor-driven cancer, and / or a syndrome caused by androgen excess, for a period of at least four weeks, for example, at least six weeks and up to eight weeks or more, such as up to ten weeks or more. In some embodiments, abiraterone decanoate may be present in a pharmaceutical composition in an amount sufficient to provide a therapeutically effective abiraterone plasma concentration of about 0.1 ng / ml or more after a single administration to a human subject suffering from a sex hormone-dependent or androgen receptor-driven disease or condition, such as a sex hormone-dependent benign or malignant condition, androgen receptor-driven cancer, and / or a syndrome caused by androgen excess, for a period of at least four weeks, for example, at least six weeks and up to eight weeks or more, such as up to ten weeks or more.

[0269] The pharmaceutical composition herein is generally in unit dosage form, which refers to the dosage form of discrete units, such as vials, ampoules, pre-filled syringes, etc., each of which contains a predetermined amount of one or more active compounds. Generally, each unit dosage form herein is for single use, wherein substantially all the active compounds contained will be applied to the subject once or taken by the subject. For the sake of clarity, one or more unit dosage forms can be applied to the subject in each administration event to meet the required dose of one or more active compounds. For example, a pre-filled syringe can be generally used for a single injection, with a disposable injection of substantially all pre-filled solutions or suspensions to the subject, and one or more such pre-filled syringes (which may have the same or different amounts of one or more active compounds) can be applied to the subject to meet the required dose of one or more active compounds in each administration event. For example, for the dosing regimen of 1800mg abiraterone decanoate every three months, each administration event requires a total dose of 1800mg abiraterone decanoate, which can be met by administering two unit dosage forms each having 900mg abiraterone decanoate.

[0270] In some embodiments, the present disclosure provides a unit dosage form comprising about 1 milliliter (ml) to about 20 ml of abiraterone decanoate solution described herein (e.g., those described in

[93] -

[103] shown in the Summary of the Invention section herein). In some embodiments, the unit dosage form may contain about 1 ml of abiraterone decanoate solution. In some embodiments, the unit dosage form may contain about 2 ml of abiraterone decanoate solution. In some embodiments, the unit dosage form may contain about 3 ml of abiraterone decanoate solution. In some embodiments, the unit dosage form may contain about 4 ml to about 10 ml (e.g., about 4 ml, about 5 ml, about 6 ml, about 7 ml, about 8 ml, about 9 ml, about 10 ml, or any range or value between the listed values) of abiraterone decanoate solution.

[0271] In some specific embodiments, the present disclosure provides a unit dosage form, the unit dosage form comprising about 1-8 milliliters, such as about 1, 2, 3, 4, 5, 6, 7 or 8 milliliters of the decanoic acid abiraterone solution herein, for example, in some embodiments, each milliliter of decanoic acid abiraterone solution comprises, consists essentially of or consists of: (a) decanoic acid abiraterone in its alkaline form in an amount of about 180 mg; (b) benzyl alcohol in an amount of about 100 mg; (c) benzyl benzoate in an amount of about 200 mg; (d) 3-mercapto-1,2-propanediol in an amount of about 0.5 mg to about 2 mg (e.g., about 0.5 mg, about 1 mg or about 2 mg); and (e) corn oil, q.s. to 1 milliliter. In some embodiments, the unit dosage form of the decanoic acid abiraterone solution is contained in a container having a head space, such as a vial, an ampoule, a bottle, etc., wherein the head space is filled with an inert gas, such as nitrogen.

[0272] In any embodiment herein, the pharmaceutical composition, such as the unit dosage form herein, can also be characterized as storage stable at room temperature, for example, when stored at 60% relative humidity (RH) ± 5% RH at room temperature (25°C ± 2°C), it remains stable for about 1 month, 2 months, 3 months, 6 months, 9 months or longer. Storage stable means that a person skilled in the art considers the pharmaceutical composition to be the same as the initial pharmaceutical composition (i.e., at the beginning of storage). Storage stability is generally characterized by one or more of the following: (1) substantially the same amount of drug-related impurities, with no significant increase in the amount of individual impurities or total impurities; (2) substantially the same amount of abiraterone decanoate; (3) substantially the same physical properties, such as viscosity, physical state, color, etc. "Substantially the same" should be understood to mean within 80%-125% or within the range of measurement error.

[0273] In some specific embodiments, the present disclosure provides a pharmaceutical composition, such as a unit dosage form, comprising abiraterone decanoate having the formula:

[0274] Pharmaceutically acceptable oils and pharmaceutically acceptable solvents, wherein abiraterone decanoate is in its basic form, which is present in a concentration of about 25 mg / ml to about 500 mg / ml, such as about 50 mg / ml, about 100 mg / ml, about 120 mg / ml, about 150 mg / ml, about 180 mg / ml, about 200 mg / ml, about 250 mg / ml, about 300 mg / ml, about 350 mg / ml, about 400 mg / ml, about 500 mg / ml. 1, or any range between the listed values, wherein the pharmaceutical composition (e.g., unit dosage form) is formulated for parenteral injection, such as intramuscular injection, intradermal injection or subcutaneous injection, wherein the pharmaceutical composition (e.g., unit dosage form) comprises abiraterone decanoate in an amount of about 50 mg to about 5,000 mg, such as about 100 mg, about 350 mg, about 500 mg, about 1000 mg, about 1500 mg, about 2000 mg, about 5000 mg, or any range between the listed values. In some embodiments, the pharmaceutical composition can be in unit dosage form. Typically, one or more (e.g., 1 kind) unit dosage forms can be administered to a human subject in need, according to the dosage. For example, in some embodiments, each unit dosage form can include about 180mg, about 360mg, about 720mg, about 1260mg or about 1800mg of Abiraterone Decanoate, wherein the concentration of Abiraterone Decanoate in the preparation is about 180mg / ml, or about 1ml, about 2mL, about 3mL, about 7ml, about 10ml of the preparation, which can be packaged in, for example, bottles, vials, ampoules or pre-filled syringes. The pharmaceutically acceptable oil in the pharmaceutical composition (for example, unit dosage form) can be any of those oils described herein. For example, in some embodiments, the pharmaceutically acceptable oil for injection of pharmaceutically acceptable oil, including oil of plant origin or synthetic fatty acid monoglyceride or diglyceride. In some embodiments, pharmaceutically acceptable oil can be natural oil, synthetic oil or semi-synthetic oil, such as fractionated coconut oil and medium chain triglyceride, such as those sold with the trademark Miglyol. In some embodiments, pharmaceutically acceptable oil can include triglycerides derived from fatty acids. In some embodiments, pharmaceutically acceptable oil may include derived from long-chain and / or medium-chain fatty acids, which may be independently polyunsaturated, monounsaturated or saturated triglycerides. In some embodiments, pharmaceutically acceptable oil may be selected from vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil (peanut oil), poppy seed oil, tea seed oil and soybean oil. In some specific embodiments, pharmaceutically acceptable oil may include corn oil, which includes triglycerides, wherein the fatty acid constituents are mainly linoleic acid, oleic acid, palmitic acid and stearic acid. Pharmaceutically acceptable solvents in pharmaceutical compositions (e.g., unit dosage forms) also include any of those solvents described herein.In some embodiments, pharmaceutically acceptable solvents (or co-solvents, if oil is counted as solvents), such as alcohols, esters, acids, etc. In some embodiments, pharmaceutically acceptable solvents may include benzyl alcohol, benzyl benzoate, ethanol, glycerol, polyethylene glycol, polysorbate 80, acetic acid and / or ethyl acetate. In some embodiments, pharmaceutically acceptable solvents may be benzyl alcohol and / or benzyl benzoate. In some embodiments, pharmaceutical compositions, such as unit dosage forms, include abiraterone decanoate, pharmaceutically acceptable oils (e.g., described herein), benzyl alcohol and benzyl benzoate. In some embodiments, pharmaceutically acceptable oil is corn oil. In some embodiments, benzyl alcohol is present in an amount of about 5% by volume-10% by volume, benzyl benzoate is present in an amount of about 10% by volume-20% by volume, and corn oil is present in an amount of about 70% by volume-85% by volume, wherein the combined volume of benzyl alcohol, benzyl benzoate and corn oil is 100%. In some embodiments, abiraterone decanoate is in a substantially pure form as described herein. In some specific embodiments, the pharmaceutical composition comprises: (a) abiraterone decanoate, such as substantially pure abiraterone decanoate in its base form herein, at a concentration of about 25 mg / ml to about 500 mg / ml (e.g., about 25 mg / ml, about 50 mg / ml, about 100 mg / ml, about 120 mg / ml, about 150 mg / ml, about 180 mg / ml, about 200 mg / ml, about 250 mg / ml, about 300 mg / ml, about 400 mg / ml, about 500 mg / ml, or any range between the recited values, such as about 100 mg / ml to about 300 mg / ml); (b) benzyl alcohol in an amount of about 50 mg to about 150 mg / mL; (c) benzyl benzoate in an amount of about 100 mg to about 300 mg / mL; (d) a pharmaceutically acceptable oil (e.g., as described herein), particularly corn oil, for example, in an amount suitable for the volume of the pharmaceutical composition. In some specific embodiments, the pharmaceutical composition comprises per milliliter (a) abiraterone decanoate, such as substantially pure abiraterone decanoate in its base form herein, in an amount of about 100 mg to about 300 mg (e.g., about 100 mg, about 150 mg, about 200 mg, or about 250 mg, or any range between the recited values); (b) benzyl alcohol in an amount of about 50 mg to about 150 mg (e.g., about 75 mg, about 100 mg, or about 125 mg, or any range between the recited values); (c) benzyl benzoate in an amount of about 100 mg to about 300 mg (e.g., about 100 mg, about 150 mg, about 200 mg, or about 250 mg, or any range between the recited values); and (d) corn oil, q.s. to 1 milliliter. In some embodiments, the weight ratio of benzyl alcohol to benzyl benzoate in the pharmaceutical composition ranges from about 2:1 to about 1:5 (eg, about 1:1 to 1:3, such as about 1:2).In some specific embodiments, the pharmaceutical composition comprises abiraterone decanoate, benzyl alcohol, benzyl benzoate and corn oil, and the respective corresponding amounts (mg / 1 ml) are substantially the same as those shown in Example 2 of the present disclosure, for example, in some embodiments, the pharmaceutical composition comprises about 200 mg of abiraterone decanoate, about 100 mg of benzyl alcohol, about 200 mg of benzyl benzoate and corn oil in an amount of 1 mL per 1 ml; or abiraterone decanoate, about 180 mg; benzyl alcohol, about 100 mg; benzyl benzoate, about 200 mg; and corn oil, in an amount of 1 mL. In some specific embodiments, the pharmaceutical composition comprises abiraterone decanoate, benzyl alcohol, benzyl benzoate, corn oil and monothioglycerol, and the respective corresponding amounts (mg / 1 ml) are substantially the same as those shown in Example 4 of the present disclosure.

[0275] In some embodiments, the disclosure provides exemplary abiraterone decanoate formulations as shown in Table C. All numerical values ​​in the table are understood to be preceded by the term "about". The concentration of abiraterone decanoate refers to the amount (mg) of abiraterone decanoate in each ml of final formulation, and the final formulation can be a solution or a suspension. The amount of oil (primary solvent) and cosolvent (benzyl alcohol and / or benzyl benzoate) in the table is expressed as the volume percentage of the solvent, and the solvent includes both oil and cosolvent. Suitable oil includes any one of the pharmaceutically acceptable oils as described herein, such as corn oil. Optional additional ingredients are not shown in Table C.

[0276] Table C. Exemplary Abiraterone Decanoate Formulations

[0277]

[0278]

[0279] A person skilled in the art can prepare the pharmaceutical composition or unit dosage form of the present invention according to the methods disclosed herein. In some embodiments, the present disclosure provides a method for preparing abiraterone decanoate formulation suitable for parenteral administration to human subjects suffering from sex hormone-dependent or androgen receptor-driven diseases or conditions, such as sex hormone-dependent benign or malignant conditions, androgen receptor-driven cancers and / or syndromes caused by androgen excess. In some embodiments, the method comprises abiraterone decanoate having the formula:

[0280] And an optional pharmaceutically acceptable antioxidant (e.g., monothioglycerol) is mixed (such as dissolved or suspended) in a pharmaceutically acceptable carrier to form a mixture (such as a solution or suspension). In some embodiments, abiraterone decanoate is in a substantially pure form as described herein. In some embodiments, the method further includes sterilizing the mixture (e.g., solution or suspension), such as by sterile filtration. In some embodiments, the method further includes filling the mixture in a container with a head space, introducing an inert gas into the head space of the container, and optionally covering / sealing the container. Exemplary manufacturing methods are also described in Example 5 herein. In some embodiments, the container can be a vial, an ampoule or a bottle. In some embodiments, the method further includes adding the mixture to a syringe. In some embodiments, dissolving or suspending can include mixing (e.g., dissolving or suspending) a crystalline form of abiraterone decanoate described herein (e.g., Form A) in a pharmaceutically acceptable carrier. In some embodiments, mixing (such as dissolving or suspending) can include mixing (e.g., dissolving or suspending) substantially pure abiraterone decanoate as described herein in a pharmaceutically acceptable carrier. Suitable pharmaceutically acceptable carriers and amounts, the amount of abiraterone decanoate, the concentration of abiraterone decanoate, pharmaceutically acceptable antioxidants (e.g., monothioglycerol) and amounts thereof include any of those described herein. For example, in some embodiments, a pharmaceutically acceptable carrier comprises a pharmaceutically acceptable oil and a pharmaceutically acceptable solvent, wherein the pharmaceutically acceptable oil comprises vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil or soybean oil, the pharmaceutically acceptable solvent comprises benzyl alcohol and / or benzyl benzoate, and wherein the abiraterone decanoate is present in a concentration of about 50 mg / mL to about 300 mg / mL, such as about 100 mg / mL to about 300 mg / mL, such as about 180 mg / mL, and wherein the pharmaceutically acceptable antioxidant is monothioglycerol of about 2 mg / ml or less. In some embodiments, the pharmaceutically acceptable carrier can be a combination of corn oil, benzyl alcohol and benzyl benzoate in any amount as described herein. In some embodiments, abiraterone decanoate is present at a concentration of 150 mg / mL to about 250 mg / mL, such as about 180 mg / mL or about 200 mg / mL. In some embodiments, the pharmaceutically acceptable antioxidant is monothioglycerol in an amount of about 0.5 mg / ml, about 1 mg / mL, about 2 mg / mL, or any range between the recited values.

[0281] Abiraterone prodrug of Formula I

[0282] In some embodiments, the pharmaceutical composition may include an abiraterone prodrug according to any of those described in U.S. Pat. No. 10,792,292B2 and PCT Application Nos. PCT / US2021 / 048607 and PCT / US2022 / 016278. For example, in some embodiments, the pharmaceutical composition may include an abiraterone prodrug of Formula I or a pharmaceutically acceptable salt thereof:

[0283]

[0284] Among them, R 1 YesR 10 , OR 10 or NHR 10 , where R 10 Selected from: C 7-30 Alkyl; C 7-30 Alkenyl; C 7-30 Alkynyl; alkyl groups typically having a total carbon number of between 5 and 16 substituted by cycloalkyl; alkyl groups typically having a total carbon number of between 7 and 16 substituted by phenyl; cycloalkyl groups typically having a total carbon number of between 5 and 16 optionally substituted by one or more alkyl groups; and branched C5 or C6 alkyl groups such as

[0285] In some preferred embodiments, R 10 It is C 7-30 As used herein, unless explicitly stated to be substituted, alkyl is understood to be unsubstituted. However, alkyl can be straight chain or branched. In some preferred embodiments, R 10 Can be a straight chain C 7-30 In some preferred embodiments, R 10 Can be branched C 7-30 In some embodiments, R 10 It is a straight chain C 7-16 Alkyl groups, such as R 10 May have the formula -(CH2) n -CH3, wherein n is an integer between 6 and 15 (e.g., 6 to 12, such as 6, 7, 8, 9, 10, 11 or 12). In some preferred embodiments, R 10 Can be branched C 7-16 alkyl.

[0286] In some embodiments, R 10 It can also be an alkyl group substituted with a cycloalkyl group. Typically, in such embodiments, R 10The total number of carbon atoms in the cycloalkyl group is between 5 and 16, that is, the total number of carbon atoms from the alkyl and cycloalkyl groups is between 5 and 16. Cycloalkyl groups are usually unsubstituted. However, in some embodiments, the cycloalkyl group may be optionally substituted with, for example, one or two lower alkyl groups (e.g., C 1-4 In some embodiments, R 10 Can be C 3-6 The alkyl group substituted by cycloalkyl generally has a total carbon number between 6 and 12. In some embodiments, R 10 Can be C 3-6 Cycloalkyl-substituted straight chain alkyl, for example, R 10 May have the formula -(CH2) n -Cy, wherein n is an integer from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6), and Cy is C 3-6 In some embodiments, R 10 May have the formula -(CH2) n -Cy, wherein n is 1 or 2, and Cy is cyclopentyl or cyclohexyl. 10 It can also be C 3-6 Cycloalkyl-substituted branched chain alkyl (e.g., branched chain C 2-6 ). As used herein, branched C2 alkyl is understood to be a 1,1-disubstituted ethyl group, for example -CH(CH3)-Cy.

[0287] In some embodiments, R 10 It can also be an alkyl group substituted with phenyl. Typically, in such embodiments, R 10 The total number of carbon atoms in R is between 7 and 16, that is, the total number of carbon atoms from the alkyl moiety and the phenyl moiety is between 5 and 16. 10 It may be a straight chain alkyl group substituted with a phenyl group, for example, R 10 May have the formula -(CH2) n -Cy, wherein n is an integer from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6), and Cy is phenyl. 10 May have the formula -(CH2) n -Cy, wherein n is 1 or 2, and Cy is phenyl. 10 It may also be a branched alkyl group substituted with a phenyl group (e.g., a branched C 2-6 ). The phenyl group is typically unsubstituted. However, in some embodiments, the phenyl group may be optionally substituted with, for example, one or two lower alkyl groups (e.g., C 1-4 alkyl) substituted.

[0288] In some embodiments, R 10can be a cycloalkyl group optionally substituted with one or more alkyl groups. In such embodiments, R 10 Typically the total number of carbon atoms is between 5 and 16, i.e., the total number of carbon atoms of the cycloalkyl group and its optional substituents is between 5 and 16. 10 Can be C 3-6 Cycloalkyl, which is unsubstituted or replaced by C 1-4 In some embodiments, R 10 Can be

[0289] In some embodiments, R 10 It can be a branched C5 or C6 alkyl group. In some specific embodiments, R 10 Can be Other branched C5 or C6 alkyl groups are also suitable.

