Abiraterone Prodrug

Abstract

Sustained release abiraterone prodrug formulations, methods, and kits for parenteral administration to subjects having sex hormone dependent benign or malignant diseases such as prostate cancer, androgen receptor driven cancers, syndromes due to androgen excess, and / or syndromes due to glucocorticoid excess such as hypercortisolism.

Description

[Technical field]

[0001] The present disclosure generally relates to novel prodrugs of abiraterone and long-acting depot-based parenteral formulations of abiraterone prodrugs. The disclosure is directed to a wide range of applications, such as intramuscular (IM) injections in patients with androgen or estrogen hormone-dependent benign or malignant diseases, or androgen receptor-driven cancers, including various cancers (such as prostate cancer, bladder cancer, hepatocellular carcinoma, lung cancer, breast cancer, and ovarian cancer), and for the treatment of non-neoplastic syndromes resulting from the overproduction of androgens (including classical and non-classical congenital adrenal hyperplasia, endometriosis, polycystic ovary syndrome, precocious puberty, hirsutism, etc.), or conditions such as Cushing's syndrome or Cushing's disease resulting from the overproduction of glucocorticoids, typically cortisol. [Background technology]

[0002] Abiraterone ((3β)-17-(pyridin-3-yl)androsta-5,16-dien-3-ol, CAS number: 154229-19-3), formula: C 24 H 31NO, mol wt: 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 CYP17A1 17α-hydroxylase and 17,20 lyase enzyme activity. 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, estriol) through the conversion of 17α-hydroxypregnenolone to the sex steroid precursor, dehydroepiandrosterone (see FIG. 1). Thus, abiraterone inhibits the synthesis of androgens and estrogens in the gonads (mainly the testes and ovaries) and extragonadally (the adrenal glands and their tumors).

[0003] Abiraterone itself is poorly absorbed, but can be administered orally as an abiraterone acetate prodrug. Abiraterone acetate is also poorly absorbed, but can be converted to abiraterone in the intestine, which makes it less absorbed into the bloodstream after cleavage of the acetate ester prodrug. Abiraterone acetate ((3β)-17-(3-pyridyl)androsta-5, acetate ester; 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.

[0004] It is known that orally administered abiraterone acetate prodrugs are not well absorbed in the gastrointestinal tract (and the prodrug is barely detectable in plasma). Instead, abiraterone acetate is hydrolyzed to abiraterone in the intraluminal environment, resulting in abiraterone supersaturation, which has been shown to play a role in generating a strong driving force for abiraterone absorption (Stappaerts et al., Eur. J. Pharmaceutics Biopharmaceutics 90:1, 2015).

[0005] Abiraterone interferes with 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. Indeed, Zytiga® (250 mg tablets) is approved in the United States for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC) and patients with metastatic castration-sensitive prostate cancer (CSPC) only in combination with prednisone. The Zytiga® prescribing information recommends oral administration of 1000 mg (4 x 250 mg tablets) once daily in combination with oral administration of prednisone (5 mg) 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.

[0006] Because administration of abiraterone acetate with food increases absorption of abiraterone acetate (and therefore potentially increases and significantly variability in exposure, which may result in a variety of side effects, including 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. Indeed, the prescribing information for Zytiga® states that the drug must be taken on an empty stomach, with no food being consumed at least 2 hours before and at least 1 hour after oral administration.

[0007] The prescribing information states that, when administered orally daily at 1,000 mg, Zytiga® to patients with metastatic CRPC, 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 confirmed that systemic exposure of abiraterone was increased when Zytiga® was administered with food. Specifically, the C 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).

[0008] The currently approved oral solid formulation of the prodrug abiraterone acetate has several drawbacks. For example, it has very low bioavailability, which imposes a high daily dosing burden on patients (4 x 250 mg tablets taken once daily). In addition, the combination of low bioavailability and high food effect results in high variability in blood levels in patients. Furthermore, abiraterone is rapidly excreted, so this approved dosing regimen requires only 100 mg of abiraterone per day. min of abiraterone, which is believed to be associated with loss of therapeutic benefit in patients with metastatic CRPC.

[0009] 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. Summary of the Invention

[0010] The present disclosure relates generally to novel abiraterone prodrugs, long-acting abiraterone prodrug formulations, and methods of using same in the treatment of subjects having, for example, sex hormone-dependent benign or malignant disorders, androgen receptor-driven cancers, and / or syndromes resulting from androgen and / or glucocorticoid excess; see also U.S. Patent No. 10,792,292 B2, issued to Propella Therapeutics, Inc. on October 6, 2020, and U.S. Provisional Application No. 63 / 073,502, filed on September 2, 2020, the contents of each of which are incorporated by reference in their entirety herein.

[0011] The novel abiraterone prodrugs may typically be fatty acid esters of abiraterone, which upon cleavage release abiraterone and a safe and degradable fatty acid moiety. Compared to oral abiraterone acetate formulations, the novel abiraterone prodrugs and formulations herein provide improved bioavailability, elimination of food effects, reduced dosage burden, reduced dosing frequency, and sustained effective plasma levels of abiraterone, e.g., greater than or equal to the daily C 100 mg / dose observed with oral administration of abiraterone acetate. min The abiraterone prodrug formulations are groundbreaking in that they provide plasma exposure above levels, for example, for at least 1 week, typically at least 2 weeks, and up to 10 weeks or more, following administration of the abiraterone prodrug formulations. 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 even less frequent administration for treating subjects with sex hormone-dependent benign or malignant diseases, androgen receptor-driven cancers, syndromes resulting from androgen excess, and / or syndromes resulting from glucocorticoid excess. This characteristic 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 taken daily).

