Abiraterone Prodrug

Abstract

Sustained release abiraterone prodrug formulations, methods, and kits for parenteral administration to human subjects suffering from a sex hormone dependent or androgen receptor driven disease or disorder, e.g., a sex hormone dependent benign or malignant disorder, e.g., prostate cancer, androgen receptor driven cancer, and / or syndromes resulting from androgen excess.

Description

[Technical field]

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

[0002] The present disclosure generally relates to novel prodrugs of abiraterone and long-acting depot-based parenteral formulations of abiraterone prodrugs. The disclosure is intended for a wide range of applications, such as for intramuscular (IM) injection in patients suffering from androgen or estrogen hormone-dependent benign or malignant disorders, including various cancers (e.g., prostate cancer, bladder cancer, hepatocellular carcinoma, lung cancer, breast cancer, and ovarian cancer, etc.), or sex hormone-dependent or androgen receptor-driven diseases or disorders, such as androgen receptor-driven cancers, and for the treatment of non-neoplastic syndromes resulting from androgen overproduction, including both classical and non-classical congenital adrenal hyperplasia, endometriosis, polycystic ovary syndrome, precocious puberty, hirsutism, etc. [Background technology]

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

[0004] Abiraterone itself is poorly absorbed, but can be administered orally as abiraterone acetate prodrug.Abiraterone acetate is also poorly absorbed, but can be converted to abiraterone in the intestine, which is poorly absorbed into the bloodstream after cleavage of the acetate prodrug.Abiraterone acetate ((3β)-17-(3-pyridyl)androsta-5, acetate; CAS number 154229-18-2) is approved in the United States under the trade name Zytiga® for the treatment of castration-resistant or castration-sensitive prostate cancer.Abiraterone acetate is currently available worldwide.

[0005] Orally administered abiraterone acetate prodrugs are known to be poorly absorbed in the gastrointestinal tract (prodrugs are barely detectable in plasma). Instead, abiraterone acetate is hydrolyzed to abiraterone in the luminal environment, generating abiraterone supersaturation, which has been shown to be a potent driving force for abiraterone absorption (Stappaerts et al., Eur. J. Pharmaceutics Biopharmaceutics 90:1, 2015).

[0006] Abiraterone blocks the normal physiological production of steroids by the adrenal glands, so its prodrug formulations are generally prescribed at low doses of steroids to prevent adrenal insufficiency. In fact, Zytiga® (250 mg tablets) is approved in the United States only in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC) and patients with metastatic castration-sensitive prostate cancer (CSPC). The prescribing information accompanying Zytiga® recommends oral administration of 1,000 mg (4 x 250 mg tablets) once daily in combination with prednisone (5 mg) orally administered twice daily for CRPC patients or once daily for CSPC patients. In Europe, Zytiga® is approved for use only in combination with either prednisone or prednisolone.

[0007] Because administration of abiraterone acetate with food can increase the absorption of abiraterone acetate and therefore lead to increased and highly variable exposure, which in some cases can lead to various side effects such as cardiovascular and / or liver toxicity, the prodrug should be taken on an empty stomach at least 1 hour before or 2 hours after a meal. In fact, the prescribing information for Zytiga® states that it must be taken on an empty stomach and that food should not be consumed at least 2 hours before and at least 1 hour after oral administration.

[0008] The prescribing information states that Zytiga® at a daily oral dose of 1,000 mg significantly reduces the steady-state C max The C value was 226±178 ng / mL (mean±SD) and the area under the curve (AUC) value was 1173±690 ng.hr / mL (mean±SD). A single-dose (1,000 mg) crossover study of Zytiga® in healthy subjects found that administration of Zytiga® with food increased systemic exposure of abiraterone. Specifically, the C value of abiraterone max The ACE and AUC values, respectively, were approximately 7-fold and 5-fold higher when Zytiga® was administered with a low-fat meal (7% fat, 300 calories) and approximately 17-fold and 10-fold higher when Zytiga® was administered with a high-fat meal (57% fat, 825 calories).

[0009] The currently approved oral solid dosage form of the prodrug abiraterone acetate has several drawbacks. For example, it has very low bioavailability, requiring patients to take a large tablet load each day (4 x 250 mg tablets once daily). In addition, it results in high fluctuations in blood levels in patients due to a combination of low bioavailability and a high food effect. Furthermore, abiraterone is rapidly excreted, so this approved dosing regimen requires only a small daily C of abiraterone. min This is believed to be associated with loss of therapeutic efficacy in metastatic CRPC patients. Furthermore, abiraterone acetate is a non-selective CYP17A1 inhibitor, inhibiting both hydroxylase and lyase activity, leading to an undesirable increase in steroids upstream of hydroxylase. For example, oral administration of abiraterone acetate has been known to increase progesterone levels, which may activate certain progesterone-activated mutant androgen receptors and result in resistance to CYP17A1 inhibition. See, for example, Chen, EJ et al. Clin. Cancer. Res. 21(6):1273-1280 (2014).

[0010] Parenteral modes of administration (e.g., parenteral routes) have been explored for other classes of drugs, however, to date there are no sustained release injectable prodrug formulations of abiraterone available on the market. Summary of the Invention

[0011] The present disclosure generally relates to novel abiraterone prodrugs, long-acting abiraterone prodrug formulations, and methods of using the same in treating human subjects having, for example, a sex hormone-dependent or androgen receptor-driven disease or disorder, such as a sex hormone-dependent benign or malignant disorder, an androgen receptor-driven cancer, and / or a syndrome resulting from androgen excess. See also U.S. Patent No. 10,792,292(B2), issued to Propella Therapeutics, Inc. on October 6, 2020, PCT Application No. PCT / US2021 / 048607, filed September 1, 2021, and PCT / US2022 / 016278, filed February 14, 2022, the contents of each of which are incorporated herein by reference in their entirety.

[0012] The novel abiraterone prodrugs may typically be fatty acid esters of abiraterone that, upon cleavage, release abiraterone and a safe, degradable fatty acid moiety. Compared to oral abiraterone acetate formulations, the novel abiraterone prodrugs and formulations herein are revolutionary in that they provide improved bioavailability, elimination of food effect, reduced dosage burden, reduced dosing frequency, and sustained effective plasma concentrations of abiraterone, e.g., for at least 1 week, typically at least 2 weeks, and up to 10 weeks or more, following administration of the abiraterone prodrug formulation. Furthermore, pharmacokinetic and pharmacodynamic studies of representative abiraterone prodrugs demonstrate that the novel abiraterone prodrugs and formulations are suitable for weekly, monthly, bimonthly, trimonthly, or less frequent administration for treating human subjects with sex hormone-dependent or androgen receptor-driven diseases or disorders, such as sex hormone-dependent benign or malignant disorders, androgen receptor-driven cancers, and / or syndromes resulting from androgen excess. This feature alone represents a significant improvement over the currently marketed Zytiga® tablets, which require a large daily dosage burden for patients (4 x 250 mg tablets once daily).

[0013] As detailed herein, the present disclosure shows that administration of abiraterone prodrugs, particularly abiraterone decanoate, can selectively inhibit CYP17A1 lyase activity over CYP17A1 hydroxylase activity in human subjects, providing a new treatment option when lyase selectivity is desired or considered beneficial. In particular, as shown in the Examples section and figures herein, human subjects treated with intramuscular injection(s) of abiraterone decanoate can achieve lyase selectivity without significant elevation of steroid levels that may result from inhibition of CYP17A1 hydroxylase activity. Furthermore, clinical results herein show that human subjects treated with abiraterone decanoate did not experience mineralocorticoid toxicity, a common side effect associated with administration of Zytiga® tablets to human subjects. See, e.g., McKay, RR et al. Cancer 125(4):524-532 (2019). The lyase selectivity found in humans after administration of abiraterone decanoate was unexpected. The same selectivity was not observed via administration of Zytiga® tablets to human subjects. For example, it is known that oral administration of abiraterone acetate can increase mineralocorticoid concentrations 80-fold, which can lead to significant side effects, and 30% of men receiving abiraterone acetate develop signs and symptoms of mineralocorticoid excess - hypertension, hypokalemia and edema - and the 40-fold increase in progesterone and pregnenolone produced from an abiraterone acetate oral regimen is likely to stimulate androgen receptors, progesterone receptors, etc., resulting in resistance to the regimen. See, e.g., Wright, C., et al. Eur, J. Endocrinol. 182(4):413-421 (2020) and Zytiga® Prescribing Information (2011). On the other hand, Figure 11 shows that the fold changes from baseline in corticosterone and progesterone observed in cohorts 3, 4, and 5 were significantly reduced compared to the changes reported in the literature for Zytiga at day 28.Additionally, the present disclosure demonstrates that administration of abiraterone prodrugs, particularly abiraterone decanoate, is effective in reducing or eliminating cancer that has metastasized to one or more lymph nodes. Without wishing to be bound by theory, it is believed that the observed effectiveness in treating cancer that has metastasized to lymph nodes is due, in part, to delivery of the agent (e.g., a lipophilic prodrug such as abiraterone decanoate) to the lymphatic system, thereby increasing the concentration of the active agent within the lymphatic system.

[0014] The present disclosure also shows that administration of abiraterone prodrugs, particularly abiraterone decanoate, can consistently reduce patients' PSA levels throughout the treatment period (see, e.g., FIG. 7). Furthermore, the response rates (in terms of reduction in PSA levels) in CRPC patients are also much higher observed in the studies described herein when compared to the response rates reported in the literature for abiraterone acetate and enzalutamide. See, e.g., FIG. 9A and FIG. 9B.

[0015] The present disclosure also indicates that certain pharma- ceutically acceptable antioxidants are advantageous in stabilizing abiraterone prodrugs, particularly abiraterone decanoate formulations, upon room temperature storage.

[0016] Additionally, the present disclosure demonstrates that administration of abiraterone prodrugs, particularly abiraterone decanoate, can be effective in treating patients whose disease (cancer) has progressed following androgen receptor antagonist-based therapy, particularly enzalutamide therapy. In some embodiments, the abiraterone prodrugs herein can also be used in combination with androgen receptor antagonists such as enzalutamide to achieve synergistic effects in inhibiting cancer growth.

[0017] The present disclosure also demonstrates that administration of abiraterone decanoate to human subjects was generally well tolerated, consistent with previous observations in animal studies in which no hepatotoxicity was observed following intramuscular administration of abiraterone decanoate at the doses tested.

[0018] Thus, the compositions and methods described herein provide a new treatment option in human subjects that is not available with the commercially available oral formulation Zytiga® tablets. Additionally, the compositions and methods described herein fulfill a long-felt and unmet need by providing an alternative to oral formulations that suffer from problems such as: (1) low bioavailability, (2) interactions with ingested food, (3) delivery of highly variable blood levels of parent drug with potential for reduced efficacy and increased side effects, (4) the need for daily dosages and high dose burden, (5) the need for castration, (6) low patient compliance due to fasting within hours of administration, high dose burden, and the need for daily supplemental prednisone or prednisolone with opposing dosing schedules due to being taken with food, and (7) undesirable mineralocorticoid excess, particularly progesterone.

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

[0109] .

[0020] [1] A method of treating a disease or disorder in a human subject in need of such treatment, 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 disorder is sex hormone dependent or androgen receptor driven, e.g., a sex hormone dependent benign or malignant disorder, or a syndrome resulting from androgen excess.

[0021] [2] The method of [1], wherein the abiraterone prodrug is abiraterone decanoate, or a pharma- ceutically acceptable salt thereof. [ka]

[0022] [3] The method of [1] or [2], wherein the method selectively inhibits CYP17A1 lyase activity over CYP17A1 hydroxylase activity in the human subject.

[0023] [4] The method according to any one of [1] to [3], wherein the disease or disorder is polycystic ovary syndrome (PCOS), congenital adrenal hyperplasia (CAH), or endometriosis.

[0024] [5] The method according to any one of [1] to [3], wherein the disease or disorder is cancer, and the cancer is a sex hormone-dependent or androgen receptor-driven cancer.

[0025] [7] The method according to [5], wherein the cancer is prostate cancer, endometrial cancer, or ovarian cancer.

[0026] [7] The method according to [5], wherein the cancer is prostate cancer.

[0027] [8] The method according to any one of [5] to [7], wherein the cancer has metastasized to one or more lymph nodes, and administering the pharmaceutical composition is effective to inhibit growth of the cancer in the one or more lymph nodes.

[0028] [9] The method according to any one of [5] to [8], wherein the cancer is prostate cancer characterized by a Gleason score of 6 or less.

[0029]

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

[0030]

[11] The method according to any one of [5] to [7], wherein the cancer is localized prostate cancer, for example, high-risk localized prostate cancer.

[0031]

[12] The method according to any one of [5] to [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.

[0032]

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

[0033]

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

[0034]

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

[0035]

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

[0036]

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

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

[0037]

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

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

[0038]

[19] The method of

[18] , wherein the pharma- ceutically acceptable carrier comprises a pharma- ceutically acceptable oil, and optionally a further pharma- ceutical acceptable solvent.

[0039]

[20] The method of

[19] , wherein the pharma- ceutically acceptable oil comprises a triglyceride (e.g., a long-chain and / or medium-chain triglyceride) and the further pharma- ceutically acceptable solvent, if present, comprises an alcohol, an ester, and / or an acidic solvent.

[0040]

[21] The method of

[19] or

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

[0041]

[22] The method according to any one of

[18] to

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

[0042]

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

[22] , wherein the pharmaceutical composition contains, 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) a suitable amount to 1 milliliter of corn oil.

[0043]

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

[22] , wherein the pharmaceutical composition contains, per milliliter, (a) abiraterone decanoate in its base 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), and (d) corn oil in an amount of about 1 milliliter.

[0044]

[25] The method according to any one of

[18] to

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

[0045]

[26] The method according to any one of [1] to

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

[0046]

[27] The method according to any one of [1] to

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

[0047]

[28] The method according to any one of [1] to

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

[0048]

[29] The pharmaceutical composition is prepared according to the U.S.P. <788> and / or <789> The method according to any one of [1] to

[28] , characterized in that, when measured according to the method described above, the particle size distribution is 1000 or less particles having a size of 10 μm or more and 300 or less particles having a size of 25 μm or more.

[0049]

[30] The pharmaceutical composition is prepared according to the U.S.P. <85> The method according to any one of [1] to

[29] , characterized in that the bacterial endotoxin is less than 100 EU / ml, for example, less than 25 EU / ml, as measured according to the method described above.

[0050]

[31] The method according to any one of [1] to

[30] , wherein the human subject is non-castrated.

[0051]

[32] The method according to any one of [1] to

[30] , wherein the human subject is castrated.

[0052]

[33] The method according to any one of [1] to

[30] and

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

[0053]

[34] The method according to any one of [1] to

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

[0054]

[35] The method according to any one of [1] to

[34] , wherein the pharmaceutical composition is administered to the human subject once every 1 to 3 months, for example, once every 3 months.

[0055]

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

[35] , wherein each administration of the pharmaceutical composition comprises administering to the human subject about 50 mg to about 2000 mg of abiraterone decanoate, e.g., 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.

[0056]

[37] The method according to any one of [1] to

[36] , further comprising administering to the human subject a first generation androgen receptor antagonist, e.g., proxalutamide, bicalutamide, flutamide, nilutamide, or topirutamide.

[0057]

[38] The method according to any one of [1] to

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

[0058]

[39] The method according to

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

[0059]

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

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

[0060]

[41] The method according to any one of [1] to

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

[0061]

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

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

[0062]

[43] The method according to any one of [1] to

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

[0063]

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

[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).

[0064]

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

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

[0065]

[46] The method according to any one of [1] to

[45] , further comprising administering to the human subject a kinase inhibitor, such as sunitinib, dasatinib, cabozantinib, erdafitinib, dovitinib, capivasertib, onvansertib, ipatasertib, afuresertib, alisertib, apitolisib, or opaganib.

[0066]

[47] The method according to any one of [1] to

[46] , further comprising administering a bone protective agent (e.g., denosumab, zolendronic acid) to the human subject, wherein the human subject has prostate cancer with bone metastasis (e.g., CRPC).

[0067]

[48] ​​The human subject is administered 1) an anti-IL23 targeting monoclonal antibody, e.g., tildrakizumab; 2) selenium, e.g., sodium selenate; 3) an EZH2 inhibitor, e.g., CPI-1205, GSK2816126, or tazemetostat; 4) a CDK4 / 6 inhibitor, e.g., palbociclib, ribociclib, abemaciclib; 6) a bromodomain and extraterminal domain (BET) inhibitor, e.g., CCS1477, INCB057643, allobresib, ZEN-3694, or molibresib (GSK525762); 7) an anti-CD105 antibody, e.g., TRC105, or carotuximab; 8) niclosamide; 9) an A2A receptor antagonist, e.g., AZD4635; The method of any one of [1] to

[47] , further comprising administering a therapeutic agent selected from 0) a PI3K inhibitor, e.g., AZD-8186, buparlisib, or dactolisib, 11) a further non-steroidal CYP17A1 inhibitor, e.g., ceviteronel, 12) an antiprogestogen, e.g., onapristone, 13) navitoclax, 14) an HSP90 inhibitor, e.g., onarespib (AT13387), 15) an HSP27 inhibitor, e.g., OGX-427, 16) a 5-α-reductase inhibitor, e.g., dutasteride, 17) metformin, 18) AMG-386, 19) dextromethorphan, 20) theophylline, 21) hydroxychloroquine, and 22) lenalidomide.

[0068]

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

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

[0069]

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

[49] , wherein (i) the human subject is chemotherapy-naïve or hormone therapy-naïve prior to administration of the pharmaceutical composition, such as a chemotherapy-naïve mCRPC patient, and / or (ii) the human subject is suffering from liver impairment, such as moderate to severe liver impairment (Child-Pugh classification B or C), prior to administration of the pharmaceutical composition.

[0070]

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

[50] , wherein: (i) the human subject has prostate cancer, and the method does not elevate the human subject's progesterone level to a level associated with poor clinical outcome and drug resistance, such as a serum or plasma progesterone level of greater than about 3 nM, when measured 4 weeks, 6 weeks, or 12 weeks after the initial administration of the pharmaceutical composition; and / or (ii) the human subject has prostate cancer, and the human subject has a serum or plasma progesterone level of greater than about 3 nM after 3 months of abiraterone treatment, such as Zytiga (oral abiraterone acetate and prednisone) treatment, prior to the initial administration of the pharmaceutical composition.

[0071]

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

[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.

[0072]

[53] The method according to 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 via the lymphatic system.

[0073]

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

[53] , wherein administration of the pharmaceutical composition is effective to achieve a sustained reduction in the human subject's serum testosterone level to 50% or less of baseline within 15 days of the initial administration of the pharmaceutical composition.

[0074]

[55] The method of

[54] , wherein the sustained reduction in serum testosterone levels is characterized in that, once the human subject's serum testosterone levels fall to below 50% of baseline, the serum testosterone levels remain below 50% of baseline for up to 8 weeks or more after the initial administration of the pharmaceutical composition.

[0075]

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

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

[0076]

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

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

[0077]

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

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

[0078]

[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., an abiraterone lipophilic ester), the pharmaceutical composition being administered in an amount effective to achieve a sustained reduction in serum testosterone levels in the human subject to 50% or less of baseline within 15 days of initial administration of the pharmaceutical composition, the administration of the pharmaceutical composition comprising: (i) a 40% or greater reduction in serum testosterone levels from baseline 4 weeks after initial administration of the pharmaceutical composition; % above baseline, and / or (ii) does not increase the serum progesterone level of the human subject by more than 40% above baseline 2 to 12 weeks after a second administration of the pharmaceutical composition, and preferably does not increase the serum progesterone level of the human subject by more than (i) 20% above baseline 4 weeks after a first administration of the pharmaceutical composition, (ii) 20% above baseline 6, 8, 10 and / or 12 weeks after a first administration of the pharmaceutical composition, and / or (iii) 20% above baseline 2 to 12 weeks after a second administration of the pharmaceutical composition.

[0079]

[60] The method of

[59] , wherein the abiraterone prodrug is abiraterone decanoate, or a pharma- ceutically acceptable salt thereof. [ka]

[0080]

[61] The method of

[59] or

[60] , wherein the human subject suffers from a sex hormone-dependent or androgen receptor-driven disease or disorder, such as a sex hormone-dependent benign or malignant disorder, or a syndrome resulting from androgen excess.

[0081]

[62] The method according to

[61] , wherein the disease or disorder is any of those described in [4] to

[17] .

[0082]

[63] The method of any one of

[59] to

[62] , wherein the sustained reduction in serum testosterone levels is characterized in that, when the serum testosterone level of the human subject falls to below 50% of baseline, the serum testosterone level remains below 50% of baseline for at least 8 weeks after initial administration of the pharmaceutical composition.

[0083]

[64] The method of

[59] to

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

[0084]

[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).

[0085]

[66] The method of

[65] , wherein the abiraterone prodrug is abiraterone decanoate, or a pharma- ceutically acceptable salt thereof. [ka]

[0086]

[67] The method of

[65] or

[66] , wherein administering the pharmaceutical composition is effective to inhibit growth of the cancer in the one or more lymph nodes.

[0087]

[68] The method of any one of

[65] to

[67] , wherein the cancer is prostate cancer, e.g., any of those described in [8] to

[17] , if applicable.

[0088]

[69] A method of treating cancer in a human subject in need of such treatment, wherein the cancer is a sex hormone dependent or androgen receptor driven cancer, and the human subject's disease has progressed during or after an androgen receptor antagonist based treatment, such as an enzalutamide based treatment, 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]

[70] The method of

[69] , wherein the abiraterone prodrug is abiraterone decanoate, or a pharma- ceutically acceptable salt thereof. [ka]

[0090]

[71] The method of

[69] or

[70] , wherein the cancer is prostate cancer, e.g., any of those described in [8] to

[17] , if applicable.

[0091]

[72] A method of treating cancer in a human subject in need of such treatment, 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, concurrently with, or following the initial parenteral administration of the pharmaceutical composition.

[0092]

[73] The method of

[72] , wherein the abiraterone prodrug is abiraterone decanoate, or a pharma- ceutically acceptable salt thereof. [ka]

[0093]

[74] The method of

[72] or

[73] , wherein the cancer is prostate cancer, e.g., any of those described in [8] to

[17] , if applicable.

[0094]

[75] The method according to any one of

[59] to

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

[18] to

[30] .

[0095]

[76] The method according to any one of

[59] to

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

[0096]

[77] The method according to any one of

[59] to

[76] , wherein the pharmaceutical composition is administered to the human subject once every 1 to 3 months, for example, once every 3 months.

[0097]

[78] The method of any one of

[59] to

[77] , wherein each administration of the pharmaceutical composition comprises administering to the human subject about 50 mg to about 2000 mg of abiraterone decanoate, e.g., 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.

[0098]

[79] The method according to any one of

[59] to

[78] , wherein the human subject is castrated.

[0099]

[80] The method according to any one of

[59] to

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

[0100]

[81] The method according to any one of

[59] to

[78] , wherein the human subject is non-castrated.

[0101]

[82] The method of any one of

[59] to

[81] , wherein (i) the human subject is chemotherapy-naïve or hormone therapy-naïve prior to administration of the pharmaceutical composition, such as a chemotherapy-naïve mCRPC patient, and / or (ii) the human subject is suffering from liver impairment, such as moderate to severe liver impairment (Child-Pugh classification B or C), prior to administration of the pharmaceutical composition.

[0102]

[83] The method of any one of

[59] to

[82] , characterized in that: (i) the human subject has prostate cancer, and the method does not elevate the human subject's progesterone level to a level associated with poor clinical outcome and drug resistance, such as a serum or plasma progesterone level of greater than about 3 nM, when measured 4 weeks, 6 weeks, or 12 weeks after the initial administration of the pharmaceutical composition; and / or (ii) the human subject has prostate cancer, and the human subject has a serum or plasma progesterone level of greater than about 3 nM after 3 months of abiraterone treatment, such as Zytiga (oral abiraterone acetate and prednisone) treatment, prior to the initial administration of the pharmaceutical composition.

[0103]

[84] The method of any one of

[65] to

[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.

[0104]

[85] The method according to any one of

[59] to

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

[0105]

[86] The method according to any one of

[59] to

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

[37] to

[49] .

[0106]

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

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

[0107]

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

[87] , wherein the abiraterone prodrug is administered in an amount effective to reduce the serum testosterone level of 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.) if the human subject is a non-castrated human subject, or to about 1 ng / dL or less if the human subject is a castrated human subject, when measured 24 weeks after the initial administration of the abiraterone prodrug.

[0108]

[89] The method according to any one of [1] to

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

[0109]

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

[40] and

[42] -

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

[0110]

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

[40] and

[42] -

[90] , wherein, if applicable, the human subject is not being treated with an agent effective to treat mineralocorticoid toxicity.

[0111]

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

[40] and

[42] -

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

[0112]

[93] A pharmaceutical composition comprising an abiraterone decanoate solution, wherein each milliliter of the abiraterone decanoate solution contains (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 aldehyde in an amount of about 50 mg to about 150 mg (e.g., about 75 mg, about 100 mg, or about 125 mg). 1. The pharmaceutical composition of claim 1, further comprising: (a) 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); (b) 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 (c) corn oil 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), [ka]

[0113]

[94] The pharmaceutical composition of

[93] , wherein each milliliter of the abiraterone decanoate solution contains: (a) abiraterone decanoate in its base 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) a qs to 1 milliliter of corn oil.

[0114]

[95] The pharmaceutical composition according to

[93] or

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

[0115]

[96] The pharmaceutical composition according to any one of

[93] to

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

[0116]

[97] The pharmaceutical composition described in any one of

[93] to

[96] , wherein the abiraterone decanoate solution is contained in a container having a headspace, such as a vial, ampule, bottle, etc., and the headspace is filled with an inert gas such as nitrogen gas.

[0117]

[98] The pharmaceutical composition according to any one of

[93] to

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

[0118]

[99] The pharmaceutical composition according to any one of

[93] to

[98] , which is storage stable at room temperature for one month or more, preferably two months or three months or more.

[0119]

[0100] The pharmaceutical composition described in any one of

[93] to

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

[0120]

[0101] A pharmaceutical composition described in any one of

[93] to

[0100] , characterized in that the abiraterone decanoate solution has a glide force of approximately 1 to 10 N when measured using a 21 G, 1.5 inch needle, and / or approximately 2 to 15 N when measured using a 23 G, 1.5 inch needle, and / or approximately 30 to 150 N when measured using a 27 G, 1.5 inch needle.

[0121] The abiraterone decanoate solution is <788> and / or <789> The pharmaceutical composition according to any one of

[93] to

[0101] , characterized in that, when measured according to the method described above, the pharmaceutical composition has 1,000 or less particles having a size of 10 μm or more and 300 or less particles having a size of 25 μm or more.

[0122] The abiraterone decanoate solution may be prepared according to USP <85> The pharmaceutical composition according to any one of

[93] to

[0102] , characterized in that it has an endotoxin level of less than 100 EU / ml, for example, less than 25 EU / ml, measured according to the method described above.

[0123]

[0104] The pharmaceutical composition is in the form of a unit dosage form, the unit dosage form containing from about 1 ml to about 20 ml of the abiraterone decanoate solution, a pharmaceutical composition described in any one of

[93] to

[0103] .

[0124]

[0105] The pharmaceutical composition is in the form of a unit dosage form, the unit dosage form containing approximately 1 ml or 2 ml of the abiraterone decanoate solution, a pharmaceutical composition described in any one of

[93] to

[0103] .

[0125]

[0106] The pharmaceutical composition is in the form of a unit dosage form, and the unit dosage form contains approximately 3 ml of the abiraterone decanoate solution. A pharmaceutical composition described in any one of

[93] to

[0103] .

[0126]

[0107] The pharmaceutical composition is in the form of a unit dosage form, the unit dosage form containing 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, a pharmaceutical composition described in any one of

[93] to

[0103] .

[0127]

[0108] The method according to any one of [1] to

[92] , wherein the pharmaceutical composition is any one of those described in

[93] to

[0107] , if applicable.

[0128]

[0109] A method according to any one of [1] to

[90] and

[0108] , comprising administering to the human subject (i) about 1260 mg of abiraterone decanoate intramuscularly once every 1 to 3 months, preferably about 1260 mg of abiraterone decanoate once every 3 months, and (ii) dexamethasone orally once a day, preferably at a daily dose of about 0.5 mg / day.