[0290] In some embodiments, R 10 It may be an unsaturated aliphatic group, such as C 7-30 Alkenyl or C 7-30 Alkynyl.

[0291] In some preferred embodiments, the compound of formula I is an ester of abiraterone, for example, R 1 YesR 10 , where R 10 In some embodiments, R in Formula I 1 Can be C 7-16 An alkyl group, for example, has the formula -(CH2) n -CH3 alkyl, wherein n is an integer between 6 and 12 (e.g., 6, 7, 8, 9, 10, 11 or 12). In some embodiments, R in Formula I 1 It can be expressed by the formula -(CH2) n -Cy represents, wherein n is an integer from 1 to 6, and Cy is C 3-6 Cycloalkyl or phenyl, for example, in more specific embodiments, n can be 1 or 2, and Cy is cyclopentyl, cyclohexyl or phenyl. In some specific embodiments, R in Formula I 1 Can be In some specific embodiments, R in Formula I 1 Can be R 1 Other suitable groups include any of the R 10 .

[0292] In some embodiments, R in Formula I 1 Can also be OR 10 or NHR 10 , where R 10Defined in this article.

[0293] Typically, the compound of formula I may be present in a formulation in a basic form, such as in a non-aqueous formulation. However, in some embodiments, pharmaceutically acceptable salts of the compound of formula I are also useful. Unless specifically mentioned as a salt thereof or inconsistent with the context, the compound of formula I may be present in its basic form in the abiraterone prodrug formulation described herein. In some embodiments, the compound of formula I may be in a substantially pure form.

[0294] Abiraterone prodrugs

[0295] In some embodiments, the pharmaceutical composition comprising abiraterone prodrug can be any of those described in U.S. Patent No. 10,792,292B2 and PCT Application No. PCT / US2021 / 048607 and No. PCT / US2022 / 016278. The abiraterone prodrug preparation can be used in the method herein. Generally, abiraterone prodrugs can be formulated into parenteral preparations, such as intramuscular, intradermal or subcutaneous preparations, and in some embodiments can be formulated into abiraterone that delivers therapeutically effective plasma concentrations over an extended period of time, for example, for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks and up to 6 weeks or 8 weeks or longer, such as up to 10 weeks or longer.

[0296] Various abiraterone prodrugs, such as abiraterone esters, carbamates or carbonates are suitable for the compositions and methods of the present disclosure. In some embodiments, the pharmaceutical composition may include a compound of formula I (e.g., any one or more as defined herein) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition may be formulated for parenteral administration, such as intramuscular injection, intradermal injection or subcutaneous injection. The pharmaceutical composition generally includes a pharmaceutically acceptable carrier. Suitable carriers include those known in the art, such as those described in the inactive ingredient database present in "Remington: The Science and Practice of Pharmacy" (formerly known as "Remington's Pharmaceutical Sciences," University of the Sciences in Philadelphia, Lippincott, Williams & Wilkins, Philadelphia, Pa. (2005)) and the FDA-approved drugs of the Center for Drug Evaluation and Research of the U.S. Food and Drug Administration. In some embodiments, a pharmaceutically acceptable carrier may be a carrier approved by the FDA for intramuscular, intradermal or subcutaneous drug products, for example, those listed in the FDA inactive ingredient database. In some embodiments, a pharmaceutically acceptable carrier can be any suitable non-aqueous vehicle for injection, such as those described in the United States Pharmacopoeia. In some embodiments, a pharmaceutically acceptable carrier can be a pharmaceutically acceptable oil, such as vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil or soybean oil. In some embodiments, a pharmaceutically acceptable oil can be suitable for use as an injection vehicle, such as an oil that meets the standards described in the corresponding United States Pharmacopoeia monograph (e.g., as described herein). In some embodiments, a pharmaceutically acceptable oil can be an oil of plant origin suitable for use as an injection vehicle. In some embodiments, a pharmaceutically acceptable oil can be a synthetic oil suitable for use as an injection vehicle, such as a synthetic fatty acid monoglyceride or diglyceride, such as those that are liquid and remain clear when cooled to 10°C and have an iodine value of no more than 140. In some embodiments, a pharmaceutically acceptable oil can be a natural oil, a synthetic oil or a semi-synthetic oil, such as fractionated coconut oil and medium-chain triglycerides, such as those sold under the trademark Miglyol. In some embodiments, pharmaceutically acceptable carriers include triglycerides derived from fatty acids. In some embodiments, pharmaceutically acceptable carriers include triglycerides derived from long-chain and / or medium-chain fatty acids, which can be independently polyunsaturated, monounsaturated or saturated. In some embodiments, two or more different pharmaceutically acceptable oils can be used. In some embodiments, pharmaceutical compositions are non-aqueous solutions or suspensions.In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable solvent, such as benzyl alcohol, benzyl benzoate or a combination thereof. In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof can be present in the pharmaceutical composition at a concentration of about 25 mg / ml to about 500 mg / ml (e.g., about 25 mg / ml, about 50 mg / ml, about 100 mg / ml, about 150 mg / ml, about 200 mg / ml, about 250 mg / ml, about 300 mg / ml, about 400 mg / ml, about 500 mg / ml or any range between the listed values).

[0297] In some embodiments, a pharmaceutical composition suitable for use in the methods herein may comprise a compound of Formula II or a pharmaceutically acceptable salt thereof.

[0298]

[0299] Where R 2 It is defined herein. In some embodiments, the pharmaceutical composition can be formulated for intramuscular injection, intradermal injection or subcutaneous injection. In some embodiments, the compound of formula II or its pharmaceutically acceptable salt can be present in the pharmaceutical composition at a concentration of about 25mg / ml to about 500mg / ml (for example, about 25mg / ml, about 50mg / ml, about 100mg / ml, about 150mg / ml, about 200mg / ml, about 250mg / ml, about 300mg / ml, about 400mg / ml, about 500mg / ml or any range between the values). In some embodiments, the pharmaceutical composition is a non-aqueous solution or suspension. In some embodiments, the compound of formula II or its pharmaceutically acceptable salt is dissolved or suspended in a pharmaceutically acceptable oil (for example, described herein), such as vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil or soybean oil. In some embodiments, the pharmaceutical composition also includes a pharmaceutically acceptable solvent, such as benzyl alcohol, benzyl benzoate or a combination thereof.

[0300] Various groups are suitable as R in formula II 2 In some embodiments, R 2 Such that the compound of formula II is an ester, carbamate or carbonate of abiraterone. 2 YesR 20 , OR 20 or NHR 20 , and R 20 Selected from: C 1-30 Alkyl; C 2-30 Alkenyl; C 2-30alkynyl; alkyl substituted with cycloalkyl, typically with a total carbon number of between 4 and 30; alkyl substituted with phenyl, typically with a total carbon number of between 7 and 30; and cycloalkyl optionally substituted with one or more alkyl, typically with a total carbon number of between 3 and 30.

[0301] In some preferred embodiments, R 20 It is C 1-16 In some embodiments, R 20 Can be a straight chain C 1-16 In some preferred embodiments, R 20 Can be branched C 3-16 In some embodiments, R 20 It can be a branched C5 or C6 alkyl group. In some specific embodiments, R 20 Can be In some embodiments, R 20 May have the formula -(CH2) n -CH3, wherein n is an integer between 0 and 12 (eg, 6 to 12, such as 6, 7, 8, 9, 10, 11 or 12).

[0302] In some embodiments, R 20 It can also be an alkyl group substituted with a cycloalkyl group. Typically, in such embodiments, R 20 The total number of carbon atoms in the cycloalkyl group is between 4 and 30, such as between 5 and 16 (i.e., the total number of carbon atoms from the alkyl and cycloalkyl groups is between 5 and 16). Cycloalkyl groups are typically unsubstituted. However, in some embodiments, the cycloalkyl group may be optionally substituted with, for example, one or two lower alkyl groups (e.g., C 1-4 In some embodiments, R 20 Can be C 3-6 The alkyl group substituted by cycloalkyl generally has a total carbon number between 6 and 12. In some embodiments, R 20 Can be C 3-6 Cycloalkyl-substituted straight chain alkyl, for example, R 20 May have the formula -(CH2) n -Cy, wherein n is an integer from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6), and Cy is C 3-6 In some embodiments, R 20 May have the formula -(CH2) n -Cy, wherein n is 1 or 2, and Cy is cyclopentyl or cyclohexyl. 20 It can also be C 3-6 Cycloalkyl-substituted branched chain alkyl (e.g., branched chain C 2-6 ).

[0303] In some embodiments, R 20 It can also be an alkyl group substituted with a phenyl group. Typically, in such embodiments, R 20 The total number of carbon atoms in R is between 7 and 30, such as between 7 and 16 (ie, the total number of carbon atoms from the alkyl moiety and the phenyl moiety is between 7 and 16). 20 It may be a straight chain alkyl group substituted with a phenyl group, for example, R 20 May have the formula -(CH2) n -Cy, wherein n is an integer from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6), and Cy is phenyl. 20 May have the formula -(CH2) n -Cy, wherein n is 1 or 2, and Cy is phenyl. 20 It may also be a branched alkyl group substituted with a phenyl group (e.g., a branched C 2-6 ). The phenyl group is typically unsubstituted. However, in some embodiments, the phenyl group may be optionally substituted with, for example, one or two lower alkyl groups (e.g., C 1-4 alkyl) substituted.

[0304] In some embodiments, R 20 can be a cycloalkyl group optionally substituted with one or more alkyl groups. In such embodiments, R 20 Typically the total number of carbon atoms is between 3 and 30, such as between 5 and 16 (i.e. the total number of carbon atoms of the cycloalkyl group and its optional substituents is between 5 and 16). 20 Can be C 3-6 Cycloalkyl, which is unsubstituted or replaced by C 1-4 In some embodiments, R 20 Can be

[0305] In some embodiments, R 20 It may be an unsaturated aliphatic group, such as C 2-30 Alkenyl or C 2-30 Alkynyl.

[0306] In some preferred embodiments, the compound of formula II is an abiraterone ester, for example, R 2 YesR 20 , where R 20 In some embodiments, R in Formula II 2 Can be C 1-16 An alkyl group, for example, has the formula -(CH2) n-CH3 alkyl, wherein n is an integer between 0 and 12. In some embodiments, R in Formula II 2 It can be expressed by the formula -(CH2) n -Cy represents, wherein n is an integer from 1 to 6, and Cy is C 3-6 Cycloalkyl or phenyl, for example, in more specific embodiments, n can be 1 or 2, and Cy is cyclopentyl, cyclohexyl or phenyl. In some specific embodiments, R in Formula II 2 Can be R 2 Other suitable groups include any of the R 20 . In some embodiments, the abiraterone ester can be the acetate, propionate, butyrate, (valeric acid ester) valerate, isohexanoate, butyrate, cyclohexanecarboxylate, phenylpropionate, hexanoate (hexanoate), enanthate (enanthate), cyclopentyl propionate, octanoate, nonanoate, decanoate, undecanoate, dodecanoate, tridecanoate, tetradecanoate, pentadecanoate or hexadecanoate of abiraterone. In some embodiments, the abiraterone ester can be abiraterone acetate, abiraterone propionate and abiraterone decanoate. In some specific embodiments, the abiraterone ester can be abiraterone valerate, abiraterone hexanoate, abiraterone enanthate, abiraterone decanoate, abiraterone isohexanoate or abiraterone cyclopentyl propionate.

[0307] In some embodiments, R in Formula II 2 Can also be OR 20 or NHR 20 , where R 20 Defined in this article.

[0308] Typically, the compound of formula II may be present in a formulation in an alkaline form, such as in a non-aqueous formulation. However, in some embodiments, a pharmaceutically acceptable salt of the compound of formula II is also useful. Unless specifically mentioned as a salt thereof or inconsistent with the context, the compound of formula II may be present in the abiraterone prodrug formulation described herein in its alkaline form. In some embodiments, the compound of formula II may be in a substantially pure form.

[0309] Pharmaceutical compositions comprising substantially pure compounds of Formula I or II (e.g., abiraterone decanoate) are typically formulated for parenteral administration. For example, in some embodiments, the pharmaceutical composition is formulated for intramuscular, intradermal, or subcutaneous injection, for example, with a desired viscosity, glide force, particle count, endotoxin, etc. In some embodiments, the pharmaceutical composition is characterized as having (1) a viscosity of less than 0.1 Pa*s, such as about 0.05 Pa*s or less; (2) a glide force of about 1-10 N when measured using a 21G, 1.5-inch needle, and / or a glide force of about 2-15 N when measured using a 23-gauge (or 23G), 1.5-inch needle, and / or a glide force of about 30-150 N when measured using a 27G, 1.5-inch needle; (3) a glide force of about 10 N when measured according to USP. <788> and / or <789> When measured, no more than 1000 particles are 10 μm or larger in size and no more than 300 particles are 25 μm or larger in size; and / or (4) less than 100 EU / ml, such as according to USP <85> The measured bacterial endotoxin was less than 25 EU / ml. Methods for measuring viscosity and sliding force are known in the art and are also illustrated in Example 2 herein. USP method cited herein <788> , <789> and <85> It is to be understood that the current versions of such methods are also known to those skilled in the art.

[0310] Generally, the Abiraterone prodrug of the present disclosure is formulated into a non-aqueous solution or suspension. In some embodiments, compared with an aqueous solution or suspension, a non-aqueous solution or suspension provides a higher level of Abiraterone in plasma in a longer duration. For example, as described in detail herein, the intramuscular injection of an aqueous suspension of an acetic acid Abiraterone prodrug and a vegetable oil solution was evaluated in rats. Surprisingly, it was determined that the vegetable oil solution (rather than an aqueous suspension) of the acetic acid Abiraterone prodrug produced the highest plasma level and the longest active drug Abiraterone exposure duration. Therefore, in some embodiments, the Abiraterone prodrug preparation herein may include the Abiraterone prodrug of the present disclosure (for example, Formula I or II compound) dissolved or dispersed in a pharmaceutically acceptable carrier. In some embodiments, a pharmaceutically acceptable carrier may be any suitable non-aqueous vehicle for injection, such as those described in the U.S. Pharmacopoeia. In some embodiments, a pharmaceutically acceptable carrier may be a pharmaceutically acceptable oil, such as vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil or soybean oil. In some embodiments, a pharmaceutically acceptable oil may be an oil suitable for use as an injection vehicle, such as an oil that satisfies the standards described in the corresponding U.S. Pharmacopoeia monograph (e.g., as described herein). In some embodiments, a pharmaceutically acceptable oil may be an oil of plant origin suitable for use as an injection vehicle. In some embodiments, a pharmaceutically acceptable oil may be a synthetic oil suitable for use as an injection vehicle, such as a synthetic fatty acid monoglyceride or diglyceride, such as those that are liquid and remain clear when cooled to 10°C and have an iodine value of no more than 140. In some embodiments, a pharmaceutically acceptable oil may be a natural oil, a synthetic oil, or a semi-synthetic oil, such as fractionated coconut oil and medium-chain triglycerides, such as those sold under the trademark Miglyol. In some embodiments, a pharmaceutically acceptable carrier includes triglycerides derived from fatty acids. In some embodiments, a pharmaceutically acceptable carrier includes triglycerides derived from long-chain and / or medium-chain fatty acids, which may be independently polyunsaturated, monounsaturated, or saturated triglycerides. In some embodiments, pharmaceutically acceptable oil can be the oil that FDA approves for intramuscular, intradermal or subcutaneous drug product, for example, any one of those listed in the FDA inactive ingredient database. In some specific embodiments, pharmaceutically acceptable oil is castor oil or corn oil. In some embodiments, two or more different pharmaceutically acceptable oils can be used.

[0311] Other ingredients may also be optionally included in the abiraterone prodrug preparation herein.In some embodiments, the abiraterone prodrug preparation may also include a pharmaceutically acceptable solvent, such as benzyl alcohol, benzyl benzoate, ethanol, glycerol, polyethylene glycol, polysorbate 80, acetic acid and ethyl acetate.It is determined that additives / co-solvents benzyl alcohol and benzyl benzoate have the advantages of increasing prodrug solubility and reducing the viscosity and slip force of the solution, see, for example, U.S. Patent No. 10,792,292B2 and PCT Application No. PCT / US2021 / 048607 and No. PCT / US2022 / 016278, which provide a more concentrated solution that is easier to be injected by a needle (e.g., No. 20-27, such as No. 22-25) of acceptable specifications for intramuscular injection.Co-solvents can be selected according to the ability of co-solvents to reduce the viscosity of the vehicle to allow injection by a suitable injection needle or cannula. Benzyl alcohol as an additive in intramuscular or subcutaneous injections also has the advantage of acting as a local anesthetic at the injection site (Wilson et al. Ann. Emer. Med. 33 (5), 495, 1999). In some embodiments, the abiraterone prodrug formulation also contains benzyl alcohol. In some embodiments, if present, a certain level of co-solvent (e.g., about 0-50% of the solvent, such as about 10%) can be included so that it does not cause irritation (or only minimal or tolerable irritation) at the injection site.

[0312] In some embodiments, abiraterone prodrug preparations may include benzyl benzoate as a cosolvent, for example, about 0-50% of the solvent, typically 0-35% or 0-30%, or about 20%. In some embodiments, abiraterone prodrug preparations may include a combination of benzyl alcohol and benzyl benzoate as a cosolvent. In some embodiments, benzyl alcohol can be present in an amount of about 0%-20% (e.g., 0%-15% or 0%-10%, such as about 10%) of the solvent, and benzyl benzoate can be present in an amount of about 0%-50% (e.g., 0%-35% or 0%-30%, such as about 20%) of the solvent, wherein the balance of the solvent can be any one or more of the pharmaceutically acceptable oils described herein, such as corn oil, castor oil, sesame oil, peanut oil, cottonseed oil and / or Miglyol812, etc. Compared with using only benzyl alcohol or benzyl benzoate, the combination of benzyl alcohol and benzyl benzoate shows a lower viscosity and slip force. Furthermore, it was unexpectedly discovered that a representative abiraterone prodrug (abiraterone decanoate) formulation comprising oil (corn oil, 70%) as well as benzyl alcohol (10%) and benzyl benzoate (20%) achieved much higher abiraterone plasma exposure in monkeys compared to a formulation having substantially the same concentration of abiraterone decanoate comprising the same oil vehicle but without benzyl benzoate (i.e., corn oil, 90% and benzyl alcohol, 10%) and when administered in the same amount.

[0313] The solubility of the abiraterone ester can be affected after adding a cosolvent to the vegetable oil vehicle. In some embodiments, the abiraterone ester is completely dissolved in the composition, while in other embodiments, the abiraterone ester is partially dispersed in the composition. In one embodiment, the abiraterone ester is completely dissolved in the vehicle.