[0129]

[0010] Embodiments of the present disclosure may fill a long-standing need in the field of sex hormone dependent disorders and oncology, including the treatment of sex hormone dependent or androgen receptor driven cancers such as prostate cancer. Embodiments of the present disclosure may also fill a long-standing need in the field of treatment of syndromes due to androgen excess syndrome.

[0011] Embodiments of the present disclosure may overcome major shortcomings and deficiencies of prior art formulations of abiraterone acetate (including commercially available oral dosage forms) by providing long-acting sustained release depot-based parenteral formulations of abiraterone prodrugs, methods of making same, methods of treatment using same, and kits for convenient administration of the formulations to subjects in need of treatment of various disorders, including prostate cancer.

[0130] Thus, features have been outlined relatively broadly in order that the detailed description which follows may be better understood, and in order that the present contribution to the art may be better appreciated. Of course, there are additional features which are further described below. Indeed, it should be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the present disclosure.

[0131] In this regard, before describing at least one embodiment in detail, it is to be understood that the invention is not limited to the details of construction and the arrangement of components set forth in the following description or illustrated in the drawings in its application. The invention is capable of other embodiments and of being practiced and carried out in various ways. Moreover, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting.

[0132] Thus, those skilled in the art will appreciate that the conception underlying this disclosure may be readily utilized as a basis for the design of other formulations, methods, systems, kits, and compositions for carrying out some of the purposes of this disclosure, and it is important, therefore, that equivalent structures are included in this disclosure insofar as they do not depart from the spirit and scope of the disclosure.

[0133] The accompanying drawings are included to provide a further understanding, are incorporated in and constitute a part of this specification, and illustrate several embodiments and, together with the description, explain the principles of the invention. [Brief description of the drawings]

[0134] [Figure 1] Biochemical pathways showing the effects of CYP17A1 inhibition on the synthesis of androgens, estrogens, glucocorticoids, progesterone and mineralocorticoids are presented. [Diagram 2] A representative analysis of a batch of high purity abiraterone decanoate is shown. [Figure 3A] The results of the change in serum testosterone levels from 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 in patients in cohorts 1, 2, 3, 4, and 5, respectively, are shown. Cohorts 1 and 2 also received prednisone 5 mg orally once or twice daily. Cohorts 3, 4, and 5 received dexamethasone 0.5 mg orally once daily. Cohorts 1, 2, 3, 4, and 5 in the other figures were each treated with the same glucocorticoid regimen. [Figure 3B] The results show the change in serum dehydroepiandrosterone sulfate (DHEA-S) levels from baseline (Cycle 1, Day 1 value) following intramuscular injection of 180 mg, 360 mg, 720 mg, 1260 mg, or 1800 mg of abiraterone decanoate in patients in cohorts 1, 2, 3, 4, and 5, respectively. [Figure 3C]1 shows the results of the change in serum dehydroepiandrosterone (DHEA) levels from baseline (Cycle 1, Day 1 value) following intramuscular injection of 180 mg, 360 mg, 720 mg, 1260 mg, or 1800 mg of abiraterone decanoate in patients in cohorts 1, 2, 3, 4, and 5, respectively. [Figure 3D] 1 shows the results of the change in serum androstenedione levels from baseline (Cycle 1, Day 1 value) following intramuscular injection of 180 mg, 360 mg, 720 mg, 1260 mg, or 1800 mg of abiraterone decanoate in patients in cohorts 1, 2, 3, 4, and 5, respectively. [Figure 3E] 1 shows the results of the change in serum progesterone levels from baseline (cycle 1, day 1 value) following intramuscular injection of 180 mg, 360 mg, 720 mg, 1260 mg, or 1800 mg of abiraterone decanoate in patients in cohorts 1, 2, 3, 4, and 5, respectively. [Figure 3F] 1 shows the results of the change in serum 11-deoxycorticosterone levels from baseline (Cycle 1, Day 1 value) following intramuscular injection of 720 mg, 1260 mg, or 1800 mg of abiraterone decanoate in patients in cohorts 3, 4, and 5, respectively. [Figure 3G] 1 shows the results of the change in serum corticosterone levels from baseline (Cycle 1, Day 1 value) following intramuscular injection of 720 mg, 1260 mg, or 1800 mg abiraterone decanoate in patients in cohorts 1, 2, 3, 4, and 5, respectively. [Figure 4A] FIG. 1 shows the time course of plasma concentrations of abiraterone decanoate following intramuscular injection of 180 mg, 360 mg, 720 mg, 1260 mg, or 1800 mg of abiraterone decanoate in patients in cohorts 1, 2, 3, 4, and 5, respectively. [Figure 4B] The plasma concentrations of abiraterone over time are shown following intramuscular injection of 180 mg, 360 mg, 720 mg, 1260 mg, or 1800 mg of abiraterone decanoate in patients in cohorts 1, 2, 3, 4, and 5, respectively. [Figure 4C] The plasma concentrations of abiraterone sulfate over time are shown following intramuscular injection of 180 mg, 360 mg, 720 mg, 1260 mg, or 1800 mg of abiraterone decanoate in patients in cohorts 1, 2, 3, 4, and 5, respectively. [Figure 4D] FIG. 1 shows the time course of plasma concentrations of abiraterone N-oxide following intramuscular injection of 180 mg, 360 mg, 720 mg, 1260 mg, or 1800 mg of abiraterone decanoate in patients in cohorts 1, 2, 3, 4, and 5, respectively. [Figure 4E] FIG. 1 shows the time course of plasma concentrations of abiraterone N-oxide sulfate following intramuscular injection of 180 mg, 360 mg, 720 mg, 1260 mg, or 1800 mg of abiraterone decanoate in patients in cohorts 1, 2, 3, 4, and 5, respectively. [Diagram 5] 1 shows the change in serum steroid levels compared to baseline following intramuscular injection of 180 mg abiraterone decanoate in patient 1. [Figure 6] 1 shows the change in serum steroid levels compared to baseline following intramuscular injection of 360 mg abiraterone decanoate in patient 2. [Figure 7] 1 shows patient swim plots for prostate specific antigen (PSA) response (% change from baseline) over the course of the study for cohorts 3, 4, and 5. [Figure 8A] Best PSA response (% change from baseline) during the study period for all patients in cohorts 3, 4, and 5 is shown. [Figure 8B] Best PSA response (% change from baseline) during the study for pre-chemotherapy CRPC patients in cohorts 3, 4, and 5 is shown. [Figure 9A]Shown is the proportion of patients achieving a ≥50% decline in PSA from baseline at any time point in the study from chemotherapy-naive CRPC patients in cohorts 3, 4, and 5, compared to literature reported values ​​from abiraterone acetate (AA) / prednisone or enzalutamide (Enza). Results for patients with CRPC prior to chemotherapy. PRL-02 represents im abiraterone decanoate treatment. [Figure 9B] The proportion of patients who achieved a ≥90% decline in PSA from baseline at any time point in the study from chemotherapy-naive CRPC patients in cohorts 3, 4, and 5 is shown, along with a comparison to literature reported values ​​from abiraterone acetate (AA) or enzalutamide (Enza). Results for patients with CRPC prior to chemotherapy. [Figure 10] 1 shows a plot of the percentage change in PSA from baseline during the study period for all patients studied with CRPC. [Figure 11A] Shown are bar graphs comparing fold increase from baseline in mean mineralocorticoids in cohorts 3, 4, or 5. Zytiga / Prednisone. [Figure 11B] Serum progesterone levels over time for patients in cohorts 4 and 5. The LLOQ was 1.59 nM. Maximum individual progesterone levels for cohorts 1-3 were 2.5 nM. [Figure 12] 1 shows a representative flow chart illustrating steps typically performed in a manufacturing process for abiraterone decanoate solution. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0135] In a broad aspect, the present disclosure relates to novel methods for treating or preventing diseases or disorders related to sex hormones. Some embodiments of the present disclosure are based, in part, on the unexpected discovery that abiraterone prodrugs can be administered to human subjects to selectively inhibit CYP17A1 lyase activity over hydroxylase activity. Some embodiments of the present disclosure are also based, in part, on the unexpected discovery that abiraterone prodrugs can be administered to human subjects to reduce or eliminate cancer that has metastasized to one or more lymph nodes. Some embodiments of the present disclosure are based, in part, on the unexpected discovery that administering abiraterone prodrugs can be effective in treating human subjects who have progressed during or after androgen receptor antagonist-based therapy, such as enzalutamide-based therapy. Data presented in the present disclosure further suggests that the abiraterone prodrugs herein can achieve synergistic effects when used in combination with androgen receptor antagonists, such as enzalutamide. Some embodiments of the present disclosure are based, in part, on Applicants' discovery that inclusion of a pharma- ceutically acceptable antioxidant, in particular monothioglycerol, in an abiraterone decanoate formulation can result in a formulation that is shelf stable for greater than nine months at room temperature.

[0136] As detailed herein and described in part in U.S. Pat. No. 10,792,292(B2), and PCT Application Nos. PCT / US2021 / 048607 and PCT / US2022 / 016278, the methods herein provide, but are not limited to, rapid and sustained reduction in serum testosterone, no need for castration, reduced or eliminated liver toxicity compared to methods using oral abiraterone acetate formulations, improved bioavailability, elimination of the food effect associated with oral abiraterone acetate formulations, reduced dosing burden, improved patient compliance, reduced dosing frequency, maintenance of stable blood levels of active drug, and reduced associated side effects. max The present invention may be more advantageous than existing methods in many aspects, including a reduction in

[0137] Without being bound by theory, the formulations and methods using abiraterone decanoate herein have the following advantages: 1) abiraterone decanoate is actively taken up or has high cell and tissue permeability, delivering higher abiraterone equivalent concentrations to tissues; 2) the efficacy of abiraterone decanoate is therefore not dependent on plasma levels, and in fact abiraterone decanoate may be delivered to tissues primarily, with plasma concentrations being secondary and due to excretion from tissues; 3) the pharmacological half-life of abiraterone decanoate is substantially greater than that of abiraterone decanoate; It is also believed to offer a distinct advantage over oral abiraterone acetate regimens in that 1) the longer CD4+ / - time may be the result of slower conversion of abiraterone decanoate to abiraterone in tissues, and 2) the high tissue concentrations of abiraterone observed from intramuscular administration of abiraterone decanoate cannot be generated by oral regimens due to the low solubility and permeability of abiraterone released in the intestinal tract (i.e., high plasma concentrations are required to achieve elevated concentrations in cells and tissues).

[0138] Thus, in various embodiments, the present disclosure provides novel methods for regulating serum steroid hormone levels, such as for lowering testosterone levels, novel methods for treating or preventing diseases or disorders mediated by or related to such steroids, such as sex hormone dependent or androgen receptor driven cancers, and / or prodrugs and formulations of abiraterone useful in the methods.

[0139] Treatment method In some embodiments, the disclosure provides a method of treating a disease or disorder in a human subject in need of treatment of the disease or disorder described herein. The method typically comprises parenterally administering to the human subject a therapeutically effective amount of a pharmaceutical composition comprising an abiraterone prodrug (e.g., an abiraterone lipophilic ester). The disease or disorder is typically sex hormone dependent or androgen receptor driven, e.g., a sex hormone dependent benign or malignant disorder, or a syndrome resulting from androgen excess.

[0140] Typically, the abiraterone prodrug is abiraterone decanoate, or a pharma- ceutically acceptable salt thereof. [ka] As used herein, the term "abiraterone decanoate" in its base form is to be understood to have the structure shown above. As used herein, "abiraterone decanoate" is to be understood as being in its base form unless expressly stated to be in a salt form or unless the context clearly indicates otherwise.

[0141] In some embodiments, the method is characterized in that administration of an abiraterone prodrug can selectively inhibit CYP17A1 lyase activity over CYP17A1 hydroxylase activity in a human subject. See, for example, any of the methods described in [3] and [4]-

[58] and

[0108] -

[0109] (as applicable) in the Summary section. As shown in Example 3 herein, the inventors unexpectedly found that intramuscular administration of abiraterone decanoate to a human subject achieved lyase selectivity not exhibited by oral abiraterone acetate (Zytiga® tablets) treatment. Serum steroid levels show that administration of abiraterone decanoate significantly reduced levels of androgens such as testosterone, but not steroids upstream of the hydroxylase, returning to baseline levels in about 4 weeks. See, for example, Figure 3E. As shown in FIG. 3E, even at the highest dose, progesterone levels returned to baseline in about 6 weeks, and progesterone levels did not increase significantly during the second cycle (i.e., after the second dose of abiraterone decanoate on day 84). Thus, the methods herein can be advantageously used to treat diseases or disorders in human subjects in which lyase selectivity is desired or deemed beneficial, such as endometrial cancer, endometriosis, ovarian cancer, and prostate cancer (such as localized prostate cancer). In some embodiments, the methods herein can be particularly useful for treating human subjects who suffer from or are susceptible to one or more side effects associated with hydroxylase inhibition, such as from oral treatment with abiraterone acetate. In some embodiments, the methods herein can be particularly useful for treating human subjects who are intolerant or sensitive to increased and / or decreased steroid levels due to hydroxylase inhibition, such as increased progesterone levels. In any of the embodiments described herein, the methods herein may also be particularly useful for treating human subjects who would benefit from selective inhibition of CYP17A1 lyase activity over CYP17A1 hydroxylase activity.For example, it has been demonstrated that progesterone acts as a carcinogenic hormone in prostate cancer, and thus elevated progesterone (e.g., plasma progesterone levels >3 nM) has also been shown to be associated with poor clinical outcomes. Hou et al. Cell Reports Medicine, 3: 100561 (2022). Also, patients who respond to abiraterone treatment (e.g., Zytiga) generally relapse within 1-2 years. Chen et al. have shown that one mechanism by which such resistance may develop may be related to elevated progesterone levels, which may lead to the selection and / or activation of tumor cells expressing certain mutant androgen receptors. See, e.g., Chen, EJ et al. Clin. Cancer. Res. 21(6): 1273-1280 (2014). Thus, prostate cancer patients who have elevated levels of progesterone and / or are susceptible to one or more side effects, such as mineralocorticoid toxicity or drug resistance, due to elevated levels of progesterone, such as after oral treatment with abiraterone acetate, may be beneficially treated using the methods herein. In some embodiments, the methods herein may be particularly useful for treating human subjects who have developed resistance to oral treatment with abiraterone acetate in combination with prednisone, including resistance due to elevated levels of progesterone. In some embodiments, the methods herein are for treating human subjects with prostate cancer, and the methods do not increase the levels of progesterone in the human subject to levels associated with poor clinical outcomes and drug resistance. In some embodiments, since the methods herein do not cause a significant increase in progesterone levels, in such patients, a separate drug for lowering the levels of progesterone is not necessary to control the side effect(s) and / or drug resistance associated with elevated levels of progesterone.

[0142] In some embodiments, the method herein is characterized in that it is for treating cancer in a human subject in need of such treatment, the cancer being 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

[0108] -

[0109] (as applicable) in the Overview section. In some embodiments, administering 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 eliminated the cancer that had metastasized to one or more lymph nodes. Without wishing to be bound by theory, it is believed that the observed efficacy in treating cancer that has metastasized to lymph nodes is due, in part, to delivery of the agent (e.g., a lipophilic prodrug such as abiraterone decanoate) to the lymphatic system, resulting in a high concentration of the active agent in 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 has metastasized to one or more lymph nodes can be prostate cancer (eg, those described herein).

[0143] In some embodiments, the method is for treating cancer in a human subject in need of such treatment, the cancer being a sex hormone dependent or androgen receptor driven cancer, and the human subject's disease has progressed during or after androgen receptor antagonist based treatment, such as enzalutamide based treatment. See, for example, any of the methods described in

[69] -

[71] and

[75] -

[92] and

[0108] -

[0109] (as applicable) in the Overview 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 and other results herein suggest that the abiraterone prodrugs herein, particularly abiraterone decanoate, may achieve synergistic effects when used in combination with an androgen receptor antagonist, such as enzalutamide.

[0144] In some embodiments, the method is for treating cancer in a human subject in need of such treatment, the cancer being a sex hormone dependent or androgen receptor driven cancer, and the human subject is further treated with an androgen receptor antagonist, such as enzalutamide, prior to, concurrently with, or after parenteral administration of the pharmaceutical composition. See, for example, any of the methods described in

[72] -

[74] and

[75] -

[92] and

[0108] -

[0109] (as applicable) in the Summary section. For example, in some embodiments, the androgen receptor antagonist, such as enzalutamide, is administered following the first parenteral administration of the pharmaceutical composition. In some embodiments, the androgen receptor antagonist, such as enzalutamide, is administered prior to the first parenteral administration of the pharmaceutical composition. Since androgen receptor antagonists such as enzalutamide (Xtandi) are typically administered orally with different dosing frequencies, the dosing regimen for parenteral administration and combined treatment of human subjects with such androgen receptor antagonist(s) is not particularly limited. For example, in some embodiments, the androgen receptor antagonist(s) can be administered to human subjects by oral administration (or another route of administration) in a dosing regimen typical of androgen receptor antagonist(s), for example, a dosing regimen approved by the U.S. Food and Drug Administration for each androgen receptor antagonist(s). For example, in some embodiments, the androgen receptor antagonist(s) is enzalutamide, and the 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 initiated at least one day prior to the first parenteral administration of the pharmaceutical composition. In some embodiments, enzalutamide treatment can be initiated on the same day as the first parenteral administration of the pharmaceutical composition. In some embodiments, enzalutamide treatment can be initiated at least one day after the first parenteral administration of the pharmaceutical composition.In some embodiments, the androgen receptor antagonist(s) can be administered to a human subject in combination with parenteral administration of the pharmaceutical composition to achieve a synergistic effect on cancer treatment.

[0145] Human subjects suitable for treatment with the methods herein are not particularly limited, including those with 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 detailed in PCT / US2022 / 016278, it has been found that administration of an abiraterone prodrug can sustainably reduce a subject's testosterone within days after the first administration of the prodrug, without the need for castration or another drug that is effective in lowering testosterone levels. However, in some embodiments, the human subject may be castrated. For example, in some embodiments, the human subject may be chemically castrated, such as by being treated with a gonadotropin releasing hormone agonist and / or antagonist. As used herein, the terms "castration," "castrate," and the like, should be understood to encompass all forms of castration, including surgical and chemical castration. In some embodiments, the methods herein may also administer a pharmaceutical composition comprising an abiraterone prodrug to a human subject, regardless of whether the human subject is castrated or not. In some embodiments, the human subject has not undergone a prostatectomy. In some embodiments, the human subject may be characterized as having liver damage, such as moderate to severe liver damage (Child-Pugh classification B or C), prior to administration of the abiraterone prodrug. In some embodiments, the human subject has prostate cancer, and the methods herein do not elevate the human subject's progesterone levels to levels associated with poor clinical outcomes and drug resistance, such as serum or plasma progesterone levels of 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 of greater than about 3 nM after 3 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 have risen above about 3 nM after three months of treatment, can be advantageously treated by switching to abiraterone acetate treatment using the methods described herein. In some embodiments, unless the context is inconsistent, a progesterone level of "3 nM" herein may refer to a plasma progesterone level. In some embodiments, unless the context is inconsistent, a progesterone level of "3 nM" herein may refer to a serum progesterone level. In some embodiments, the human subject may be characterized as being sensitive to or intolerant of gonadotropin releasing hormone antagonists and / or agonists. In some embodiments, the human subject may be characterized as being chemotherapy naive or hormone therapy naive before being administered the pharmaceutical composition herein. However, in some embodiments, the human subject may be treated with chemotherapy or hormone therapy before being administered the pharmaceutical composition herein. For example, in some embodiments, the human subject may have a disease or disorder (e.g., prostate cancer) that is progressing during or after chemotherapy and / or hormone therapy, such as a taxane-based chemotherapy regimen, e.g., docetaxel-based chemotherapy or cabazitaxel-based chemotherapy. In some embodiments, the human subject's disease is progressing during or after androgen receptor antagonist-based therapy, such as enzalutamide-based therapy. In some embodiments, the human subject's disease is progressing during or after oral abiraterone acetate-based therapy, such as oral abiraterone acetate and prednisone-based therapy. For example, in some embodiments, the human subject has developed resistance to abiraterone acetate combined with prednisone treatment, including resistance due to elevated levels of progesterone.As discussed above, human subjects suffering from or susceptible to one or more side effects associated with inhibition of CYP17A1 hydroxylase activity may also be advantageously treated with the methods herein that selectively inhibit lyase activity over hydroxylase activity. In some embodiments, the methods herein may also include identifying and / or selecting a human subject having any one or more of the characteristics described herein, and administering a pharmaceutical composition described herein to the human subject identified and / or selected as having one or more of the characteristics described herein, e.g., any of the characteristics described in [4]-

[17] ,

[31] -

[33] ,

[61] -

[62] ,

[64] ,

[65] ,

[69] ,

[79] -

[84] , and

[89] in the Summary section. In some embodiments, the methods herein may also include determining whether a human subject has any one or more of the characteristics described herein, and administering a pharmaceutical composition described herein to a human subject determined to have one or more of the characteristics described herein, e.g., any of the characteristics described in [4]-

[17] ,

[31] -

[33] ,

[61] -

[62] ,

[64] ,

[65] ,

[69] ,

[79] -

[84] , and

[89] in the Summary section.

[0146] In the methods herein, if the human subject is not castrated and / or does not wish to be castrated, another drug effective to reduce serum and / or gonadal testosterone levels is not administered to the human subject simultaneously with administration of the abiraterone prodrug, during treatment with the abiraterone prodrug, or in any other manner that would interfere with treatment with the abiraterone prodrug. For example, in some embodiments, the human subject is not being treated with a gonadal testosterone suppressant other than the abiraterone prodrug administered in an amount effective to reduce the serum testosterone level of the human subject. In some embodiments, the human subject is not being treated with a gonadotropin releasing hormone antagonist and / or agonist in an amount effective to reduce the serum testosterone level of the human subject. In some embodiments, the human subject is not being treated with any gonadal testosterone suppressant other than the abiraterone prodrug administered. In some embodiments, the human subject is not being treated with a gonadotropin releasing hormone antagonist and / or agonist. In some embodiments, the human subject has not been treated with a drug selected from buserelin, leuprolide, deslorelin, fertirelin, histyrelin, gonadorelin, lecirelin, goserelin, nafarelin, peforelin, and triptorelin. In some embodiments, the human subject has not been treated with a drug selected from abarelix, cetrorelix, degarelix, ganirelix, elagolix, linzagolixa, and relugolix. In some embodiments, the human subject may be sensitive to or intolerant to gonadotropin releasing hormone antagonists and / or agonists.

[0147] Various diseases or disorders are suitable for treatment with the methods described herein. For example, in some embodiments, the disease or disorder can be a sex hormone-dependent benign or malignant disorder, an androgen receptor-driven cancer, or a syndrome resulting from androgen excess. In some embodiments, the hormone-dependent benign or malignant disorder can be an androgen-dependent disorder or an estrogen-dependent disorder, such as an androgen- or estrogen-dependent cancer. In some embodiments, the sex hormone-dependent benign or malignant disorder can be prostate cancer or breast cancer. In some embodiments, the sex hormone-dependent benign or malignant disorder is CRPC or CSPC. In some embodiments, the sex hormone-dependent benign or malignant disorder can be metastatic CRPC or metastatic CSPC. In some embodiments, the sex hormone-dependent benign or malignant disorder can also be ovarian cancer, bladder cancer, hepatocellular carcinoma, or lung cancer. Various non-neoplastic syndromes resulting from androgen excess, such as endometriosis, polycystic ovary syndrome, classical or non-classical congenital adrenal hyperplasia, precocious puberty, and hirsutism, can also be treated with the methods herein.

[0148] In some specific embodiments, the methods herein are for treating polycystic ovary syndrome (PCOS), congenital adrenal hyperplasia (CAH), or endometriosis.

[0149] In some specific embodiments, the method herein is for treating sex hormone-dependent or androgen receptor-driven cancer.In some embodiments, the sex hormone-dependent or androgen receptor-driven cancer is metastasized to one or more lymph nodes, and administering the pharmaceutical composition is effective for inhibiting the growth of cancer in one or more lymph nodes.In some embodiments, the sex hormone-dependent or androgen receptor-driven cancer is prostate cancer that is metastasized to one or more lymph nodes, and administering the pharmaceutical composition is effective for inhibiting the growth of cancer in one or more lymph nodes.

[0150] In some embodiments, the sex hormone dependent or androgen receptor driven cancer can be androgen receptor positive salivary duct carcinoma, or androgen receptor positive glioblastoma multiforme.

[0151] In some specific embodiments, the methods herein are for treating prostate cancer, endometrial cancer, or ovarian cancer.

[0152] In some embodiments, the methods herein are for treating prostate cancer (eg, any of those described herein).

[0153] Suitable prostate cancers to be treated by the methods herein include, but are not limited to, any of the prostate cancers for which abiraterone or its derivatives (particularly abiraterone acetate) have been approved for sale (e.g., in the United States or Europe) or for which abiraterone or its derivatives (e.g., abiraterone acetate) are or have been in clinical trials (e.g., clinical trials registered on the website clinicaltrials.gov as of the filing date of this application).For example, in some embodiments, the prostate cancer can be primary / localized prostate cancer (newly diagnosed or early stage), advanced prostate cancer (e.g., after castration for recurrent prostate cancer, locally advanced prostate cancer, etc.), recurrent prostate cancer (e.g., prostate cancer that has not responded 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, the prostate cancer is localized prostate cancer, e.g., high-risk localized prostate cancer. In some embodiments, the human subject with prostate cancer is characterized by an elevated amount of prostate specific antigen, for example after radical prostatectomy. In some embodiments, the 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, the prostate cancer is newly diagnosed high-risk metastatic hormone-sensitive prostate cancer. In some embodiments, the prostate cancer is CRPC, and in some embodiments, the patient with CRPC is chemotherapy-naive. In some embodiments, the prostate cancer is metastatic CRPC (mCRPC), and in some embodiments, the patient with mCRPC is chemotherapy-naive. In some embodiments, the prostate cancer is metastatic CRPC (mCRPC), and the human subject is asymptomatic or mildly symptomatic after failure of androgen deprivation therapy, where chemotherapy is not yet clinically indicated. In some embodiments, the prostate cancer is metastatic CRPC (mCRPC) and the human subject's disease has progressed during or after a taxane-based chemotherapy regimen, such as a docetaxel- or cabazitaxel-based chemotherapy regimen.In some embodiments, the prostate cancer is refractory prostate cancer. As used herein, unless otherwise specified, the phrase "refractory prostate cancer" refers to prostate cancer that does not respond to anti-cancer treatment or does not respond adequately to anti-cancer treatment. Refractory prostate cancer can also include recurring or relapsing prostate cancer. As used herein, unless otherwise specified, the phrase "recurrent prostate cancer" refers to prostate cancer that once responded to anti-cancer treatment but no longer responds to such treatment or does not respond adequately to such treatment. As used herein, unless otherwise specified, the phrase "recurrent (or recurrent) prostate cancer" refers to prostate cancer that has recurred after a patient has previously been diagnosed with prostate cancer and treated, or has previously been diagnosed as cancer-free.

[0154] Prostate cancer can be characterized by a specific Gleason score. Typically, a pathologist looks at how cancer cells are arranged within the prostate and assigns a score on a scale of 3 to 5 from two different locations: an area where the cancer is most obvious and another area of ​​growth. Cancer cells that look similar to healthy cells are given a lower score. Cancer cells that don't look like healthy cells or that look more invasive are given a higher score. The scores from the two areas are added together for an overall score of 6 to 10.

[0155] The method herein is not particularly limited to prostate cancer having a particular Gleason score.For example, in some embodiments, prostate cancer may be characterized as having a Gleason score of 6 or less. In some embodiments, prostate cancer may be characterized as having a Gleason score of 7 or less. In some embodiments, prostate cancer may be characterized as having a Gleason score of 8 or less. In some embodiments, prostate cancer may be characterized as having a Gleason score of 9 or less. In some embodiments, prostate cancer may be characterized as having a Gleason score of 10 or less.