[0314] Abiraterone prodrug formulations may also contain pharmaceutically acceptable preservatives, polymers, antioxidants, antimicrobial agents, chelating agents and other excipients, such as citric acid, glucose, ascorbic acid, benzalkonium chloride, benzoic acid, sodium sulfobutyl ether β-cyclodextrin, calcium chloride, sodium carboxymethylcellulose, chlorobutanol, creatine, cross-linked carboxymethylcellulose, dipotassium hydrogen phosphate, sodium docusate, sodium edetate, glycerol, sodium hyaluronate, hydroxypropyl β-cyclodextrin, lactic acid, lactose, egg whites, Phospholipids, maleic acid, mannitol, meglumine, methylcellulose, methylparaben, microcrystalline cellulose, pyridinium chloride, monothioglycerol, phenol, poloxamer 188, polysaccharide lactic acid, polysorbate 20, polysorbate 40, polysorbate 80, propylparaben, sodium acetate, sodium benzoate, sodium citrate, sorbitan monolaurate, sorbitol, sucrose, tartaric acid, trisodium citrate, tromantanamine, tromethamine and urea. For example, in some embodiments, the abiraterone prodrug formulation may contain a pharmaceutically acceptable antioxidant such as monothioglycerol.

[0315] Abiraterone prodrug formulations can be sterilized by methods known to those skilled in the art (eg, gamma irradiation, micron filtration, and autoclaving).

[0316] Abiraterone extended release

[0317] Abiraterone prodrugs and abiraterone prodrug formulations of the present disclosure (e.g., those containing compounds of Formula I or II as described herein) are generally formulated preferably as parenteral formulations, such as intramuscular, intradermal or subcutaneous formulations to human subjects in need, such as those suffering from sex hormone-dependent or androgen receptor-driven diseases or conditions, such as sex hormone-dependent benign or malignant conditions, androgen receptor-driven cancers and / or syndromes caused by androgen excess Provide long-acting release of abiraterone. In some embodiments, abiraterone prodrugs and abiraterone prodrug formulations of the present disclosure (e.g., those containing compounds of Formula I or II as described herein) can be formulated to deliver therapeutic plasma levels of abiraterone to subjects suffering from sex hormone-dependent benign or malignant conditions, androgen receptor-driven cancers and / or syndromes caused by androgen excess after a single administration over an extended period of time (e.g., at least 1 week, such as at least two weeks, at least 3 weeks, at least 4 weeks and up to 6 weeks or 8 weeks or longer, such as up to 10 weeks or longer, etc.). In some embodiments, the therapeutic plasma concentration of Abiraterone can be at least 1 ng / ml, such as a concentration of at least 2 ng / ml, at least 4 ng / ml, at least 8 ng / ml. In some embodiments, the therapeutic plasma concentration of Abiraterone can also be about 0.5 ng / ml or higher. In some embodiments, the therapeutic plasma concentration of Abiraterone can also be about 0.1 ng / ml or higher.

[0318] Unit dosage form

[0319] In some embodiments, the Abiraterone prodrugs and Abiraterone prodrug preparations disclosed herein (e.g., those containing Formula I or II compounds as described herein) can be formulated into unit dosage forms. In some embodiments, the unit dosage form can include a sufficient amount of the corresponding prodrug so that after a single administration (e.g., intramuscular injection) to a human subject, for example, a disease or condition driven by sex hormone dependence or androgen receptor, such as sex hormone-dependent benign or malignant conditions (e.g., metastatic CRPC or metastatic CSPC), androgen receptor-driven cancer and / or a syndrome caused by androgen excess, the unit dosage form provides a therapeutically effective Abiraterone plasma concentration in the human subject for at least two weeks, such as at least 3 weeks, at least 4 weeks, at least 5 weeks and up to 6 weeks or 8 weeks or longer, such as up to 10 weeks or longer. In some embodiments, the therapeutic plasma concentration of Abiraterone can be at least 1ng / ml, for example, at least 2ng / ml, at least 4ng / ml, at least 8ng / ml. In some embodiments, the therapeutic plasma concentration of abiraterone can also be about 0.5ng / ml or higher. In some embodiments, the therapeutic plasma concentration of abiraterone can also be about 0.1ng / ml or higher. In some embodiments, the unit dosage form is a parenteral preparation, such as an intramuscular, intradermal or subcutaneous preparation. In some embodiments, the unit dosage form is a non-aqueous solution or suspension. In some embodiments, the unit dosage form includes abiraterone prodrug (for example, a compound of Formula I or Formula II) dissolved or suspended in a pharmaceutically acceptable oil such as a vegetable oil such as castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil or soybean oil. In some embodiments, two or more different pharmaceutically acceptable oils can be used in the unit dosage form. In some embodiments, the unit dosage form may also include a pharmaceutically acceptable solvent, such as alcohol, ester and / or acid, such as benzyl alcohol, benzyl benzoate or a combination thereof. Other suitable ingredients for unit dosage forms include those described herein.

[0320] Abiraterone prodrugs (e.g., compounds of Formula I or Formula II) are typically present in unit dosage forms at a concentration of about 25 mg / ml to about 500 mg / ml (e.g., about 25 mg / ml, about 50 mg / ml, about 100 mg / ml, about 150 mg / ml, about 200 mg / ml, about 250 mg / ml, about 300 mg / ml, about 400 mg / ml, about 500 mg / ml, or any range between the values). The amount of abiraterone prodrugs in a unit dosage form can vary, depending on various factors, such as the clearance rate of the corresponding abiraterone prodrugs, the expected frequency of administration, and the required plasma level. Typically, the amount of abiraterone prodrugs can be in the range of about 50 mg to about 2000 mg, and if expressed as the equivalent of abiraterone, typically the range can be about 25 mg to about 1750 mg. In some embodiments, the amount of abiraterone prodrugs can also be higher, such as in the range of about 50 mg to about 5000 mg. In some embodiments, to achieve a less frequent dosing frequency, such as once a month, once every two months, or once every three months, the prodrug can be included in a unit dosage form in an amount and / or concentration that is safe and tolerated by a human subject user. Typically, the unit dosage form is formulated to have a viscosity suitable for parenteral injection, such as suitable for intramuscular, intradermal, or subcutaneous injection.

[0321] In some embodiments, the unit dosage form can be formulated to achieve certain pharmacokinetic (PK) characteristics, such as PK characteristics with a substantially flat curve after the initial rising phase. Typically, after the unit dosage form is administered to a human subject, during the first hours to days (e.g., 5 days or a week) after administration, the plasma concentration of abiraterone in the human subject can increase and then gradually stabilize. In some embodiments, after this initial rising phase, the plasma concentration of abiraterone in the human subject can stabilize and can be substantially constant over an extended period of time, such as at least several days (e.g., 2, 3, 4, 5 or 6 days), or at least 1 week, at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, etc.

[0322] In some embodiments, the unit dosage form is suitable for administration once a month (or once a month or more, such as once every two months, or once every three months), and when administered once (e.g., intramuscularly) to a human subject in need thereof, the unit dosage form achieves a PK profile characterized by one or more of the following: (a) the unit dosage form provides a therapeutically effective plasma concentration of abiraterone in a human subject for at least 4 weeks, such as up to 6 weeks or 8 weeks, or up to 10 weeks or more; (b) a single dose C of abiraterone is maxbetween about 1 ng / ml and about 300 ng / ml, such as between 1 ng / ml and about 10 ng / ml; (c) no food effect; (d) comparable to a 1000 mg oral dose once daily without food. The C of abiraterone observed at steady state max In comparison, a single dose of abiraterone max (e) a single dose of abiraterone on day 28 after administration of C min Between about 0.1 ng / ml and about 8 ng / ml; (f) the plasma concentration of abiraterone remains substantially constant after administration, for example, for at least 1 week, for example, 1 week to 3 weeks, 1 week to 10 weeks, or 2 weeks to 8 weeks. In some embodiments, substantially constant over a period of time may mean that the highest concentration observed on any day (i.e., 24 hours) during the period of time is not higher than 4 times, for example, not higher than 2 times, the lowest concentration observed on the same day. No food effect is generally understood to mean that no significant difference in PK is observed when a unit dosage form is administered to a subject who has eaten or not eaten. For example, in some embodiments, no food effect may mean that the C of abiraterone between subjects administered in a fed state or a fasted state is not higher than 4 times, for example, not higher than 2 times. max and AUC are substantially the same (e.g., between 80% and 125%). As used herein, a single dose of C max It should be understood as the C achieved after a single administration to a naive subject (generally referring to a human subject who has not received any abiraterone drug for at least 3 days, such as at least 1 week, prior to administration and in whom plasma abiraterone has not been observed prior to administration). max The single dose C used in this paper min It refers to the minimum concentration observed on a given day following a single administration to untreated subjects, for example, on day 28 following administration.

[0323] In some embodiments, the unit dosage form is suitable for monthly (or more than monthly, such as once every two months, or once every three months) administration, and when the unit dosage form is administered (e.g., intramuscularly) to a human subject in need thereof once a month (or more than monthly, such as once every two months, or once every three months), the unit dosage form achieves (a) a steady-state C of abiraterone between about 1 ng / ml and about 300 ng / ml, such as between about 1 ng / ml and about 10 ng / ml; max ; (b) no food effect; (c) no effect compared to the effect of taking 1000 mg orally once daily without food. The C of abiraterone observed at steady state max Compared with abiraterone, the steady-state C max (d) a steady-state C between about 0.1 ng / ml and about 8 ng / ml min; and (g) the plasma concentration of abiraterone remains substantially constant after each administration, e.g., for at least 1 week, e.g., 1 week to 3 weeks, 1 week to 10 weeks, or 2 weeks to 8 weeks. Steady state C as used herein max or C min It is understood that after steady state is reached, the C is usually observed after several administrations to human subjects. max or C min .

[0324] In some embodiments, the unit dosage form can be packaged in a container such as a vial or an ampoule. In some embodiments, the unit dosage form may be included in a pre-filled syringe or a medicine box with a syringe (such as a disposable syringe). Other packaging and / or containers are also available, which is known to those skilled in the art. In some embodiments, a medicine box comprising multiple unit dosage forms described herein is also provided. In some embodiments, the medicine box may also include a syringe. Typically, one or more (such as 1) unit dosage forms are used to meet the required single dose. In some embodiments, the present disclosure provides abiraterone prodrug formulations that allow multiple single uses. In some embodiments, the present disclosure provides abiraterone prodrug formulations that can be subdivided into multiple unit dosage forms. In some embodiments, the unit dosage form may include any pharmaceutical composition described herein, such as those shown in the Summary of the Invention section

[18] -

[30] or

[93] -

[107] . In some embodiments, the unit dosage form comprises about 180 mg, about 360 mg, about 720 mg, about 1260 mg, about 1800 mg, or any range or value between the recited values ​​of abiraterone decanoate.

[0325] Exemplary Specific Formulations

[0326] In some embodiments, the present disclosure also provides some specific abiraterone prodrug preparations, which can be unit dosage forms or multi-unit dosage forms in some embodiments. For example, the following table (Table A and Table B) shows some representative abiraterone ester prodrug preparations in oil vehicles. All numerical values ​​in the table should be understood as being preceded by the term "about". The concentration of abiraterone prodrug refers to the amount (mg) of abiraterone prodrug in each ml of the final preparation, and the final preparation can be a solution or a suspension. The amount of oil (main solvent) and cosolvent in the table is expressed as the volume percentage of the solvent, and the solvent includes both oil and cosolvent. Suitable oil includes any pharmaceutically acceptable oil described herein. Suitable cosolvents also include any of those described herein, such as alcohol, ester and / or acid, such as benzyl alcohol, benzyl benzoate or a combination thereof, see, for example, Table B. An example of a suitable cosolvent is benzyl alcohol. An example of a suitable cosolvent is a combination of benzyl alcohol and benzyl benzoate. In some embodiments, cosolvents are not included in the preparation. In some embodiments, cosolvents do not include benzyl benzoate. Other optional ingredients are described herein.

[0327] Table A. Exemplary Formulations

[0328]

[0329] In some embodiments, the present disclosure provides an Abiraterone prodrug preparation comprising an Abiraterone prodrug and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier includes a pharmaceutically acceptable oil (e.g., as described herein), benzyl alcohol and benzyl benzoate. In some embodiments, the Abiraterone prodrug can be Abiraterone decanoate. In some embodiments, the Abiraterone prodrug can be Abiraterone isocaproate. Pharmaceutically acceptable oils generally include triglycerides derived from fatty acids. In some embodiments, pharmaceutically acceptable oils can be natural oils, synthetic oils or semi-synthetic oils, such as fractionated coconut oil and medium-chain triglycerides, such as those sold with the trademark Miglyol. In some embodiments, pharmaceutically acceptable oils can be selected from vegetable oils, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil (peanut oil), poppy seed oil, tea seed oil and soybean oil. In some embodiments, the present disclosure provides some exemplary preparations shown in Table B.

[0330] Table B. Additional Exemplary Formulations

[0331]

[0332] As used herein, when the solvent system of the abiraterone prodrug formulation comprises two or more solvents (including oil), the abiraterone prodrug formulation can be expressed as a solution of abiraterone prodrug at a specified concentration in a solvent system having x% oil and y% co-solvent (e.g., 90% corn oil and 10% benzyl alcohol). In such expressions, unless otherwise indicated or clearly contrary to the context, x% and y% should be understood as being based on volume percentages, whether or not followed by "v / v".

[0333] Combination therapy

[0334] In some embodiments, the methods herein may include administering one or more other drugs or agents (e.g., another cancer chemotherapy drug, a hormone replacement drug, or a hormone ablation drug) to a human subject simultaneously or sequentially with the administration of an abiraterone prodrug by the same route of administration or a different route of administration. In some embodiments, the other drugs or agents may be steroids, such as prednisone, prednisolone, and / or methylprednisolone. In some embodiments, the other drugs or agents may be chemotherapeutic drugs, such as paclitaxel, mitoxantrone, and / or docetaxel. In some embodiments, the other agents or drugs may be GnRH agonists, such as leuprolide, deslorelin, goserelin, or triptorelin, such as leuprolide acetate (e.g., a long-acting intramuscular injection formulation). In some embodiments, other agents or drugs can be seocalcitol, bicalutamide, flutamide, glucocorticoids, including but not limited to hydrocortisone, prednisone, prednisolone or dexamethasone. The amount of other drugs or agents to be administered can vary, and can generally be an amount that is effective to treat a corresponding disease or disorder (e.g., prostate cancer) alone or in combination with abiraterone prodrugs or abiraterone prodrug preparations of the present disclosure.

[0335] Other suitable other drugs or agents include those described herein. For example, useful other drugs or agents include, but are not limited to, anticancer agents, hormone ablators, antiandrogens, differentiation agents, antitumor agents, kinase inhibitors, antimetabolites, alkylating agents, antibiotic agents, immune agents, interferons, intercalating agents, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, mitotic inhibitors, matrix metalloproteinase inhibitors, gene therapy agents, and antiandrogens.

[0336] For example, suitable anticancer agents include, but are not limited to, acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, amsacrine, anagrelide, anastrozole, ancestim, bexarotene, broxuridine, capecitabine, itabine, celmoleukin, cetrorelix, cladribine, clotrimazole, daclizumab, dexrazoxane, dilazep, docosanol, doxifluridine, bromocriptine, carmustine, cytarabine, diclofenac, edelfosine ne), edrecolomab, eflornithine, e mitefur, exemestane, exisulind, fadrozole, filgrastim, finasteride, flu darabine phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, glycopine, heptaplatin, ibandronic acid, imiquimod, iobenguane, irinotecan, irsogladine, lanreotide, leflunomide, lenograstim, lentinan sulfate sulfate), letrozole, liarozole, lobaplatinplatin), lonidamine, masoprocol, me larsoprol, metoclopramide, mifepristone, miltefosine, mirimostim, mitoguazone, mitolactol, molgramostim, nafarelin, nartograstim, nedaplatin, nilutamide, noscapine, oprelvekin, osatero ne, oxaliplatin, pamidronic acid, pe gaspargase, pentosan polysulfate sodium), pentostatin, picibanil, pirarubicin, porfimer sodium, raloxifene, raltitrexed, rasburicase, rituximab, romurtide, sargramostim, sizofiran, sobuzoxane, sonermin, suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide olomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alfa, topotecan, toremifene, trastuzumab, treosulfan, tretinoin, trilostane

[00136] The invention relates to the treatment of leukemia, leukemia and schizosin. Suitable anti-androgen agents include, but are not limited to, bicalutamide, flutamide and nilutamide. Suitable differentiation agents include, but are not limited to, polyamine inhibitors; vitamin D and its analogs, such as calcitriol, doxorcalciferol, and siocalciferol; metabolites of vitamin A, such as ATRA, retinoic acid, retinoids; short chain fatty acids; phenylbutyric acid; and nonsteroidal anti-inflammatory agents; anti-tumor agents, including, but not limited to, tubulin interacting agents, topoisomerase inhibitors and agents, acitretin, alstonine, amonafide, amphetamine, amsacrine, ankinomycin, anti-tumor substances, aphidicolin glycinate, asparaginase, ba ccharin, batracylin, benfluron, benz otript, bromofosfamide, caracemide, carmethizole hydrochloride, hydrochloride), chlorsulfaquinoxalone, clanfenur, claviridenone, crisnat ol, curaderm, cytarabine, cytocytin, dacarbazine, datelliptinium, dihaemat oporphyrin ether, dihydrolenperone, dinaline, distamycin, docetaxel, elliprabin, el liptinium acetate, epothilones, ergotamine, etoposide, etretinate, fenretinide, gallium nitratenitrate), genkwadaphnin, hexadecylphosphocholine, homoharringtonine, hydroxyurea, ilmofosine, isoglutamine, isotretinoin, leukoregulin, lonidamine, merbarone, merocyanine derivatives, methylanilinoacridine, minactivin, mitonafide, mitozoordine, toquidone, mitoxantrone, mopidamol, motretinide, N-(retinyl) amino acids, N-acylated-dehydroalanine, nafazatrom, nocodazole derivatives, ocreotide, oqu uizanocinc, paclitaxel, pancratistatin, pazelliptine, piroxantrone, polyhaematoporphyrin, polypicric acid acid, probimane, procarbazine, proglumide, razoxane, retelliptine, spatol, spirocyclopropane derivatives, spirogermanium, strypoldinone, superoxide dismutase, teniposide, thaliblastine, tocotrienol, topotecan, ukrain, vinblastine sulfate, vincristine, vindesine, vinestramide, vinorelbine, vintriptol, vinzolidine, and withaferinithanolide; kinase inhibitors, including p38 inhibitors and CDK inhibitors, TNF inhibitors, matrix metalloproteinase inhibitors (MMPs), COX-2 inhibitors, including celecoxib, rofecoxib, parecoxib, val decoxib, and etoricoxib; SOD mimetics or α vβ3 inhibitors. Suitable antimetabolites may be selected from, but are not limited to, 5-FU-fibrinogen, acanthiform acid, aminothiadiazole, brequinar sodium, carmofur, cyclopentylcytosine, cytarabine phosphate stearate, cytarabine conjugates, deazaguanine, dideoxycytidine, dideoxyguanosine, didox, doxifluridine, fazarabine, floxuridine, fludarabine phosphate phosphate), 5-fluorouracil, N-(2'-furanyl)-5-fluorouracil, isopropylpyrrolizine, methobenzaprim, methotrexate, norspermidine, pentostatin, pirituxim, plicamycin, thioguanine, tiazofurin, trimetrexate, tyrosine kinase inhibitors, and uricytin. Suitable alkylating agents may be selected from the group consisting of, but are not limited to, aldophosphamide analogs, hexamethylmelamine, anaxirone, bestrabucil, budotitane, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, cyplatate, diphenylspiromustine, diplatin cytostatics, elmustine, estramustine phosphate sodium, fotemustine, hepsulfam, ifosfamide, iproplatin, lomustine, mafosfamide, mitolactol, oxaliplatin, prednimustine, ranimustine, semmustine,ustine, spiromustine, tauromustine, temozolomide, teroxirone, tetraplatin and trimelamol. Suitable antibiotic agents may be selected from, but are not limited to, aclarubicin, actinomycin D, actinoplanone, adriamycin, aeroplysinin derivatives, amrubicin, anthracycline, azin o-mycin-A, bisucaberin, bleomycin sulfate, bry ostatin-1, calichemycin, chromoximycin, dactinomycin, daunorubicin, ditrisa rubicin, dauno ... B), dexamethasone, doxorubicin, doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin, esorubicin, esperamicin-A1, esperamicin-A1b, fostriecin, glidobactin, gregatin-A, grincamycin, herbimycin mycin), corticosteroids (such as hydrocortisone), idarubicin, illudins, kazusamycin, kesarirhodins, menogaril, mitomycin, neoenactin, oxalysine, oxaunomycin, peplomycin, pilatin, pirarubicin, porothramycin, prednisone, prednisolone, pyrind anycin A, rapamycin, rhizoxin, rodorubicin,The present invention relates to steroids which include, but are not limited to, orubicin, sibanomicin, siwenmycin, sorangicin-A, sparsomycin, talisomycin, terpentecin, thrazine, tricrozarin A and zorubicin. Non-limiting examples of suitable steroids include hydrocortisone, prednisone, prednisolone or dexamethasone.