[0156] Prostate cancer may be characterized by a particular level of prostate specific antigen (PSA). For example, in combination with other indicators, a PSA level less than 10 ng / ml, a Gleason score ≦6, and a clinical stage ≦T2a may be considered a low risk of having prostate cancer or developing metastatic disease of prostate cancer, or dying from prostate cancer. A PSA level of 10-20 ng / ml, a Gleason score of 7, or a clinical stage of T2b / c may be considered a medium risk. A PSA level greater than 20 ng / ml, a Gleason score ≧8, or a clinical stage ≧T3 may be considered a high risk. Furthermore, in some cases, a patient with prostate cancer after a particular treatment may have an undetectable PSA for a period of time. In some cases, a subsequent rise in PSA levels above the nadir, such as ≧0.2 ng / ml, ≧2.0 ng / ml, etc., may indicate recurrent prostate cancer. The methods herein are not particularly limited to treating a human subject with any particular level of PSA. In some embodiments, a human subject may be characterized as having an increase in PSA relative to nadir of 2.0 ng / ml or greater.

[0157] In some embodiments, the methods herein are for treating newly diagnosed high-risk metastatic hormone-sensitive prostate cancer.

[0158] In some embodiments, the methods herein can also be used to treat breast cancer.The breast cancer suitable for treatment by 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.

[0159] In some embodiments, diseases or disorders associated with 21-hydroxylase deficiency may also be treated using the methods herein.

[0160] In some embodiments, the methods herein can be used to treat a human subject having cancer, e.g., prostate cancer, breast cancer, adrenal cancer, leukemia, lymphoma, myeloma, Waldenstrom's macroglobulinemia, monoclonal gammopathy, benign monoclonal gammopathy, heavy chain disease, bone and connective tissue sarcoma, brain cancer, 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, penal cancer, oral cancer, skin cancer, kidney cancer, Werm's tumor, and / or bladder cancer.

[0161] 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 subjected to surgery. In some embodiments, the methods are for treating prostate cancer and include combination therapy, which further includes administering to the human subject one or more additional therapies, for example, as described herein below under the section entitled Combination Treatments for Prostate Cancer. Non-limiting examples of useful additional therapies also include any of those described in the Summary section of this specification at

[37] -

[49] .

[0162] In some embodiments according to the methods herein, abiraterone prodrugs, particularly abiraterone decanoate, are administered to a human subject in combination with dexamethasone. For example, in any of the methods described herein, unless otherwise specified or contrary to context, the method may include administering abiraterone decanoate and dexamethasone to a human subject. In some embodiments, the method is for treating prostate cancer, e.g., for treating a human subject who is a chemotherapy-naive CRPC patient, including chemotherapy-naive mCRPC patients. In some embodiments, the method may include administering to the human subject (i) intramuscularly, preferably about 1260 mg of abiraterone decanoate once every 1-3 months, once every 3 months, and (ii) dexamethasone orally once daily. In some embodiments, dexamethasone is administered orally to the human subject at a dose of about 0.1-1 mg / day, such as about 0.5 mg / day. Additional therapies may also be used in combination with the abiraterone decanoate and dexamethasone treatment, including, but not limited to, any of such other therapies described herein, such as any of the applicable therapies described in the Summary section of this specification at

[37] -

[49] .

[0163] It is believed that the combination treatment of dexamethasone and abiraterone prodrug (preferably abiraterone decanoate) is advantageous compared to the combination with another glucocorticoid, such as prednisone or prednisolone.In the context of oral abiraterone acetate, it has been shown that dexamethasone can be advantageously used to provide better control of upstream steroid levels, better control of ACTH levels, better efficacy in treating prostate cancer, better and more durable PSA response and progression-free survival (PFS), reduced agonist activity of glucocorticoid receptor (which is a resistance mechanism to abiraterone acetate and prednisone treatment), and longer half-life, etc.Without being bound by theory, it is believed that the longer half-life is one of the reasons why dexamethasone is a suitable glucocorticoid for combination with the long-acting abiraterone prodrug herein, particularly abiraterone decanoate. Furthermore, it has been shown that in patients who have progressed on abiraterone acetate and prednisone treatment, switching the glucocorticoid partner of abiraterone acetate from prednisone to dexamethasone can lead to the elimination of clinical resistance in prostate cancer.See, for example, 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).

[0164] In some embodiments according to the methods herein, glucocorticoid replacement therapy (e.g., administering a glucocorticoid such as hydrocortisone, prednisone, prednisolone, methylprednisolone, or dexamethasone) is undesirable. For example, glucocorticoids may be contraindicated in human subjects who may have an underlying disease such as diabetes. In some embodiments, the methods may also be characterized in that the human subject is not treated with glucocorticoid replacement therapy. In some embodiments, the human subject is not treated with an agent selected from hydrocortisone, prednisone, prednisolone, methylprednisolone, and dexamethasone. In some embodiments, the methods herein may include administering to the human subject a mineralocorticoid receptor antagonist such as eplerenone. For example, in any of the embodiments herein, if glucocorticoid replacement therapy is not desired and / or is not administered, the method may include administering to the human subject a mineralocorticoid receptor antagonist, such as eplerenone.

[0165] In some embodiments according to the methods herein, no drug is required to treat mineralocorticoid toxicity and is not administered to the human subject. As discussed herein, in some embodiments, administration of an abiraterone prodrug, such as intramuscular administration of abiraterone decanoate to a human subject, can achieve lyase selectivity and does not cause a significant increase in mineralocorticoid levels and / or does not cause toxicity due to mineralocorticoid excess. Thus, in some embodiments, the human subject is not treated with a drug that is effective in treating mineralocorticoid toxicity. In particular, in some embodiments, the human subject is not treated with a drug that is a glucocorticoid or a mineralocorticoid receptor antagonist.

[0166] Pharmaceutical compositions and abiraterone prodrugs suitable for the methods herein include, but are not limited to, any of the abiraterone decanoate formulations described herein, such as any of those described in the Summary section of the present specification, such as

[18] to

[30] or

[93] to

[0107] in the Summary section of the present specification, any of those described in the Examples section, and any of the abiraterone prodrugs and abiraterone prodrug formulations described in U.S. Patent No. 10,792,292(B2), and PCT Application Nos. PCT / US2021 / 048607 and PCT / US2022 / 016278. Typically, pharmaceutical compositions suitable for the methods herein are long-acting parenteral formulations comprising an abiraterone prodrug. In some embodiments, the long-acting parenteral formulations may be formulated to deliver therapeutically effective plasma levels of abiraterone to a human subject for an extended period of time (e.g., at least 1 week, e.g., at least 2 weeks, at least 3 weeks, at least 4 weeks, and up to 6 or 8 weeks or more) following a single administration. In some embodiments, the therapeutically effective plasma concentration of abiraterone may be at a concentration of at least 1 ng / ml, e.g., 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 may be about 0.5 ng / ml or greater. In some embodiments, the therapeutically effective plasma concentration of abiraterone may be about 0.1 ng / ml or greater. In some embodiments, the pharmaceutical composition may be formulated to be administered to a human subject and provide (a) a plasma concentration of abiraterone of greater than 0.5 ng / ml for a period of at least two weeks following a single dose, or (b) a single dose or steady-state C of abiraterone of about 1 ng / ml to about 300 ng / ml, e.g., about 1 ng / ml to about 10 ng / ml. max or (c) both (a) and (b), as described herein.

[0167] The route of administration and dosing regimen for the methods herein are also not particularly limited and include any of those described herein. Typically, the pharmaceutical composition can be administered to the human subject via intramuscular, intradermal, or subcutaneous injection. For example, in some specific embodiments, the pharmaceutical composition is administered to the human subject via intramuscular injection. Parenteral administration herein can be advantageous in some embodiments. For example, in some embodiments, parenteral administration can be performed regardless of whether the human subject has food, and thus, in some embodiments, the abiraterone prodrug or abiraterone prodrug formulation of the present disclosure can be administered to the human subject with or without food. In other words, the fed or fasted state of the human subject is not important. This eliminates the restriction associated with the currently marketed Zytiga® formulation that the drug "must be taken on an empty stomach with water, at least 1 hour before or 2 hours after a meal." Thus, the methods herein can improve patient compliance, among other advantages.

[0168] Dosages and frequencies for the methods herein are also not particularly limited and include any of those described herein. Generally, the pharmaceutical composition is administered to a human subject once a week or more than once a week. For example, in some embodiments, the methods herein include administering an abiraterone prodrug or abiraterone prodrug formulation herein at a dosing frequency ranging from once a week to once every several months. In some embodiments, the pharmaceutical composition is administered to a human subject once a month or more than once a month, for example, once every two months or once every three months.

[0169] In some specific embodiments, the methods herein may include administering an abiraterone prodrug or abiraterone prodrug formulation herein at a dosing frequency ranging from once a month to once every few months, e.g., once a month, once every two months, once every three months, or less frequently. The dosage of the abiraterone prodrug herein (e.g., abiraterone decanoate) for each administration may typically range from 0.5 mg / kg to 200 mg / kg of body weight of a human subject, e.g., 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). In some embodiments, the administering provides any of the pharmacokinetic profiles described herein, e.g., (a) a plasma concentration of abiraterone greater than 0.5 ng / ml for a period of at least 2 weeks (e.g., up to 10 weeks or more) from a single dose, (b) a single dose or steady-state C of abiraterone of about 1 ng / ml to about 300 ng / ml, e.g., about 1 ng / ml to about 10 ng / ml. max In some embodiments, the administering may also provide a concentration of abiraterone in a tissue of the human subject that is at least 10-fold higher than the plasma concentration of abiraterone 7 days after administration (i.e., 168 hours from the time of administration), the tissue being selected from liver, lung, testis, inguinal lymph node, iliac lymph node, adrenal gland, and prostate.

[0170] Typically, the amount of abiraterone prodrug (e.g., abiraterone decanoate) administered can be adjusted to be effective to achieve a sustained reduction in serum testosterone levels in the human subject to 50% or less below baseline, e.g., about 60% or less below baseline, about 70% or less below baseline, about 80% or less below baseline, or about 90% below baseline, about 95% or less below baseline, within 15 days of 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 levels in the human subject fall to 50% or less below baseline, the serum testosterone levels remain at 50% or less below 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 amount effective to reduce serum testosterone levels in the human subject to 80% or less below baseline, as 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 amount effective to reduce the serum testosterone level of a human subject to 85% or less below 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 amount effective to reduce the serum testosterone level of a human subject to 90% or less below 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 amount effective to reduce serum testosterone levels, when measured 24 weeks after the first administration of the abiraterone prodrug, 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.) if the human subject is a non-castrated human subject, or to about 1 ng / dL or less if the human subject is a castrated human subject.As exemplified herein, abiraterone prodrugs (e.g., abiraterone decanoate) can be administered to a human subject without significantly increasing mineralocorticoid levels, with any such increase returning to baseline levels within 4-6 weeks after the first administration of the abiraterone prodrug. In some preferred embodiments, administration of an abiraterone prodrug (e.g., abiraterone decanoate) does not increase serum progesterone levels in a human subject by more than 40% above baseline 4 weeks after the first administration of the abiraterone prodrug. In some embodiments, administration of an abiraterone prodrug (e.g., abiraterone decanoate) does not increase serum progesterone levels in a human subject by more than 40% above baseline 2-12 weeks after the second administration of the abiraterone prodrug. In some embodiments, administration of the pharmaceutical composition does not elevate serum progesterone levels in a 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 abiraterone prodrug.

[0171] In some embodiments, particularly in the methods of treating prostate cancer herein, the dosage and frequency of administration of the abiraterone prodrug herein (e.g., abiraterone decanoate) can be adjusted such that administration provides an amount of abiraterone 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.) in a non-castrated human subject, or to about 1 ng / dL or less in a castrated human subject (e.g., a human subject chemically castrated with a GnRH agonist and / or antagonist), within 15 days (e.g., within 7 days, 7-15 days, etc.) of the first administration of the abiraterone prodrug. For example, in some embodiments, administering provides an amount of abiraterone 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.) in a non-castrated human subject, or to about 1 ng / dL or less in a castrated human subject, when measured 15 days after the first administration of an abiraterone prodrug. In some embodiments, administering provides an amount of abiraterone effective to achieve a sustained reduction in serum testosterone levels, such as achieving and maintaining serum testosterone levels 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.) in a non-castrated human subject, or about 1 ng / dL or less in a castrated human subject, within 15 days (e.g., within 7 days, 7-15 days, etc.) of the first administration of the abiraterone prodrug. In some embodiments, the dosage and frequency of the abiraterone prodrug herein (e.g., abiraterone decanoate) can be adjusted such that administering provides an amount of abiraterone effective to reduce serum testosterone levels by 50% or more, preferably 75% or more, from baseline within 15 days (e.g., within 7 days, 7-15 days, etc.) of the first administration of the abiraterone prodrug.For example, in some embodiments, administering provides an effective amount of abiraterone to reduce serum testosterone levels by 50% or more, preferably 75% or more, from baseline when measured 15 days after the first administration of an abiraterone prodrug. In some embodiments, administering provides an effective amount of abiraterone to achieve a sustained reduction in serum testosterone levels from baseline of 50% or more, 75% or more, etc., within 15 days (e.g., within 7 days, 7-15 days, etc.) of the first administration of an abiraterone prodrug. For clarity, the phrase "sustained reduction in serum testosterone levels" should be understood to refer to serum testosterone levels remaining at a reduced level, such as about 50 ng / dL or less in a non-castrated human subject, or about 1 ng / dL or less in a castrated human subject, or 50% or less compared to baseline, for a sustained period of time (which may be 1 day or more, 3 days or more, 7 days or more, and up to a month, or several months). As exemplified herein, serum testosterone levels can be reduced in a dose-dependent manner over an extended period of time.

[0172] In some embodiments, the method herein may be characterized in that the administration of the pharmaceutical composition reduces the level of prostate specific antigen in human subjects.For example, in some preferred embodiments, the level of prostate specific antigen can be reduced to 50% or less, preferably 90% or less, compared to baseline PSA level at at least one time point after the first administration of the pharmaceutical composition and / or after one or more subsequent administrations of the pharmaceutical composition.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 the treatment period.

[0173] In some embodiments, the methods herein may be characterized by achieving any one or more of the following outcomes: (a) objective response rate based on RECIST v1.1 (minimum time for confirmation of CR and PR is 4 weeks); (b) PSA decline of 50% or more from baseline confirmed by a second consecutive PSA assessment at least 3 weeks later; (c) conversion of circulating tumor cell counts (CTCs) to a blood nadir of less than 5 cells / 7.5 mL (for subjects with CTC counts ≥ 5 cells / 7.5 mL at baseline) confirmed by an additional assessment at least 3 weeks later; and (4) progression-free survival (rPFS) by imaging. In some embodiments, the methods herein may be characterized by achieving any one or more of the following outcomes that are better than corresponding treatment with oral Zytiga® tablets: (1) overall survival, defined as the time from first administration of study drug to date of death from any cause; (2) best overall response (BOR) based on RECIST v1.1, defined as the best radiological response among responses at all time points; (3) DOR (defined as the length of time from the date of first documented confirmed response) to date of documented progression or death from any cause using CTC and / or PSA and / or RECIST v1.1 and PCWG3.

[0174] In any of the embodiments herein, unless otherwise specified or clearly contradicted by context, the methods herein may include administering abiraterone decanoate intramuscularly to a human subject at a dosing frequency of once every 1 to 3 months, e.g., once every 3 months, where each administration comprises administering to the human subject about 50 mg to about 2000 mg of abiraterone decanoate, e.g., about 180 mg, about 360 mg, about 720 mg, about 1260 mg, about 1800 mg, or any range between the recited values. In some preferred embodiments, the methods herein may include administering abiraterone decanoate intramuscularly to a human subject at a dosing frequency of once every 3 months, where each administration comprises administering to the human subject about 1260 mg of abiraterone decanoate. In some preferred embodiments, the methods herein may comprise administering abiraterone decanoate intramuscularly to a human subject at a dosing frequency of once every three months, each administration comprising administering about 1260 mg of abiraterone decanoate to the human subject, and administering dexamethasone orally to the human subject at a daily dose of about 0.5 mg / day.

[0175] How to Lower Steroid Hormone Levels Some embodiments of the present disclosure relate to methods for lowering serum steroid hormone levels in a human subject in need thereof, in particular, methods for lowering serum steroid hormone levels by selectively inhibiting CYP17A1 lyase activity over hydroxylase activity.

[0176] In some embodiments, the disclosure provides a method of lowering 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 of baseline within 15 days of the initial administration of the pharmaceutical composition, and wherein the administration of the pharmaceutical composition comprises: (i) a sustained reduction in serum testosterone levels in the human subject to 50% or less of baseline within 15 days of the initial administration of the pharmaceutical composition; and / or (ii) does not elevate serum progesterone levels in a human subject by more than 40% above baseline 2 to 12 weeks after a second administration of the pharmaceutical composition, and preferably does not elevate serum progesterone levels in a human subject by more than (i) 20% above baseline 4 weeks after a first administration of the pharmaceutical composition, (ii) 20% above baseline 6, 8, 10, and / or 12 weeks after a first administration of the pharmaceutical composition, and / or (iii) 20% above baseline 2 to 12 weeks after a second administration of the pharmaceutical composition. Typically, the amount of abiraterone prodrug (e.g., abiraterone decanoate) administered can be adjusted to be effective to achieve a sustained reduction in serum testosterone levels in the human subject of 50% or less below baseline, e.g., about 60% or less below baseline, about 70% or less below baseline, about 80% or less below baseline, or about 90% below baseline, about 95% or less below baseline, within 15 days of the first administration of the pharmaceutical composition. In some embodiments, a sustained reduction in serum testosterone levels is characterized in that once the human subject's serum testosterone levels fall to 50% or less below baseline, the serum testosterone levels remain at 50% or less below 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 amount effective to reduce the serum testosterone level of a human subject to 80% or less below baseline, e.g., 85% or less below baseline, or 90% or less below 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 amount effective to reduce the serum testosterone level of a 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, when measured 24 weeks after the first administration of the abiraterone prodrug.

[0177] In some specific embodiments, the disclosure provides a method of lowering 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 administration of the pharmaceutical composition does not elevate serum progesterone levels in the human subject by (i) more than 40% above baseline from a first administration of the pharmaceutical composition, and / or (ii) more than 40% above baseline 2 to 12 weeks after a second administration of the pharmaceutical composition, and preferably does not elevate serum progesterone levels in the human subject by (i) more than 20% above baseline 4 weeks after a first administration of the pharmaceutical composition, (ii) more than 20% above baseline 6, 8, 10, and / or 12 weeks after a first administration of the pharmaceutical composition, and / or (iii) more than 20% above baseline 2 to 12 weeks after a second administration of the pharmaceutical composition. Typically, particularly where the human subject is characterized as having prostate cancer, administering provides an effective amount of abiraterone 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.) in a non-castrated human subject, or about 1 ng / dL or less in a castrated human subject, within 15 days (e.g., within 7 days, 7-15 days, etc.) of the first administration of the abiraterone prodrug. For example, in some embodiments, the administering provides an effective amount of abiraterone 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.) in a non-castrated human subject, or to about 1 ng / dL or less in a castrated human subject, when measured 15 days after the first administration of an abiraterone prodrug.In some embodiments, the administering provides an amount of abiraterone effective to achieve a sustained reduction in serum testosterone levels, such as achieving and maintaining a serum testosterone level of 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 about 1 ng / dL or less in a castrated human subject, within 15 days (e.g., within 7 days, 7-15 days, etc.) of the first administration of the abiraterone prodrug. Typically, the administering provides an amount of abiraterone effective to reduce serum testosterone levels from baseline by 50% or more, preferably 75% or more, within 15 days (e.g., within 7 days, 7-15 days, etc.) of the first administration of the abiraterone prodrug. For example, in some embodiments, the administering provides an effective amount of abiraterone to reduce serum testosterone levels by 50% or more, preferably 75% or more, from baseline when measured 15 days after the first administration of the abiraterone prodrug. In some embodiments, the administering provides an effective amount of abiraterone to achieve a sustained reduction in serum testosterone levels from baseline by 50% or more, such as 75% or more, within 15 days (e.g., within 7 days, 7-15 days, etc.) of the first administration of the abiraterone prodrug. In some embodiments, the sustained reduction in serum testosterone levels is characterized in that once the human subject's serum testosterone levels fall below 50% below baseline, the serum testosterone levels remain below 50% of baseline for up to 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 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 about 1 ng / dL or less in a castrated human subject, the serum testosterone level remains about 50 ng / dL or less in a non-castrated human subject, or about 1 ng / dL or less in a castrated human subject, for up to 8 weeks or more after the initial administration of the pharmaceutical composition.

[0178] Human subjects suitable for treatment with the methods herein for reducing serum testosterone levels include, but are not limited to, any of those described herein. In some embodiments, the human subject may be a non-castrated human subject. In some embodiments, the human subject may be castrated. For example, in some embodiments, the human subject may be chemically castrated, such as treated with a gonadotropin releasing hormone agonist and / or antagonist. In some embodiments, the human subject may be characterized as suffering from liver damage, such as moderate to severe liver damage (Child-Pugh classification B or C), prior to administration of the abiraterone prodrug. In some embodiments, the human subject has prostate cancer, and the methods herein do not elevate the human subject's progesterone levels to levels associated with poor clinical outcomes and drug resistance, such as serum or plasma progesterone levels of greater than about 3 nM, as 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 by having a serum or plasma progesterone level of greater than about 3 nM after 3 months of abiraterone treatment, such as Zytiga (oral abiraterone acetate and prednisone) treatment, prior to the first administration of the pharmaceutical composition herein. In some embodiments, the human subject may be characterized as being sensitive to or intolerant of gonadotropin releasing hormone antagonists and / or agonists. In some embodiments, the human subject may be characterized as being chemotherapy naive or hormone therapy naive prior to administration of the pharmaceutical composition herein. However, in some embodiments, the human subject may be treated with chemotherapy or hormone therapy prior to administration of the pharmaceutical composition herein. For example, in some embodiments, the human subject may have a disease or disorder (e.g., prostate cancer) that is progressing during or after chemotherapy and / or hormone therapy, such as a taxane-based chemotherapy regimen, e.g., docetaxel-based chemotherapy or cabazitaxel-based chemotherapy.In some embodiments, the disease in the human subject progresses during or after androgen receptor antagonist-based therapy, such as enzalutamide-based therapy. In some embodiments, the disease in the human subject progresses during or after oral abiraterone acetate-based therapy, such as oral abiraterone acetate and prednisone-based therapy. For example, in some embodiments, the human subject has developed resistance to abiraterone acetate in combination with prednisone therapy, including resistance due to elevated levels of progesterone. As discussed above, human subjects suffering from or susceptible to one or more side effects associated with inhibition of CYP17A1 hydroxylase activity may also be advantageously treated with the methods herein that selectively inhibit lyase activity over hydroxylase activity.

[0179] A human subject in need of testosterone reduction typically suffers from one or more diseases or disorders mediated or associated with androgens. For example, in some embodiments, the human subject suffers from a sex hormone-dependent or androgen receptor-driven disease or disorder, such as a sex hormone-dependent benign or malignant disorder, or a syndrome resulting from androgen excess. Suitable diseases or disorders include any of those described herein, such as any of those described in the Overview section [4]-

[17] . In some embodiments, the human subject is characterized as having a sex hormone-dependent cancer or an androgen receptor-driven cancer, such as any of those described herein. In some embodiments, the sex hormone-dependent or androgen receptor-driven cancer has metastasized to one or more lymph nodes. In some embodiments, administering the pharmaceutical composition is effective to inhibit the growth of the cancer in one or more lymph nodes. In some embodiments, the human subject is characterized as having androgen receptor-positive salivary duct cancer, or androgen receptor-positive glioblastoma multiforme. In some embodiments, the human subject is characterized as having prostate cancer (e.g., any of those described herein). For example, in some embodiments, the prostate cancer may be primary / localized prostate cancer (newly diagnosed or early stage), advanced prostate cancer (e.g., locally advanced prostate cancer after castration for recurrent prostate cancer, etc.), recurrent prostate cancer (e.g., prostate cancer that has not responded 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, the prostate cancer is CRPC, and in some embodiments, the patient with CRPC is chemotherapy-naive. In some embodiments, the prostate cancer is metastatic CRPC (mCRPC), and in some embodiments, the patient with mCRPC is chemotherapy-naive. In some embodiments, the human subject suffers from endometrial or ovarian cancer. In some embodiments, the human subject suffers from polycystic ovary syndrome (PCOS), congenital adrenal hyperplasia (CAH), or endometriosis.In some embodiments, the human subject has newly diagnosed high-risk metastatic hormone-sensitive prostate cancer. In some embodiments, the human subject has not undergone a prostatectomy. In some embodiments, the human subject is further treated with radiation therapy.

[0180] Pharmaceutical compositions and abiraterone prodrugs suitable for the methods herein for reducing serum testosterone levels include, but are not limited to, any of the abiraterone decanoate formulations described herein, such as any of those described in the Summary section of the present specification, such as

[18] -

[30] or

[93] -

[0107] of the Summary section of the present specification, any of those described in the Examples section, and any of the abiraterone prodrugs and abiraterone prodrug formulations described in U.S. Patent No. 10,792,292(B2), and PCT Application Nos. PCT / US2021 / 048607 and PCT / US2022 / 016278. Typically, the pharmaceutical composition is a long-acting parenteral formulation comprising an abiraterone prodrug. In some embodiments, the long-acting parenteral formulation can be formulated to deliver effective plasma levels of abiraterone for an extended period of time (e.g., at least 1 week, e.g., at least 2 weeks, at least 3 weeks, at least 4 weeks, and up to 6 or 8 weeks or more) after a single administration, and reduce serum testosterone levels in a human subject (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 by 50% or more compared to baseline). In some embodiments, the effective plasma concentration of abiraterone can be at a concentration of at least 1 ng / ml, e.g., 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 be about 0.5 ng / ml or more. In some embodiments, the effective plasma concentration of abiraterone can be about 0.1 ng / ml or more. In some embodiments, the pharmaceutical composition may be formulated to be administered to a human subject and provide (a) a plasma concentration of abiraterone of greater than 0.5 ng / ml for a period of at least two weeks following a single dose, or (b) a single dose or steady-state C of abiraterone of about 1 ng / ml to about 300 ng / ml, e.g., about 1 ng / ml to about 10 ng / ml. max or (c) provide both (a) and (b).

[0181] The route of administration and the administration regimen for the method of the present invention for reducing serum testosterone level are also not particularly limited and include any of those described herein. Typically, the pharmaceutical composition can be administered to the human subject via intramuscular injection, intradermal injection, or subcutaneous injection. For example, in some specific embodiments, the pharmaceutical composition is administered to the human subject via intramuscular injection. Generally, the pharmaceutical composition is administered to the human subject once a week or more than once a week. For example, in some embodiments, the pharmaceutical composition is administered to the human subject once a month or more than once a month, for example, once every two months or once every three months.

[0182] In some embodiments, the disclosure provides a method of reducing androgen and / or estrogen levels in a human subject in need of reduced androgen (e.g., testosterone and / or dihydrotestosterone) and / or estrogen levels, the method comprising administering to the human subject any of the abiraterone prodrugs or abiraterone prodrug formulations of the disclosure. In some embodiments, the human subject suffers from an androgen receptor-driven cancer. In some embodiments, the human subject suffers from a syndrome resulting from androgen excess, such as congenital adrenal hyperplasia (e.g., classical or non-classical congenital adrenal hyperplasia), endometriosis, polycystic ovary syndrome, precocious puberty, hirsutism, etc. In some embodiments, the human subject suffers from an androgen and / or estrogen-related cancer, such as prostate cancer or breast cancer. In some embodiments, the human subject suffers from a sex hormone-dependent cancer as described herein. Pharmaceutical compositions, subjects, dosing regimens, and routes of administration suitable for the methods include any described herein in any combination, such as any described in connection with the methods set forth in the Summary section of this specification.

[0183] Abiraterone Prodrugs and Formulations Various abiraterone prodrugs and abiraterone prodrug formulations are also provided herein and may be used in the methods herein. For example, in some embodiments, the abiraterone drug may be an abiraterone lipophilic ester, such as acetate, propionate, butanoate, (vaterate) pentanoate, isocaproate, bucyclate, cyclohexanecarboxylate, phenylpropionate, caproate (hexanoate), enanthate (heptanoate), cypionate, octanoate, nonanoate, decanoate, undecanoate, dodecanoate, tridecanoate, tetradecanoate, pentadecanoate, or hexadecanoate. Other suitable abiraterone prodrugs include any of those described in U.S. Patent No. 10,792,292(B2), and PCT Application Nos. PCT / US2021 / 048607 and PCT / US2022 / 016278, the contents of each of which are incorporated herein by reference in their entirety. Any of the abiraterone decanoate formulations described in U.S. Provisional Patent Application No. 63,425,839 can be used in the methods herein.