[0337] Combination therapy for prostate cancer

[0338] Prostate cancer treatment generally involves multiple therapies, including, for example, radiotherapy, surgery, androgen deprivation therapy, hormone therapy, chemotherapy, immunotherapy and various drug combinations. Searching on the website clinicaltrials.gov, more than 250 clinical trials that list abiraterone / abiraterone acetate as intervention agents have been identified, many of which include conjoint therapies for the treatment of prostate cancer. As discussed herein, compared with oral abiraterone acetate preparations, the abiraterone prodrug herein can provide increased bioavailability, eliminate food effects, reduce pill burden, low frequency of dosing frequency and sustained effective abiraterone plasma levels and long-term CYP17A1 inhibition, up to 70 days or longer dihydrotestosterone and testosterone levels after the administration of the abiraterone prodrug preparation, without the undesirable increase of steroids such as progesterone upstream of the CYP17A1 hydroxylase. Considering its excellent pharmacokinetic and / or pharmacodynamic characteristics, the abiraterone prodrug herein can also be advantageously used in various conjoint therapies to replace or supplement the oral administration of abiraterone acetate.

[0339] In some embodiments, the present disclosure provides a method for treating prostate cancer (e.g., any of those described herein) in a human subject in need, the method comprising administering to the human subject a therapeutically effective amount of abiraterone prodrug (e.g., abiraterone decanoate) or abiraterone prodrug preparation herein and one or more additional therapies. One or more additional therapies may be administered to a human subject simultaneously or in any order with the administration of abiraterone prodrug or abiraterone prodrug preparation herein, and the administration of abiraterone prodrug or abiraterone prodrug preparation herein may be performed by the same or different administration routes. In some embodiments, the method herein includes treating a human subject with radiotherapy or surgery. In some embodiments, the method includes administering to a human subject one or more other agents selected from the following: anticancer agents, hormone ablators, anti-androgens, differentiation agents, anti-tumor agents, kinase inhibitors, antimetabolites, alkylating agents, antibiotic agents, immune agents, interferons, intercalating agents, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, mitotic inhibitors, matrix metalloproteinase inhibitors, gene therapy agents, or combinations thereof. In some embodiments, the method includes administering one or more other agents selected from the following to the human subject: a chemotherapeutic drug, a hormone replacement drug, or a hormone ablation drug. In some embodiments, the method includes treating the human subject with androgen deprivation therapy. Although many of the conjoint therapies below are described as being related to various treatments of prostate cancer, the disclosure is not limited thereto. And in some embodiments, the conjoint therapies described below may also be used to treat other diseases or conditions described herein, such as other cancers described herein.

[0340] In more specific embodiments, conjoint therapy generally includes applying glucocorticoid to human subjects.For example, in some embodiments, described method includes applying one or more selected from following agent to human subjects: hydrocortisone, prednisone, prednisolone, methylprednisolone and dexamethasone, preferably dexamethasone.However, in some embodiments, glucocorticoid replacement therapy (for example, applying glucocorticoid, such as hydrocortisone, prednisone, prednisolone, methylprednisolone or dexamethasone) is not needed.For example, for human subjects who may suffer from potential illness (such as diabetes), glucocorticoid may be contraindicated.In some embodiments, described method can also be characterized in that human subjects are not treated with glucocorticoid replacement therapy.In some embodiments, human subjects are not treated with the agent selected from hydrocortisone, prednisone, prednisolone, methylprednisolone and dexamethasone.In some embodiments, described method can include applying mineralocorticoid receptor antagonist, such as eplerenone to human subjects. For example, in any embodiment herein, when glucocorticoid replacement therapy is not needed and / or not used, the method may include administering a mineralocorticoid receptor antagonist, such as eplerenone, to a human subject. In some embodiments, it is not necessary and the agent for treating mineralocorticoid toxicity is not administered to a human subject. In some embodiments, the method may also be characterized in that a human subject is not treated with an agent that effectively treats mineralocorticoid toxicity. In some embodiments, the method may be characterized in that a human subject is not treated with an agent that is a glucocorticoid or a mineralocorticoid receptor antagonist.

[0341] The combination therapy for the method herein may also include androgen deprivation therapy, such as by administering a gonadotropin-releasing hormone (GnRH) analog to a human subject. When included, the suitable GnRH analog for combination therapy is not particularly limited, and includes a GnRH agonist and a GnRH antagonist. For example, in some embodiments, the method may include administering a gonadotropin-releasing hormone (GnRH) agonist to a human subject, such as buserelin, leuprorelin, deserelin, futirelin, histrelin, gonadorelin, lanreotide, goserelin, nafarelin, perforelin or triptorelin, and / or a GnRH antagonist, such as abarelix, cetrorelix, degarelix, ganirelix, ailagog, linzagolik or regrelik. In some embodiments, any of the GnRH agonists and GnRH antagonists described herein are not administered to a human subject.

[0342] Inhibition of androgen receptor activity

[0343] In some embodiments, the combination therapy includes treating the human subject to reduce androgen receptor (AR) activity, such as an AR antagonist or an agent that otherwise downregulates or inhibits AR activity.

[0344] In some embodiments, the method may include administering an androgen receptor (AR) antagonist to a human subject. Various AR antagonists are known in the art, including but not limited to the 1st and 2nd generation AR antagonists, see, for example, Rice, MA et al., Front Oncol.9:801 (2019), and 3rd generation AR antagonists, such as N-terminal domain inhibitors. In some embodiments, the method includes administering a 1st generation androgen receptor antagonist to a human subject, including but not limited to proxalutamide, bicalutamide, flutamide, nilutamide, topilutamide, etc. In some embodiments, the method includes administering a 2nd generation androgen receptor antagonist to a human subject, including but not limited to, for example, apalutamide, darolutamide, or enzalutamide. In some embodiments, the method includes administering apalutamide to a human subject. In some preferred embodiments, the method includes administering enzalutamide to a human subject. In some embodiments, the method includes administering a 3rd generation androgen receptor antagonist, such as an N-terminal domain inhibitor, to a human subject. N-terminal domain inhibitors are known in the art. Non-limiting useful examples include any of those described in U.S. Application Publication No. 2020 / 0123117, the contents of which are incorporated herein by reference. It should be noted that in embodiments in which AR antagonists are administered, one or more such antagonists may be administered alone or in any combination, which may be selected from a single 1st, 2nd or 3rd generation AR antagonist.

[0345] In addition to agents that directly target androgen receptors, other methods and / or agents that regulate androgen receptor activity, including, for example, methods and / or agents that regulate upstream kinase activity and / or androgen receptor transcriptional activity, may also be used in the combined therapies herein. For example, in some embodiments, the combined therapy may include administering one or more upstream kinase regulators to a human subject, whose activation or inhibition may reduce AR activity. Such upstream kinases are known in the art, for example, as described in Shah, K. and Bradbury, NA, Cancer cell microenviron. 2 (4): doi: 10.14800 / ccm. 1023 (2015), and Koul HK et al. Genes & Cancer 4 (9-10): 342-359 (2013). In some embodiments, the method comprises administering to a human subject one or more kinase modulators selected from the group consisting of FLT-3 (FMS-like tyrosine kinase) inhibitors, AXL (anexelekto) inhibitors, (e.g., gilteritinib), CDK (cyclin-dependent kinase) inhibitors (such as CDK1, 2, 4, 5, 6, 7 or 9 inhibitors), retinoblastoma (Rb) inhibitors, protein kinase B (AKT) inhibitors, SRC inhibitors, IκB kinase 1 (IKK1) inhibitors, PIM-1 modulators, Lemur tyrosine kinase 2 (LMTK2) modulators, Lyn inhibitors, AuroraA inhibitors, ANPK (alpha nuclear protein kinase) inhibitors, extracellular signal-regulated kinase (ERK) modulators, c-jun N-terminal kinase (JNK) modulators, large MAP kinase (BMK) modulators, p38 mitogen-activated protein kinase (MAPK) modulators, and combinations thereof. Suitable kinase modulators / inhibitors are not particularly limited and include any of those known, for example, small molecule drugs, polypeptides (including antibodies, such as monoclonal antibodies or antigen-binding fragments thereof), RNA- or DNA-based agents.

[0346] In some embodiments, the combination therapy may include administering to a human subject an agent that down-regulates AR or otherwise inhibits AR activity. Without wishing to be bound by theory, AR activity may be affected at the genome and / or transcriptional level of AR itself, or using various molecules that interfere with transcription and / or translation (e.g., RNA silencing agents (e.g., antisense, siRNA, shRNA, microRNA), ribozymes and DNA enzymes), those AR upstream targets that play a role in regulating AR activity and those downstream targets regulated by AR are affected at the genome and / or transcriptional level, or using, for example, antagonists, enzymes that cleave polypeptides, small molecules that interfere with protein activity (e.g., competitive ligands), etc., are affected at the protein level.

[0347] In some embodiments, AR downregulation or inhibition of AR activity can be achieved by RNA silencing of target genes (e.g., AR or suitable upstream and downstream targets of AR as described herein, etc.). As used herein, the phrase "RNA silencing" refers to a group of regulatory mechanisms mediated by RNA molecules (e.g., RNA interference (RNAi), transcriptional gene silencing (TGS), post-transcriptional gene silencing (PTGS), inhibition, co-repression and translation repression), which lead to the inhibition or "silencing" of corresponding protein coding gene expression. RNA silencing has been observed in many types of organisms, including plants, animals and fungi.

[0348] As used herein, the term "RNA silencing agent" refers to an RNA that can specifically inhibit or "silence" the expression of a target gene. In some embodiments, RNA silencing agents can prevent the complete processing (e.g., full translation and / or expression) of mRNA molecules by a post-transcriptional silencing mechanism. RNA silencing agents include non-coding RNA molecules, for example, RNA duplexes comprising paired chains, and precursor RNAs from which such small non-coding RNAs can be generated. Exemplary RNA silencing agents include double-stranded RNA (dsRNA), such as short interfering RNA (siRNA), miRNA, and shRNA. In one embodiment, RNA silencing agents can induce RNA interference. In another embodiment, RNA silencing agents can mediate translation repression. The chains of double-stranded interfering RNA (e.g., siRNA) can be connected to form a hairpin or stem-loop structure (e.g., shRNA or sh-RNA). Therefore, as noted, the RNA silencing agents of some embodiments of the present disclosure can also be short hairpin RNA (shRNA).

[0349] It should be understood that the RNA silencing agents of some embodiments of the present disclosure need not be limited to those molecules containing only RNA, but further encompass chemically modified nucleotides and non-nucleotides.

[0350] In some embodiments, the RNA silencing agents provided herein can be functionally associated with cell penetrating peptides. As used herein, "cell penetrating peptides" are peptides comprising short (about 12-30 residues) amino acid sequences or functional motifs that confer non-energy-dependent (i.e., non-endocytic) translocation properties associated with transport membrane permeation complexes across cytoplasmic membranes and / or nuclear membranes.

[0351] According to another embodiment, RNA silencing agent can be miRNA or its mimics.Term " microRNA ", " miRNA " and " miR " are synonymous and refer to the set of non-coding single-stranded RNA molecules of regulating gene expression of about 19-28 nucleotides in length.MiRNA is present in a wide range of organisms, and has been confirmed to play a role in development, homeostasis and disease etiology.Term " microRNA mimics " refers to synthetic non-coding RNA that can enter RNAi pathway and regulate gene expression.MiRNA mimics imitate the function of endogenous microRNA (miRNA) and can be designed as mature double-stranded molecules or simulation precursors (for example, or precursor miRNA).

[0352] Downregulation of AR or inhibition of AR activity can also be achieved by gene editing of target genes (e.g., AR or suitable upstream and downstream targets of AR as described herein, etc.). For example, gene editing can be performed using a clustered regularly spaced short palindromic repeat sequence CRISPR-CAS9 system. The CRISPR-CAS9 system has been described in the literature and can include, for example, CAS9 and guide RNA. Other gene editing techniques have also been described in the literature and can also be used.

[0353] Another agent capable of downregulating a target (e.g., AR or suitable upstream and downstream targets of AR as described herein, etc.) is a DNA enzyme molecule capable of specifically cleaving the mRNA transcript or DNA sequence of the target. DNA enzymes are single-stranded polynucleotides capable of cleaving single-stranded and double-stranded target sequences. (Breaker et al., Chemistry and Biology 1995; 2: 655; Santoro et al., Proc. Natl. Acad. Sci. USA 1997; 943: 4262.) A general model of DNA enzymes (the "10-23" model) has been proposed. The "10-23" DNA enzyme has a catalytic domain of 15 deoxyribonucleotides, flanked by substrate recognition domains each having 7 to 9 deoxyribonucleotides. This type of DNA enzyme can effectively cleave its substrate RNA at a purine: pyrimidine junction. (Santoro et al., Khachigian, Curr. Opin. Mol. Ther. 2002; 4: 119-121.)

[0354] Downregulation of a target (eg, AR or suitable upstream and downstream targets of AR as described herein, etc.) can also be affected by using antisense polynucleotides that are capable of specifically hybridizing to an mRNA transcript encoding the target.

[0355] Another agent capable of downregulating a target (e.g., AR or suitable upstream and downstream targets of AR as described herein, etc.) is a ribozyme molecule capable of specifically cleaving mRNA transcripts encoding the target. Ribozymes are increasingly used to sequence-specifically inhibit gene expression by cleaving mRNA encoding a target protein. (Welch et al., Curr. Opin. Biotechnol. 1998; 9: 486-96.)

[0356] Another agent capable of downregulating a target (e.g., AR or suitable upstream and downstream targets of AR as described herein, etc.) is any molecule that binds and / or cleaves a target. Such a molecule may be an antagonist of a target or an inhibitory peptide of a target.

[0357] Another agent that can be used with some embodiments of the present disclosure to downregulate a target (eg, AR or suitable upstream and downstream targets of AR as described herein, etc.) is a molecule that prevents target activation and / or substrate binding.

[0358] Another agent that can be used with some embodiments of the present disclosure to downregulate AR or inhibit the activity of AR is an androgen receptor degrader, such as those based on proteolytic targeting chimeric (PROTAC) technology. See, e.g., Kregel, S. et al. Neoplasia 22 (2): 111-119 (2020).

[0359] Another agent that can be used together with some embodiments of the present disclosure to downregulate a target (e.g., AR or suitable upstream and downstream targets of AR as described herein, etc.) is to suppress or downregulate the activation of target transcriptional activity, more specifically to suppress or downregulate the transcriptional activity of AR. For example, such agents can interfere with the nuclear translocation of AR, downregulate the protein level of AR, reduce the binding of hormones to AR, interfere with the recruitment of transcriptional cofactors (e.g., steroid receptor coactivator 1 (SRC1) and transcriptional intermediate factor 2 (TIF2)), interfere with AR-DNA binding, such as binding to specific DNA response elements (ARE or androgen response elements), inhibit AR recruitment to AR target gene enhancers, and / or inhibit AR-chromatin binding, etc. or otherwise inhibit DNA binding-dependent or non-DNA binding-dependent AR signaling pathways. Suitable agents that can inhibit or interfere with AR transcriptional activity include any of those agents known in the art and any of those agents that can inhibit or interfere with such activity as exemplified herein. For example, it is known that certain AR antagonists such as the first generation AR antagonists (e.g., bicalutamide) inhibit AR transcriptional activity by inhibiting the nuclear translocation of AR. Other agents, such as arsenic compounds (e.g., arsenic trioxide), are also known to inhibit AR transcriptional activity. See, for example, Rosenblatt AE et al., Mol. Endocrinol. 23 (3): 412-421 (2009).

[0360] In some embodiments, the combination therapy may include administering one or more chemotherapeutic agents to a human subject. Suitable chemotherapeutic agents include any of those known in the art. In some embodiments, the method includes administering a taxane-based chemotherapeutic agent (e.g., docetaxel, cabazitaxel, paclitaxel, etc.) and / or a platinum-based chemotherapeutic agent (e.g., cisplatin, carboplatin, oxaliplatin, etc.) to a human subject.

[0361] In some embodiments, the combination therapy may include treating the human subject with radiation therapy. Suitable radiation therapy includes any of those known in the art. In some embodiments, the method includes treating the human subject with stereotactic body radiation therapy or neutron radiation.

[0362] In some embodiments, combination therapy can include treating a human subject with radium-223, such as Xofigo (radium-223 dichloride) injection.