[0184] In any of the embodiments described herein, unless otherwise stated or contrary to context, the abiraterone prodrug may be abiraterone decanoate, or a pharma- ceutically acceptable salt thereof. [ka]

[0185] Typically, pharmaceutical compositions comprising an abiraterone prodrug (or alternatively referred to herein as abiraterone prodrug formulations) are formulated for parenteral administration. For example, in some embodiments, the pharmaceutical compositions may be formulated for intramuscular, intradermal, or subcutaneous injection.

[0186] In some embodiments, the pharmaceutical composition comprises an abiraterone decanoate solution comprising abiraterone decanoate dissolved in a pharma- ceutically acceptable carrier and a pharma- ceutically acceptable antioxidant. For purposes herein, a liquid mixture of abiraterone decanoate, a pharma- ceutically acceptable carrier, a pharma- ceutically acceptable antioxidant, and optionally other components, can be characterized as an abiraterone decanoate solution when the amount of abiraterone decanoate in the liquid mixture is less than the saturation point (i.e., the maximum solubility of abiraterone decanoate) in the pharma- ceutically acceptable carrier at 25° C., taking into account any effects on the solubility of abiraterone decanoate in the pharma- ceutically acceptable carrier caused by the antioxidant and any other components.

[0187] The pharmaceutical composition is generally a non-aqueous formulation, e.g., an oil-based formulation, and includes a non-aqueous pharma- ceutically acceptable carrier (e.g., as described herein). The pharmaceutical composition typically includes an abiraterone prodrug and a pharma- ceutically acceptable carrier. The pharma- ceutically acceptable carrier is not particularly limited. For example, in some embodiments, the pharma- ceutically acceptable carrier includes a pharma- ceutically acceptable injectable oil, e.g., an oil derived from a plant or a synthetic mono- or diglyceride of a fatty acid. In some embodiments, the pharma- ceutically acceptable oil can be a natural oil, a synthetic oil, or a semi-synthetic oil, e.g., fractionated coconut oil and medium-chain triglycerides (such as those sold under the trademark Miglyol). In some embodiments, the pharma- ceutical acceptable carrier includes a triglyceride derived from a fatty acid. In some embodiments, the pharma- ceutical acceptable carrier includes a triglyceride derived from a long-chain fatty acid and / or a medium-chain fatty acid, which can be, independently, polyunsaturated, monounsaturated, or saturated. As will be appreciated by those skilled in the art, medium chain fatty acids typically contain 6-12 carbons, such as caproic acid, caprylic acid, capric acid, lauric acid, etc., and short chain fatty acids typically have less than 6 carbons, while long chain fatty acids typically contain 13-21 carbons. In some embodiments, the pharmaceutically acceptable carrier comprises a pharmaceutically acceptable oil, which may be selected from vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea oil, and soybean oil. In some particular embodiments, the pharmaceutically acceptable carrier comprises corn oil, which contains triglycerides in which the fatty acid components are primarily linoleic acid, oleic acid, palmitic acid, and stearic acid.

[0188] In some embodiments, in addition to a pharma- ceutically acceptable oil, the pharma- ceutically acceptable carrier may further include a pharma- ceutically acceptable solvent (or co-solvent if the oil is considered a solvent), such as an alcohol, ester, acid, etc. In some embodiments, the pharma- ceutically acceptable solvent may include benzyl alcohol, benzyl benzoate, ethanol, glycerol, polyethylene glycol, polysorbate 80, acetic acid, and / or ethyl acetate. In some embodiments, the pharma- ceutically acceptable solvent may be benzyl alcohol and / or benzyl benzoate. In some embodiments, the pharma- ceutically acceptable solvent may be benzyl alcohol. In some embodiments, the pharma- ceutically acceptable solvent may be a combination of benzyl alcohol and benzyl benzoate. The solubility of an abiraterone prodrug, such as abiraterone decanoate, in a pharma- ceutically acceptable oil may be significantly enhanced by the combination of benzyl alcohol and benzyl benzoate.

[0189] In some embodiments, the pharma- ceutically acceptable carrier may include a pharma- ceutically acceptable oil and an additional pharma- ceutically acceptable solvent, the pharma-ceutically acceptable oil being selected from vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy oil, tea oil, and soybean oil, and the additional pharma-ceutically acceptable solvent includes benzyl alcohol, benzyl benzoate, or a combination thereof. In some embodiments, the pharma-ceutically acceptable carrier includes corn oil, benzyl alcohol, and benzyl benzoate. In some embodiments, when the combined volume of benzyl alcohol, benzyl benzoate, and corn oil is taken as 100%, benzyl alcohol is present in an amount of about 5-10% by volume, benzyl benzoate is present in an amount of about 10-20% by volume, and corn oil is present in an amount of about 70-85% by volume.

[0190] Pharmaceutically acceptable antioxidants suitable for the pharmaceutical compositions herein are not particularly limited. For example, in some embodiments, the pharmaceutical compositions herein include [ka] The pharmaceutical compositions herein may include a thio-containing antioxidant such as 3-mercapto-1,2-propanediol, also known as monothioglycerol, which has the chemical structure: In some embodiments, the pharmaceutical compositions herein may include a tocopherol-type antioxidant such as α-tocopherol. Exemplary Formulations Comprising Abiraterone Decanoate

[0191] In some particular embodiments, the pharmaceutical composition comprises abiraterone decanoate having the formula: [ka] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Abiraterone decanoate is typically present in the pharmaceutical composition in its basic form, and should be understood as such unless the context clearly indicates otherwise. In some embodiments, abiraterone decanoate may also be in a substantially pure form as described herein. For example, the pharmaceutical composition can be prepared from mixing substantially pure abiraterone decanoate with a pharmaceutically acceptable carrier and any other ingredients. In some particular embodiments, the substantially pure abiraterone decanoate is in a crystalline form as described herein, preferably crystalline form A, and the pharmaceutical composition can be prepared by mixing (e.g., dissolving, suspending, or otherwise forming a mixture) the crystalline form (e.g., form A) with a pharmaceutically acceptable carrier and any other ingredients.

[0192] In some specific embodiments, the pharmaceutical composition comprises (1) abiraterone decanoate, (2) a pharma- ceutically acceptable oil (e.g., as described herein), (3) a pharma- ceutically acceptable solvent (e.g., as described herein), and (4) 3-mercapto-1,2-propanediol.

[0193] In some specific embodiments, the pharmaceutical composition comprises (1) abiraterone decanoate, (2) benzyl alcohol, (3) benzyl benzoate, (4) corn oil, and (5) 3-mercapto-1,2-propanediol.

[0194] Abiraterone decanoate is typically prepared in a highly pure form suitable for, for example, pharmaceutical use. In some embodiments, the present disclosure provides abiraterone decanoate in a substantially pure form, such as having a purity of 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%) by weight, HPLC area, or both. In some embodiments, abiraterone decanoate can be characterized by a weight purity and / or an HPLC area purity of about 95%, about 97%, about 99%, about 99.5%, about 99.9%, or any range between the specified values. For example, in some embodiments, abiraterone decanoate can be characterized by a weight purity of about 95%, about 97%, about 99%, about 99.5%, about 99.9%, or any range between the specified values. In some embodiments, abiraterone decanoate can also be characterized as having a low palladium content, such as less than 150 ppm, less than 100 ppm, less than 50 ppm, or less than 10 ppm. In some embodiments, abiraterone decanoate meets the specifications set forth in Table D herein (see Example 1B). Exemplary procedures for preparing substantially pure abiraterone decanoate are provided in the Examples section. Suitable HPLC methods for measuring the purity of abiraterone decanoate are also described in the Examples section. Substantially pure abiraterone decanoate can be in a solid form (e.g., a crystalline form described herein, preferably Form A, an amorphous form, or a combination thereof), or can be in a solution, suspension, or another form. For the avoidance of doubt, references herein to abiraterone prodrug formulations comprising substantially pure abiraterone decanoate and one or more other ingredients should be understood as mixtures of substantially pure abiraterone decanoate and one or more other ingredients; for example, such formulations may be obtained by directly or indirectly mixing (e.g., dissolving, suspending, or otherwise forming a mixture) substantially pure abiraterone decanoate with one or more other ingredients, such as a pharma- ceutically acceptable oil, solvent, etc.

[0195] In some specific embodiments, the pharmaceutical composition comprises abiraterone decanoate, a pharma- ceutically acceptable oil (e.g., as described herein), benzyl alcohol, and benzyl benzoate. In some embodiments, the pharma- ceutically acceptable oil is corn oil. In some embodiments, benzyl alcohol is present in an amount of about 5-10% by volume, benzyl benzoate is present in an amount of about 10-20% by volume, and corn oil is present in an amount of about 70-85% by volume, where the combined volume of benzyl alcohol, benzyl benzoate, and corn oil is taken as 100%.

[0196] The pharmaceutical composition typically contains abiraterone decanoate at a concentration of about 25 mg / ml to about 500 mg / ml. In some embodiments, abiraterone decanoate may be present at a concentration of 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 350 mg / ml, about 400 mg / ml, about 500 mg / ml, or any range between the recited values. In some embodiments, abiraterone decanoate may be present at a concentration of about 100 mg / ml to about 300 mg / ml, such as about 150 mg / ml to about 250 mg / ml, about 200 mg / ml to about 300 mg / ml, etc.

[0197] In some embodiments, the pharmaceutical composition may include abiraterone decanoate in its base form, corn oil, benzyl alcohol, and benzyl benzoate. In some embodiments, the abiraterone decanoate is present in the pharmaceutical composition in an amount of about 50-300 mg / mL. In some embodiments, the benzyl alcohol is in an amount of about 50-150 mg / mL. In some embodiments, the benzyl benzoate is in an amount of about 100-300 mg / mL. In some embodiments, the pharmaceutical composition can contain, 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 of about 1 milliliter. In some embodiments, the weight ratio of benzyl alcohol to benzyl benzoate in the pharmaceutical composition is in the range of about 2:1 to about 1:5 (e.g., about 1:1 to 1:3, e.g., about 1:2).

[0198] In some embodiments, the pharmaceutical composition comprises an abiraterone decanoate solution, wherein each milliliter of the abiraterone decanoate solution contains (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), (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) a quantity to 1 milliliter of corn oil, wherein the abiraterone decanoate has the following structure: [ka]

[0199] In some embodiments, each milliliter of the abiraterone decanoate solution herein comprises, consists essentially of, or consists of: (a) abiraterone decanoate in its base 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) an amount of about 1 milliliter of corn oil.

[0200] 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, for example, about 1:2).

[0201] In some specific embodiments, each milliliter of the abiraterone decanoate solution herein comprises, consists essentially of, or consists of (a) abiraterone decanoate in its base 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) an amount of about 1 milliliter of corn oil.

[0202] In some embodiments, a pharmaceutical composition can be prepared by mixing (e.g., dissolving) abiraterone decanoate, such as substantially pure abiraterone decanoate, with a pharma- ceutically acceptable carrier and a pharma- ceutically acceptable antioxidant. For example, in some embodiments, a pharmaceutical composition can be prepared by mixing (e.g., dissolving) substantially pure abiraterone decanoate in a basic form with corn oil, benzyl alcohol, benzyl benzoate, and 3-mercapto-1,2-propanediol, where the amounts of each component can be any of those described herein.

[0203] The abiraterone decanoate solution will typically be contained in a container having 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 gas.

[0204] In some embodiments, the abiraterone decanoate solution may also be contained in a syringe. Exemplary Formulations Comprising Substantially Pure Abiraterone Decanoate

[0205] In some particular embodiments, the pharmaceutical composition has the formula: [ka] or a pharma- ceutically acceptable salt thereof, dispersed or dissolved in a pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises substantially pure abiraterone decanoate in its base form, dispersed or dissolved in a pharma- ceutically acceptable carrier. In some embodiments, the substantially pure abiraterone decanoate has a weight purity of at least 95% by weight, preferably at least 98%, e.g., about 98.5%, about 99%, about 99.5%, or more. In some embodiments, the substantially pure abiraterone decanoate can be characterized by a weight purity and / or an HPLC area purity of about 95%, about 97%, about 99%, about 99.5%, about 99.9%, or any range between the specified values. In some embodiments, substantially pure abiraterone decanoate can be characterized by a weight purity of about 95%, about 97%, about 99%, about 99.5%, about 99.9%, or any range between the specified values. In some embodiments, substantially pure abiraterone decanoate can also be characterized by a low palladium content, such as less than 150 ppm, less than 100 ppm, less than 50 ppm, or less than 10 ppm. Abiraterone is typically synthesized in a step of palladium-catalyzed cross-coupling reaction. Thus, available abiraterone generally has undesirable levels of palladium residues, which may be carried in the crude abiraterone decanoate product. As described herein, the present disclosure shows that it is possible to reduce the palladium content of abiraterone decanoate to less than 5 ppm, particularly less than 3.7 ppm in Example 1B, using a process of recrystallization using acetone and water as solvents and activated charcoal. In some embodiments, the substantially pure abiraterone decanoate meets the specifications set forth in Table D herein (see Example 1B). In some embodiments, the substantially pure abiraterone decanoate includes impurities derived from ethyl prasterone. For example, in some embodiments, the substantially pure abiraterone decanoate includes ethyl prasterone decanoate having the formula: [ka] Typically, if present, substantially pure abiraterone decanoate contains ethyl prasterone decanoate in an amount of less than 2% by weight, e.g., less than 1% by weight, less than 0.5% by weight, e.g., less than 0.3% by weight, less than 0.2% by weight, or less than 0.1% by weight. The amount of ethyl prasterone decanoate can be readily determined by HPLC methods such as those described herein. In some embodiments, substantially pure abiraterone decanoate may also contain detectable amounts of ethyl prasterone decanoate. The abiraterone starting material is readily available from commercial sources in high purity. In the cross-coupling reaction to introduce the 3-pyridyl group into abiraterone, [ka] The abiraterone starting material obtained from a process using may contain small amounts of impurities that may ultimately be converted to ethylprasterone. In some embodiments, substantially pure abiraterone decanoate is an abiraterone starting material that has no detectable amounts of ethylprasterone, e.g., [ka] The substantially pure abiraterone decanoate may be prepared from a solid form, such as a crystalline form described herein. For example, in some embodiments, the substantially pure abiraterone decanoate may be crystalline form A, characterized by an X-ray powder diffraction (XRPD) spectrum having one or more of the following peaks: 4.6, 6.9, 8.7, 17.5, 18.3, 18.6, 19.1, 19.6, and 20.8, 2θ±0.2° (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9); a differential scanning calorimetry (DSC) pattern 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.

[0206] In some embodiments, the pharmaceutical composition comprises substantially pure abiraterone decanoate in its basic form, dispersed or dissolved in a pharma- ceutically acceptable carrier comprising a pharma- ceutically acceptable oil (e.g., as described herein) and optionally a further pharma- ceutically acceptable solvent (e.g., as described herein). In some embodiments, the pharma- ceutically acceptable oil comprises a triglyceride (e.g., a long-chain and / or medium-chain triglyceride), and the further pharma- ceutically acceptable solvent, if present, comprises an alcohol, an ester, and / or an acidic solvent. In some embodiments, the pharma- ceutically acceptable oil is selected from vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy oil, tea oil, and soybean oil, and the further pharma- ceutically acceptable solvent, if present, comprises benzyl alcohol, benzyl benzoate, or a combination thereof. In some embodiments, the pharma- ceutically acceptable carrier comprises corn oil, benzyl alcohol, and benzyl benzoate.

[0207] In some specific embodiments, the pharmaceutical composition comprises substantially pure abiraterone decanoate in its base form, which is dissolved in a pharma- ceutically 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 base form, which is dissolved in corn oil, benzyl alcohol, and benzyl benzoate. In some embodiments, the pharmaceutical composition comprises: (a) substantially pure abiraterone decanoate in its base form in 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, e.g., 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; and (d) a pharma- ceutically acceptable oil (e.g., as described herein), such as corn oil (e.g., in an amount appropriate to 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 of values ​​recited); (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 of values ​​recited); (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 of values ​​recited); and (d) aliquots to 1 milliliter of corn oil. 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, e.g., about 1:2).In some embodiments, the pharmaceutical composition can be prepared by mixing (e.g., dissolving) substantially pure abiraterone decanoate with a pharma- ceutically 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.

[0208] In some embodiments, the pharmaceutical composition comprises substantially pure abiraterone decanoate in its base form, dissolved in a pharma- ceutically acceptable oil (e.g., as described herein), benzyl alcohol, and benzyl benzoate, and a pharma- ceutically acceptable antioxidant. In some embodiments, the pharmaceutical composition comprises substantially pure abiraterone decanoate in its base form, dissolved in corn oil, benzyl alcohol, and benzyl benzoate, and 3-mercapto-1,2-propanediol. In some embodiments, the pharmaceutical composition comprises an abiraterone decanoate solution, wherein each milliliter of the abiraterone decanoate solution contains (a) 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, about 150 mg, about 180 mg, about 200 mg, or about 250 mg), (b) a substantially pure abiraterone decanoate in its base form in an amount of about 50 mg to about 150 mg (e.g., about 75 mg, about 100 mg, or about 125 mg), and (c) a substantially pure abiraterone decanoate in its base form 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) a quantity to 1 milliliter of corn oil, wherein the abiraterone decanoate has the following structure: [ka] In some embodiments, each milliliter of the abiraterone decanoate solution herein comprises, consists essentially of, or consists of: (a) substantially pure abiraterone decanoate in its base 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) an amount of about 1 milliliter of corn oil. 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, for example, about 1:2).

[0209] Pharmaceutical compositions comprising substantially pure abiraterone decanoate are typically formulated for parenteral administration. For example, in some embodiments, the pharmaceutical compositions have, for example, desirable viscosity, glide force, particle count, endotoxins, etc., and are formulated for intramuscular, intradermal, or subcutaneous injection. In some embodiments, the pharmaceutical compositions have (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 21 G, 1.5 inch needle, and / or about 2-15 N, when measured using a 23 G, 1.5 inch needle, and / or about 30-150 N, when measured using a 27 G, 1.5 inch needle; (3) a viscosity of about 10 N, when measured using a 21 G, 1.5 inch needle, and / or about 2-15 N, when measured using a 27 G, 1.5 inch needle; (4) a viscosity of about 10 N, when measured using a 21 G, 1.5 inch needle, and / or about 2-15 N, when measured using a 27 G, 1.5 inch needle; (5) a viscosity of about 10 N, when measured using a 21 G, 1.5 inch needle, and / or about 2-15 N, when measured using a 27 G, 1.5 inch needle; <788> and / or <789> (4) Not more than 1,000 particles having a size equal to or greater than 10 microns and not more than 300 particles having a size equal to or greater than 25 microns, when measured according to U.S.P. <85> The viscosity and glide force are characterized as having less than 100 EU / ml, e.g., less than 25 EU / ml, of endotoxins, as measured according to USP method 14. Methods for measuring viscosity and glide force are known in the art and are also exemplified in Example 2 herein. Glide force measurements can be performed using a 5 mL fill in a 5 mL syringe or a 2 mL fill in a 3 mL syringe. USP methods referenced herein <788> , <789> , and <85> should be understood as current versions of such methods, which are also known by those skilled in the art.

[0210] In any of the embodiments described herein, unless otherwise specified or contrary to context, a pharmaceutical composition comprising abiraterone decanoate (which may alternatively be referred to as an abiraterone prodrug formulation) may be any of the pharmaceutical compositions comprising substantially pure abiraterone decanoate described herein.

[0211] The abiraterone decanoate in the pharmaceutical composition is typically included in a therapeutically effective amount for treating a disease or disorder described herein, such as prostate cancer. In some embodiments, the abiraterone decanoate may be present in the pharmaceutical composition in an amount sufficient to provide a therapeutically effective plasma concentration of abiraterone for a period of at least 1 week, e.g., at least 2 weeks, at least 4 weeks, and up to 6 or 8 weeks or more, e.g., up to 10 weeks or more, after a single administration to a human subject having a sex hormone-dependent or androgen receptor-driven disease or disorder, e.g., a sex hormone-dependent benign or malignant disorder, an androgen receptor-driven cancer, and / or a syndrome resulting from androgen excess. In some embodiments, abiraterone decanoate may be present in the pharmaceutical composition in an amount sufficient to provide a therapeutically effective plasma concentration of abiraterone of about 1 ng / ml or more, e.g., about 2 ng / ml or more, about 4 ng / ml or more, about 5 ng / ml or more, about 8 ng / ml or more, for a period of at least 1 week, e.g., at least 2 weeks, at least 4 weeks, and up to 6 or 8 weeks or more, e.g., up to 10 weeks or more, following a single administration to a human subject having a sex hormone dependent or androgen receptor driven disease or disorder, e.g., a sex hormone dependent benign or malignant disorder, an androgen receptor driven cancer, and / or a syndrome resulting from androgen excess. In some embodiments, abiraterone decanoate may be present in the pharmaceutical composition in an amount sufficient to provide a therapeutically effective plasma concentration of abiraterone of about 0.5 ng / ml or greater for a period of at least 4 weeks, e.g., at least 6 weeks, and up to 8 weeks or more, e.g., up to 10 weeks or more, following a single administration to a human subject having a sex hormone dependent or androgen receptor driven disease or disorder, e.g., a sex hormone dependent benign or malignant disorder, an androgen receptor driven cancer, and / or a syndrome resulting from androgen excess.In some embodiments, abiraterone decanoate may be present in the pharmaceutical composition in an amount sufficient to provide a therapeutically effective plasma concentration of abiraterone of about 0.1 ng / ml or greater for a period of at least 4 weeks, e.g., at least 6 weeks, and up to 8 weeks or more, e.g., up to 10 weeks or more, following a single administration to a human subject having a sex hormone dependent or androgen receptor driven disease or disorder, e.g., a sex hormone dependent benign or malignant disorder, an androgen receptor driven cancer, and / or a syndrome resulting from androgen excess.

[0212] The pharmaceutical compositions herein are usually in unit dosage form, which refers to individual unit dosage forms, such as vials, ampoules, pre-filled syringes, each containing a predetermined amount of active compound(s). Usually, each unit dosage form herein is for single use, and substantially all of the contained active compound(s) are administered to or taken by the subject at one time. For clarity, one or more unit dosage forms may be administered to the subject at each administration event to meet the desired dose of active compound(s). For example, a pre-filled syringe may typically be used for single injection to inject substantially all of the pre-filled solution or suspension into the subject at one time, and one or more of such pre-filled syringes may have the same or different amounts of active compound(s) and may be administered to the subject to meet the desired dose of active compound(s) at each administration event. For example, for a dosing regimen of 1800 mg abiraterone decanoate every three months, a total dose of 1800 mg abiraterone decanoate is required at each dosing event, which can be met by administering two unit dosage forms, each having 900 mg abiraterone decanoate.

[0213] In some embodiments, the disclosure provides a unit dosage form comprising about 1 milliliter (ml) to about 20 ml of an abiraterone decanoate solution described herein (e.g., those listed in

[93] to

[0103] shown in the Summary section of the present specification). In some embodiments, the unit dosage form may comprise about 1 ml of an abiraterone decanoate solution. In some embodiments, the unit dosage form may comprise about 2 ml of an abiraterone decanoate solution. In some embodiments, the unit dosage form may comprise about 3 ml of an abiraterone decanoate solution. In some embodiments, the unit dosage form may comprise 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 recited values) of an abiraterone decanoate solution.

[0214] In some specific embodiments, the disclosure provides a unit dosage form comprising about 1 to 8 milliliters, e.g., about 1, 2, 3, 4, 5, 6, 7, or 8 milliliters of the abiraterone decanoate solution herein, e.g., in some embodiments, each milliliter of the abiraterone decanoate solution comprises, consists essentially of, or consists of (a) abiraterone decanoate in its base 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) a quantity of corn oil up to 1 milliliter. In some embodiments, the abiraterone decanoate solution in the unit dosage form is contained in a container having a headspace, such as a vial, ampoule, bottle, or the like, and the headspace is filled with an inert gas, such as nitrogen gas.

[0215] In any of the embodiments herein, pharmaceutical compositions such as the unit dosage forms herein can also be characterized as being storage stable at room temperature, e.g., stable when stored at room temperature (25±2°C) and 60% relative humidity (RH)±5%RH for about 1 month, 2 months, 3 months, 6 months, 9 months or more. Storage stability means that the pharmaceutical composition is acceptable by those of skill in the art as equivalent to the initial pharmaceutical composition, i.e., the pharmaceutical composition at the start of storage. Storage stability is typically characterized by one or more of the following: (1) substantially the same amount of drug-related impurities, without significant increase in either individual impurities or overall impurities, (2) substantially the same amount of abiraterone decanoate, (3) substantially the same physical properties, e.g., viscosity, physical state, color, etc. "Substantially the same" should be understood to mean within 80-125% or within measurement error.

[0216] In some specific embodiments, the present disclosure provides abiraterone decanoate having the formula: [ka] A pharmaceutical composition, e.g., a unit dosage form, is provided that includes a pharma- ceutically acceptable oil and a pharma-ceutically acceptable solvent, and the abiraterone decanoate is in its basic form, which may be in a concentration of about 25 mg / ml to about 500 mg / ml, e.g., 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, about 600 mg / ml, about 700 mg / ml, about 800 mg / ml, about 900 mg / ml, about 1000 mg / ml, about 1200 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, about 150 mg / ml, about 200 mg / ml, about 350 mg / ml, about 400 mg / ml, about 500 mg / ml, about 500 mg / ml, about 600 mg / ml, about 700 mg / ml, about 800 mg / ml, about 900 mg / ml, about 1000 mg / ml, about 150 mg / ml, about 200 mg / ml, about 350 mg / ml, about 400 mg / ml, about 5 ... The pharmaceutical composition, e.g., the unit dosage form, is present at a concentration of about 100 mg / ml, or any range between the recited values, and the pharmaceutical composition, e.g., the unit dosage form, is formulated for parenteral injection, such as intramuscular, intradermal, or subcutaneous injection, and the pharmaceutical composition, e.g., the unit dosage form, comprises an amount of abiraterone decanoate of about 50 mg to about 5,000 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 recited values. In some embodiments, the pharmaceutical composition may be in a unit dosage form. Typically, depending on the dosage, one or more (e.g., one) of the unit dosage forms may be administered to a human subject in need thereof. For example, in some embodiments, each unit dosage form may contain about 180 mg, about 360 mg, about 720 mg, about 1260 mg, or about 1800 mg of abiraterone decanoate, and the concentration of abiraterone decanoate in the formulation may be about 180 mg / ml, or about 1 ml, about 2 ml, about 3 ml, about 7 ml, about 10 ml of the formulation, which may be packaged, for example, in a bottle, vial, ampoule, or prefilled syringe. The pharmaceutically acceptable oil in the pharmaceutical composition, e.g., unit dosage form, may be any of those described herein. For example, in some embodiments, the pharmaceutically acceptable oil is a pharmaceutically acceptable injectable oil comprising a vegetable-derived oil or a synthetic mono- or diglyceride of a fatty acid. In some embodiments, the pharmaceutically acceptable oil may be a natural oil, a synthetic oil, or a semi-synthetic oil, e.g., fractionated coconut oil and medium-chain triglycerides (such as those sold under the trademark Miglyol). In some embodiments, the pharma- ceutically acceptable oil can include triglycerides derived from fatty acids.In some embodiments, the pharma- ceutically acceptable oil may comprise triglycerides derived from long-chain and / or medium-chain fatty acids, which may be independently polyunsaturated, monounsaturated, or saturated. In some embodiments, the pharma-ceutically acceptable oil may be selected from vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy oil, tea oil, and soybean oil. In some particular embodiments, the pharma-ceutically acceptable oil may comprise corn oil, which comprises triglycerides whose fatty acid components are primarily linoleic acid, oleic acid, palmitic acid, and stearic acid. The pharma-ceutically acceptable solvent in the pharmaceutical composition, e.g., unit dosage form, may also comprise any of those described herein. In some embodiments, the pharma-ceutically acceptable solvent (or co-solvent, in the case where the oil is considered a solvent), may be an alcohol, an ester, an acid, or the like. In some embodiments, the pharma- ceutically acceptable solvent may include benzyl alcohol, benzyl benzoate, ethanol, glycerol, polyethylene glycol, polysorbate 80, acetic acid, and / or ethyl acetate. In some embodiments, the pharma- ceutical composition, e.g., unit dosage form, includes abiraterone decanoate, a pharma- ceutical acceptable oil (e.g., as described herein), benzyl alcohol, and benzyl benzoate. In some embodiments, the pharma- ceutical acceptable oil is corn oil. In some embodiments, benzyl alcohol is present in an amount of about 5-10% by volume, benzyl benzoate is present in an amount of about 10-20% by volume, and corn oil is present in an amount of about 70-85% by volume, where the combined volume of benzyl alcohol, benzyl benzoate, and corn oil is taken as 100%. In some embodiments, the abiraterone decanoate is in a substantially pure form as described herein.In some particular embodiments, the pharmaceutical composition comprises: (a) 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, e.g., about 100 mg / ml, about 200 mg / ml, about 300 mg / ml, about 400 mg / ml, about 500 mg / ml, or any range between the recited values, e.g., about 100 mg / ml, about 200 mg / ml, about 300 mg / ml, about 400 mg / ml, about 500 mg / ml, or any range between the recited values, e.g., about 100 mg / ml, about 200 mg / ml, about 25 ... (b) abiraterone decanoate, such as a substantially pure abiraterone decanoate herein in its base form, in an amount of about 50 mg to about 150 mg / mL; (c) benzyl alcohol in an amount of about 100 mg to about 300 mg / mL; and (d) a pharma- ceutically acceptable oil (e.g., as described herein), in particular corn oil (e.g., in an amount appropriate to the volume of the pharmaceutical composition). In some particular embodiments, the pharmaceutical composition comprises, per milliliter, (a) abiraterone decanoate, such as a substantially pure abiraterone decanoate herein in its base form 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 of 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 of 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 of recited values); and (d) corn oil in an amount of about 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, e.g., about 1:2).In some specific embodiments, the pharmaceutical composition comprises abiraterone decanoate, benzyl alcohol, benzyl benzoate, and corn oil, each in substantially the same respective amounts (mg per milliliter) as set forth in Example 2 of the present disclosure, for example, in some embodiments, the pharmaceutical composition comprises about 200 mg abiraterone decanoate, about 100 mg benzyl alcohol, about 200 mg benzyl benzoate, and qs-1 mL corn oil, or about 180 mg abiraterone decanoate, about 100 mg benzyl alcohol, about 200 mg benzyl benzoate, and qs-1 mL corn oil, in some specific embodiments, the pharmaceutical composition comprises abiraterone decanoate, benzyl alcohol, benzyl benzoate, corn oil, and monothioglycerol, each in substantially the same respective amounts (mg per milliliter) as set forth in Example 4 of the present disclosure.