[0363] In some embodiments, the combination therapy may include administering one or more immunotherapies to a human subject. Suitable immunotherapies include any of those known in the art. In some embodiments, the method includes administering Sipuleucel-T to a human subject. In some embodiments, the method includes administering an immune checkpoint inhibitor to a human subject. For example, in some embodiments, the method includes administering an anti-PD-1 antibody, such as pembrolizumab or nivolumab, and / or an anti-PD-L1 antibody, such as avelumab or atezolizumab, to a human subject. In some embodiments, the method includes administering an anti-CTLA-4 antibody, such as ipilimumab, to a human subject.

[0364] In some embodiments, the combination therapy may include administering a bispecific T cell engager (BiTE) therapy, such as blinatumomab or solitonumab, to a human subject.

[0365] In some embodiments, the combination therapy may include administering one or more poly ADP ribose polymerase (PARP) inhibitors to a human subject. In some embodiments, the human subject with prostate cancer also has a DNA repair defect. In some embodiments, the human subject with prostate cancer does not have a DNA repair defect. Suitable PARP inhibitors include any of those known in the art. For example, in some embodiments, the method includes administering to a human subject a PARP inhibitor selected from niraparib, rucaparib, olaparib, talazoparib, veliparib, and fluzoparib.

[0366] In some embodiments, the combination therapy may include administering one or more kinase inhibitors to a human subject. In some embodiments, a human subject is characterized as having an abnormal level of the corresponding kinase. In some embodiments, the kinase inhibitor may reduce the activity of the androgen receptor or otherwise be beneficial to cancer treatment. Suitable kinase inhibitors include any of those known in the art. For example, in some embodiments, the method includes administering to a human subject a kinase inhibitor selected from sunitinib, dasatinib, cabozantinib, erdafitinib, dovitinib, capivasertib, onvansertib, ipatasertib, afuresertib, asetinib, aapitolisib and opaganib.

[0367] In some embodiments, the combination therapy may include administering one or more bone protective agents to a human subject. In such embodiments, generally, the human subject is characterized as having prostate cancer (e.g., CRPC) with bone metastasis. Suitable bone protective agents include any of those known in the art. For example, in some embodiments, the method includes administering a bone protective agent selected from denosumab and zolendronic acid to a human subject.

[0368] In some embodiments, the combination therapy may include administering to a human subject one or more additional agents useful for treating prostate cancer, alone or in combination with an abiraterone drug such as an abiraterone prodrug herein. Such additional agents are not particularly limited. For example, in some embodiments, the method includes administering to a human subject a therapeutic agent selected from the following: 1) an anti-IL23 targeted monoclonal antibody, such as tetracycline; 2) selenium, such as sodium selenite; 3) an EZH2 inhibitor, such as CPI-1205, GSK2816126, or tazemetostat; 4) a CDK4 / 6 inhibitor, such as palbociclib, ribociclib, abemaciclib; 6) a bromodomain and super-terminal domain (BET) inhibitor, such as CCS1477, INCB057643, alobrexib, ZEN-3694, or molibuxib (GSK525762); 7) an anti-CD105 antibody, such as TRC105 or carlotuximab; 8 ) niclosamide; 9) an A2A receptor antagonist such as AZD4635; 10) a phosphatidylinositol 3-kinase (PI3K) inhibitor such as AZD-8186, buparib or datoxib; 11) another nonsteroidal CYP17A1 inhibitor such as sevitenel; 12) an antiprogestin such as onapristone; 13) navitol; 14) an HSP90 inhibitor such as orecoxib (AT13387); 15) an HSP27 inhibitor such as OGX-427; 16) a 5-α-reductase inhibitor such as dutasteride; 17) metformin; 18) AMG-386; 19) dextromethorphan; 20) theophylline; 21) hydroxychloroquine; and 22) lenalidomide. In some embodiments, the combination therapy may include administering to a human subject one or more kinase regulators selected from the group consisting of FLT-3 (FMS-like tyrosine kinase) inhibitors, AXL (anexelekto) inhibitors, (e.g., gilteritinib), CDK (cyclin-dependent kinase) inhibitors (such as CDK1, 2, 4, 5, 6, 7 or 9 inhibitors), retinoblastoma (Rb) inhibitors, protein kinase B (AKT) inhibitors, SRC inhibitors, IκB kinase 1 (IKK1) inhibitors, PIM-1 regulators, Lemur tyrosine kinase 2 (LMTK2) regulators, Lyn inhibitors, AuroraA inhibitors, ANPK (a nuclear protein kinase) inhibitors, extracellular signal-regulated kinase (ERK) regulators, c-jun N-terminal kinase (JNK) regulators, large MAP kinase (BMK) regulators, p38 mitogen-activated protein kinase (MAPK) regulators, and combinations thereof. In some embodiments, cell therapy, such as T cell-mediated cell therapy including central memory T cells, may also be part of the combination therapy.

[0369] In some embodiments, the combination therapy may include administering to the human subject one or more agents selected from the following: 1) poly (ADP-ribose) polymerase (PARP) inhibitors, including but not limited to olaparib, niraparib, rucaparib, talazopanib; 2) androgen receptor ligand binding domain inhibitors, including but not limited to enzalutamide, apalutamide, darolutamide, bicalutamide, nilutamide, flutamide, ODM-204, TAS3681; 3) additional CYP17A1 inhibitors, including but not limited to galitone (ga leterone), abiraterone, abiraterone acetate; 4) microtubule inhibitors, including but not limited to docetaxel, paclitaxel, cabazitaxel (XRP-6258); 5) PD-1 or PD-L1 modulators, including but not limited to pembrolizumab, durvalumab, nivolumab or atezolizumab; 6) gonadotropin-releasing hormone agonists, including but not limited to cyproterone acetate and leuprolide; 7) 5-α reductase inhibitors, including but not limited to finasteride, dutasteride, torosterone, beclosterol, azostellate, FCE 28260, SKF105, 111; 8) vascular endothelial growth factor inhibitors, including but not limited to bevacizumab (Avastin); 9) histone deacetylase inhibitors, including but not limited to OSU-HDAC42; 10) integrin α-v-β-3 inhibitors, including but not limited to VITAXIN; 11) receptor tyrosine kinase inhibitors, including but not limited to sunitinib; 12) phosphatidylinositol 3-kinase inhibitors, including but not limited to alpelisib, buparlisib, and idealisib; 13) anaplastic lymphoma kinase (ALK) inhibitors, including but not limited to crizotinib and alectinib; 14) endothelin A receptor antagonists, including but not limited to ZD-4054; 15) anti-CTLA4 inhibitors, including but not limited to MDX-010 (ipilimumab); 16) heat shock protein 27 (HSP27) inhibitors, including but not limited to OGX 427; 17) androgen receptor degraders, including but not limited to ARV-330 and ARV-110; 18) androgen receptor DNA binding domain inhibitors, including but not limited to VPC-14449; 19) bromodomain and extra-terminal motif (BET) inhibitors, including but not limited to BI-894999, GSK525762, and GS-5829; 20) androgen receptor N-terminal domain inhibitors, including but not limited to sintokamide; 21) alpha particle emitting radioactive therapeutic agents, including but not limited to radium 233 or its salts; 22) niclosamide; or its related compounds;23) Selective estrogen receptor modulators (SERMs), including but not limited to tamoxifen, raloxifene, toremifene, arzoxifene, bazedoxifene, pipindoxifene, lasofoxifene, and enclomiphene; 24) Selective estrogen receptor degraders (SERDs), including but not limited to fulvestrant, ZB716, OP-1074, elacestrant, AZD9496, GDC0810, GDC0927, GW5638, and GW7604; 25) Aromatase inhibitors, including but not limited to anastrazole, exemestane, and letrozole; 26) Selective progesterone receptor modulators (SPRMs) ), including but not limited to mifepristone, lonaprison, onapristone, asoprisnil, lonaprisnil, ulipristal, telapristone; 27) glucocorticoid receptor inhibitors, including but not limited to mifepristone, COR108297, COR125281, ORIC-101, PT150; 28) CDK4 / 6 inhibitors, including palbociclib, abemaciclib, ribociclib; 29) HER2 receptor antagonists, including but not limited to trastuzumab and neratinib; 30) mammalian target of rapamycin (mTOR) inhibitors, including but not limited to everolimus and temsirolimus. ;

[0370] The combination therapy herein is not particularly limited to any specific number of additional therapies. For example, in addition to administering the abiraterone prodrug or abiraterone prodrug preparation herein and optional glucocorticoids such as hydrocortisone, prednisone, prednisolone, methylprednisolone and dexamethasone, the combination therapy may generally include 1, 2, 3, 4, 5, 6 or more additional therapies described herein. For example, in some embodiments, the combination therapy may include an additional therapy, such as any of those described herein, such as GnRH agonists, GnRH antagonists, androgen receptor antagonists, chemotherapy, PARP inhibitors, kinase inhibitors, immunotherapy, radiotherapy, surgery, androgen deprivation therapy, etc. In some embodiments, the combination therapy may include two or more additional therapies described herein. For example, in some specific embodiments, the combination therapy may include administering PARP inhibitors and androgen deprivation therapy to human subjects. In some embodiments, the combination therapy may include administering GnRH agonists and radiotherapy to human subjects. In some embodiments, the combination therapy may include administering GnRH agonists, chemotherapeutic agents and radiation therapy to human subjects. In some embodiments, the combination therapy may include administering to a human subject an androgen receptor antagonist (e.g., 1st, 2nd, and / or 3rd generation AR antagonist), a GnRH agonist, and optional radiotherapy, chemotherapeutic agents, indomethacin, or a 5-alpha reductase inhibitor. In some embodiments, the combination therapy may include administering to a human subject an androgen receptor antagonist (e.g., 1st, 2nd, and / or 3rd generation AR antagonist) and radiotherapy. In some embodiments, the combination therapy may include administering to a human subject an androgen receptor antagonist (e.g., 1st, 2nd, and / or 3rd generation AR antagonist) and a chemotherapeutic agent. In some embodiments, the combination therapy may include administering to a human subject an androgen receptor antagonist (e.g., 1st, 2nd, and / or 3rd generation AR antagonist) and an anti-CTLA4 antibody. It should be understood that the combinations discussed are examples of useful combinations, which are by no means limiting, and allow other combinations of additional therapies described herein. However, in some embodiments, the combination therapy does not include administering to the human subject a GnRH agonist, a GnRH antagonist, androgen deprivation therapy, and / or does not include castration of the human subject.

[0371] In any combination therapy described herein, unless otherwise indicated or contradicted by context, the method can include administering abiraterone decanoate as described herein, or a pharmaceutical composition comprising abiraterone decanoate as described herein, in combination with one or more additional therapies.

[0372] It should be noted that in some embodiments, the methods for treating prostate cancer herein (e.g., any of those described herein) are not combined with a combination therapy. For example, the method includes administering a therapeutically effective amount of abiraterone prodrug (e.g., abiraterone decanoate) or abiraterone prodrug formulation herein to a human subject without one or more additional therapies described herein.

[0373] Dosage regimen

[0374] Abiraterone prodrugs and formulations disclosed herein can generally provide a long-acting release of Abiraterone to human subject users. This long-acting release profile allows abiraterone to be administered to human subject users at low dosing frequencies (such as once a week, once a month, once every two months, once every three months, or even less frequently), which can improve patient compliance and reduce pill burden.

[0375] In some embodiments, the method herein can have a dosing regimen of once a week or more than once a week. Typically, the scope of dosing frequency can be from once a week to once every several months, such as from once a week to once every eight weeks, or from once a week to once every three months, for example, once a month, once every two months or once every three months. In some embodiments, the dosage of each dosage is about 50 mg to about 5000 mg (e.g., about 500 mg, about 1000 mg, about 1500 mg, about 2000 mg, about 5000 mg, or any range between the listed values) of abiraterone prodrug. In some embodiments, the amount of abiraterone prodrug administered per dose is about 0.5 mg / kg to about 200 mg / kg (e.g., about 0.5 mg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 20 mg / kg, about 30 mg / kg, about 50 mg / kg, about 90 mg / kg, about 100 mg / kg, about 200 mg / kg, or any range between the recited values) of body weight of a human subject.

[0376] Abiraterone prodrugs suitable for use in the above-mentioned once a week or once a week or more dosing methods include those described herein. In some embodiments, the abiraterone prodrug can be a lipophilic ester of abiraterone described herein, such as acetate, propionate, butyrate, (valeric acid ester) valerate, isohexanoate, butanecarboxylate, cyclohexanecarboxylate, phenylpropionate, hexanoate (hexanoate), heptanoate (heptanoate), cyclopentylpropionate, octanoate, nonanoate, decanoate, undecanoate, dodecanoate, tridecanoate, tetradecanoate, pentadecanoate and hexadecanoate. In some preferred embodiments, the abiraterone prodrug can be a compound of formula I, such as a compound of formula I, wherein R 1 It is C 7-16 Alkyl groups, for example, have the formula -(CH2)n -CH3 alkyl, wherein n is an integer between 6 and 12 (e.g., n is 6, 7, 8, 9, 10); or R 1 From the formula -(CH2) n -Cy represents, wherein n is an integer from 1 to 6, and Cy is C 3-6 Cycloalkyl or phenyl, for example, in more specific embodiments, n may be 1 or 2, and Cy is cyclopentyl, cyclohexyl or phenyl; or R 1 for or R 1 for In some embodiments, the abiraterone prodrug may be a compound of Formula II, wherein R in Formula II is 2 It is C 1-16 Alkyl groups, for example, have the formula -(CH2) n -CH3 alkyl, wherein n is an integer between 0 and 12; or R in formula II 2 It can be expressed by the formula -(CH2) n -Cy represents, where n is an integer from 1 to 6, and Cy is C 3-6 Cycloalkyl or phenyl, for example, in more specific embodiments, n can be 1 or 2, and Cy is cyclopentyl, cyclohexyl or phenyl; or R in formula II 1 Can be In any of the embodiments described herein, unless otherwise indicated or directly contradicted by context, the abiraterone prodrug can be abiraterone decanoate.

[0377] In some embodiments, administration once a month or more than once a month is required, for example, the range of administration frequency is from once a month to once every several months, such as from once a month to once every two months, or from once a month to once every three months. In such embodiments, the abiraterone prodrug not only needs to slowly release the abiraterone, but also needs to release enough plasma concentrations of the abiraterone so that it can be beneficial to human subject users. Administration once a month or more than once a month is usually parenteral administration, such as intramuscular, intradermal or subcutaneous. In any embodiment herein, unless directly contradictory, administration can be intramuscular administration.

[0378] The abiraterone prodrugs and abiraterone prodrug formulations disclosed herein can be administered to human subjects in need as the sole source of abiraterone. However, in some embodiments, other abiraterone drugs / formulations are not excluded. For example, in some embodiments, administration herein can be combined with abiraterone acetate such as Oral administration of the preparations is combined simultaneously or sequentially in any order. In some embodiments, human subjects can use abiraterone prodrugs and abiraterone prodrug preparations as a supplement to existing abiraterone therapy. Moreover, the administration herein is not limited to the administration of a single abiraterone prodrug or abiraterone prodrug preparation of the present disclosure. In some embodiments, two or more abiraterone prodrugs and abiraterone prodrug preparations of the present disclosure can be administered to human subjects.

[0379] In some embodiments, the methods herein may include an initial treatment period with a higher dosing frequency, such as weekly or biweekly dosing, prior to monthly or more dosing. The initial treatment period may include administration of the same abiraterone prodrug or a different abiraterone drug, such as a different abiraterone prodrug. However, in some embodiments, the methods herein do not include such an initial treatment period.

[0380] As discussed herein, the abiraterone prodrugs and abiraterone prodrug formulations disclosed herein have many advantages over currently marketed Advantages of the product. For example, administration of the abiraterone prodrugs and abiraterone prodrug formulations disclosed herein to human subjects generally results in a C max Reduced (e.g., compared to 1000 mg without food) After once-daily oral dosing, the C of abiraterone observed at steady state max At least 30% lower than the previous day).

[0381] Thus, in some embodiments, the present disclosure provides a method for treating a patient having side effects associated with high abiraterone exposure, such as having abiraterone C max The method comprises administering to a human subject an abiraterone prodrug and an abiraterone prodrug formulation of the present disclosure, wherein the abiraterone prodrug and the abiraterone prodrug formulation of the present disclosure are administered to the human subject ... The administration reduces side effects compared to once daily oral dosing. Suitable routes of administration, dosage amounts, and frequencies include those described herein. FDA approved Various side effects or adverse reactions are described in the prescribing information, see, for example, the February 2018 or June 2019 versions. In some embodiments, the present disclosure provides a method of treating a subject who is also administered a drug whose metabolism is inhibited by abiraterone, such as a drug that is a substrate for CYP2D6 and / or CYP2C8, the method comprising administering to a human subject an abiraterone prodrug or abiraterone prodrug formulation of the present disclosure, wherein the abiraterone prodrug is administered to the subject without food. In some embodiments, the present disclosure provides a method of treating a human subject suffering from or at risk of hypertension, hypokalemia, or fluid retention caused by excess mineralocorticoids, the method comprising administering to the human subject an abiraterone prodrug and abiraterone prodrug formulation of the present disclosure, wherein the abiraterone prodrug is administered to the human subject at a dose of 1000 mg without food. The administration reduces hypertension, hypokalemia, and fluid retention or the risk of hypertension, hypokalemia, and fluid retention compared to administration of a once daily oral dose. In some embodiments, the present disclosure provides a method of treating a human subject having or at risk of adrenal insufficiency, the method comprising administering to the human subject an abiraterone prodrug and abiraterone prodrug formulation of the present disclosure, wherein the administration reduces hypertension, hypokalemia, and fluid retention or the risk of hypertension, hypokalemia, and fluid retention compared to administration of a once daily oral dose. The administration reduces adrenal insufficiency or the risk of developing adrenal insufficiency compared to administration of a once daily oral dose. In some embodiments, the present disclosure provides a method for treating Method for treating a human subject with severe or fatal hepatotoxicity after administration of abiraterone prodrugs and abiraterone prodrug formulations of the present disclosure to a human subject, wherein the administration reduces hepatotoxicity. Without wishing to be bound by theory, it is believed that administration of abiraterone prodrugs and abiraterone prodrug formulations of the present disclosure generally results in reduced but effective abiraterone exposure, and is therefore beneficial to subjects requiring lower doses of abiraterone (e.g., as described above). Suitable dosing regimens, routes of administration include those described herein.