[0217] In some embodiments, the disclosure provides exemplary abiraterone decanoate formulations shown in Table C. All numerical values ​​in the table should be understood to be preceded by the term "about." The concentration of abiraterone decanoate refers to the amount of abiraterone decanoate (mg) per ml of the final formulation, which may be a solution or suspension. The amount of oil (primary solvent) and co-solvent (benzyl alcohol and / or benzyl benzoate) in the table is expressed as a volume percent of the solvent, including both the oil and the co-solvent. Suitable oils include any of the pharma- ceutically acceptable oils described herein, such as corn oil. Optional additional ingredients are not shown in Table C. [Table 1]

[0218] The pharmaceutical compositions or unit dosage forms herein may be prepared by one of skill in the art in view of the methods disclosed herein. In some embodiments, the present disclosure provides a method for preparing an abiraterone decanoate formulation suitable for parenteral administration to a human subject having a sex hormone-dependent or androgen receptor-driven disease or disorder, such as a sex hormone-dependent benign or malignant disorder, an androgen receptor-driven cancer, and / or a syndrome resulting from androgen excess. In some embodiments, the method comprises mixing (e.g., dissolving or suspending) abiraterone decanoate, which has the following formula in a pharma- ceutically acceptable carrier: [ka] and optionally a pharma- ceutically acceptable antioxidant (e.g., monothioglycerol) to form a mixture (such as a solution or suspension). In some embodiments, the abiraterone decanoate is in a substantially pure form as described herein. In some embodiments, the method further comprises sterilizing the mixture (e.g., solution or suspension), such as by sterile filtration. In some embodiments, the method further comprises filling the mixture into a container having a headspace, introducing an inert gas into the headspace of the container, and optionally capping / sealing the container. An exemplary manufacturing process is also described in Example 5 herein. In some embodiments, the container may be a vial, an ampoule, or a bottle. In some embodiments, the method further comprises adding the mixture to a syringe. In some embodiments, the dissolving or suspending may comprise mixing (e.g., dissolving or suspending) a crystalline form of abiraterone decanoate described herein (e.g., Form A) in a pharma- ceutically acceptable carrier. In some embodiments, mixing (e.g., dissolving or suspending) can include mixing (e.g., dissolving or suspending) the substantially pure abiraterone decanoate described herein in a pharma- ceutically acceptable carrier. Suitable pharma-ceutically acceptable carriers and amounts, amounts of abiraterone decanoate, concentrations of abiraterone decanoate, pharma-ceutically acceptable antioxidants (e.g., monothioglycerol), and amounts thereof include any of those described herein. For example, in some embodiments, the pharma- ceutically acceptable carrier comprises a pharma- ceutically acceptable oil and a pharma- ceutically acceptable solvent, the pharma- ceutically acceptable oil comprises vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy oil, tea oil, or soybean oil, the pharma- ceutically acceptable solvent comprises benzyl alcohol and / or benzyl benzoate, abiraterone decanoate is present in a concentration of about 50 mg / mL to about 300 mg / mL, e.g., about 100 mg / mL to about 300 mg / mL, e.g., about 180 mg / mL, and the pharma- ceutically acceptable antioxidant is monothioglycerol in an amount of about 2 mg / mL or less.In some embodiments, the pharma- ceutically acceptable carrier can be a combination of corn oil, benzyl alcohol, and benzyl benzoate in any amount described herein. In some embodiments, abiraterone decanoate is present in a concentration of 150 mg / mL to about 250 mg / mL, e.g., about 180 mg / mL or about 200 mg / mL. In some embodiments, the pharma- ceutically acceptable antioxidant is monothioglycerol, which can be in an amount of about 0.5 mg / mL, about 1 mg / mL, about 2 mg / mL, or any range between the recited values.

[0219] Abiraterone Prodrugs of Formula I In some embodiments, the pharmaceutical composition may include an abiraterone prodrug according to any of those described in U.S. Patent No. 10,792,292(B2) 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 pharma- ceutically acceptable salt thereof: [ka] R 1 is R 10 , OR 10 or NHR 10 and R 10 is C 7-30 Alkyl;C 7-30 Alkenyl; C 7-30 alkynyl; alkyl substituted with cycloalkyl, typically having a total of 5 to 16 carbon atoms; alkyl substituted with phenyl, typically having a total of 7 to 16 carbon atoms; cycloalkyl optionally substituted with one or more alkyl, typically having a total of 5 to 16 carbon atoms; and [ka] and the like.

[0220] In some preferred embodiments, R10 is C 7-30 As used herein, unless expressly stated to be substituted, alkyl is to be understood as unsubstituted. However, alkyl can be either linear or branched. In some embodiments, R 10 is a linear C 7-30 In some embodiments, R 10 is a branched C 7-30 In some embodiments, R 10 is a straight chain C 7-16 alkyl, e.g., R 10 is the formula -(CH2) n In some embodiments, R 10 is a branched C 7-16 It may be alkyl.

[0221] In some embodiments, R 10 R may also be an alkyl substituted with a cycloalkyl. Typically, in such embodiments, R 10 has a total of 5 to 16 carbon atoms, i.e., the total number of carbon atoms from the alkyl and cycloalkyl portions is 5 to 16. Cycloalkyls are typically unsubstituted. However, in some embodiments, cycloalkyls are optionally substituted with, for example, one or two lower alkyls (e.g., C 1-4 In some embodiments, R 10 Typically, the total number of carbon atoms is 6 to 12. 3-6 In some embodiments, R 10 is C 3-6 It may be a linear alkyl substituted with a cycloalkyl, for example, R 10 is the formula -(CH2) n -Cy, where n is an integer from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6), and Cy is C 3-6cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). In some embodiments, R 10 is the formula -(CH2) n -Cy, n is 1 or 2, and Cy is cyclopentyl or cyclohexyl. 10 Also, C 3-6 Cycloalkyl-substituted branched alkyl (e.g., branched C 2-6 As used herein, a branched C2 alkyl is to be understood as a 1,1-disubstituted ethyl group, for example, -CH(CH3)-Cy.

[0222] In some embodiments, R 10 may also be an alkyl substituted with phenyl. Typically, in such embodiments, R 10 has a total of 7 to 16 carbon atoms, i.e., the total number of carbon atoms from the alkyl and phenyl portions is 5 to 16. In some embodiments, R 10 can be a linear alkyl substituted with phenyl, e.g., R 10 is the formula -(CH2) n -Cy, where n is an integer from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6), and Cy is phenyl. 10 is the formula -(CH2) n -Cy, n is 1 or 2, and Cy is phenyl. 10 Also includes branched alkyl substituted with phenyl (e.g., branched C 2-6 ). Phenyl is typically unsubstituted. However, in some embodiments, phenyl can be optionally substituted with, for example, one or two lower alkyl (e.g., C 1-4 It may be substituted with alkyl.

[0223] In some embodiments, R 10 may be cycloalkyl optionally substituted with one or more alkyl. In such embodiments, R10 Typically, the total number of carbon atoms in cycloalkyl and its optional substituents is 5 to 16. In some embodiments, R 10 is unsubstituted or C 1-4 C is substituted with alkyl. 3-6 In some particular embodiments, R 10 teeth, [ka] It could be.

[0224] In some embodiments, R 10 may be a branched C5 or C6 alkyl. In some embodiments, R 10 teeth, [ka] Other branched C5 or C6 alkyls are also suitable.

[0225] In some embodiments, R 10 is an unsaturated aliphatic group, e.g., C 7-30 Alkenyl or C 7-30 It may be alkynyl.

[0226] In some preferred embodiments, the compound of formula I is an ester of abiraterone, e.g., R 1 is R 10 and R 10 is defined herein. In some embodiments, R of formula I 1 is C 7-16 Alkyl, e.g., -(CH2) n In some embodiments, R of formula I can be an alkyl having a formula of -CH3, where n is an integer from 6 to 12 (e.g., 6, 7, 8, 9, 10, 11, or 12). 1 is a compound of the formula -(CH 2n -Cy, where n is an integer from 1 to 6, and Cy is C3-6 For example, in more specific embodiments, n can be 1 or 2 and Cy is cyclopentyl, cyclohexyl, or phenyl. 1 teeth, [ka] In some particular embodiments, R of formula (I) may be 1 teeth, [ka] R 1 Other suitable groups include those defined herein. 10 Contains either:

[0227] In some embodiments, R of formula I 1 Also, OR 10 or NHR 10 R 10 is defined herein.

[0228] Typically, the compound of formula I can be present in the formulation in a basic form, for example in a non-aqueous formulation. However, in some embodiments, pharma- ceutically acceptable salts of the compound of formula I are also useful. Unless specifically stated in its salt form or inconsistent with the context, the compound of formula I can be in its basic form in the abiraterone prodrug formulations described herein. In some embodiments, the compound of formula I can be in substantially pure form.

[0229] Abiraterone Prodrug Formulations In some embodiments, a pharmaceutical composition comprising an abiraterone prodrug may be an abiraterone prodrug formulation according to any of those described in U.S. Patent No. 10,792,292(B2), and PCT Application Nos. PCT / US2021 / 048607 and PCT / US2022 / 016278, and may be used in the methods herein. Typically, the abiraterone prodrug may be formulated as a parenteral formulation, such as an intramuscular, intradermal, or subcutaneous formulation, and in some embodiments, may be formulated to deliver a therapeutically effective plasma concentration of abiraterone over an extended period of time, such as at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, and up to 6 or 8 weeks or more, e.g., up to 10 weeks or more.

[0230] 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 can include a compound of formula I (e.g., any one or more as defined herein), or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition can be formulated for parenteral administration, such as intramuscular, intradermal, or subcutaneous injection. Pharmaceutical compositions typically include a pharma- ceutically acceptable carrier. Suitable carriers include those known in the art, such as those described in "Remington: The Science and Practice of Pharmacy" (formerly "Remington's Pharmaceutical Sciences," University of the Sciences in Philadelphia, Lippincott, Williams & Wilkins, Philadelphia, Pa. (2005)), and in the database of inactive ingredients present in FDA-approved drugs from the Center for Drug Evaluation and Research of the U.S. Food and Drug Administration. In some embodiments, the pharmaceutically acceptable carrier may be a carrier approved by the FDA for use in intramuscular, intradermal, or subcutaneous formulations, e.g., listed in the FDA's database of inactive ingredients. In some embodiments, the pharmaceutically acceptable carrier may be any suitable non-aqueous vehicle suitable for injection, such as those listed in the United States Pharmacopeia. In some embodiments, the pharmaceutically acceptable carrier may be a pharmaceutically acceptable oil, e.g., vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy oil, tea oil, or soybean oil. In some embodiments, the pharmaceutically acceptable oil may be an oil suitable for use as a vehicle for injection (e.g., as described herein), e.g., meeting the criteria described in the corresponding United States Pharmacopeia monograph. In some embodiments, the pharmaceutically acceptable oil may be a plant-derived oil suitable for use as a vehicle for injection.In some embodiments, the pharma- ceutically acceptable oil may be a synthetic oil suitable for use as an injection vehicle, e.g., a synthetic mono- or diglyceride of fatty acids, e.g., liquid, clear when cooled to 10° C., and having an iodine value of 140 or less. In some embodiments, the pharma-ceutically acceptable oil may be a natural, synthetic, or semi-synthetic oil, e.g., fractionated coconut oil and medium chain triglycerides (such as those sold under the trademark Miglyol). In some embodiments, the pharma-ceutically acceptable carrier comprises a triglyceride derived from a fatty acid. In some embodiments, the pharma-ceutically acceptable carrier comprises a triglyceride derived from a long chain fatty acid and / or a medium chain fatty acid, which may be independently polyunsaturated, monounsaturated, or saturated. In some embodiments, two or more different pharma-ceutically acceptable oils may be used. In some embodiments, the pharmaceutical composition is a non-aqueous solution or suspension. In some embodiments, the pharmaceutical composition further comprises a pharma-ceutically acceptable solvent, such as benzyl alcohol, benzyl benzoate, or a combination thereof. In some embodiments, the compound of formula I or a pharma- ceutically 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 recited values).

[0231] In some embodiments, a pharmaceutical composition suitable for use in the methods herein can include a compound of formula II, or a pharma- ceutically acceptable salt thereof: [ka] R 2is defined herein. In some embodiments, the pharmaceutical composition may be formulated for intramuscular, intradermal, or subcutaneous injection. In some embodiments, the compound of formula II or a pharma- ceutically acceptable salt thereof may 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 recited values). In some embodiments, the pharmaceutical composition is a non-aqueous solution or suspension. In some embodiments, the compound of formula II or a pharma- ceutically acceptable salt thereof is dissolved or suspended in a pharma- ceutically acceptable oil (e.g., as described herein), such as vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy oil, tea oil, or soybean oil. In some embodiments, the pharmaceutical composition further comprises a pharma- ceutically acceptable solvent, such as benzyl alcohol, benzyl benzoate, or a combination thereof.

[0232] R in Formula II 2 A variety of groups are suitable as R. 2 can be selected such that the compound of formula II is an ester, carbamate, or carbonate of abiraterone. 2 is R 20 , O-R20, or NHR 20 and R 20 is C 1-30 Alkyl;C 2-30 Alkenyl, C 2-30 alkynyl; alkyl substituted with cycloalkyl, typically having a total of 4 to 30 carbon atoms; alkyl substituted with phenyl, typically having a total of 7 to 30 carbon atoms; and cycloalkyl optionally substituted with one or more alkyl, typically having a total of 3 to 30 carbon atoms.

[0233] In some preferred embodiments, R 20 is C 1-16 In some embodiments, R20 is a linear C 1-16 In some embodiments, R 20 is a branched C 3-16 In some embodiments, R 20 may be a branched C5 or C6 alkyl. In some embodiments, R 20 teeth, [ka] In some embodiments, R 20 is the formula -(CH2) n -CH3, where n is an integer from 0 to 12 (e.g., 6 to 12, for example, 6, 7, 8, 9, 10, 11, or 12).

[0234] In some embodiments, R 20 R may also be an alkyl substituted with a cycloalkyl. Typically, in such embodiments, R 20 has a total of 4 to 30 carbon atoms, e.g., 5 to 16 carbon atoms (i.e., the total number of carbon atoms from the alkyl and cycloalkyl portions is 5 to 16). Cycloalkyl is typically unsubstituted. However, in some embodiments, cycloalkyl is optionally substituted with, for example, one or two lower alkyl groups (e.g., C 1-4 In some embodiments, R 20 Typically, the total number of carbon atoms is 6 to 12. 3-6 In some embodiments, R 20 is C 3-6 It may be a linear alkyl substituted with a cycloalkyl, for example, R 20 is the formula -(CH2) n -Cy, where n is an integer from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6), and Cy is C 3-6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). In some embodiments, R 20 is the formula -(CH2) n-Cy, n is 1 or 2, and Cy is cyclopentyl or cyclohexyl. 20 Also, C 3-6 Cycloalkyl-substituted branched alkyl (e.g., branched C 2-6 ).

[0235] In some embodiments, R 20 may also be an alkyl substituted with phenyl. Typically, in such embodiments, R 20 has a total of 7 to 30 carbon atoms, e.g., 7 to 16 carbon atoms (i.e., the total number of carbon atoms from the alkyl and phenyl portions is 7 to 16). 20 can be a linear alkyl substituted with phenyl, e.g., R 20 is the formula -(CH2) n -Cy, where n is an integer from 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6), and Cy is phenyl. 20 is the formula -(CH2) n -Cy, n is 1 or 2, and Cy is phenyl. 20 Also includes branched alkyl substituted with phenyl (e.g., branched C 2-6 ). Phenyl is typically unsubstituted. However, in some embodiments, phenyl can be optionally substituted with, for example, one or two lower alkyl (e.g., C 1-4 It may be substituted with alkyl.

[0236] In some embodiments, R 20 may be cycloalkyl optionally substituted with one or more alkyl. In such embodiments, R 20 Typically, R has a total of 3 to 30 carbon atoms, for example, 5 to 16 carbon atoms (i.e., the total number of carbon atoms in cycloalkyl and its optional substituents is 5 to 16). 20 is unsubstituted or C 1-4 C is substituted with alkyl. 3-6In some particular embodiments, R 20 teeth, [ka] It could be.

[0237] In some embodiments, R 20 is an unsaturated aliphatic group, e.g., C 2-30 Alkenyl or C 2-30 It may be alkynyl.

[0238] In some preferred embodiments, the compound of formula II is an abiraterone ester, e.g., R 2 is R 20 and R 20 is defined herein. In some embodiments, R of formula II 2 is C 1-16 Alkyl, e.g., -(CH2) n In some embodiments, R of Formula II can be an alkyl having a formula of —CH3, where n is an integer from 0 to 12. 2 is a compound of the formula -(CH 2n -Cy, where n is an integer from 1 to 6, and Cy is C 3-6 For example, in more specific embodiments, n can be 1 or 2 and Cy is cyclopentyl, cyclohexyl, or phenyl. 2 teeth, [ka] R 2 Other suitable groups include those defined herein. 20In some embodiments, the abiraterone ester can be the acetate, propionate, butanoate, (vaterate), pentanoate, isocaproate, bucyclate, cyclohexanecarboxylate, phenylpropionate, caproate (hexanoate), enanthate (heptanoate), cypionate, octanoate, noncanoate, decanoate, undecanoate, dodecanoate, tridecanoate, tetradecanoate, pentadecanoate, or hexadecanoate ester 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 pentanoate, abiraterone hexanoate, abiraterone heptanoate, abiraterone decanoate, abiraterone isocaproate, or abiraterone cypionate.

[0239] In some embodiments, R of formula II 2 Also, OR 20 or NHR 20 R 20 is defined herein.

[0240] Generally, the compound of formula II can be present in the formulation in a basic form, for example in a non-aqueous formulation. However, in some embodiments, pharma- ceutically acceptable salts of the compound of formula II are also useful. Unless specifically stated in its salt form or inconsistent with the context, the compound of formula II can be in its basic form in the abiraterone prodrug formulations described herein. In some embodiments, the compound of formula II can be in substantially pure form.

[0241] Pharmaceutical compositions comprising a substantially pure compound of Formula I or II (e.g., abiraterone decanoate) are typically formulated for parenteral administration. For example, in some embodiments, the pharmaceutical compositions have, for example, desirable viscosity, glide force, particle count, endotoxin, and the like, and are formulated for intramuscular, intradermal, or subcutaneous injection. In some embodiments, the pharmaceutical compositions have (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 21 G, 1.5 inch needle, and / or about 2-15 N, when measured using a 23 G, 1.5 inch needle, and / or about 30-150 N, when measured using a 27 G, 1.5 inch needle; (3) a viscosity of about 100 N, when measured using a 21 G, 1.5 inch needle, and / or about 100 N, when measured using a 27 G, 1.5 inch needle; <788> and / or <789> (4) Not more than 1,000 particles having a size equal to or greater than 10 microns and not more than 300 particles having a size equal to or greater than 25 microns, when measured according to U.S.P. <85> The viscosity and glide force are characterized as having less than 100 EU / ml, e.g., less than 25 EU / ml of endotoxins, as measured according to USP method 14. Methods for measuring viscosity and glide force are known in the art and are exemplified in Example 2 herein. <788> , <789> , and <85> should be understood as current versions of such methods, which are also known by those skilled in the art.

[0242] Typically, the abiraterone prodrug of the present disclosure is formulated as a non-aqueous solution or suspension. In some embodiments, the non-aqueous solution or suspension provides higher levels of abiraterone in plasma for a longer period of time when compared to an aqueous solution or suspension. For example, as detailed herein, IM injections of aqueous suspensions and vegetable oil solutions of abiraterone acetate prodrugs were evaluated in rats. Surprisingly, it was found that the vegetable oil solution (not the aqueous suspension) of abiraterone acetate prodrugs provided the highest plasma levels and longest exposure period of the active drug abiraterone. Thus, in some embodiments, the abiraterone prodrug formulations herein may include the abiraterone prodrug of the present disclosure (e.g., a compound of formula I or II) dissolved or dispersed in a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutically acceptable carrier may be any suitable non-aqueous vehicle suitable for injection, such as those described in the United States Pharmacopeia. In some embodiments, the pharma- ceutically acceptable carrier can be a pharma- ceutically acceptable oil, such as vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy oil, tea oil, or soybean oil. In some embodiments, the pharma- ceutically acceptable oil can be an oil suitable for use as an injection vehicle (e.g., as described herein), e.g., meeting the criteria set forth in the corresponding United States Pharmacopeia monograph. In some embodiments, the pharma- ceutically acceptable oil can be a plant-derived oil suitable for use as an injection vehicle. In some embodiments, the pharma- ceutically acceptable oil can be a synthetic oil suitable for use as an injection vehicle, e.g., a synthetic mono- or diglyceride of fatty acids, e.g., liquid, clear when cooled to 10° C., and having an iodine value of 140 or less. In some embodiments, the pharma- ceutically acceptable oil can be a natural, synthetic, or semi-synthetic oil, e.g., fractionated coconut oil and medium chain triglycerides (such as those sold under the trademark Miglyol). In some embodiments, the pharma- ceutically acceptable carrier comprises a triglyceride derived from a fatty acid.In some embodiments, the pharma- ceutically acceptable carrier comprises a triglyceride derived from long-chain fatty acids and / or medium-chain fatty acids, which may be independently polyunsaturated, monounsaturated, or saturated. In some embodiments, the pharma-ceutically acceptable oil may be any of those approved for use by the FDA in intramuscular, intradermal, or subcutaneous formulations, such as those listed in the FDA's database of inactive ingredients. In some particular embodiments, the pharma-ceutically acceptable oil is castor oil or corn oil. In some embodiments, two or more different pharma-ceutically acceptable oils may be used.

[0243] Other ingredients may also be optionally included in the abiraterone prodrug formulations herein. In some embodiments, the abiraterone prodrug formulation may further include a pharma- ceutically acceptable solvent, such as benzyl alcohol, benzyl benzoate, ethanol, glycerol, polyethylene glycol, polysorbate 80, acetic acid, and ethyl acetate. The additives / co-solvents benzyl alcohol and benzyl benzoate have been found to have the advantage of increasing the solubility of the prodrug as well as reducing the viscosity and / or glide force of the solution. See, e.g., U.S. Pat. No. 10,792,292(B2), and PCT Application Nos. PCT / US2021 / 048607 and PCT / US2022 / 016278. These provided more concentrated solutions that were easier to inject through acceptable gauge needles for IM injection (e.g., 20-27 gauge, such as 22-25 gauge). A co-solvent can be selected based on its ability to reduce the viscosity of the vehicle to allow injection through a suitable needle or cannula. Benzyl alcohol as an additive in IM or subcutaneous injections also has the advantage that it can act 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 further comprises benzyl alcohol. In some embodiments, a co-solvent, if present, can be included in an amount (e.g., about 0-50% of the solvent, e.g., about 10%) such that it does not cause irritation (or only minimal or tolerable irritation) at the injection site.

[0244] In some embodiments, the abiraterone prodrug formulation may include benzyl benzoate as a co-solvent, e.g., about 0-50%, typically 0-35% or 0-30%, or about 20% of the solvent. In some embodiments, the abiraterone prodrug formulation may include a combination of benzyl alcohol and benzyl benzoate as co-solvents. In some embodiments, the benzyl alcohol may be present in an amount of about 0-20% (e.g., 0-15% or 0-10%, e.g., about 10%) of the solvent, the benzyl benzoate may be present in an amount of about 0-50% (e.g., 0-35% or 0-30%, e.g., about 20%) of the solvent, and the remainder of the solvent may be any one or more of the pharma- ceutically acceptable oils described herein, e.g., corn oil, castor oil, sesame oil, peanut oil, cottonseed oil, and / or Miglyol 812. The combination of benzyl alcohol and benzyl benzoate has been shown to achieve lower viscosity and glide force when compared to the use of benzyl alcohol or benzyl benzoate alone.Furthermore, it was unexpectedly found that a representative abiraterone prodrug (abiraterone decanoate) formulation containing oil (corn oil, 70%) and benzyl alcohol (10%) and benzyl benzoate (20%) achieved much higher abiraterone plasma exposure in monkeys when compared to the same oil vehicle without benzyl benzoate, i.e., a formulation containing 90% corn oil and 10% benzyl alcohol, having substantially the same concentration of abiraterone decanoate and administered in the same amount.

[0245] The solubility of the abiraterone ester may be affected by the addition of a co-solvent 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.

[0246] Abiraterone prodrug formulations may also contain pharma- ceutically acceptable preservatives, polymers, antioxidants, antimicrobial agents, chelating agents, and other excipients, such as citric acid, dextrose, ascorbic acid, benzalkonium chloride, benzoic acid, betadex sulfobutyl ether sodium, calcium chloride, sodium carbomethoxycellulose, chlorobutanol, creatine, croscarmellose, dipotassium hydrogen phosphate, sodium docusate, sodium edetate, glycerin, sodium hyaluronate, hydroxypropyl betadex. , lactic acid, lactose, lecithin, maleic acid, mannitol, meglumine, methylcellulose, methylparaben, microcrystalline cellulose, miripitium chloride, momothioglycerol, phenol, poloxamer 188, polyglactin, polysorbate 20, polysorbate 40, polysorbate 80, propylparaben, sodium acetate, sodium benzoate, sodium citrate, sorbitan monolaurate, sorbitol, sucrose, tartaric acid, trisodium citrate, tromantadine, tromethamine, and urea. For example, in some embodiments, the abiraterone prodrug formulation may contain a pharma- ceutically acceptable antioxidant, such as monothioglycerol.

[0247] Abiraterone prodrug formulations can be sterilized by methods known to those of skill in the art (e.g., gamma irradiation, micron filtration, and autoclave sterilization).

[0248] Abiraterone long-acting release The abiraterone prodrugs and abiraterone prodrug formulations of the disclosure (e.g., those containing a compound of Formula I or II described herein) are typically formulated to provide long-acting release of abiraterone to a human subject in need thereof, e.g., a human subject having a sex hormone-dependent or androgen receptor-driven disease or disorder, e.g., a sex hormone-dependent benign or malignant disorder, an androgen receptor-driven cancer, and / or a syndrome resulting from androgen excess, preferably as a parenteral formulation, e.g., an intramuscular, intradermal, or subcutaneous formulation. In some embodiments, the disclosed abiraterone prodrugs and abiraterone prodrug formulations (e.g., those containing a compound of Formula I or II described herein) can be formulated to deliver therapeutic plasma levels of abiraterone to subjects with hormone-dependent benign or malignant disorders, androgen receptor-driven cancers, and / or syndromes resulting from androgen excess over an extended period of time (e.g., at least 1 week, e.g., at least 2 weeks, at least 3 weeks, at least 4 weeks, and up to 6 or 8 weeks or more, e.g., up to 10 weeks or more) following a single administration. In some embodiments, the therapeutic plasma concentration of abiraterone can be at a concentration of at least 1 ng / ml, e.g., 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 be about 0.5 ng / ml or more. In some embodiments, the therapeutic plasma concentration of abiraterone can be about 0.1 ng / ml or more.

[0249] Unit dosage form In some embodiments, the abiraterone prodrugs and abiraterone prodrug formulations of the present disclosure (e.g., those containing a compound of Formula I or II described herein) may be formulated as a unit dosage form. In some embodiments, the unit dosage form may contain a sufficient amount of each prodrug such that after a single administration (e.g., intramuscular injection) to a human subject, e.g., a human subject having a sex hormone-dependent or androgen receptor-driven disease or disorder, e.g., a sex hormone-dependent benign or malignant disorder (e.g., metastatic CRPC or metastatic CSPC), an androgen receptor-driven cancer, and / or a syndrome resulting from androgen excess, the unit dosage form provides a therapeutically effective plasma concentration of abiraterone in the human subject for a period of at least 2 weeks, e.g., at least 3 weeks, at least 4 weeks, at least 5 weeks, and up to 6 or 8 weeks or more, e.g., up to 10 weeks or more. In some embodiments, the therapeutic range plasma concentration of abiraterone may be at a concentration of at least 1 ng / ml, e.g., at least 2 ng / ml, at least 4 ng / ml, at least 8 ng / ml. In some embodiments, the therapeutic range plasma concentration of abiraterone may be about 0.5 ng / ml or more. In some embodiments, the therapeutic range plasma concentration of abiraterone may be about 0.1 ng / ml or more. In some embodiments, the unit dosage form is a parenteral formulation, such as an intramuscular, intradermal, or subcutaneous formulation. In some embodiments, the unit dosage form is a non-aqueous solution or suspension. In some embodiments, the unit dosage form comprises an abiraterone prodrug (e.g., a compound of Formula I or II) dissolved or suspended in a pharmaceutically acceptable oil, e.g., a vegetable oil, e.g., castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy oil, tea oil, or soybean oil. In some embodiments, two or more different pharmaceutically acceptable oils may be used in the unit dosage form. In some embodiments, the unit dosage form may further comprise a pharmaceutically acceptable solvent, e.g., an alcohol, an ester, and / or an acid, e.g., benzyl alcohol, benzyl benzoate, or a combination thereof. Other suitable ingredients for unit dosage forms include those described herein.

[0250] Abiraterone prodrugs (e.g., compounds of formula I or II) can typically be present in a unit dosage 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 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 recited values). The amount of abiraterone prodrug in a unit dosage form can vary depending on various factors, such as the clearance rate of the respective abiraterone prodrug, the intended dosing frequency, and the desired plasma level. Typically, the abiraterone prodrug can range from about 50 mg to about 2000 mg, and when expressed as an equivalent amount of abiraterone, can typically range from about 25 mg to about 1750 mg. In some embodiments, the amount of abiraterone prodrug may also be higher, for example, in the range of about 50 mg to about 5000 mg. In some embodiments, to achieve less frequent dosing frequencies, such as once a month, once every two months, or once every three months, the prodrug may be included in the unit dosage form in an amount and / or concentration that is safely tolerated by the human subject user. Typically, the unit dosage form is formulated to have a viscosity suitable for parenteral injection, such as one suitable for intramuscular, intradermal, or subcutaneous injection.

[0251] In some embodiments, the unit dosage form can be formulated to achieve a particular pharmacokinetic (PK) profile, for example, a PK profile with a substantially flat curve after an initial rise period. Typically, after the unit dosage form is administered to a human subject, the plasma concentration of abiraterone in the human subject can rise from the first few hours to several days (e.g., 5 days or 1 week) after administration, which then gradually plateaus. In some embodiments, after this initial rise period, the plasma concentration of abiraterone in the human subject can plateau and be substantially constant for an extended period of time, for example, 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.

[0252] In some embodiments, the unit dosage form is suitable for administration once a month (or more than once a month, such as once every two months or once every three months), such that upon single administration (e.g., intramuscularly) to a human subject in need thereof, said 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, e.g., up to 6 or 8 weeks, or up to 10 weeks or more; (b) a single-dose C of abiraterone of about 1 ng / ml to about 300 ng / ml, e.g., about 1 ng / ml to about 10 ng / ml. max (c) no food effect; (d) C of abiraterone observed at steady state at a once-daily oral dose of 1000 mg Zytiga® without food. max A single dose of abiraterone C of at least 30% reduced compared to max (e) a single dose of abiraterone C 28 days after administration of about 0.1 ng / ml to about 8 ng / ml min , (f) the plasma concentration of abiraterone remains substantially constant, e.g., for at least 1 week, e.g., 1-3 weeks, 1-10 weeks, or 2-8 weeks, after administration. In some embodiments, substantially constant over a period of time can mean that the highest concentration observed on any one day (i.e., 24 hour period) during that period is no more than 4-fold, e.g., no more than 2-fold, the lowest concentration observed on that same day. No food effect should generally be understood to mean that there is no significant difference in PK whether the unit dosage form is administered to a subject with or without food, e.g., in some embodiments, no food effect means that abiraterone has a C max As used herein, the AUC and the AUC are substantially the same (e.g., 80% to 125%). max is the C achieved after a single dose in treatment-naive subjects (generally referring to human subjects who have not received abiraterone within at least 3 days, such as at least 1 week, prior to dosing and who have no observable plasma abiraterone prior to dosing).max As used herein, the single dose C min refers to the minimum concentration observed on a given day, e.g., day 28 post-dose, following a single dose to untreated subjects.

[0253] In some embodiments, the unit dosage form is suitable for administration once per month (or more than once per month, such as once every two months or once every three months), such that upon administration (e.g., intramuscular administration) of the unit dosage form once per month (or more than once per month, such as once every two months or once every three months) to a human subject in need thereof, the unit dosage form achieves: (a) a steady-state C of abiraterone of about 1 ng / ml to about 300 ng / ml, e.g., about 1 ng / ml to about 10 ng / ml. max (b) no effect of food; (c) C observed at steady state with a once-daily oral dose of 1000 mg Zytiga® without food. max The steady-state C of abiraterone was reduced by at least 30% compared to max (d) Steady-state C of abiraterone from about 0.1 ng / ml to about 8 ng / ml min and (g) the plasma concentration of abiraterone remains substantially constant, e.g., for at least 1 week, e.g., 1 to 3 weeks, 1 to 10 weeks, or 2 to 8 weeks, after each administration. max or C min refers to the C observed after steady state is reached, typically following several doses in human subjects. max or C min It should be understood as follows.

[0254] In some embodiments, the unit dosage form may be packaged in a container such as a vial or an ampoule. In some embodiments, the unit dosage form may be included in a kit with a syringe, such as a prefilled syringe or a disposable syringe. Other packaging and / or containers are also useful and are known to those of skill in the art. In some embodiments, a kit is also provided that includes a plurality of the unit dosage forms described herein. In some embodiments, the kit may further include a syringe. Typically, one or more (e.g., one) unit dosage forms are used to fill a desired single dose. In some embodiments, the present disclosure provides an abiraterone prodrug formulation that allows for multiple single uses. In some embodiments, the present disclosure provides an abiraterone prodrug formulation that may be subdivided into multiple unit dosage forms. In some embodiments, the unit dosage form may include any of the pharmaceutical compositions described herein, such as those shown in

[18] -

[30] or

[93] -

[0107] of the Overview section. In some embodiments, the unit dosage form contains about 180 mg, about 360 mg, about 720 mg, about 1260 mg, about 1800 mg, or any range or value between the recited values.

[0255] Exemplary Specific Formulations In some embodiments, the present disclosure also provides some specific abiraterone prodrug formulations, which in some embodiments may be in unit dosage form or multiple unit dosage forms. For example, the following tables (Tables A and B) show some representative abiraterone ester prodrug formulations in an oil vehicle. All numerical values ​​in the tables should be understood to be preceded by the term "about". The concentration of abiraterone prodrug refers to the amount of abiraterone prodrug (mg) per ml of the final formulation, which may be a solution or suspension. The amount of oil (primary solvent) and co-solvent in the tables is expressed as a volume percent of the solvent, including both the oil and the co-solvent. Suitable oils include any of the pharma- ceutically acceptable oils described herein. Suitable co-solvents also include any of those described herein, such as alcohols, esters, and / or acids, such as benzyl alcohol, benzyl benzoate, or combinations thereof. See, for example, Table B. One example of a suitable co-solvent is benzyl alcohol. One example of a suitable co-solvent is a combination of benzyl alcohol and benzyl benzoate. In some embodiments, no co-solvent is included in the formulation. In some embodiments, the co-solvent does not include benzyl benzoate. Other optional ingredients are described herein. [Table 2]

[0256] In some embodiments, the disclosure provides an abiraterone prodrug formulation comprising an abiraterone prodrug and a pharma- ceutically acceptable carrier, the pharma-ceutically acceptable carrier comprising a pharma-ceutically 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. The pharma-ceutically acceptable oil typically comprises a triglyceride derived from a fatty acid. In some embodiments, the pharma-ceutically 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, the pharma-ceutically acceptable oil can be selected from vegetable oils, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy oil, tea oil, and soybean oil. In some embodiments, the disclosure provides certain exemplary formulations as shown in Table B. [Table 3]

[0257] As used herein, when the solvent system of an abiraterone prodrug formulation includes two or more solvents (including oil), the abiraterone prodrug formulation may be expressed as a solution of abiraterone prodrug in a solvent system having x% oil and y% co-solvent at a particular concentration (e.g., 90% corn oil and 10% benzyl alcohol). In such expressions, whether followed by "v / v" or not, x% and y% should be understood to be based on volume percentages unless otherwise specified or clearly contrary from the context.

[0258] Combination treatment 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, either via the same or a different route of administration, simultaneously or sequentially with the administration of the abiraterone prodrug. In some embodiments, the other drug or agent may be a steroid, e.g., prednisone, prednisolone, and / or methylprednisolone. In some embodiments, the other drug or agent may be a chemotherapy drug, e.g., paclitaxel, mitoxantrone, and / or docetaxel. In some embodiments of the methods herein, the other drug or agent may be a GnRH agonist, e.g., leuprolide, deslorelin, goserelin, or triptorelin, e.g., leuprolide acetate (e.g., a long-acting IM injectable formulation). In some embodiments, the other agent or drug may be seocalcitol, bicalutamide, flutamide, glucocorticoids, including but not limited to hydrocortisone, prednisone, prednisolone, or dexamethasone. The amount of the other drug or drug administered may vary and typically will be an amount effective to treat the respective disease or disorder (e.g., prostate cancer) either alone or in combination with an abiraterone prodrug or abiraterone prodrug formulation of the present disclosure.

[0259] Additional suitable other drugs or agents include those described herein. For example, useful other drugs or agents include, but are not limited to, anti-cancer agents, hormone ablation agents, anti-androgen agents, differentiation agents, anti-tumor agents, kinase inhibitors, antimetabolites, alkylating agents, antibiotic agents, immunological agents, interferon-type agents, intercalating agents, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, mitotic inhibitors, matrix metalloproteinase inhibitors, gene therapy agents, and anti-androgen agents.

[0260] For example, suitable anti-cancer drugs include acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, amsacrine, anagrelide, anastrozole, ansetimibe, bexarotene, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, daclizumab, dexrazoxane, dilazep, docosanol, doxifluridine, bromocriptine, carmustine, cytarabine, diclofenac, ectopyrrole, endothelial cell graft ... Delfosine, edrecolomab, eflonitine, emitefur, exemestane, exurin, fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, glycopin, heptaplatin, ibandronate, imiquimod, iobenguane, irinotecan, irsogladine, lanreotide, leflunomide, lenograstim, lentinan sulfate, letrozole, liarozole, lobaplatin, lonidamine, masoprocor ru, melarsoprol, metoclopramide, mifepristone, miltefosine, millimostim, mitoguazone, mitolactol, molgramostim, nafarelin, nartograstim, nedaplatin, nilutamide, noscapine, oprelvekin, osaterone, oxaliplatin, pamidronate, pegaspargase, pentosan polysulfate sodium, pentostatin, picibanil, pirarubicin, porfimer sodium, raloxifene, raltitrexed, rasburicase, rituximab, Examples of suitable antiandrogens include, but are not limited to, romurtide, sargramostim, sizofiran, sobuzoxane, sonermin, suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxidomide, thalidomide, thymalfasin, thyrotropin alpha, topotecan, toremifene, trastuzumab, treosulfan, tretinoin, trilostane, trimetrexate, ubenimex, valrubicin, verteporfin, and vinorelbine.Suitable antiandrogens include, but are not limited to, bicalutamide, flutamide, and nilutamide.Suitable differentiation agents include polyamine inhibitors;Vitamin D and its analogs, such as calcitriol, doxercalciferol, and seocalcitol; metabolites of vitamin A, such as ATRA, retinoic acid, retinoids; short chain fatty acids; phenyl butyrate; and nonsteroidal anti-inflammatory drugs; including, but not limited to, tubulin interacting agents, topoisomerase inhibitors and agents, acitretin, alstonine, amonafide, amfetinil, amsacrine, anquinomycin, antineoplastons, aphidicolin glycinate, asparaginase, baccharin, batracillin, benflurone, benzotrypto, bromophosphamide, caracemide, carmethizole hydrochloride, chlorsulfaquinoxalone, clanfenur, claviridinone, crisnatol, cladarm, cytarabine, cytocytin, dacarbazine, daterliptinium, dihematoporphyrin e ether, dihydrolenperone, dinaline, distamycin, docetaxel, elipravine, elliptinium acetate, epothilone, ergotamine, etoposide, etretinate, fenretinide, gallium nitrate, genquadaphnine, hexadecylphosphocholine, homoharringtonine, hydroxyurea, irmofosine, isoglutamine, isotretinoin, leukoregulin, lonidamine, mervalone, merocyanine derivative Conductors, methylanilinoacridine, minactivin, mitonafide, mitoxantrone, mopidamol, motretinide, N-(retinoyl)amino acids, N-acylated dehydroalanine, nafazatrom, nocodazole derivatives, octreotide, oxanosine, paclitaxel, pancratistatin, pazeriptin, piroxantrone, polyhematoporphyrin, polyprenic acid (polyprenic acid) antitumor agents, including vinblastine, procarbazine, proglumide, razoxane, leteriptin, spatol, spirocyclopropane derivatives, spirogermanium, stripolidinone, superoxide dismutase, teniposide, thaliblastine, tocotrienols, topotecan, ukrain, vinblastine sulfate, vincristine, vindesine, binestramide, vinorelbine, vintriptol, vinzolidine, and withanolides; kinase inhibitors, including p38 inhibitors and CDK inhibitors; TNF inhibitors; metallomatrix protease inhibitors (MMP);COX-2 inhibitors, including celecoxib, rofecoxib, parecoxib, valdecoxib, and etoricoxib; SOD mimetics; or alpha; vThese include, but are not limited to, β3 inhibitors. Suitable antimetabolites may be selected from, but are not limited to, 5-FU-fibrinogen, acanthifolic acid, aminothiadiazole, brequinar sodium, carmofur, cyclopentylcytosine, cytarabine phosphate stearate, cytarabine conjugates, dezaguanine, dideoxycytidine, dideoxyguanosine, didox, doxifluridine, fazarabine, floxuridine, fludarabine phosphate, 5-fluorouracil, N-(2'-furanidyl)-5-fluorouracil, isopropylpyrrolidine, methobenzaprim, methotrexate, norspermidine, pentostatin, piritrexim, plicamycin, thioguanine, tiazofurin, trimetrexate, tyrosine kinase inhibitors, and uricytin. Suitable alkylating agents may be selected from, but are not limited to, aldo-phosphamide analogs, altretamine, anaxylon, bestravucil, budotitane, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, ciplatate, diphenylspiromustine, biplatinum cytostatic agents, ermustine, estramustine sodium phosphate, fotemustine, hepsulfam, ifosfamide, iproplatin, lomustine, mafosfamide, mitolactol, oxaliplatin, prednimustine, ranimustine, semustine, spiromustine, tauromustine, temozolomide, teroxylon, tetraplatin, and trimelamol.Suitable antibiotics include aclarubicin, actinomycin D, actinoplanon, adriamycin, aeroprisinin derivatives, amrubicin, anthracyclines, azinomycin-A, viscaverin, bleomycin sulfate, bryostatin-1, calicheamicin, chromoximycin, dactinomycin, daunorubicin, ditrysarubicin B, dexamethasone, doxorubicin, doxorubicin-fibrinogen, elsamycin-A, epirubicin, erbstatin, esorubicin, esperamicin-A1, esperamicin-A1b, fostriecin, glidobactin, gregati ... The steroids may be selected from, but are not limited to, corticosteroids such as sirolimus-A, glinkamycin, hydrocortisone, idarubicin, iludin, kadusamycin, kesarilodin, menogaril, mitomycin, neoenactin, oxalicin, oxaunomycin, peplomycin, pyratin, pirarubicin, polothramycin, prednisone, prednisolone, pyrindamycin A, rapamycin, rhizoxin, lodorubicin, sivanomycin, siwenmycin, sorangicin-A, sparsomycin, tallysomycin, turpentesin, thorazine, triclozaline A, and zorubicin. Non-limiting examples of suitable steroids include hydrocortisone, prednisone, prednisolone, or dexamethasone.

[0261] Combination treatment for prostate cancer Treatment of prostate cancer often involves multiple therapies, including, for example, radiation therapy, surgery, androgen deprivation therapy, hormone therapy, chemotherapy, immunotherapy, and combinations of various drugs. A search on the website clinicaltrials.gov identified over 250 clinical trials with abiraterone / abiraterone acetate described as an intervention agent, many of which involve combination therapy to treat prostate cancer. As discussed herein, compared to oral abiraterone acetate formulations, the abiraterone prodrugs herein can provide increased bioavailability, elimination of food effects, reduced dosage burden, reduced dosing frequency, and sustained effective plasma levels of abiraterone, as well as extended CYP17A1 inhibition, with reduced dihydrotestosterone and testosterone levels for up to 70 days or more after administration of the abiraterone prodrug formulation, without undesirable increases in steroids upstream of CYP17A1 hydroxylase, such as progesterone. Given their superior pharmacokinetic and / or pharmacodynamic profiles, the abiraterone prodrugs herein may be advantageously used in a variety of combination therapies to replace or complement oral administration of abiraterone acetate.

[0262] In some embodiments, the disclosure provides a method of treating prostate cancer (e.g., any of those described herein) with a combination therapy in a human subject in need of such treatment, the method comprising administering to the human subject a therapeutically effective amount of an abiraterone prodrug (e.g., abiraterone decanoate) or abiraterone prodrug formulation herein and one or more additional therapies. The one or more additional therapies can be administered to the human subject in any order, simultaneously or sequentially with administration of the abiraterone prodrug or abiraterone prodrug formulation herein, which may be via the same or different routes of administration. In some embodiments, the method herein comprises treating the human subject with radiation therapy or surgery. In some embodiments, the method includes administering to the human subject one or more other agents selected from anti-cancer agents, hormone ablation agents, anti-androgen agents, differentiation agents, anti-tumor agents, kinase inhibitors, antimetabolites, alkylating agents, antibiotic agents, immune agents, interferon-type agents, 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 to the human subject one or more other agents selected from chemotherapeutic agents, hormone replacement agents, or hormone ablation agents. In some embodiments, the method includes treating the human subject with androgen ablation therapy. Many of the combination therapies below are described in connection with various treatments for prostate cancer, although the disclosure is not so limited. Also, in some embodiments, the combination therapies described below may also be used to treat other diseases or disorders described herein, such as other cancers described herein.

[0263] In more specific embodiments, the combination therapy typically includes administering a glucocorticoid to the human subject. For example, in some embodiments, the method includes administering one or more agents selected from hydrocortisone, prednisone, prednisolone, methylprednisolone, and dexamethasone, preferably dexamethasone, to the human subject. However, in some embodiments, glucocorticoid replacement therapy (e.g., administering a glucocorticoid such as hydrocortisone, prednisone, prednisolone, methylprednisolone, or dexamethasone) is undesirable. For example, glucocorticoids may be contraindicated in human subjects who may have an underlying disease such as diabetes. In some embodiments, the method may also be characterized in that the human subject is not treated with glucocorticoid replacement therapy. In some embodiments, the human subject is not treated with an agent selected from hydrocortisone, prednisone, prednisolone, methylprednisolone, and dexamethasone. In some embodiments, the method may include administering to the human subject a mineralocorticoid receptor antagonist, such as eplerenone. For example, in any of the embodiments herein, if glucocorticoid replacement therapy is not desired and / or is not administered, the method may include administering to the human subject a mineralocorticoid receptor antagonist, such as eplerenone. In some embodiments, no agent for treating mineralocorticoid toxicity is required and is not administered to the human subject. In some embodiments, the method may also be characterized in that the human subject is not treated with an agent effective to treat mineralocorticoid toxicity. In some embodiments, the method may be characterized in that the human subject is not treated with an agent that is a glucocorticoid or a mineralocorticoid receptor antagonist.

[0264] The combination therapy for the methods herein may also include androgen deprivation therapy, such as by administering a gonadotropin-releasing hormone (GnRH) analog to the human subject. If included, the GnRH analog suitable for combination therapy is not particularly limited and includes both GnRH agonists and GnRH antagonists. For example, in some embodiments, the method may include administering a gonadotropin-releasing hormone (GnRH) agonist, such as buserelin, leuprolide, deslorelin, ferirelin, histrelin, gonadorelin, resilelin, goserelin, nafarelin, peforelin, or triptorelin, and / or a GnRH antagonist, such as abarelix, cetrorelix, degarelix, ganirelix, elagolix, linzagorixa, or relugolix to the human subject. In some embodiments, the human subject has not been administered any of the GnRH agonists and GnRH antagonists described herein.

[0265] Inhibition of androgen receptor activity In some embodiments, the combination therapy includes treating a human subject to reduce androgen receptor (AR) activity, for example, with an AR antagonist or an agent that downregulates or inhibits AR activity.

[0266] In some embodiments, the method may include administering to the human subject an androgen receptor (AR) antagonist. Various AR antagonists are known in the art, including, but not limited to, first and second generation AR antagonists (see, e.g., Rice, MA, et al. Front Oncol. 9:801 (2019)), and third generation AR antagonists, e.g., N-terminal domain inhibitors. In some embodiments, the method includes administering to the human subject a first generation androgen receptor antagonist, including, but not limited to, proxalutamide, bicalutamide, flutamide, nilutamide, topirutamide, and the like. In some embodiments, the method includes administering to the human subject a second generation androgen receptor antagonist, including, but not limited to, apalutamide, darolutamide, or enzalutamide. In some embodiments, the method includes administering to the human subject apalutamide. In some preferred embodiments, the method comprises administering enzalutamide to the human subject. In some embodiments, the method comprises administering a third generation androgen receptor antagonist, such as an N-terminal domain inhibitor, to the human subject. N-terminal domain inhibitors are known in the art. Non-limiting useful examples include any of those described in US Patent Publication No. 2020 / 0123117, the contents of which are incorporated herein by reference. It should be noted that in embodiments in which an AR antagonist is administered, one or more such antagonists can be administered, which may be selected from a first, second, or third AR antagonist alone, or any combination.

[0267] In addition to agents that directly target the androgen receptor, other methods and / or agents that modulate the activity of the androgen receptor, including, for example, regulating upstream kinase activity and / or androgen receptor transcription activity, can also be used in the combination therapy herein.For example, in some embodiments, the combination therapy can include administering to a human subject one or more upstream kinase modulators, the activation or inhibition of which can 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 & Cancer4(9-10):342-359(2013). In some embodiments, the method comprises administering to the human subject one or more kinase modulators selected from an FLT-3 (FMS-like tyrosine kinase) inhibitor, an AXL (anexelekto) inhibitor (e.g., gilteritinib), a CDK (cyclin-dependent kinase) inhibitor such as a CDK1, 2, 4, 5, 6, 7 or 9 inhibitor, a retinoblastoma (Rb) inhibitor, a protein kinase B (AKT) inhibitor, an SRC inhibitor, an IκB kinase 1 (IKK1) inhibitor, a PIM-1 modulator, a Lemur tyrosine kinase 2 (LMTK2) modulator, a Lyn inhibitor, an Aurora A inhibitor, an ANPK (nuclear protein kinase) inhibitor, an extracellular signal-regulated kinase (ERK) modulator, a c-jun N-terminal kinase (JNK) modulator, a Big MAP kinase (BMK) modulator, a p38 mitogen-activated protein kinase (MAPK) modulator, and combinations thereof. Suitable kinase modulators / inhibitors are not particularly limited and include any of those known in the art, for example, small molecule drugs, polypeptides including antibodies, such as monoclonal antibodies or antigen-binding fragments thereof, RNA or DNA based agents.

[0268] In some embodiments, the combination therapy may comprise administering to human subjects an agent that downregulates AR or inhibits AR activity.Without being bound by theory, AR activity can be affected at the genome level and / or transcription level of AR itself, or at the genome level and / or transcription level of the upstream target of AR that plays a role in regulating AR activity and the downstream target that is controlled by AR, using various molecules that inhibit transcription and / or translation (e.g., RNA silencing agents (e.g., antisense, siRNA, shRNA, microRNA), ribozyme and DNAzyme), or at the protein level, using, for example, antagonists, enzymes that cleave polypeptides, small molecules that inhibit the activity of proteins (e.g., competitive ligands), etc.

[0269] In some embodiments, the downregulation of AR or inhibition of AR activity can be achieved through RNA silencing of target genes (such as AR or suitable upstream and downstream targets of AR as described herein).As used herein, the phrase "RNA silencing" refers to a group of regulatory mechanisms (such as RNA interference (RNAi), transcriptional gene silencing (TGS), post-transcriptional gene silencing (PTGS), quelling, co-suppression, and translational suppression) mediated by RNA molecules that result in the inhibition or "silencing" of the expression of corresponding protein-coding genes.RNA silencing has been observed in many types of organisms, including plants, animals, and fungi.

[0270] 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, the RNA silencing agent can prevent complete processing (e.g., complete translation and / or expression) of an mRNA molecule via a post-transcriptional silencing mechanism. RNA silencing agents include non-coding RNA molecules, such as RNA duplexes that include paired strands, and precursor RNAs from which such small non-coding RNAs can be generated. Exemplary RNA silencing agents include double-stranded RNAs, such as small interfering RNAs (siRNAs) (dsRNAs), miRNAs, and shRNAs. In one embodiment, the RNA silencing agent can induce RNA interference. In another embodiment, the RNA silencing agent can mediate translational suppression. The strands of a double-stranded interfering RNA (e.g., siRNA) may be connected to form a hairpin or stem-loop structure (e.g., shRNA or sh-RNA). Thus, as described above, the RNA silencing agent of some embodiments of the present disclosure may also be a short hairpin RNA (shRNA).

[0271] It will be understood that the RNA silencing agents of some embodiments of the present disclosure need not be limited to those molecules that contain only RNA, but further encompass chemically modified nucleotides and non-nucleotides.