[0382] Exemplary Methods Using Abiraterone Decanoate

[0383] In some specific embodiments, the present disclosure also provides a method for treating a sex hormone-dependent or androgen receptor-driven disease or condition, such as a sex hormone-dependent benign or malignant condition, an androgen receptor-driven cancer, and / or a syndrome caused by androgen excess, the method comprising administering to a human subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising abiraterone decanoate as described herein (e.g., any of those described in the Summary of the Invention section of this article, such as

[18] -

[30] or

[93] -

[107] of the Summary of the Invention section of this article, or any of those described in the Examples section). Administration is not limited to any particular route. However, abiraterone decanoate is usually administered parenterally, for example, via intramuscular injection, intradermal injection, or subcutaneous injection. In some embodiments, administration is performed by intramuscular injection. Unlike oral administration of abiraterone acetate, a pharmaceutical composition comprising abiraterone decanoate as described herein (e.g., a unit dosage form as described herein) can be administered to a human subject in need thereof with or without food. In some embodiments, the human subject is a non-castrated human subject. In some embodiments, the human subject is a castrated human subject. In some embodiments, the method herein can also apply a pharmaceutical composition comprising abiraterone decanoate to a human subject, without considering whether the human subject is castrated. In some embodiments, the method herein can also advantageously treat a human subject with liver damage before applying abiraterone decanoate, such as a human subject with moderate to severe liver damage (Child-Pugh B or C class). In some embodiments, the method herein can also advantageously treat a human subject with prostate cancer, and the method herein will not increase the progesterone level in the human subject to a level associated with adverse clinical outcomes and drug resistance, such as serum or plasma progesterone levels greater than about 3nM when measured 4 weeks, 6 weeks or 12 weeks after the first application of a pharmaceutical composition. In some embodiments, the method herein can also advantageously treat a human subject with prostate cancer, and the human subject is characterized as before the first application of the pharmaceutical composition herein, in abiraterone treatment, such as Zytiga (oral abiraterone acetate and prednisone) treatment for three months with serum or plasma progesterone levels greater than about 3nM.

[0384] The sex hormone-dependent benign or malignant conditions that can be treated with the method include any of those described herein, such as sex hormone-dependent cancer. In some embodiments, sex hormone-dependent benign or malignant conditions can be selected from androgen-dependent conditions and estrogen-dependent conditions, such as androgen-dependent or estrogen-dependent cancers. In some embodiments, sex hormone-dependent benign or malignant conditions can be selected from prostate cancer, breast cancer, ovarian cancer, bladder cancer, hepatocellular carcinoma, and lung cancer, etc. In some embodiments, sex hormone-dependent benign or malignant conditions can be prostate cancer or breast cancer. In some embodiments, sex hormone-dependent benign or malignant conditions are CRPC or CSPC. In some embodiments, sex hormone-dependent benign or malignant conditions can be metastatic CRPC or metastatic CSPC. In some embodiments, prostate cancer is CRPC, and in some embodiments, patients with CRPC have not received chemotherapy. In some embodiments, prostate cancer is metastatic CRPC (mCRPC), and in some embodiments, patients with mCRPC have not received chemotherapy. The syndrome caused by androgen excess that can be treated with the method includes any of those described herein. In some embodiments, the methods herein can be methods for treating non-neoplastic syndromes due to androgen excess in human subjects, such as endometriosis, polycystic ovary syndrome, congenital adrenal hyperplasia (e.g., classic or nonclassical congenital adrenal hyperplasia), precocious puberty, hirsutism, etc.

[0385] In some embodiments, the methods are used to treat sex hormone-dependent or androgen receptor-driven cancers, such as prostate cancer (e.g., as described herein), androgen receptor-positive salivary duct carcinoma, or androgen receptor-positive glioblastoma multiforme.

[0386] The methods herein can be used together with one or more additional therapies for the corresponding disease or condition. For example, the methods can include administering one or more other drugs or agents (e.g., as described herein, such as another cancer chemotherapy drug, a hormone replacement drug, or a hormone ablation drug) to a human subject simultaneously or sequentially by the same route of administration or a different route of administration. Non-limiting examples of useful additional therapies also include any of those described in

[37] -

[49] in the Summary of the Invention section herein.

[0387] In some embodiments, the method herein (for example, treating prostate cancer, or treating classic or non-classical congenital adrenal hyperplasia) can include applying a kind of agent to human subjects, and the agent offsets the reduction of one or more glucocorticoids.In some embodiments, the method herein can include applying to human subjects in need one or more symptoms related to adrenal insufficiency, such as agents of acute stress, fatigue, etc. In some specific embodiments, the method herein can include applying steroids, such as corticosteroids to human subjects. In some embodiments, the method can include applying glucocorticoids to human subjects. In some specific embodiments, the method also includes applying prednisone, prednisolone and / or methylprednisolone to human subjects. In some specific embodiments, the method includes applying hydrocortisone, prednisone, prednisolone, methylprednisolone and / or dexamethasone to human subjects. In some embodiments, the method also includes applying an agent for effectively treating cortisol deficiency to human subjects, such as hydrocortisone, prednisone, prednisolone, methylprednisolone and / or dexamethasone. In any such embodiments, the agent can be administered to the human subject via the same or different routes of administration, simultaneously with the administration of abiraterone decanoate or sequentially in any order.

[0388] In some embodiments according to the method herein, abiraterone prodrug (particularly abiraterone decanoate) is administered to a human subject in combination with dexamethasone. For example, in any method described herein, unless otherwise specified or contrary to the context, the method may include administering abiraterone decanoate and dexamethasone to a human subject. In some embodiments, the method is used to treat prostate cancer, such as for treating a CRPC patient who has not received chemotherapy, including a human subject of mCRPC patients who have not received chemotherapy. In some embodiments, the method may include administering abiraterone decanoate intramuscularly to a human subject (i) once every one to three months, preferably, administering about 1260 mg abiraterone decanoate intramuscularly once every three months; and (ii) oral administration of dexamethasone once daily. In some embodiments, dexamethasone is orally administered to a human subject at a dose of about 0.1 to 1 mg / day (such as about 0.5 mg / day). Additional therapies may also be used in conjunction with abiraterone decanoate and dexamethasone treatment, including but not limited to any of such other therapies described herein, such as any of those applicable therapies described in

[37] -

[49] in the Summary of the Invention section herein.

[0389] However, in some embodiments, glucocorticoid replacement therapy (for example, glucocorticoids, such as hydrocortisone, prednisone, prednisolone, methylprednisolone or dexamethasone) is not needed. For example, for human subjects who may suffer from potential illness (such as diabetes), glucocorticoids may be contraindicated. In some embodiments, the feature of the method can also be that human subjects are not treated with glucocorticoid replacement therapy. In some embodiments, human subjects are not treated with an agent selected from hydrocortisone, prednisone, prednisolone, methylprednisolone and dexamethasone. In some embodiments, the method can include applying a mineralocorticoid receptor antagonist to human subjects, such as eplerenone. For example, in any embodiment herein, when glucocorticoid replacement therapy is not needed and / or not applied, the method can include applying a mineralocorticoid receptor antagonist to human subjects, such as eplerenone.

[0390] In some embodiments, the methods herein do not result in reduced glucocorticoid levels, and therefore do not require glucocorticoid replacement therapy. In such embodiments, even if glucocorticoids are not contraindicated for human subjects, human subjects can avoid the use of glucocorticoid replacement therapy and / or mineralocorticoid receptor antagonists.

[0391] In some embodiments, the method herein will not cause the mineralocorticoid level to significantly improve and / or will not cause the toxicity due to excessive mineralocorticoid. In some embodiments, the method herein is characterized in that it is not necessary and the agent for treating mineralocorticoid toxicity is not applied to human subjects. In some embodiments, the method herein is characterized in that human subjects are not treated with an agent that effectively treats mineralocorticoid toxicity. In some embodiments, the method herein is characterized in that human subjects are not treated with an agent as a glucocorticoid or mineralocorticoid receptor antagonist.

[0392] In some embodiments, the method is for treating prostate cancer and includes a combination therapy that further includes administering to the human subject one or more additional therapies, e.g., as described herein under the section entitled Combination Therapy for Prostate Cancer. Non-limiting examples of useful additional therapies also include any of those described in

[37] -

[49] in the Summary of the Invention section herein.

[0393] In some embodiments, the method herein may be characterized by weekly or even lower frequency of administration. Typically, the scope of administration frequency can be from weekly to once every several months, such as from weekly to once every three months, or from weekly to once every eight weeks, such as once a month, once every two months or once every three months. In some embodiments, the method includes once a week, once every two weeks, once every three weeks, once a month or more than once a month, such as once every two months or once every three months, to human subjects, the pharmaceutical composition (for example, unit dosage form described herein) comprising decanoic acid abiraterone is applied. In some embodiments, the method includes once every two weeks, once a month or more than once a month, for example, once every two months or once every three months, to human subjects, the pharmaceutical composition (for example, unit dosage form described herein) comprising decanoic acid abiraterone is applied. In some embodiments, the dosage of each dose is about 50 mg to about 5000 mg (e.g., about 100 mg, about 350 mg, about 500 mg, about 1000 mg, about 1500 mg, about 2000 mg, about 5000 mg, or any range between the listed values) of abiraterone decanoate. In some embodiments, the dosage of each dose of abiraterone decanoate is about 0.5 mg / kg to about 200 mg / kg (e.g., about 0.5 mg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 20 mg / kg, about 30 mg / kg, about 50 mg / kg, about 90 mg / kg, about 100 mg / kg, about 200 mg / kg, or any range between the listed values) human subject body weight. In some embodiments, administration is performed via intramuscular injection. In some embodiments, the administration of a single dose provides a therapeutically effective abiraterone plasma concentration of at least one week, for example, at least two weeks, such as at least three weeks, at least four weeks, and up to six weeks or eight weeks or longer, such as up to ten weeks or longer. In some embodiments, the administration of a single dose provides an abiraterone plasma concentration higher than 1.0 ng / ml (e.g., between about 1 ng / ml and about 8 ng / ml, or about 2 ng / ml or higher, about 4 ng / ml or higher, about 5 ng / ml or higher, or about 8 ng / ml or higher), for at least one week, for example, at least two weeks, such as at least 3 weeks, at least 4 weeks, and up to 6 weeks or 8 weeks or longer, such as up to 10 weeks or longer. In some embodiments, the administration provides a single dose or steady-state C of abiraterone between about 1 ng / ml and about 300 ng / ml, for example, between about 1 ng / ml and about 10 ng / ml. max. In some embodiments, administration can also provide abiraterone concentrations in tissues of human subjects that are at least 10 times higher than the abiraterone plasma concentration 7 days after administration (i.e., 168 hours from the time of administration), wherein the tissues are selected from the liver, lungs, testicles, inguinal lymph nodes, iliac lymph nodes, adrenal glands, and prostates. In some embodiments, the abiraterone decanoate preparation can be administered to human subjects in need as the sole source of abiraterone. However, in some embodiments, the abiraterone decanoate preparation can also be administered to subjects in need as a supplement to another abiraterone therapy.

[0394] In some embodiments, particularly in the methods of treating prostate cancer herein, the amount and frequency of administration of abiraterone decanoate can be adjusted so that administration provides an effective amount of abiraterone to reduce serum testosterone levels in non-castrated human subjects to about 50 ng / dL or less (e.g., about 40 ng / dL or less, about 30 ng / dL or less, about 20 ng / dL or less, about 10 ng / dL or less, etc.) within 15 days (e.g., within 7 days, within 7-15 days, etc.) after the first administration of abiraterone decanoate, or to reduce serum testosterone levels in castrated human subjects to about 1 ng / dL or less. For example, in some embodiments, administration provides an effective amount of abiraterone to reduce serum testosterone levels in non-castrated human subjects to about 50 ng / dL or less (e.g., about 40 ng / dL or less, about 30 ng / dL or less, about 20 ng / dL or less, about 10 ng / dL or less, etc.) when measured on day 15 after the first administration of abiraterone decanoate, or to reduce serum testosterone levels in castrated human subjects to about 1 ng / dL or less. In some embodiments, administration provides an effective amount of abiraterone to achieve a sustained reduction in serum testosterone levels, such as within 15 days (e.g., within 7 days, between 7-15 days, etc.) after the first administration of abiraterone decanoate, to achieve and maintain serum testosterone levels in non-castrated human subjects at about 50 ng / dL or less (e.g., about 40 ng / dL or less, about 30 ng / dL or less, about 20 ng / dL or less, about 10 ng / dL or less, etc.), or in castrated human subjects to achieve and maintain serum testosterone levels at about 1 ng / dL or less. In some embodiments, the amount and frequency of administration of abiraterone decanoate can be adjusted so that administration provides an effective amount of abiraterone to reduce serum testosterone levels from baseline by 50% or more, preferably 75% or more, within 15 days (e.g., within 7 days, between 7-15 days, etc.) after the first administration of abiraterone decanoate. For example, in some embodiments, the administration provides an effective amount of abiraterone to reduce serum testosterone levels from baseline by 50% or more, preferably 75% or more, when measured on the 15th day after the first administration of abiraterone decanoate. In some embodiments, the administration provides an effective amount of abiraterone to achieve a sustained reduction in serum testosterone levels, such as within 15 days (e.g., within 7 days, between 7-15 days, etc.) after the first administration of abiraterone decanoate, reducing from baseline by 50% or more, 75% or more.

[0395] In some specific embodiments, the present disclosure provides a method of treating a sex hormone-dependent or androgen receptor-driven disease or condition in a human subject in need thereof, such as a sex hormone-dependent benign or malignant condition or a syndrome caused by androgen excess (e.g., any of those described herein), the method comprising administering abiraterone decanoate intramuscularly to a human subject at a dosing frequency of once every 1-3 months (such as once every three months), wherein each administration comprises administering to the human subject about 50 mg to about 2000 mg of abiraterone decanoate, such as about 180 mg, about 360 mg, about 720 mg, about 1260 mg, about 1800 mg, or any range between the recited values. In some embodiments, administration of abiraterone decanoate selectively inhibits CYP17A1 lyase activity over CYP17A1 hydroxylase activity in a human subject. In some embodiments, sex hormone-dependent or androgen receptor-driven diseases or conditions, such as sex hormone-dependent benign or malignant conditions or syndromes caused by androgen excess, are diseases or conditions in which lytic enzyme selectivity is desirable or believed to be beneficial in human subjects, such as endometrial cancer, endometriosis, ovarian cancer, and prostate cancer (such as localized prostate cancer, etc.).

[0396] In some specific embodiments, the present disclosure provides a method for treating prostate cancer (e.g., any of those described herein) in a human subject in need thereof, the method comprising administering abiraterone decanoate intramuscularly to a human subject at a dosing frequency of once every 1-3 months (such as once every three months), wherein each administration comprises administering to the human subject about 50 mg to about 2000 mg of abiraterone decanoate, such as about 180 mg, about 360 mg, about 720 mg, about 1260 mg, about 1800 mg, or any range between the listed values. In some embodiments, prostate cancer is CRPC or CSPC. In some embodiments, prostate cancer is metastatic CRPC or metastatic CSPC. In some embodiments, prostate cancer is localized prostate cancer. In some embodiments, prostate cancer is CRPC, and in some embodiments, patients with CRPC have not received chemotherapy. In some embodiments, prostate cancer is metastatic CRPC (mCRPC), and in some embodiments, patients with mCRPC have not received chemotherapy. Non-limiting examples of prostate cancer also include any of those described in [8]-

[17] in the Summary of the Invention section herein. In some embodiments, the method for treating prostate cancer includes a combination therapy, which further includes administering one or more additional therapies to a human subject, for example, as described herein under the section entitled Combined Therapy for Prostate Cancer. For example, in some embodiments, a human subject is treated with an androgen receptor antagonist (e.g., enzalutamide), such as orally administering enzalutamide to a human subject once a day at a daily dose of about 160 mg. In some embodiments, the method includes administering abiraterone decanoate and dexamethasone to a human subject, such as a human subject of a CRPC patient who has not received chemotherapy, including mCRPC patients who have not received chemotherapy. In some embodiments, the method may include administering abiraterone decanoate intramuscularly to a human subject (i) once every one to three months, preferably, administering about 1260 mg abiraterone decanoate intramuscularly once every three months; and (ii) orally administering dexamethasone once a day. In some embodiments, dexamethasone is orally administered to a human subject at a dose of about 0.1 to 1 mg / day (such as about 0.5 mg / day). Non-limiting examples of useful additional therapies also include any of those described in

[37] -

[49] in the Summary of the Invention section herein. However, in some embodiments, an agent for treating mineralocorticoid toxicity is not required and is not administered to the human subject. In some embodiments, the human subject is not treated with an agent that is effective in treating mineralocorticoid toxicity. In some embodiments, the human subject is not treated with an agent that is a glucocorticoid or mineralocorticoid receptor antagonist.

[0397] In some specific embodiments, the present disclosure provides a method for treating cancer in a human subject in need, wherein the cancer is a sex hormone-dependent or androgen receptor-driven cancer, and the cancer has metastasized to one or more lymph nodes, and the method includes administering abiraterone decanoate intramuscularly to a human subject at a dosing frequency of once every 1-3 months (such as once every three months), wherein each administration includes administering about 50 mg to about 2000 mg of abiraterone decanoate to the human subject, such as about 180 mg, about 360 mg, about 720 mg, about 1260 mg, about 1800 mg, or any range between the listed values. In some embodiments, the administration of abiraterone decanoate can effectively inhibit the growth of cancer in one or more lymph nodes. In some embodiments, cancer is prostate cancer (e.g., any of those described herein). For example, in some embodiments, prostate cancer is CRPC or CSPC. In some embodiments, prostate cancer is CRPC, and in some embodiments, patients with CRPC have not received chemotherapy. In some embodiments, prostate cancer is metastatic CRPC (mCRPC), and in some embodiments, patients with mCRPC have not received chemotherapy. Non-limiting examples of prostate cancer also include any of those described in [8]-

[17] in the Summary of the Invention section herein. In some embodiments, the method includes a combination therapy, which further includes administering one or more additional therapies to a human subject, for example, as described herein under the section entitled Combined Therapy for Prostate Cancer. For example, in some embodiments, a human subject is treated with an androgen receptor antagonist (e.g., enzalutamide), such as orally administering enzalutamide to a human subject once a day at a daily dose of about 160 mg. In some embodiments, the method includes administering abiraterone decanoate and dexamethasone to a human subject, such as a human subject of a CRPC patient who has not received chemotherapy, including mCRPC patients who have not received chemotherapy. In some embodiments, the method may include administering abiraterone decanoate intramuscularly to a human subject (i) once every one to three months, preferably, administering about 1260 mg of abiraterone decanoate intramuscularly once every three months; and (ii) orally administering dexamethasone once a day. In some embodiments, dexamethasone is orally administered to a human subject at a dose of about 0.1 to 1 mg / day (such as about 0.5 mg / day). Non-limiting examples of useful additional therapies also include any of those described in

[37] -

[49] in the Summary of the Invention section herein. However, in some embodiments, an agent for treating mineralocorticoid toxicity is not required and is not administered to a human subject. In some embodiments, a human subject is not treated with an agent that is effective for treating mineralocorticoid toxicity. In some embodiments, a human subject is not treated with an agent that is a glucocorticoid or mineralocorticoid receptor antagonist.