[0272] In some embodiments, the RNA silencing agents provided herein may be functionally associated with a cell-penetrating peptide. As used herein, a "cell-penetrating peptide" is a peptide that contains a short (about 12-30 residues) amino acid sequence or functional motif that confers energy-independent (i.e., non-endocytic) translocation properties associated with the transport of membrane-permeable complexes across the plasma membrane and / or nuclear membrane of a cell.

[0273] According to another embodiment, the RNA silencing agent can be a miRNA or a mimic thereof. The terms "microRNA", "miRNA" and "miR" are synonymous and refer to a collection of non-coding single-stranded RNA molecules, approximately 19-28 nucleotides in length, that control gene expression. miRNAs are found in a wide range of organisms and have been shown to be involved in development, homeostasis, and disease pathogenesis. The term "microRNA mimic" refers to synthetic non-coding RNAs that can enter the RNAi pathway and regulate gene expression. miRNA mimics mimic the function of endogenous microRNAs (miRNAs) and can be designed as mature double-stranded molecules or mimic precursors (e.g., pre-miRNAs).

[0274] Downregulation of AR or inhibition of AR activity can also be achieved by gene editing of target gene (such as AR as described herein, or suitable upstream and downstream target of AR). Gene editing can be carried out, for example, by using clustered regularly interspaced short palindromic repeats CRISPR-CAS9 system. CRISPR-CAS9 system is described in the literature, and can include, for example, CAS9 and guide RNA. Other gene editing techniques are also described in the literature and can be used.

[0275] Another agent capable of downregulating a target (such as AR or suitable upstream and downstream targets of AR as described herein) is a DNAzyme molecule that can specifically cleave the target's mRNA transcript or DNA sequence. A DNAzyme is a single-stranded polynucleotide that can cleave both 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 DNAzymes (the "10-23" model) has been proposed. The "10-23" DNAzyme has a catalytic domain of 15 deoxyribonucleotides, flanked by two substrate recognition domains of 7-9 deoxyribonucleotides each. This type of DNAzyme can efficiently cleave its substrate RNA at purine:pyrimidine junctions (Santoro et al., Khachigian, Curr. Opin. Mol. Ther. 2002;4:119-121).

[0276] Downregulation of a target (such as, for example, AR, or suitable upstream and downstream targets of AR, as described herein) can also be affected by using antisense polynucleotides capable of specifically hybridizing to the mRNA transcript encoding the target.

[0277] Another agent that can downregulate a target (such as AR as described herein, or suitable upstream and downstream targets of AR) is a ribozyme molecule that can specifically cleave the mRNA transcript that codes for the target. Ribozymes are increasingly used for sequence-specific inhibition of gene expression by cleaving the mRNA that codes for a protein of interest. (Welch et al., Curr. Opin. Biotechnol. 1998; 9: 486-96).

[0278] Another agent capable of downregulating a target (such as, for example, the AR described herein, or suitable upstream and downstream targets of the AR) is any molecule that binds to and / or cleaves the target. Such a molecule may be an antagonist of the target, or an inhibitory peptide of the target.

[0279] Another agent that can be used 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) is a molecule that prevents activation and / or substrate binding of the target.

[0280] 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 one based on proteolytic targeting chimera (PROTAC) technology. See, for example, Kregel, S. et al. Neoplasia 22(2):111-119 (2020).

[0281] Another agent that can be used with some embodiments of the present disclosure to downregulate a target (such as AR described herein, or suitable upstream and downstream targets of AR) is one that suppresses or downregulates the activation of the transcriptional activity of the target, more specifically, the transcriptional activity of AR. For example, such an agent can interfere with the nuclear translocation of AR, downregulate the protein level of AR, reduce hormone binding to AR, interfere with the recruitment of transcriptional cofactors (such as steroid receptor coactivator 1 (SRC1) and transcriptional intermediary 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, 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 known in the art and any of those exemplified herein that can inhibit or interfere with such activity. For example, certain AR antagonists, such as first-generation AR antagonists (e.g., bicalutamide), are known to inhibit AR transcription activity by inhibiting AR nuclear translocation.Other drugs, such as arsenic compounds (e.g., arsenic trioxide), are also known to inhibit AR transcription activity.See, for example, Rosenblatt AE, et al, Mol.Endocrinol.23(3):412-421(2009).

[0282] In some embodiments, the combination therapy may include administering one or more chemotherapeutic agents to the human subject. Suitable chemotherapeutic agents include any known in the art. In some embodiments, the method includes administering a taxane chemotherapeutic agent (e.g., docetaxel, cabazitaxel, paclitaxel, etc.) and / or a platinum chemotherapeutic agent (e.g., cisplatin, carboplatin, oxaliplatin, etc.) to the human subject.

[0283] In some embodiments, the combination therapy may include treating the human subject with radiation therapy. Suitable radiation therapies include any known in the art. In some embodiments, the method includes treating the human subject with stereotactic body radiation therapy or neutron radiation.

[0284] In some embodiments, the combination therapy may include treating a human subject with radium-223, for example, Xofigo (radium-223 dichloride) injections.

[0285] In some embodiments, the combination therapy may include administering one or more chemotherapeutic agents to the human subject. Suitable immunotherapies include any known in the art. In some embodiments, the method includes administering sipuleucel-T to the human subject. In some embodiments, the method includes administering an immune checkpoint inhibitor to the 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 the human subject. In some embodiments, the method includes administering an anti-CTLA-4 antibody, such as ipilimumab, to the human subject.

[0286] In some embodiments, the combination therapy may include administering a bispecific T cell engager (BiTE) therapy, such as blinatumomab or solitomab, to a human subject.

[0287] In some embodiments, the combination therapy may comprise administering one or more poly ADP ribose polymerase (PARP) inhibitors to the human subject. In some embodiments, the human subject with prostate cancer also has a DNA repair deficiency. In some embodiments, the human subject with prostate cancer does not have a DNA repair deficiency. Suitable PARP inhibitors include any of those known in the art. For example, in some embodiments, the method comprises administering a PARP inhibitor selected from niraparib, rucaparib, olaparib, talazoparib, veliparib, and fluzoparib to the human subject.

[0288] In some embodiments, the combination therapy may include administering one or more kinase inhibitors to the human subject. In some embodiments, the human subject is characterized by having abnormal levels of each kinase. In some embodiments, the kinase inhibitor may reduce the activity of the androgen receptor or be beneficial in cancer treatment. Suitable kinase inhibitors include any known in the art. For example, in some embodiments, the method includes administering to the human subject a kinase inhibitor selected from sunitinib, dasatinib, cabozantinib, erdafitinib, dovitinib, capivasertib, onvansertib, ipatasertib, afuresertib, alisertib, apitolisib, and opaganib.

[0289] In some embodiments, the combination therapy may include administering one or more bone protective agents to the human subject. In such embodiments, the human subject is typically characterized as having prostate cancer with bone metastasis (e.g., CRPC). Suitable bone protective agents include any known in the art. For example, in some embodiments, the method includes administering to the human subject a bone protective agent selected from denosumab and zolendronic acid.

[0290] In some embodiments, the combination therapy may include administering to a human subject one or more additional agents useful for treating prostate cancer, either by themselves 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 involves administering to a human subject: 1) an anti-IL23 targeting monoclonal antibody, e.g., tildrakizumab; 2) selenium, e.g., sodium selenate; 3) an EZH2 inhibitor, e.g., CPI-1205, GSK2816126, or tazemetostat; 4) a CDK4 / 6 inhibitor, e.g., palbociclib, ribociclib, abemaciclib; 6) a bromodomain and extraterminal domain (BET) inhibitor, e.g., CCS1477, INCB057643, allobresib, ZEN-3694, or molibresib (GSK525762); 7) an anti-CD105 antibody, e.g., TRC105, or carotuximab; 8) niclosamide; 9) an A2A receptor antagonist, e.g. , AZD4635, 10) a phosphoinositide-3-kinase (PI3K) inhibitor, e.g., AZD-8186, buparlisib, or dactolisib, 11) a further non-steroidal CYP17A1 inhibitor, e.g., ceviteronel, 12) an antiprogestogen, e.g., onapristone, 13) navitoclax, 14) an HSP90 inhibitor, e.g., onarespib (AT13387), 15) an HSP27 inhibitor, e.g., OGX-427, 16) a 5-α-reductase inhibitor, e.g., 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 modulators selected from 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 (nuclear protein kinase) inhibitors, extracellular signal-regulated kinase (ERK) modulators, c-jun N-terminal kinase (JNK) modulators, Big MAP kinase (BMK) modulators, p38 mitogen-activated protein kinase (MAPK) modulators, 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.

[0291] In some embodiments, the combination therapy includes: 1) a poly(ADP-ribose) polymerase (PARP) inhibitor, including but not limited to, olaparib, niraparib, rucaparib, talazoparib; 2) an androgen receptor ligand binding domain inhibitor, including but not limited to, enzalutamide, apalutamide, darolutamide, bicalutamide, nilutamide, flutamide, ODM-204, TAS3681; 3) an additional inhibitor of CYP17A1, including but not limited to, galeterone, abiraterone, abiraterone acetate; 4) an additional inhibitor of CYP17A1, including but not limited to, 5) microtubule inhibitors, including but not limited to docetaxel, paclitaxel, cabazitaxel (XRP-6258); 6) gonadotropin-releasing hormone agonists, including but not limited to cyproterone acetate, leuprolide; 7) 5-alpha reductase inhibitors, including but not limited to finasteride, dutasteride, turosteride, bexlosteride, izonsteride, FCE28260, 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 alpha-v-beta-3 inhibitors, including but not limited to VITAXIN; 11) receptor tyrosine kinase inhibitors, including but not limited to sunitsumib; 12) phosphoinositide 3-kinase inhibitors, including but not limited to alpelisib, buparlisib, and idealisib; 13) crizotinib, arefotidine, arbutinib, and rivaroxaban; 14) endothelin receptor A 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 OGX427; 17) androgen receptor degraders, including but not limited to ARV-330, ARV-110; 18) androgen receptor DNA binding domain inhibitors, including but not limited to VPC-14449;19) Bromodomain and extraterminal motif (BET) inhibitors, including but not limited to BI-894999, GSK525762, GS-5829; 20) Androgen receptor N-terminal domain inhibitors, including but not limited to synthokamide; 21) Alpha particle emitting radiotherapeutic agents, including but not limited to radium-233 or a salt thereof; 22) Niclosamide, or related compounds thereof; 23) Selective estrogen receptor modulators (SERMs), including but not limited to tamoxifen, raloxifene, toremifene, arzoxifene, bazedoxifene, pipindoxifene, lasofoxifene, enclomiphene; 24) Selective estrogen receptor degraders (SERDs), including but not limited to fulvestrant, ZB716, OP-1074, elacestrant, AZD9496, GDC0810, GDC0927, GW5638, GW7604. ), 25) aromatase inhibitors, including but not limited to anastrazole, exemestane, letrozole; 26) selective progesterone receptor modulators (SPRMs), including but not limited to mifepristone, lonaprizone, 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 but not limited to palbociclib, abemaciclib, ribociclib; 29) HER2 receptor antagonists, including but not limited to trastuzumab, neratinib; 30) mammalian target of rapamycin (mTOR) inhibitors, including but not limited to everolimus, temsirolimus.

[0292] The combination therapy herein is not particularly limited to any particular number of additional therapies. For example, in addition to administering the abiraterone prodrug or abiraterone prodrug formulation herein and any glucocorticoid, such as hydrocortisone, prednisone, prednisolone, methylprednisolone, and dexamethasone, the combination therapy may generally include one, two, three, four, five, six or more additional therapies described herein. For example, in some embodiments, the combination therapy may include one additional therapy, such as any one of those described herein, such as a GnRH agonist, a GnRH antagonist, an androgen receptor antagonist, chemotherapy, a PARP inhibitor, a kinase inhibitor, immunotherapy, radiation therapy, 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 a PARP inhibitor and an androgen deprivation therapy to a human subject. In some embodiments, the combination therapy may include administering a GnRH agonist and radiation therapy to a human subject. In some embodiments, the combination therapy may include administering a GnRH agonist, a chemotherapeutic agent, and radiation therapy to a human subject. In some embodiments, the combination therapy may include administering an androgen receptor antagonist (e.g., a first, second, and / or third generation AR antagonist), a GnRH agonist, and optionally radiation therapy, a chemotherapeutic agent, indomethacin, or a 5-alpha reductase inhibitor to a human subject. In some embodiments, the combination therapy may include administering an androgen receptor antagonist (e.g., a first, second, and / or third generation AR antagonist) and radiation therapy to a human subject. In some embodiments, the combination therapy may include administering an androgen receptor antagonist (e.g., a first, second, and / or third generation AR antagonist) and a chemotherapeutic agent to a human subject. In some embodiments, the combination therapy can include administering to a human subject an androgen receptor antagonist (e.g., a first, second, and / or third generation AR antagonist) and an anti-CTLA4 antibody.It should be understood that these combinations discussed are examples of useful combinations and are in no way limiting, and other combinations of additional therapies described herein are permissible. However, in some embodiments, the combination therapy does not include administering a GnRH agonist, a GnRH antagonist, androgen deprivation therapy to the human subject, and / or does not include castration of the human subject.

[0293] In any of the combination therapies described herein, the methods may 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, unless otherwise specified or contrary to context.

[0294] It should be noted that in some embodiments, the methods of treating prostate cancer herein (e.g., any of those described herein) are not used in combination with a combination therapy. For example, the methods include administering a therapeutically effective amount of an abiraterone prodrug (e.g., abiraterone decanoate) or an abiraterone prodrug formulation to a human subject without one or more additional therapies described herein.

[0295] Dosing regimen The abiraterone prodrugs and formulations of the present disclosure can generally provide a long-acting release of abiraterone to a human subject user. This long-acting release profile allows abiraterone to be administered to a human subject user at a reduced dosing frequency, 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 dosage burden.

[0296] In some embodiments, the methods herein may have a dosing regimen of once a week or more than once a week. Typically, dosing frequency may range from once a week to once every several months, e.g., once a week to once every 8 weeks, or once a week to once every 3 months, e.g., once a month, once every 2 months, or once every 3 months. In some embodiments, the dosage of each dose 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 recited values) of abiraterone prodrug. In some embodiments, the dosage of the abiraterone prodrug for each dose can be from about 0.5 mg / kg to about 200 mg / kg of the body weight of a human subject (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).

[0297] Abiraterone prodrugs suitable for the above administration methods of once weekly or more than once weekly include those described herein. In some embodiments, the abiraterone prodrug can be a lipophilic ester of abiraterone described herein, such as acetate, propionate, butanoate, (vaterate) pentanoate, isocaproate, bucyclate, cyclohexanecarboxylate, phenylpropionate, caproate (hexanoate), enanthate (heptanoate), cypionate, octanoate, noncanoate, 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, where R 1 is C 7-16 Alkyl, e.g., -(CH2) n-CH3, where n is an integer from 6 to 12 (e.g., n is 6, 7, 8, 9, 10), or R 1 is the formula -(CH2) n -Cy (n is an integer from 1 to 6, and Cy is C 3-6 cycloalkyl or phenyl, for example, in more specific embodiments, n is 1 or 2 and Cy is cyclopentyl, cyclohexyl, or phenyl; or 1 teeth, [ka] or R 1 teeth, [ka] In some embodiments, the abiraterone prodrug can be a compound of formula II, where R 2 is C 1-16 Alkyl, e.g., -(CH2) n -CH3 (n is an integer from 0 to 12), or R of formula II 2 is the formula -(CH2) n -Cy (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 2 teeth, [ka] In any of the embodiments described herein, unless otherwise stated or directly contradicted by context, the abiraterone prodrug may be abiraterone decanoate.

[0298] In some embodiments, monthly or more than monthly dosing is desirable, e.g., dosing frequency ranges from once a month to once every few months, e.g., once a month to once every two months, or once a month to once every three months. In such embodiments, the abiraterone prodrug should not only release abiraterone slowly, but also release abiraterone at sufficient plasma concentrations so that abiraterone may be beneficial to a human subject user. Monthly or more than monthly dosing is typically parenteral, such as intramuscular, intradermal, or subcutaneous. In any of the embodiments herein, administration may be intramuscular, unless directly contrary.

[0299] The abiraterone prodrug and abiraterone prodrug formulations of the present disclosure can be administered to a human subject in need thereof 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 oral administration of abiraterone acetate, such as the Zytiga® formulation, either simultaneously or in any order. In some embodiments, a human subject can use the abiraterone prodrug and abiraterone prodrug formulations as an add-on to existing abiraterone therapy. Furthermore, administration herein is not limited to administering a single abiraterone prodrug or abiraterone prodrug formulation of the present disclosure. In some embodiments, two or more abiraterone prodrug and abiraterone prodrug formulations of the present disclosure can be administered to a human subject.

[0300] In some embodiments, prior to the monthly or more than monthly administration, the methods herein can include an initial treatment period at a higher dosing frequency, such as weekly or biweekly administration. The initial treatment period can include administering the same abiraterone prodrug, or a different abiraterone drug, such as a different abiraterone prodrug. In some embodiments, the methods herein do not include such an initial treatment period.

[0301] As discussed herein, the disclosed abiraterone prodrugs and abiraterone prodrug formulations have many advantages over the currently marketed Zytiga® product. For example, administering the disclosed abiraterone prodrugs and abiraterone prodrug formulations to a human subject generally reduces the C max (e.g., the C of abiraterone observed at steady state when Zytiga® is administered orally at 1000 mg once daily without food) max (at least 30% lower than

[0302] Thus, in some embodiments, the present disclosure provides a C maxThe present invention provides a method of treating a subject having side effects associated with high abiraterone exposure, including having side effects associated with high abiraterone exposure, comprising administering to a human subject an abiraterone prodrug and abiraterone prodrug formulation of the present disclosure, wherein the administration reduces side effects compared to administering a 1000 mg oral dose of Zytiga® once daily without food. Suitable routes of administration, dosages, and frequencies include those described herein. Various side effects or adverse effects are described in the FDA-approved prescribing information for Zytiga® (see, e.g., February 2018 or June 2019 version). In some embodiments, the disclosure also provides a method of treating a subject administered a drug whose metabolism is inhibited by abiraterone, e.g., a drug that is a substrate for CYP2D6 and / or CYP2C8, the method comprising administering to the human subject an abiraterone prodrug and abiraterone prodrug formulation of the disclosure, the administration reduces the inhibition of the metabolism of the drug compared to administering a 1000 mg oral dose of Zytiga® once daily without food. In some embodiments, the disclosure provides a method of treating a human subject suffering from or at risk of suffering from hypertension, hypokalemia, or fluid retention due to mineralocorticoid excess, the method comprising administering to the human subject an abiraterone prodrug and abiraterone prodrug formulation of the disclosure, the administration reduces or reduces the risk of hypertension, hypokalemia, and fluid retention compared to administering a 1000 mg oral dose of Zytiga® once daily without food. In some embodiments, the disclosure provides methods of treating a human subject suffering from or at risk of suffering from adrenal cortical insufficiency, the methods comprising administering to the human subject an abiraterone prodrug and abiraterone prodrug formulation of the disclosure, wherein the administration reduces the adrenal cortical insufficiency or the risk of suffering therefrom compared to administering a 1000 mg oral dose of Zytiga® once daily without food.In some embodiments, the present disclosure provides a method of treating a human subject with severe or fatal hepatotoxicity after taking Zytiga®, the method comprising administering to the human subject an abiraterone prodrug and abiraterone prodrug formulation of the present disclosure, which administration reduces hepatotoxicity. Without being bound by theory, it is believed that administering the abiraterone prodrug and abiraterone prodrug formulation of the present disclosure typically results in reduced but effective abiraterone exposure, which is therefore beneficial for subjects who require lower doses of abiraterone, for example, as described above. Suitable dosing regimens, routes of administration include those described herein.

[0303] Exemplary Methods of Using Abiraterone Decanoate In some specific embodiments, the present disclosure also provides a method of treating a sex hormone-dependent or androgen receptor-driven disease or disorder, e.g., a sex hormone-dependent benign or malignant disorder, an androgen receptor-driven cancer, and / or a syndrome resulting from androgen excess, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising abiraterone decanoate as described herein (e.g., any of those described in the Summary section of the present specification, e.g.,

[18] -

[30] or

[93] -

[0107] of the Summary section of the present specification, or any of those described in the Examples section) to a human subject in need thereof. The administration is not limited to any particular route. However, abiraterone decanoate is typically administered parenterally, e.g., via intramuscular, intradermal, or subcutaneous injection. In some embodiments, the administration is 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 methods herein can also administer a pharmaceutical composition comprising abiraterone decanoate to a human subject, whether the human subject is castrated or not. In some embodiments, the methods herein can also advantageously treat a human subject suffering from liver impairment, such as moderate to severe liver impairment (Child-Pugh classification B or C), prior to administration of abiraterone decanoate. In some embodiments, the methods herein can also advantageously treat a human subject suffering from prostate cancer, wherein the methods herein do not elevate the level of progesterone in the human subject to a level associated with poor clinical outcomes and drug resistance, such as serum or plasma progesterone levels of greater than about 3 nM, when measured 4 weeks, 6 weeks, or 12 weeks after the initial administration of the pharmaceutical composition.In some embodiments, the methods herein are for treating a human subject suffering from prostate cancer, wherein the human subject is characterized as having a serum or plasma progesterone level of greater than about 3 nM after 3 months of abiraterone treatment, such as Zytiga (oral abiraterone acetate and prednisone) treatment, prior to the first administration of a pharmaceutical composition herein.

[0304] Sex hormone-dependent benign or malignant disorders that may be treated with the method include any of those described herein, such as sex hormone-dependent cancers. In some embodiments, the sex hormone-dependent benign or malignant disorder may be selected from androgen-dependent disorders and estrogen-dependent disorders, such as androgen-dependent or estrogen-dependent cancers. In some embodiments, the sex hormone-dependent benign or malignant disorder may be selected from prostate cancer, breast cancer, ovarian cancer, bladder cancer, hepatocellular carcinoma, and lung cancer, etc. In some embodiments, the sex hormone-dependent benign or malignant disorder may be prostate cancer or breast cancer. In some embodiments, the sex hormone-dependent benign or malignant disorder is CRPC or CSPC. In some embodiments, the sex hormone-dependent benign or malignant disorder may be metastatic CRPC or metastatic CSPC. In some embodiments, the prostate cancer is CRPC, and in some embodiments, the patient with CRPC is chemotherapy naive. In some embodiments, the prostate cancer is metastatic CRPC (mCRPC), and in some embodiments, the patient with mCRPC is chemotherapy naive. The syndromes caused by androgen excess that can be treated by this method include those described herein.In some embodiments, the method herein can be a method for treating non-neoplastic syndromes caused by androgen excess in human subjects, such as endometriosis, polycystic ovarian syndrome, congenital adrenal hyperplasia (e.g., classical or non-classical congenital adrenal hyperplasia), precocious puberty, hirsutism, etc.

[0305] In some particular embodiments, the method is for treating a sex hormone dependent or androgen receptor driven cancer, such as prostate cancer (e.g., as described herein), androgen receptor positive salivary duct carcinoma, or androgen receptor positive glioblastoma multiforme.

[0306] The methods herein can be used in combination with one or more additional therapies for the respective disease or disorder. For example, the methods 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, as described herein) to a human subject, either simultaneously or sequentially, via the same or different routes of administration. Non-limiting examples of useful additional therapies also include any of those described in

[37] -

[49] in the Summary section of this specification.

[0307] In some embodiments, the methods herein (e.g., treating prostate cancer or treating classical or non-classical congenital adrenal hyperplasia) may include administering to a human subject an agent that counteracts the reduction of glucocorticoid(s). In some embodiments, the methods herein may include administering to a human subject in need of an agent effective for treating one or more symptoms associated with adrenal insufficiency, such as acute stress, fatigue, etc. In some specific embodiments, the methods herein may include administering to a human subject a steroid, such as a corticosteroid. In some embodiments, the method may include administering to a human subject a glucocorticoid. In some specific embodiments, the method also includes administering to a human subject prednisone, prednisolone, and / or methylprednisolone. In some specific embodiments, the method includes administering to a human subject hydrocortisone, prednisone, prednisolone, methylprednisolone, and / or dexamethasone. In some embodiments, the method also includes administering to the human subject an agent effective for treating a cortisol deficiency, such as hydrocortisone, prednisone, prednisolone, methylprednisolone, and / or dexamethasone. In any such embodiment, the agent may be administered to the human subject via the same or different route of administration, either simultaneously or sequentially, with respect to the administration of abiraterone decanoate.

[0308] In some embodiments according to the methods herein, abiraterone prodrugs, particularly abiraterone decanoate, are administered to a human subject in combination with dexamethasone. For example, in any of the methods described herein, unless otherwise specified or contrary to context, the method may include administering abiraterone decanoate and dexamethasone to a human subject. In some embodiments, the method is for treating prostate cancer, e.g., for treating a human subject who is a chemotherapy-naive CRPC patient, including chemotherapy-naive mCRPC patients. In some embodiments, the method may include administering to the human subject (i) intramuscularly, preferably about 1260 mg of abiraterone decanoate once every 1-3 months, once every 3 months, and (ii) dexamethasone orally once daily. In some embodiments, dexamethasone is administered orally to the human subject at a dose of about 0.1-1 mg / day, such as about 0.5 mg / day. Additional therapies may also be used in combination with the abiraterone decanoate and dexamethasone treatment, including, but not limited to, any of such other therapies described herein, such as any of the applicable therapies described in the Summary section of this specification at

[37] -

[49] .

[0309] However, in some embodiments, glucocorticoid replacement therapy (e.g., administering a glucocorticoid such as hydrocortisone, prednisone, prednisolone, methylprednisolone, or dexamethasone) is not desired. For example, glucocorticoids may be contraindicated in a human subject who may have an underlying disease such as diabetes. In some embodiments, the method may also be characterized in that the human subject is not being treated with glucocorticoid replacement therapy. In some embodiments, the human subject is not being treated with an agent selected from hydrocortisone, prednisone, prednisolone, methylprednisolone, and dexamethasone. In some embodiments, the method may include administering to the human subject a mineralocorticoid receptor antagonist, such as eplerenone. For example, in any of the embodiments herein, if glucocorticoid replacement therapy is not desired and / or is not administered, the method may include administering to the human subject a mineralocorticoid receptor antagonist, such as eplerenone.

[0310] In some embodiments, the methods herein do not cause a reduction in glucocorticoid levels such that glucocorticoid replacement therapy is not required. In such embodiments, the human subject can avoid glucocorticoid replacement therapy and / or the use of mineralocorticoid receptor antagonists, even if glucocorticoids are not contraindicated for the human subject.

[0311] In some embodiments, the methods herein do not cause a significant increase in mineralocorticoid levels and / or do not cause toxicity due to mineralocorticoid excess. In some embodiments, the methods herein are characterized in that no medication to treat mineralocorticoid toxicity is required and is not administered to the human subject. In some embodiments, the methods herein are also characterized in that the human subject is not treated with a medication effective to treat mineralocorticoid toxicity. In some embodiments, the methods herein are characterized in that the human subject is not treated with a medication that is a glucocorticoid or a mineralocorticoid receptor antagonist.

[0312] In some embodiments, the method is for treating prostate cancer and includes a combination therapy, which further includes administering to the human subject one or more additional therapies, e.g., as described herein under the section entitled Combination Therapies for Prostate Cancer. Non-limiting examples of useful additional therapies also include any of those described in the Summary section of this specification at

[37] -

[49] .

[0313] In some embodiments, the methods herein can be characterized by a dosing frequency of once a week, or even less frequently. Typically, the dosing frequency can range from once a week to once every few months, e.g., once a week to once every three months, or once a week to once every eight weeks, e.g., once a month, once every two months, or once every three months. In some embodiments, the methods include administering a pharmaceutical composition comprising abiraterone decanoate (e.g., a unit dosage form described herein) to a human subject once a week, once every two weeks, once every three weeks, once a month, or more than once a month, e.g., once every two months, or once every three months. In some embodiments, the methods include administering a pharmaceutical composition comprising abiraterone decanoate (e.g., a unit dosage form described herein) to a human subject once a week, once a month, or more than once a month, e.g., once every two months, or once every three months. 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 recited values) of abiraterone decanoate. In some embodiments, the dosage of abiraterone decanoate for each dose can be about 0.5 mg / kg to about 200 mg / kg of body weight of a human subject (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). In some embodiments, administration is via intramuscular injection. In some embodiments, administration of a single dose provides therapeutically effective plasma concentrations of abiraterone for at least 1 week, e.g., at least 2 weeks, e.g., at least 3 weeks, at least 4 weeks, and up to 6 or 8 weeks or more, e.g., up to 10 weeks or more.In some embodiments, administration of a single dose provides a plasma concentration of abiraterone of greater than 1.0 ng / ml (e.g., from about 1 ng / ml to about 8 ng / ml, or from about 2 ng / ml or more, from about 4 ng / ml or more, from about 5 ng / ml or more, or from about 8 ng / ml or more) for a period of at least 1 week, e.g., at least 2 weeks, e.g., at least 3 weeks, at least 4 weeks, and up to 6 or 8 weeks or more, e.g., up to 10 weeks or more, etc. In some embodiments, administration provides a single dose or steady state C of abiraterone of about 1 ng / ml to about 300 ng / ml, e.g., from about 1 ng / ml to about 10 ng / ml. max In some embodiments, the administering may also provide a concentration of abiraterone in a tissue of the human subject that is at least 10 times higher than the plasma concentration of abiraterone 7 days after administration (i.e., 168 hours from the time of administration), the tissue being selected from the liver, lung, testis, inguinal lymph node, iliac lymph node, adrenal gland, and prostate. In some embodiments, the abiraterone decanoate formulation may be administered to a human subject in need thereof as the sole source of abiraterone. However, in some embodiments, the abiraterone decanoate formulation may also be administered to a human subject in need thereof as an add-on to another abiraterone therapy.

[0314] In some embodiments, particularly in the methods of treating prostate cancer herein, the dosage and frequency of administration of abiraterone decanoate can be adjusted such that administration provides an amount of abiraterone 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.) in a non-castrated human subject, or to about 1 ng / dL or less in a castrated human subject, within 15 days (e.g., within 7 days, 7-15 days, etc.) of the first administration of abiraterone decanoate. For example, in some embodiments, administering provides an effective amount of abiraterone 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.) in a non-castrated human subject, or to about 1 ng / dL or less in a castrated human subject, when measured 15 days after the first administration of abiraterone decanoate. In some embodiments, administering provides an amount of abiraterone effective to achieve a sustained reduction in serum testosterone levels, such as achieving and maintaining a serum testosterone level of 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 about 1 ng / dL or less in a castrated human subject, within 15 days (e.g., within 7 days, 7-15 days, etc.) of the first administration of abiraterone decanoate. In some embodiments, the dosage and frequency of abiraterone decanoate can be adjusted such that administering provides an amount of abiraterone effective to reduce serum testosterone levels by 50% or more, preferably 75% or more, from baseline within 15 days (e.g., within 7 days, 7-15 days, etc.) of the first administration of abiraterone decanoate. For example, in some embodiments, administering provides an effective amount of abiraterone to reduce serum testosterone levels by 50% or more, preferably 75% or more, from baseline when measured 15 days after the first administration of abiraterone decanoate.In some embodiments, the administering provides an amount of abiraterone effective to achieve a sustained reduction in serum testosterone levels from baseline of 50% or more, 75% or more, etc., within 15 days (e.g., within 7 days, 7-15 days, etc.) of the first administration of abiraterone decanoate.

[0315] In some particular embodiments, the disclosure provides a method of treating a sex hormone dependent or androgen receptor driven disease or disorder, e.g., a sex hormone dependent benign or malignant disorder, or a syndrome resulting from androgen excess (e.g., any of those described herein), in a human subject in need thereof, the method comprising administering abiraterone decanoate intramuscularly to the human subject at an administration frequency of once every 1 to 3 months, e.g., once every 3 months, each administration comprising administering about 50 mg to about 2000 mg of abiraterone decanoate, e.g., about 180 mg, about 360 mg, about 720 mg, about 1260 mg, about 1800 mg, or any range between the recited values, to the human subject. In some embodiments, administration of abiraterone decanoate selectively inhibits CYP17A1 lyase activity over CYP17A1 hydroxylase activity in the human subject. In some embodiments, the sex hormone dependent or androgen receptor driven disease or disorder, e.g., a sex hormone dependent benign or malignant disorder, or a syndrome resulting from androgen excess, is a disease or disorder of a human subject in which lyase selectivity is desired or deemed beneficial, e.g., endometrial cancer, endometriosis, ovarian cancer, and prostate cancer (such as localized prostate cancer).

[0316] In some particular embodiments, the disclosure provides a method of 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 the human subject at an administration frequency of once every 1 to 3 months, e.g., once every 3 months, each administration comprising administering about 50 mg to about 2000 mg of abiraterone decanoate to the human subject, e.g., 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, the prostate cancer is CRPC or CSPC. In some embodiments, the prostate cancer is metastatic CRPC or metastatic CSPC. In some embodiments, the prostate cancer is localized prostate cancer. In some embodiments, the prostate cancer is CRPC, and in some embodiments, the patient with CRPC is chemotherapy naive. In some embodiments, the prostate cancer is metastatic CRPC (mCRPC), and in some embodiments, the patient with mCRPC is chemotherapy naive. Non-limiting examples of prostate cancer also include any of those described in the Summary section of this specification, [8]-

[17] . In some embodiments, the method of treating prostate cancer includes combination therapy, which further includes administering to the human subject one or more additional therapies, e.g., as described herein under the section entitled Combination Therapies for Prostate Cancer. For example, in some embodiments, the human subject is treated with an androgen receptor antagonist, e.g., enzalutamide, e.g., by orally administering enzalutamide at a daily dose of about 160 mg once daily. In some embodiments, the method includes administering abiraterone decanoate and dexamethasone to the human subject, e.g., a human subject who is a chemotherapy naive CRPC patient, including a chemotherapy naive mCRPC patient. In some embodiments, the methods may include administering to a human subject: (i) abiraterone decanoate intramuscularly once every 1-3 months, preferably about 1260 mg once every 3 months, and (ii) dexamethasone orally once daily.In some embodiments, dexamethasone is orally administered to the human subject at a dose of about 0.1-1 mg / day, such as about 0.5 mg / day. Non-limiting examples of useful additional therapies also include any of those described in the Summary section of this specification at

[37] -

[49] . However, in some embodiments, a drug to treat mineralocorticoid toxicity is not required and is not administered to the human subject. In some embodiments, the human subject is not treated with a drug that is effective to treat mineralocorticoid toxicity. In some embodiments, the human subject is not treated with a drug that is a glucocorticoid or a mineralocorticoid receptor antagonist.

[0317] In some specific embodiments, the disclosure provides a method of treating cancer in a human subject in need of such treatment, the cancer being a sex hormone dependent or androgen receptor driven cancer that has metastasized to one or more lymph nodes, the method comprising administering abiraterone decanoate intramuscularly to the human subject at an administration frequency of once every 1 to 3 months, e.g., once every 3 months, each administration comprising administering about 50 mg to about 2000 mg of abiraterone decanoate to the human subject, e.g., 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, administering abiraterone decanoate is effective to inhibit the growth of the cancer in one or more lymph nodes. In some embodiments, the cancer is prostate cancer (e.g., any of those described herein). For example, in some embodiments, the prostate cancer is CRPC or CSPC. In some embodiments, the prostate cancer is CRPC, and in some embodiments, the patient with CRPC is chemotherapy naive. In some embodiments, the prostate cancer is metastatic CRPC (mCRPC), and in some embodiments, the patient with mCRPC is chemotherapy naive. Non-limiting examples of prostate cancer also include any of those described in the Summary section of this specification, [8]-

[17] . In some embodiments, the method includes combination therapy, which further includes administering to the human subject one or more additional therapies, e.g., as described herein under the section titled Combination Treatments for Prostate Cancer. For example, in some embodiments, the human subject is treated with an androgen receptor antagonist, e.g., enzalutamide, e.g., by orally administering enzalutamide at a daily dose of about 160 mg once daily. In some embodiments, the method includes administering abiraterone decanoate and dexamethasone to the human subject, e.g., a human subject who is a chemotherapy naive CRPC patient, including a chemotherapy naive mCRPC patient.In some embodiments, the method may include administering to the human subject (i) about 1260 mg of abiraterone decanoate intramuscularly once every 1-3 months, preferably about 1260 mg once every 3 months, and (ii) dexamethasone orally once daily. In some embodiments, dexamethasone is administered orally to the human subject at a dose of about 0.1-1 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 section of this specification. However, in some embodiments, a drug to treat mineralocorticoid toxicity is not required and is not administered to the human subject. In some embodiments, the human subject is not treated with a drug effective to treat mineralocorticoid toxicity. In some embodiments, the human subject is not treated with a drug that is a glucocorticoid or a mineralocorticoid receptor antagonist.

[0318] In some specific embodiments, the present disclosure provides a method of treating cancer in a human subject in need of such treatment, wherein the cancer is a sex hormone dependent or androgen receptor driven cancer, and the human subject's disease is progressing during or after androgen receptor antagonist based treatment, such as enzalutamide based treatment, and the method comprises administering abiraterone decanoate intramuscularly to the human subject at an administration frequency of once every 1 to 3 months, e.g., once every 3 months, each administration comprising administering about 50 mg to about 2000 mg of abiraterone decanoate to the human subject, e.g., 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, the cancer is prostate cancer (e.g., any of those described herein). For example, in some embodiments, the prostate cancer is CRPC or CSPC. In some embodiments, the prostate cancer is metastatic CRPC or metastatic CSPC. In some embodiments, the prostate cancer is localized prostate cancer. In some embodiments, the prostate cancer is CRPC, and in some embodiments, the patient with CRPC is chemotherapy naive. In some embodiments, the prostate cancer is metastatic CRPC (mCRPC), and in some embodiments, the patient with mCRPC is chemotherapy naive. Non-limiting examples of prostate cancer also include any of those described in the Summary section of this specification, [8]-

[17] . In some embodiments, the method includes a combination therapy, which further includes administering to the human subject one or more additional therapies, for example, those described herein under the section titled Combination Treatments for Prostate Cancer. For example, in some embodiments, the human subject is treated with an androgen receptor antagonist, e.g., enzalutamide, e.g., by orally administering enzalutamide at a daily dose of about 160 mg once daily. In some embodiments, the methods include administering abiraterone decanoate and dexamethasone to a human subject, e.g., a human subject who is a chemotherapy-naïve CRPC patient, including a chemotherapy-naïve mCRPC patient.In some embodiments, the method may include administering to the human subject (i) about 1260 mg of abiraterone decanoate intramuscularly once every 1-3 months, preferably about 1260 mg once every 3 months, and (ii) dexamethasone orally once daily. In some embodiments, dexamethasone is administered orally to the human subject at a dose of about 0.1-1 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 section of this specification. However, in some embodiments, a drug to treat mineralocorticoid toxicity is not required and is not administered to the human subject. In some embodiments, the human subject is not treated with a drug effective to treat mineralocorticoid toxicity. In some embodiments, the human subject is not treated with a drug that is a glucocorticoid or a mineralocorticoid receptor antagonist.

[0319] In some specific embodiments, the disclosure provides a method of treating cancer in a human subject in need of such treatment, the cancer being a sex hormone dependent or androgen receptor driven cancer, the method comprising administering abiraterone decanoate intramuscularly to the human subject at a dosing frequency of once every 1 to 3 months, e.g., once every 3 months, each administration comprising administering about 50 mg to about 2000 mg of abiraterone decanoate, e.g., about 180 mg, about 360 mg, about 720 mg, about 1260 mg, about 1800 mg, or any range between the recited values, to the human subject, the human subject being further treated with an androgen receptor antagonist, such as enzalutamide, prior to, concurrently with, or following parenteral administration of abiraterone decanoate. In some embodiments, the human subject is further treated with enzalutamide. In some embodiments, enzalutamide may be orally administered to the human subject once daily at a daily dose of about 160 mg. In some embodiments, enzalutamide treatment can be initiated at least one day prior to the first administration of abiraterone decanoate. In some embodiments, enzalutamide treatment can be initiated on the same day as the first administration of abiraterone decanoate. In some embodiments, enzalutamide treatment can be initiated at least one day after the first parenteral administration of abiraterone decanoate. In some embodiments, androgen receptor antagonist(s) can be administered to a human subject in combination with parenteral administration of a pharmaceutical composition to achieve a synergistic effect on cancer treatment. In some embodiments, the cancer is prostate cancer (e.g., any of those described herein). For example, in some embodiments, the prostate cancer is CRPC or CSPC. In some embodiments, the prostate cancer is metastatic CRPC or metastatic CSPC. In some embodiments, the prostate cancer is localized prostate cancer. In some embodiments, the prostate cancer is CRPC, and in some embodiments, the patient with CRPC is chemotherapy naive. In some embodiments, the prostate cancer is metastatic CRPC (mCRPC), and in some embodiments, patients with mCRPC are chemotherapy naive.Non-limiting examples of prostate cancer also include any of those described in the Summary section herein, [8]-

[17] . In some embodiments, the method includes a combination therapy, which further includes administering to the human subject one or more additional therapies, e.g., as described herein under the section entitled Combination Treatment for Prostate Cancer. For example, in some embodiments, the human subject is treated with an androgen receptor antagonist, e.g., enzalutamide, e.g., by orally administering enzalutamide at a daily dose of about 160 mg once daily. In some embodiments, the method includes administering abiraterone decanoate and dexamethasone to the human subject, e.g., a human subject who is a chemotherapy-naïve CRPC patient, including a chemotherapy-naïve mCRPC patient. In some embodiments, the method may include administering to the human subject (i) intramuscularly, once every 1-3 months, preferably about 1260 mg abiraterone decanoate once every 3 months, and (ii) orally dexamethasone once daily. In some embodiments, dexamethasone is orally administered to the human subject at a dose of about 0.1-1 mg / day, such as about 0.5 mg / day. Non-limiting examples of useful additional therapies also include any of those described in the Summary section of this specification at

[37] -

[49] . However, in some embodiments, a drug to treat mineralocorticoid toxicity is not required and is not administered to the human subject. In some embodiments, the human subject is not treated with a drug that is effective to treat mineralocorticoid toxicity. In some embodiments, the human subject is not treated with a drug that is a glucocorticoid or a mineralocorticoid receptor antagonist.

[0320] In some specific embodiments, the disclosure provides a method of lowering serum testosterone levels in a human subject in need thereof, the method comprising administering abiraterone decanoate intramuscularly to the human subject at an administration frequency of once every 1-3 months, e.g., once every 3 months, each administration comprising administering about 50 mg to about 2000 mg of abiraterone decanoate to the human subject, e.g., 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 is initiated (i) 4 weeks after the first administration of abiraterone decanoate; and / or (ii) does not elevate serum progesterone levels in a human subject to more than 40% above baseline 2 to 12 weeks after a second dose of abiraterone decanoate, and preferably does not elevate serum progesterone levels in a human subject to more than 20% above baseline 4 weeks after a first dose of abiraterone decanoate, (ii) more than 20% above baseline 6, 8, 10, and / or 12 weeks after a first dose of abiraterone decanoate, and / or (iii) more than 20% above baseline 2 to 12 weeks after a second dose of abiraterone decanoate. In some embodiments, abiraterone decanoate is administered in an amount effective to achieve a sustained reduction in serum testosterone levels in a human subject to 50% or less below baseline within 15 days of the first dose of abiraterone decanoate. In some embodiments, abiraterone decanoate is administered in an amount effective to reduce serum testosterone levels, when measured 15 days after the first administration of abiraterone decanoate, 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.) if the human subject is a non-castrated human subject, or to about 1 ng / dL or less if the human subject is a castrated human subject.In some embodiments, abiraterone decanoate is administered in an amount effective to reduce the serum testosterone level of a human subject to 80% or less below baseline, e.g., 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 the serum testosterone level of a 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, when measured 24 weeks after the first administration of abiraterone decanoate. In some embodiments, abiraterone decanoate is administered in an amount effective to achieve a sustained reduction in serum testosterone levels from baseline by 50% or more, 75% or more, etc., within 15 days (e.g., within 7 days, 7-15 days, etc.) of the first administration of abiraterone decanoate. In some embodiments, the sustained reduction in serum testosterone levels is characterized in that once the human subject's serum testosterone levels fall below 50% below baseline, the serum testosterone levels remain below 50% of 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 human subject's serum testosterone level is 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 about 1 ng / dL or less in a castrated human subject, the serum testosterone level remains about 50 ng / dL or less in a non-castrated human subject, or about 1 ng / dL or less in a castrated human subject, for up to 8 weeks or more after the initial administration of abiraterone decanoate. In some embodiments, the human subject is afflicted with prostate cancer (e.g., any of those described herein).

[0321] In some specific embodiments, the 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 to 3 months, e.g., once every 3 months, each administration comprising administering to the human subject about 50 mg to about 2000 mg, e.g., about 180 mg, about 360 mg, about 720 mg, about 1260 mg, about 1800 mg, or any range between the recited values, of abiraterone decanoate, the administration of abiraterone decanoate being continued for at least 4 weeks after the first administration of abiraterone decanoate. and / or (ii) does not elevate the serum progesterone level of the human subject by more than 40% above baseline after administration of the first dose of abiraterone decanoate, and / or by more than 40% above baseline after administration of the second dose of abiraterone decanoate, and preferably does not elevate the serum progesterone level of the human subject by more than 20% above baseline after administration of the first dose of abiraterone decanoate, by more than 20% above baseline after administration of the first dose of abiraterone decanoate, by more than 6, 8, 10, and / or 12 weeks after administration of the first dose of abiraterone decanoate, and / or by more than 20% above baseline after administration of the second dose of abiraterone decanoate. In some embodiments, the human subject suffers from a sex hormone-dependent or androgen receptor-driven disease or disorder. In some embodiments, the human subject suffers from a sex hormone-dependent benign or malignant disorder, e.g., as described herein. In some embodiments, the human subject suffers from a syndrome resulting from androgen excess, e.g., as described herein.

[0322] In some specific embodiments, the present disclosure also provides a method of reducing androgen and / or estrogen levels in a human subject in need of reduced androgen (e.g., testosterone and / or dihydrotestosterone) and / or estrogen levels, the method comprising administering abiraterone decanoate intramuscularly to the human subject at an administration frequency of once every 1-3 months, e.g., once every 3 months, each administration comprising administering about 50 mg to about 2000 mg of abiraterone decanoate to the human subject, e.g., about 180 mg, about 360 mg, about 720 mg, about 1260 mg, about 1800 mg, or any range between the recited values, wherein administration of abiraterone decanoate is , (i) does not elevate serum progesterone levels in a human subject by more than 40% above baseline 4 weeks after the first administration of abiraterone decanoate, and / or (ii) does not elevate serum progesterone levels in a human subject by more than 40% above baseline 2 to 12 weeks after the second administration of abiraterone decanoate, and preferably does not elevate serum progesterone levels in a human subject by more than 20% above baseline 4 weeks after the first administration of abiraterone decanoate, (ii) does not elevate serum progesterone levels in a human subject by more than 20% above baseline 6, 8, 10, and / or 12 weeks after the first administration of abiraterone decanoate, and / or (iii) does not elevate serum progesterone levels in a human subject by more than 20% above baseline 2 to 12 weeks after the second administration of abiraterone decanoate. In some embodiments, the human subject suffers from a syndrome resulting from androgen excess, such as congenital adrenal hyperplasia (e.g., classical or non-classical congenital adrenal hyperplasia), endometriosis, polycystic ovary syndrome, precocious puberty, hirsutism, etc. In some embodiments, the human subject suffers from an androgen and / or estrogen-related cancer, such as prostate cancer or breast cancer. In some embodiments, the human subject suffers from an androgen receptor-driven cancer, such as those described herein.

[0323] Suitable human subjects for treatment with the methods herein, including administering abiraterone decanoate, are not particularly limited. In some embodiments, the human subject may be a non-castrated human subject. In some embodiments, the human subject may be castrated. For example, in some embodiments, the human subject may be chemically castrated, such as treated with a gonadotropin releasing hormone agonist and / or antagonist. In some embodiments, the human subject may be characterized as suffering from liver damage, such as moderate to severe liver damage (Child-Pugh classification B or C), prior to administration of abiraterone decanoate. In some embodiments, the methods herein may also advantageously treat a human subject suffering from prostate cancer, where the methods herein do not elevate the level of progesterone in the human subject to levels associated with poor clinical outcomes and drug resistance, such as serum or plasma progesterone levels of 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 a serum or plasma progesterone level of greater than about 3 nM after 3 months of abiraterone treatment, such as Zytiga (oral abiraterone acetate and prednisone) treatment, prior to the first administration of the pharmaceutical composition herein. In some embodiments, the human subject may be characterized as being sensitive to or intolerant of gonadotropin releasing hormone ant...

Claims

1. A pharmaceutical composition for use in a method for treating a disease or disorder selected from endometrial cancer, endometriosis, ovarian cancer, and prostate cancer in a human subject in need of such treatment, said method comprising selectively inhibiting CYP17A1 lyase activity over CYP17A1 hydroxylase activity in said human subject, said pharmaceutical composition comprising abiraterone decanoate in its basic form and a pharmaceutically acceptable carrier, said method comprising intramuscularly administering a therapeutically effective amount of said pharmaceutical composition to said human subject once every one to three months, wherein each administration of said pharmaceutical composition comprises administering between 50 mg and 2000 mg of abiraterone decanoate to said human subject. 【Chemistry 1】

2. A pharmaceutical composition for use as described in claim 1, wherein the human subject suffers from or is susceptible to one or more side effects associated with inhibition of hydroxylase activity, or is intolerant of or otherwise susceptible to increased and / or decreased steroid levels due to hydroxylase inhibition.

3. 2. The pharmaceutical composition for use according to claim 1, wherein the disease or disorder is a cancer selected from prostate cancer, endometrial cancer, and ovarian cancer.

4. The pharmaceutical composition for use according to claim 3, wherein the cancer is prostate cancer.

5. A pharmaceutical composition for use as described in claim 4, wherein the human subject suffers from or is susceptible to one or more side effects associated with inhibition of hydroxylase activity, or is intolerant of or otherwise susceptible to increased and / or decreased steroid levels due to hydroxylase inhibition.

6. 4. The pharmaceutical composition for use according to claim 3, wherein the cancer has metastasized to one or more lymph nodes and administering the pharmaceutical composition is effective to inhibit growth of the cancer in the one or more lymph nodes.

7. A pharmaceutical composition for use as described in claim 4, wherein the cancer has metastasized to one or more lymph nodes and administering the pharmaceutical composition is effective in inhibiting the growth of the cancer in the one or more lymph nodes. (i) the cancer is prostate cancer characterized by a Gleason score of 6 or less, and / or (ii) the human subject has measurable prostate-specific antigen; A pharmaceutical composition for use according to claim 4. (i) the cancer is localized prostate cancer, or (ii) 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; or (iii) the cancer is newly diagnosed high-risk metastatic hormone-sensitive prostate cancer; or (iv) the cancer is metastatic CRPC (mCRPC) and the human subject is asymptomatic or has mild symptoms after androgen deprivation therapy failure, for which chemotherapy is not yet clinically indicated, or (v) the cancer is metastatic CRPC (mCRPC) and the human subject's disease has progressed during or after a taxane-based chemotherapy regimen; or (vi) the cancer is refractory prostate cancer; A pharmaceutical composition for use according to claim 4.

10. (i) the human subject's disease has progressed during or after androgen receptor antagonist-based therapy, and / or (ii) 5. The pharmaceutical composition for use according to claim 4, wherein the human subject has developed resistance to treatment with abiraterone acetate in combination with prednisone.

11. (A) The pharmaceutical composition comprises: each milliliter containing: (a) abiraterone decanoate in its base form in an amount of 100 mg to 300 mg; (b) benzyl alcohol in an amount of 50 mg to 150 mg; (c) benzyl benzoate in an amount of 100 mg to 300 mg; and (d) corn oil in an amount sufficient to bring the total volume to 1 milliliter; each milliliter containing (a) abiraterone decanoate in its base form in an amount of 180 mg; (b) benzyl alcohol in an amount of 50 mg to 150 mg; (c) benzyl benzoate in an amount of 100 mg to 300 mg; and (d) corn oil in an amount sufficient to bring the total volume to 1 milliliter; and / or (B) the pharmaceutical composition is administered to the human subject once every three months, and each administration of the pharmaceutical composition comprises administering 1260 mg of abiraterone decanoate to the human subject. A pharmaceutical composition for use according to any one of claims 1 to 10.

12. A pharmaceutical composition for use according to any one of claims 1 to 10, wherein the method further comprises administering enzalutamide to the human subject.

13. The method comprising: (A) further comprising administering to the human subject one or more agents selected from hydrocortisone, prednisone, prednisolone, methylprednisolone, and dexamethasone; and / or (B) administering to the human subject: (1) a poly ADP-ribose polymerase (PARP) inhibitor; and / or (2) a chemotherapeutic agent; and / or (3) an immunotherapy; and / or (4) a bispecific T-cell engager (BiTE) therapy; and / or (5) a kinase inhibitor; and / or (6) a bone protective agent, wherein the human subject is characterized as having prostate cancer with bone metastasis; and / or (7) an anti-IL23 targeting monoclonal antibody; and / or (8) selenium; and / or (9) an EZH2 inhibitor; and / or (10) a CDK4 / 6 inhibitor; and / or (11) a bromodomain and extraterminal domain (BET) inhibitor; and / or (12) an anti-CD105 antibody; and / or further comprising administering (13) niclosamide; and / or (14) an A2A receptor antagonist; and / or (15) a PI3K inhibitor; and / or (16) an additional non-steroidal CYP17A1 inhibitor; and / or (17) an antiprogestogen; and / or (18) navitoclax; and / or (19) an HSP90 inhibitor; and / or (20) an HSP27 inhibitor; and / or (21) a 5-α-reductase inhibitor; and / or (22) metformin; and / or (23) AMG-386; and / or (24) dextromethorphan; and / or (25) theophylline; and / or (26) hydroxychloroquine; and / or (27) lenalidomide. A pharmaceutical composition for use according to any one of claims 1 to 10.

14. (A) The human subject is (i) chemotherapy-naive or hormone therapy-naive prior to administration of the pharmaceutical composition, and / or (ii) the human subject suffers from liver impairment, such as moderate to severe liver impairment (Child-Pugh classification B or C), prior to receiving the pharmaceutical composition; and / or (B) (i) the human subject has prostate cancer and the method does not elevate the level of progesterone in the human subject to a level associated with poor clinical outcome and drug resistance, such as greater than 3 nM serum or plasma progesterone, when measured 4 weeks, 6 weeks, or 12 weeks after initial administration of the pharmaceutical composition; and / or (ii). the human subject has prostate cancer, and the human subject is characterized by having a serum or plasma progesterone level greater than 3 nM after 3 months of abiraterone treatment prior to the first administration of the pharmaceutical composition; and / or (C) 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. A pharmaceutical composition for use according to any one of claims 1 to 10.

15. The pharmaceutical composition for use according to any one of claims 1 to 10, wherein the method comprises administering to the human subject (i) 1260 mg of abiraterone decanoate intramuscularly once every three months, and (ii) dexamethasone orally once daily at a daily dose of 0.5 mg / day.

16. 1. A pharmaceutical composition comprising an abiraterone decanoate solution, wherein each milliliter of the abiraterone decanoate solution contains: (a) abiraterone decanoate in its base form in an amount of 100 mg to 300 mg; (b) benzyl alcohol in an amount of 50 mg to 150 mg; (c) benzyl benzoate in an amount of 100 mg to 300 mg; (d) 3-mercapto-1,2-propanediol in an amount of 0.5 mg to 20 mg; and (e) corn oil in an amount sufficient to bring the total volume to 1 milliliter, wherein the abiraterone decanoate has the following structure: 【Chemistry 2】

17. 17. The pharmaceutical composition of claim 16, wherein each milliliter of the abiraterone decanoate solution comprises: (a) abiraterone decanoate in its base form in an amount of 180 mg; (b) benzyl alcohol in an amount of 50 mg to 150 mg; (c) benzyl benzoate in an amount of 100 mg to 300 mg; (d) 3-mercapto-1,2-propanediol in an amount of 0.5 mg to 2 mg; and (e) corn oil in an amount sufficient to bring the total volume to 1 milliliter.

Images