[0398] In some specific embodiments, the present disclosure provides a method for treating a cancer in a human subject in need, wherein the cancer is a sex hormone-dependent or androgen receptor-driven cancer, wherein the disease of the human subject progresses during or after treatment based on androgen receptor antagonists (such as treatment based on enzalutamide), the method comprising administering abiraterone decanoate intramuscularly to a human subject at a dosing frequency of once every 1-3 months (such as once every three months), wherein each administration includes administering abiraterone decanoate of about 50 mg to about 2000 mg to the human subject, such as about 180 mg, about 360 mg, about 720 mg, about 1260 mg, about 1800 mg or any range between the listed values. In some embodiments, cancer is prostate cancer (e.g., any of those described herein). For example, in some embodiments, prostate cancer is CRPC or CSPC. In some embodiments, prostate cancer is metastatic CRPC or metastatic CSPC. In some embodiments, prostate cancer is localized prostate cancer. In some embodiments, prostate cancer is CRPC, and in some embodiments, patients with CRPC have not received chemotherapy. In some embodiments, prostate cancer is metastatic CRPC (mCRPC), and in some embodiments, patients with mCRPC have not received chemotherapy. Non-limiting examples of prostate cancer also include any of those described in [8]-

[17] in the Summary of the Invention section herein. In some embodiments, the method includes a combination therapy, which further includes administering one or more additional therapies to a human subject, for example, as described herein under the section entitled Combined Therapy for Prostate Cancer. For example, in some embodiments, a human subject is treated with an androgen receptor antagonist (e.g., enzalutamide), such as orally administering enzalutamide to a human subject once a day at a daily dose of about 160 mg. In some embodiments, the method includes administering abiraterone decanoate and dexamethasone to a human subject, such as a human subject of a CRPC patient who has not received chemotherapy, including mCRPC patients who have not received chemotherapy. In some embodiments, the method may include administering abiraterone decanoate intramuscularly to a human subject (i) once every one to three months, preferably, administering about 1260 mg abiraterone decanoate intramuscularly once every three months; and (ii) orally administering dexamethasone once a day. In some embodiments, dexamethasone is orally administered to a human subject at a dose of about 0.1 to 1 mg / day (such as about 0.5 mg / day). Non-limiting examples of useful additional therapies also include any of those described in

[37] -

[49] in the Summary of the Invention section herein. However, in some embodiments, an agent for treating mineralocorticoid toxicity is not required and is not administered to a human subject. In some embodiments, a human subject is not treated with an agent effective for treating mineralocorticoid toxicity.In some embodiments, the human subject has not been treated with an agent that is a glucocorticoid or mineralocorticoid receptor antagonist.

[0399] In some specific embodiments, the present disclosure provides a method for treating cancer in a human subject in need, wherein the cancer is a sex hormone-dependent or androgen receptor-driven cancer, the method comprising administering abiraterone decanoate intramuscularly to a human subject at a dosing frequency of once every 1-3 months (such as once every three months), wherein each administration includes administering about 50 mg to about 2000 mg of abiraterone decanoate to the human subject, such as about 180 mg, about 360 mg, about 720 mg, about 1260 mg, about 1800 mg, or any range between the listed values, wherein before, at the same time or after the administration of abiraterone decanoate, the human subject is further treated with an androgen receptor antagonist (such as enzalutamide). In some embodiments, the human subject is further treated with enzalutamide. In some embodiments, enzalutamide can be orally administered to a human subject once a day at a daily dose of about 160 mg. In some embodiments, enzalutamide treatment can be started at least one day before the first administration of abiraterone decanoate. In some embodiments, enzalutamide treatment can start on the same day as the first administration of abiraterone decanoate. In some embodiments, enzalutamide treatment can start at least one day after the first parenteral administration of abiraterone decanoate. In some embodiments, one or more androgen receptor antagonists can be administered to human subjects in conjunction with the parenteral administration of a pharmaceutical composition to achieve a synergistic effect on cancer treatment. In some embodiments, cancer is prostate cancer (e.g., any of those described herein). For example, in some embodiments, prostate cancer is CRPC or CSPC. In some embodiments, prostate cancer is metastatic CRPC or metastatic CSPC. In some embodiments, prostate cancer is localized prostate cancer. In some embodiments, prostate cancer is CRPC, and in some embodiments, patients with CRPC have not received chemotherapy. In some embodiments, prostate cancer is metastatic CRPC (mCRPC), and in some embodiments, patients with mCRPC have not received chemotherapy. Non-limiting examples of prostate cancer also include any of those described in [8]-

[17] in the Summary of the Invention section herein. In some embodiments, the method includes a combination therapy that further includes administering one or more additional therapies to a human subject, for example, as described herein under the section entitled Combination Therapy for Prostate Cancer. For example, in some embodiments, a human subject is treated with an androgen receptor antagonist (e.g., enzalutamide), such as orally administering enzalutamide to a human subject once a day at a daily dose of about 160 mg. In some embodiments, the method includes administering abiraterone decanoate and dexamethasone to a human subject, such as a human subject of a CRPC patient who has not received chemotherapy, including a mCRPC patient who has not received chemotherapy.In some embodiments, the method may include administering abiraterone decanoate intramuscularly to a human subject (i) once every one to three months, preferably, administering about 1260 mg of abiraterone decanoate intramuscularly once every three months; and (ii) administering dexamethasone orally once daily. In some embodiments, dexamethasone is orally administered to a human subject at a dose of about 0.1 to 1 mg / day (such as about 0.5 mg / day). Non-limiting examples of useful additional therapies also include any of those described in

[37] -

[49] in the Summary of the Invention section herein. However, in some embodiments, an agent for treating mineralocorticoid toxicity is not required and is not administered to a human subject. In some embodiments, a human subject is not treated with an agent that is effective in treating mineralocorticoid toxicity. In some embodiments, a human subject is not treated with an agent that is a glucocorticoid or mineralocorticoid receptor antagonist.

[0400] In some specific embodiments, the present disclosure provides a method of reducing serum testosterone levels in a human subject in need thereof, the method comprising administering abiraterone decanoate intramuscularly to the human subject at a dosing frequency of once every 1-3 months (such as once every three months), wherein each administration comprises administering to the human subject about 50 mg to about 2000 mg of abiraterone decanoate, such as about 180 mg, about 360 mg, about 720 mg, about 1260 mg, about 1800 mg, or any range between the recited values, wherein the administration of abiraterone decanoate does not increase serum progesterone levels in the human subject. (i) an increase of more than 40% over baseline 4 weeks after the first administration of abiraterone decanoate; and / or (ii) an increase of more than 40% over baseline 2 weeks to 12 weeks after the second administration of abiraterone decanoate, preferably, without causing the serum progesterone level in the human subject to (i) increase more than 20% over baseline 4 weeks after the first administration of abiraterone decanoate; (ii) increase more than 20% over baseline 6 weeks, 8 weeks, 10 weeks and / or 12 weeks after the first administration of abiraterone decanoate; and / or (iii) increase more than 20% over baseline 2 weeks to 12 weeks after the second administration of abiraterone decanoate. In some embodiments, abiraterone decanoate is administered in an effective amount to achieve a sustained decrease in serum testosterone levels in a human subject to 50% or less below baseline within 15 days after the first administration of abiraterone decanoate. In some embodiments, abiraterone decanoate is administered in an effective amount to reduce serum testosterone levels to about 50 ng / dL or less (e.g., about 40 ng / dL or less, about 30 ng / dL or less, about 20 ng / dL or less, about 10 ng / dL or less, etc.) when the human subject is a non-castrated human subject when measured on the 15th day after the first administration of abiraterone decanoate, or to about 1 ng / dL or less when the human subject is a castrated human subject. In some embodiments, abiraterone decanoate is administered in an effective amount to reduce serum testosterone levels in a human subject to 80% or less below baseline, such as 85% or less below baseline or 90% or less below baseline, when measured 24 weeks after the first administration of abiraterone decanoate. In some embodiments, abiraterone decanoate is administered in an amount effective to reduce serum testosterone levels to about 50 ng / dL or less (e.g., about 40 ng / dL or less, about 30 ng / dL or less, about 20 ng / dL or less, about 10 ng / dL or less, etc.) when the human subject is a non-castrated human subject, or to about 1 ng / dL or less when the human subject is a castrated human subject, when measured 24 weeks after the first administration of abiraterone decanoate.In some embodiments, abiraterone decanoate is administered in an effective amount to achieve a sustained reduction in serum testosterone levels, such as a 50% or greater, 75% or greater reduction from baseline within 15 days (e.g., within 7 days, between 7-15 days, etc.) after the first administration of abiraterone decanoate. In some embodiments, the sustained reduction in serum testosterone levels is characterized in that once serum testosterone levels in a human subject are reduced to 50% or less below baseline, the serum testosterone levels remain below 50% or less below baseline for up to 8 weeks or more after the first administration of abiraterone decanoate. In some embodiments, the sustained reduction in serum testosterone levels is characterized in that once the serum testosterone level in the human subject is reduced to about 50 ng / dL or less (e.g., about 40 ng / dL or less, about 30 ng / dL or less, about 20 ng / dL or less, about 10 ng / dL or less, etc.) in a non-castrated human subject or to 1 ng / dL or less in a castrated human subject, the serum testosterone level remains at about 50 ng / dL or less in a non-castrated human subject or at about 1 ng / dL or less in a castrated human subject for up to 8 weeks or more after the first administration of abiraterone decanoate. In some embodiments, the human subject suffers from prostate cancer (e.g., any of those described herein).

[0401] In some specific embodiments, the present disclosure also provides a method of inhibiting CYP17A1 lyase activity in a human subject in need thereof, the method comprising administering abiraterone decanoate intramuscularly to the human subject at a dosing frequency of once every 1-3 months (such as once every three months), wherein each administration comprises administering to the human subject about 50 mg to about 2000 mg of abiraterone decanoate, such as about 180 mg, about 360 mg, about 720 mg, about 1260 mg, about 1800 mg, or any range between the recited values, wherein the administration of abiraterone decanoate does not increase the serum pregnancy rate in the human subject. Ketone levels (i) increase by more than 40% over baseline 4 weeks after the first administration of abiraterone decanoate; and / or (ii) increase by more than 40% over baseline 2 weeks to 12 weeks after the second administration of abiraterone decanoate, preferably, do not increase serum progesterone levels in the human subject (i) increase by more than 20% over baseline 4 weeks after the first administration of abiraterone decanoate; (ii) increase by more than 20% over baseline 6 weeks, 8 weeks, 10 weeks and / or 12 weeks after the first administration of abiraterone decanoate; and / or (iii) increase by more than 20% over baseline 2 weeks to 12 weeks after the second administration of abiraterone decanoate. In some embodiments, the human subject suffers from a disease or condition that is sex hormone-dependent or androgen receptor-driven. In some embodiments, the human subject suffers from a sex hormone-dependent benign or malignant condition, for example, as described herein. In some embodiments, the human subject suffers from a syndrome caused by androgen excess, for example, as described herein.

[0402] In some specific embodiments, the present disclosure also provides a method of reducing the level of androgens (e.g., testosterone and / or dihydrotestosterone) and / or estrogens in a human subject in need thereof, the method comprising administering abiraterone decanoate intramuscularly to the human subject at a dosing frequency of once every 1-3 months (such as once every three months), wherein each administration comprises administering to the human subject about 50 mg to about 2000 mg of abiraterone decanoate, such as about 180 mg, about 360 mg, about 720 mg, about 1260 mg, about 1800 mg, or any range between the recited values, wherein the administration of abiraterone decanoate does not cause the human subject to The serum progesterone level in the human subject (i) increases by more than 40% over baseline 4 weeks after the first administration of abiraterone decanoate; and / or (ii) increases by more than 40% over baseline 2 weeks to 12 weeks after the second administration of abiraterone decanoate, preferably, does not increase the serum progesterone level in the human subject (i) by more than 20% over baseline 4 weeks after the first administration of abiraterone decanoate; (ii) increases by more than 20% over baseline 6 weeks, 8 weeks, 10 weeks and / or 12 weeks after the first administration of abiraterone decanoate; and / or (iii) increases by more than 20% over baseline 2 weeks to 12 weeks after the second administration of abiraterone decanoate. In some embodiments, the human subject suffers from a syndrome...

Claims

1. A method of treating a disease or condition in a human subject in need thereof, the method comprising parenterally administering to the human subject a therapeutically effective amount of a pharmaceutical composition comprising an abiraterone prodrug (e.g., an abiraterone lipophilic ester), wherein the disease or condition is sex hormone-dependent or androgen receptor-driven, such as a sex hormone-dependent benign or malignant condition or a syndrome caused by androgen excess.

2. The method of claim 1, wherein the abiraterone prodrug is abiraterone decanoate or a pharmaceutically acceptable salt thereof, 3. The method of claim 1 or 2, wherein the method selectively inhibits CYP17A1 lyase activity compared to CYP17A1 hydroxylase activity in the human subject.

4. The method of any one of claims 1-3, wherein the disease or condition is polycystic ovary syndrome (PCOS), congenital adrenal hyperplasia (CAH), or endometriosis.

5. The method of any one of claims 1-3, wherein the disease or condition is cancer, wherein the cancer is a sex hormone-dependent or androgen receptor-driven cancer.

6. The method of claim 5, wherein the cancer is prostate cancer, endometrial cancer, or ovarian cancer.

7. The method of claim 5, wherein the cancer is prostate cancer.

8. The method of any one of claims 5-7, wherein the cancer has metastasized to one or more lymph nodes, and the administration of the pharmaceutical composition is effective to inhibit the growth of the cancer in the one or more lymph nodes.

9. The method of any one of claims 5-8, wherein the cancer is prostate cancer characterized by a Gleason score ≤6.

10. The method of any one of claims 5-9, wherein the human subject has a measurable prostate specific antigen.

11. The method of any one of claims 5-7, wherein the cancer is localized prostate cancer, such as high-risk localized prostate cancer.

12. The method of any one of claims 5-7, wherein the cancer is metastatic castration-sensitive prostate cancer, non-metastatic castration-sensitive prostate cancer, non-metastatic castration-resistant prostate cancer, or metastatic castration-resistant prostate cancer.

13. The method of any one of claims 5-7, wherein the cancer is newly diagnosed high-risk metastatic hormone-sensitive prostate cancer.

14. The method of any one of claims 5-7, wherein the cancer is metastatic CRPC (mCRPC), wherein the human subject is asymptomatic or has mild symptoms after failure of androgen deprivation therapy, and wherein chemotherapy is not clinically indicated.

15. The method of any one of claims 5-7, wherein the cancer is metastatic CRPC (mCRPC), wherein the human subject's disease progressed during or after a taxane-based chemotherapy regimen, such as a docetaxel-based or cabazitaxel-based chemotherapy regimen.

16. The method of any one of claims 5-7, wherein the cancer is refractory prostate cancer.

17. The method of any one of claims 5-16, wherein (i) the human subject's disease progresses during or after an androgen receptor antagonist-based therapy, such as an enzalutamide-based therapy; and / or (ii) the human subject has developed resistance to the combination therapy with abiraterone acetate and prednisone, including resistance due to elevated progesterone levels.

18. The method of any one of claims 1-17, wherein the pharmaceutical composition comprises abiraterone decanoate in its base form and a pharmaceutically acceptable carrier.

19. The method of claim 18, wherein the pharmaceutically acceptable carrier comprises a pharmaceutically acceptable oil and optionally another pharmaceutically acceptable solvent.

20. The method of claim 19, wherein the pharmaceutically acceptable oil comprises a triglyceride (e.g., long chain and / or medium chain triglycerides) and the another pharmaceutically acceptable solvent, if present, comprises an alcohol, ester and / or acid solvent.

21. The method of claim 19 or 20, wherein the pharmaceutically acceptable oil is selected from vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil and soybean oil, and the other pharmaceutically acceptable solvent, if present, comprises benzyl alcohol, benzyl benzoate or a combination thereof.

22. The method of any one of claims 18-21, wherein the pharmaceutically acceptable carrier comprises corn oil, benzyl alcohol, and benzyl benzoate.

23. The method of any one of claims 1-22, wherein the pharmaceutical composition comprises per milliliter (a) abiraterone decanoate in its base form in an amount of about 100 mg to about 300 mg (e.g., about 100 mg, about 120 mg, about 150 mg, about 180 mg, about 200 mg, or about 250 mg); (b) benzyl alcohol in an amount of about 50 mg to about 150 mg (e.g., about 75 mg, about 100 mg, or about 125 mg); (c) benzyl benzoate in an amount of about 100 mg to about 300 mg (e.g., about 100 mg, about 150 mg, about 200 mg, or about 250 mg); and (d) corn oil, q.s. to 1 milliliter.

24. The method of any one of claims 1-22, wherein the pharmaceutical composition comprises per milliliter (a) about 180 mg of abiraterone decanoate in its base form; (b) about 50 mg to about 150 mg (e.g., about 75 mg, about 100 mg, or about 125 mg) of benzyl alcohol; (c) about 100 mg to about 300 mg (e.g., about 100 mg, about 150 mg, about 200 mg, or about 250 mg) of benzyl benzoate; and (d) corn oil, qs to 1 milliliter.

25. The method of any one of claims 18-24, wherein the weight ratio of benzyl alcohol to benzyl benzoate in the pharmaceutical composition ranges from about 2:1 to about 1:5 (e.g., about 1:1 to 1:3, such as about 1:2).

26. The method of any one of claims 1-25, wherein the abiraterone prodrug is abiraterone decanoate, and the abiraterone decanoate is substantially pure, e.g., characterized as having a purity of at least 95%, preferably at least 98%, such as about 98.5%, about 99%, about 99.5% or more by weight.

27. The method of any one of claims 1-26, wherein the pharmaceutical composition is characterized as having a viscosity of less than 0.1 Pa*s, such as about 0.05 Pa*s or less.

28. The method of any one of claims 1-27, wherein the pharmaceutical composition is characterized as having a glide force of about 1-10 N when measured using a 21G, 1.5 inch needle, and / or having a glide force of about 2-15 N when measured using a 23G, 1.5 inch needle, and / or having a glide force of about 30-150 N when measured using a 27G, 1.5 inch needle.

29. The method of any one of claims 1-28, wherein the pharmaceutical composition is characterized as <788> and / or <789> When measured, it has no more than 1000 particles with a size of 10 μm or more, and no more than 300 particles with a size of 25 μm or more.

30. The method of any one of claims 1-29, wherein the pharmaceutical composition is characterized as having <85> Bacterial endotoxins measured at less than 100 EU / ml, such as less than 25 EU / ml.

31. The method of any one of claims 1-30, wherein the human subject is non-castrated.

32. The method of any one of claims 1-30, wherein the human subject is castrated.

33. The method of any one of claims 1-30 and 32, wherein the human subject is treated with a gonadotropin-releasing hormone agonist and / or antagonist.

34. The method of any one of claims 1-33, wherein the pharmaceutical composition is administered to the human subject by intramuscular injection.

35. The method of any one of claims 1-34, wherein the pharmaceutical composition is administered to the human subject once every 1-3 months, such as once every three months.

36. The method of any one of claims 1-35, wherein each administration of the pharmaceutical composition comprises administering to the human subject about 50 mg to about 2000 mg of abiraterone decanoate, such as about 180 mg, about 360 mg, about 720 mg, about 1260 mg, about 1800 mg, or any range between the recited values, preferably, the pharmaceutical composition is administered to the human subject once every three months, and each administration of the pharmaceutical composition comprises administering to the human subject about 1260 mg of abiraterone decanoate.

37. The method of any one of claims 1-36, further comprising administering to the subject a first generation androgen receptor antagonist, such as paxlovid, bicalutamide, flutamide, nilutamide, topilutamide.

38. The method of any one of claims 1-37, further comprising administering to the human subject a 2nd generation androgen receptor antagonist (e.g., apalutamide, darolutamide, or enzalutamide).

39. The method of claim 38, wherein the second generation androgen receptor antagonist is enzalutamide.

40. The method of any one of claims 1-39, further comprising administering to the human subject a 3rd generation androgen receptor antagonist (such as an N-terminal domain inhibitor) or an androgen receptor degrader molecule, alone or in combination with one or more 1st or 2nd generation androgen receptor antagonists.

41. The method of any one of claims 1-40, further comprising administering to the human subject one or more agents selected from the group consisting of hydrocortisone, prednisone, prednisolone, methylprednisolone, and dexamethasone, preferably dexamethasone.

42. The method of any one of claims 1-41, further comprising administering to the human subject a poly ADP ribose polymerase (PARP) inhibitor, such as niraparib, rucaparib, olaparib, talazoparib, veliparib, and fluzoparib.

43. The method of any one of claims 1-42, further comprising administering to the human subject a chemotherapeutic agent, such as a taxane-based chemotherapeutic agent (e.g., docetaxel, cabazitaxel, paclitaxel, etc.) or a platinum-based chemotherapeutic agent (e.g., cisplatin, carboplatin, oxaliplatin, etc.).

44. The method of any one of claims 1-43, further comprising administering to the human subject an immunotherapy, such as Sipuleucel-T, an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody such as pembrolizumab or nivolumab, or an anti-PD-L1 antibody such as avelumab or atezolizumab), or an anti-CTLA-4 antibody (e.g., ipilimumab), etc.

45. The method of any one of claims 1-44, further comprising administering to the human subject a bispecific T cell engager (BiTE) therapy, such as blinatumomab or solitonumab.

46. ​​The method of any one of claims 1-45, further comprising administering to the human subject a kinase inhibitor, such as sunitinib, dasatinib, cabozantinib, erdafitinib, dovitinib, capasitinib, onvansetinib, iparectinib, afrottinib, asetinib, abotinib, opanib, etc.

47. The method of any one of claims 1-46, further comprising administering a bone protective agent (e.g., denosumab, zoledronic acid) to the human subject, and wherein the human subject is characterized as having prostate cancer (e.g., CRPC) with bone metastases.

48. The method of any one of claims 1-47, further comprising administering to the human subject a therapeutic agent selected from the group consisting of: 1) an anti-IL23 targeted monoclonal antibody, such as tetracycline; 2) selenium, such as sodium selenite; 3) an EZH2 inhibitor, such as CPI-1205, GSK2816126, or tazemetostat; 4) a CDK4 / 6 inhibitor, such as palbociclib, ribociclib, abemaciclib; 6) a bromodomain and extra-terminal domain (BET) inhibitor, such as CCS1477, INCB057643, alobrexib, ZEN-3694, or molibicib (GSK525762); 7) an anti-CD105 antibody, such as TRC 105 or carlotuximab; 8) niclosamide; 9) A2A receptor antagonist, such as AZD4635; 10) PI3K inhibitor, such as AZD-8186, buparib or datoxib; 11) another nonsteroidal CYP17A1 inhibitor, such as sevitenel; 12) an antiprogestin, such as onapristone; 13) navitoclax; 14) an HSP90 inhibitor, such as orecoxib (AT13387); 15) an HSP27 inhibitor, such as OGX-427; 16) a 5-α-reductase inhibitor, such as dutasteride; 17) metformin; 18) AMG-386; 19) dextromethorphan; 20) theophylline; 21) hydroxychloroquine; and 22) lenalidomide.

49. The method of any one of claims 1-48, further comprising administering to the human subject one or more kinase modulators selected from the group consisting of FLT-3 (FMS-like tyrosine kinase) inhibitors, AXL (anexelekto) inhibitors (e.g., gilteritinib), CDK (cyclin-dependent kinase) inhibitors (such as CDK1, 2, 4, 5, 6, 7, or 9 inhibitors), retinoblastoma (Rb) inhibitors, protein kinase B (AKT) inhibitors, SRC inhibitors, IκB kinase 1 (IKK1) inhibitors, PIM-1 modulators, Lemur tyrosine kinase 2 (LMTK2) modulators, Lyn inhibitors, Aurora A inhibitors, ANPK (alpha nuclear protein kinase) inhibitors, extracellular signal-regulated kinase (ERK) modulators, c-jun N-terminal kinase (JNK) modulators, large MAP kinase (BMK) modulators, p38 mitogen-activated protein kinase (MAPK) modulators, and combinations thereof.

50. The method of any one of claims 1-49, wherein the human subject (i) is chemotherapy-naive or hormonal therapy-naive, such as a chemotherapy-naive mCRPC patient, prior to administration of the pharmaceutical composition; and / or (ii) wherein the human subject suffers from liver impairment, such as moderate to severe liver impairment (Child-Pugh B or C class), prior to administration of the pharmaceutical composition.

51. The method of any one of claims 1-50, wherein (i) the human subject has prostate cancer and the method does not increase progesterone levels in the human subject to levels associated with adverse clinical outcomes and drug resistance, such as serum or plasma progesterone greater than about 3 nM when measured 4 weeks, 6 weeks, or 12 weeks after the first administration of the pharmaceutical composition; and / or (ii) the human subject has prostate cancer and the human subject is characterized as having a serum or plasma progesterone level greater than about 3 nM after three months of treatment with abiraterone, such as Zytiga (oral abiraterone acetate and prednisone), prior to the first administration of the pharmaceutical composition.

52. The method of any one of claims 1-51, wherein the human subject suffers from, or is susceptible to, one or more side effects associated with inhibiting CYP17A1 hydroxylase activity, such as mineralocorticoid toxicity.

53. The method of any one of claims 1-52, wherein the abiraterone prodrug is abiraterone decanoate and at least a portion of the administered abiraterone decanoate is absorbed through the lymphatic system.

54. The method of any one of claims 1-53, wherein said administration of said pharmaceutical composition is effective to achieve a sustained reduction in serum testosterone levels in said human subject to 50% or less below baseline within 15 days following said first administration of said pharmaceutical composition.

55. The method of claim 54, wherein the sustained reduction in serum testosterone levels is characterized in that once the serum testosterone levels in the human subject are reduced to 50% or less below baseline, the serum testosterone levels remain at 50% or less below baseline for up to 8 weeks or more following the first administration of the pharmaceutical composition.

56. The method of any one of claims 1-55, wherein said administration of said pharmaceutical composition does not increase serum progesterone levels in said human subject by more than (i) 40% over baseline 4 weeks after said first administration of said pharmaceutical composition; and / or (ii) more than 40% over baseline 2 weeks to 12 weeks after a second administration of said pharmaceutical composition.

57. The method of any one of claims 1-55, wherein said administration of said pharmaceutical composition does not increase serum progesterone levels in said human subject by (i) more than 20% over baseline 4 weeks after said first administration of said pharmaceutical composition; (ii) more than 20% over baseline 6 weeks, 8 weeks, 10 weeks and / or 12 weeks after said first administration of said pharmaceutical composition; and / or (iii) more than 20% over baseline 2 weeks to 12 weeks after said second administration of said pharmaceutical composition.

58. A method as described in any one of claims 1-57, wherein, where applicable, said administration of said pharmaceutical composition reduces the level of prostate-specific antigen in said human subject, preferably, at least at one time point after said first administration of said pharmaceutical composition and / or after one or more subsequent administrations of said pharmaceutical composition, said prostate-specific antigen level is reduced to 50% or less, preferably 90% or less, compared to a baseline PSA level.

59. A method of reducing serum testosterone levels in a human subject in need thereof, the method comprising parenterally administering to the human subject an effective amount of a pharmaceutical composition comprising an abiraterone prodrug (e.g., abiraterone lipophilic ester), wherein the pharmaceutical composition is administered in an amount effective to achieve a sustained reduction in serum testosterone levels in the human subject to 50% or less below baseline within 15 days after the first administration of the pharmaceutical composition, wherein the administration of the pharmaceutical composition does not increase serum progesterone levels in the human subject by (i) 4 weeks after the first administration of the pharmaceutical composition; and / or (ii) increases by more than 40% over baseline 2 weeks to 12 weeks after the second administration of the pharmaceutical composition, preferably, does not increase serum progesterone levels in the human subject (i) by more than 20% over baseline 4 weeks after the first administration of the pharmaceutical composition; (ii) by more than 20% over baseline 6 weeks, 8 weeks, 10 weeks and / or 12 weeks after the first administration of the pharmaceutical composition; and / or (iii) by more than 20% over baseline 2 weeks to 12 weeks after the second administration of the pharmaceutical composition.

60. The method of claim 59, wherein the abiraterone prodrug is abiraterone decanoate or a pharmaceutically acceptable salt thereof, 61. The method of claim 59 or 60, wherein the human subject suffers from a disease or condition that is sex hormone-dependent or androgen receptor-driven, such as a sex hormone-dependent benign or malignant condition or a syndrome caused by androgen excess.

62. The method of claim 61, wherein the disease or condition is any one of those described in claims 4-17.

63. The method of any one of claims 59-62, wherein the sustained reduction in serum testosterone levels is characterized in that once the serum testosterone levels in the human subject are reduced to 50% or less below baseline, the serum testosterone levels remain below 50% or less below baseline for up to 8 weeks or more after the first administration of the pharmaceutical composition.

64. The method of any one of claims 59-63, wherein the human subject suffers from, or is susceptible to, one or more side effects associated with inhibiting CYP17A1 hydroxylase activity, such as mineralocorticoid toxicity.

65. A method of treating cancer in a human subject in need thereof, wherein the cancer is a sex hormone-dependent or androgen receptor-driven cancer that has metastasized to one or more lymph nodes, the method comprising parenterally administering to the human subject a therapeutically effective amount of a pharmaceutical composition comprising an abiraterone prodrug (e.g., an abiraterone lipophilic ester).

66. The method of claim 65, wherein the abiraterone prodrug is abiraterone decanoate or a pharmaceutically acceptable salt thereof, 67. The method of claim 65 or 66, wherein the administration of the pharmaceutical composition is effective to inhibit the growth of the cancer in the one or more lymph nodes.

68. The method of any one of claims 65-67, wherein the cancer is prostate cancer.

69. A method of treating cancer in a human subject in need thereof, wherein the cancer is a sex hormone-dependent or androgen receptor-driven cancer, wherein the human subject's disease progresses during or after androgen receptor antagonist-based therapy, such as enzalutamide-based therapy, the method comprising parenterally administering to the human subject a therapeutically effective amount of a pharmaceutical composition comprising an abiraterone prodrug (e.g., an abiraterone lipophilic ester).

70. The method of claim 69, wherein the abiraterone prodrug is abiraterone decanoate or a pharmaceutically acceptable salt thereof, 71. The method of claim 69 or 70, wherein the cancer is prostate cancer.

72. A method of treating cancer in a human subject in need thereof, wherein the cancer is a sex hormone-dependent or androgen receptor-driven cancer, the method comprising parenterally administering to the human subject a therapeutically effective amount of a pharmaceutical composition comprising an abiraterone prodrug (e.g., an abiraterone lipophilic ester), wherein the human subject is further treated with an androgen receptor antagonist, such as enzalutamide, prior to, simultaneously with, or after the first parenteral administration of the pharmaceutical composition.

73. The method of claim 72, wherein the abiraterone prodrug is abiraterone decanoate or a pharmaceutically acceptable salt thereof, 74. The method of claim 72 or 73, wherein the cancer is prostate cancer.

75. The method of any one of claims 59-74, wherein the pharmaceutical composition is as described in any one of claims 18-30.

76. The method of any one of claims 59-75, wherein the pharmaceutical composition is administered to the human subject by intramuscular injection.

77. The method of any one of claims 59-76, wherein the pharmaceutical composition is administered to the human subject once every 1-3 months, such as once every three months.

78. The method of any one of claims 59-77, wherein each administration of the pharmaceutical composition comprises administering to the human subject about 50 mg to about 2000 mg of abiraterone decanoate, such as about 180 mg, about 360 mg, about 720 mg, about 1260 mg, about 1800 mg, or any range between the recited values, preferably, the pharmaceutical composition is administered to the human subject once every three months and each administration of the pharmaceutical composition comprises administering to the human subject about 1260 mg of abiraterone decanoate.

79. The method of any one of claims 59-78, wherein the human subject is castrated.

80. The method of any one of claims 59-79, wherein the human subject is treated with a gonadotropin-releasing hormone agonist and / or antagonist.

81. The method of any one of claims 59-78, wherein the human subject is non-castrated.

82. A method as described in any of claims 59-81, wherein (i) the human subject is chemotherapy-naive or hormonal therapy-naive prior to administration of the pharmaceutical composition, such as an mCRPC patient who has not received chemotherapy; and / or (ii) the human subject suffers from liver impairment, such as moderate to severe liver impairment (Child-Pugh B or C class), prior to administration of the pharmaceutical composition.

83. The method of any one of claims 59-82, wherein (i) the human subject has prostate cancer and the method does not increase progesterone levels in the human subject to levels associated with adverse clinical outcomes and drug resistance, such as serum or plasma progesterone levels greater than about 3 nM when measured 4 weeks, 6 weeks, or 12 weeks after the first administration of the pharmaceutical composition; and / or (ii) the human subject has prostate cancer and the human subject is characterized as having a serum or plasma progesterone level greater than about 3 nM after three months of treatment with abiraterone, such as Zytiga (oral abiraterone acetate and prednisone), prior to the first administration of the pharmaceutical composition.

84. The method of any one of claims 65-83, wherein the human subject suffers from, or is susceptible to, one or more side effects associated with inhibiting CYP17A1 hydroxylase activity, such as mineralocorticoid toxicity.

85. The method of any one of claims 59-84, wherein the abiraterone prodrug is abiraterone decanoate and at least a portion of the administered abiraterone decanoate is absorbed through the lymphatic system.

86. The method of any one of claims 59-85, further comprising administering to the human subject one or more additional therapies of any one of claims 37-49.

87. The method of any one of claims 1-86, wherein the abiraterone prodrug is administered in an effective amount to reduce the serum testosterone level in the human subject to 90% or less below baseline when measured 24 weeks after the first administration of the abiraterone prodrug.

88. The method of any one of claims 1-87, wherein the abiraterone prodrug is administered in an effective amount to reduce the serum testosterone level in the human subject to about 50 ng / dL or less (e.g., about 40 ng / dL or less, about 30 ng / dL or less, about 20 ng / dL or less, about 10 ng / dL or less, etc.) when the human subject is a non-castrated human subject, or to about 1 ng / dL or less when the human subject is a castrated human subject.

89. The method of any one of claims 1-88, wherein the human subject would benefit from selective inhibition of CYP17A1 lyase activity as compared to CYP17A1 hydroxylase activity.

90. The method of any one of claims 1-40 and 42-89, where applicable, wherein the administration of the pharmaceutical composition does not cause mineralocorticoid toxicity in the human subject.

91. The method of any one of claims 1-40 and 42-90, where applicable, wherein the human subject is not treated with an agent effective to treat mineralocorticoid toxicity.

92. The method of any one of claims 1-40 and 42-90, where applicable, wherein the human subject is not treated with an agent that is a glucocorticoid or mineralocorticoid receptor antagonist.

93. A pharmaceutical composition comprising an abiraterone decanoate solution, wherein each milliliter of the abiraterone decanoate solution comprises: (a) abiraterone decanoate in its alkaline form in an amount of about 100 mg to about 300 mg (e.g., about 100 mg, about 120 mg, about 150 mg, about 180 mg, about 200 mg, or about 250 mg); and (b) benzyl alcohol in an amount of about 50 mg to about 150 mg (e.g., about 75 mg, about 1 00mg or about 125mg); (c) benzyl benzoate in an amount of about 100mg to about 300mg (e.g., about 100mg, about 150mg, about 200mg or about 250mg); (d) 3-mercapto-1,2-propanediol in an amount of about 0.5mg to about 20mg (e.g., about 0.5mg, about 1mg, about 2mg or about 5mg); and (e) corn oil, q.s. to 1 ml, wherein the abiraterone decanoate has the following structure:

94. The pharmaceutical composition of claim 93, wherein each milliliter of the abiraterone decanoate solution comprises: (a) abiraterone decanoate in its alkaline form in an amount of about 180 mg; (b) benzyl alcohol in an amount of about 50 mg to about 150 mg (e.g., about 75 mg, about 100 mg, or about 125 mg); (c) benzyl benzoate in an amount of about 100 mg to about 300 mg (e.g., about 100 mg, about 150 mg, about 200 mg, or about 250 mg); (d) 3-mercapto-1,2-propanediol in an amount of about 0.5 mg to about 2 mg (e.g., about 0.5 mg, about 1 mg, or about 2 mg); and (e) corn oil, q.s. to 1 milliliter.

95. The pharmaceutical composition of claim 93 or 94, wherein the weight ratio of benzyl alcohol to benzyl benzoate in the pharmaceutical composition ranges from about 2:1 to about 1:5 (e.g., about 1:1 to 1:3, such as about 1:2).

96. The method of any one of claims 1-92, wherein the pharmaceutical composition is any one of those according to claims 93-95.

97. The method of any one of claims 1-90 and 96, comprising administering to the human subject (i) abiraterone decanoate intramuscularly once every one to three months, preferably, about 1260 mg abiraterone decanoate intramuscularly once every three months; and (ii) dexamethasone orally once daily, preferably at a daily dose of about 0.5 mg / day.

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