[0012] As described in detail herein, the present disclosure further shows that administering an abiraterone prodrug, such as abiraterone decanoate, can achieve sustained reduction in serum androgen levels without the need to castrate the subject or administer an effective amount of another drug to the subject to reduce serum androgen levels. The present disclosure also shows that administration of abiraterone prodrugs is generally well tolerated. For example, no liver toxicity was observed from intramuscular administration of abiraterone decanoate at the doses tested. In addition, the present disclosure provides novel parenteral formulations of abiraterone prodrugs, particularly abiraterone decanoate formulations that may be more suitable for pharmaceutical development. The compositions and methods described herein fulfill a long-standing unmet need by providing an alternative to oral formulations that suffer from: (1) low bioavailability; (2) interactions with ingested food; (3) delivery of parent drug with widely variable blood levels that can reduce efficacy and increase side effects; (4) the need for daily dosing and high dose burden; (5) the need for castration; and (6) poor patient compliance due to the need for daily dosing of supplemental prednisone or prednisolone with fasting within hours of dosing, high dose burden, and conflicting dosing schedules because it must be taken with food.

[0013] In some embodiments, the present disclosure provides: [1] A method of treating a sex hormone dependent cancer or an androgen receptor driven cancer in a subject in need thereof, e.g., an uncastrated subject, comprising administering, typically parenterally, to the subject a pharmaceutical composition comprising a therapeutically effective amount of an abiraterone prodrug (e.g., an abiraterone lipophilic ester). [2] The method of [1], wherein the subject is not treated with an amount of a gonadotropin releasing hormone agonist and / or antagonist effective to reduce the subject's serum testosterone level. [3] The method of [1], wherein the subject is not being treated with a drug selected from buserelin, leuprolide, deslorelin, fertirelin, histrelin, gonadorelin, resilient, goserelin, nafarelin, perforelin, and triptorelin. [4] The method of [1] or [3], wherein the subject is not being treated with a drug selected from abarelix, cetrorelix, degarelix, ganirelix, elagolix, linzagolixa, and relugolix. [5] Any one of the methods, [1] to [4], wherein the subject is sensitive or otherwise intolerant to gonadotropin-releasing hormone antagonists and / or agonists. [6] The method according to any one of [1] to [5], wherein the subject is not treated with glucocorticoid replacement therapy.

[0014] [7] The method according to any one of [1] to [6], wherein the abiraterone prodrug comprises abiraterone decanoate or a pharma- ceutically acceptable salt thereof. [ka] [8] The method according to any one of [1] to [7], wherein the pharmaceutical composition comprises an abiraterone prodrug and a pharma- ceutically acceptable carrier. [9] The method of [8], wherein the pharma- ceutically acceptable carrier comprises a pharma- ceutically acceptable oil, and optionally a further pharma- ceutical acceptable solvent.

[10] The method of [9], 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.

[11] The method of [9] or

[10] , 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 seed oil, and soybean oil, and the further pharma- ceutically acceptable solvent, if present, comprises benzyl alcohol, benzyl benzoate, or a combination thereof.

[12] The method according to any one of [8] to

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

[0015]

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

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

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

[13] , wherein the pharmaceutical composition has a viscosity of less than 0.1 Pa*s, for example, about 0.05 Pa*s or less.

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

[14] , 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 a glide force of about 2 to 15 N when measured using a 23 G, 1.5 inch needle, and / or a glide force of about 30 to 150 N when measured using a 27 G, 1.5 inch needle.

[16] Pharmaceutical compositions are disclosed in the U.S.P. <788> and / or <789> The method according to any one of [1] to

[15] , characterized in that the particle size 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, as measured according to the above.

[17] Pharmaceutical compositions are <85> The method according to any one of [1] to

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

[0016]

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

[17] , wherein the subject has not undergone prostatectomy.

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

[18] , wherein the subject is further treated with radiation therapy.

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

[19] , wherein the sex hormone-dependent or androgen receptor-driven cancer is androgen receptor-positive salivary duct carcinoma or androgen receptor-positive glioblastoma multiforme.

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

[19] , wherein the sex hormone-dependent or androgen receptor-driven cancer is prostate cancer.

[22] The method of

[21] , wherein the prostate cancer is localized prostate cancer, e.g., high-risk localized prostate cancer.

[23] The method according to

[21] , wherein 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.

[24] The method according to

[21] , wherein the prostate cancer is newly diagnosed high-risk metastatic hormone-sensitive prostate cancer.

[25] The method according to

[21] , wherein the prostate cancer is metastatic CRPC, and the subject is an asymptomatic or mildly symptomatic subject after failure of androgen deprivation therapy who has no demonstrated clinical need for chemotherapy.

[26] The method of

[21] , wherein the prostate cancer is metastatic CRPC and the subject's disease has progressed during or after a taxane-based chemotherapy regimen, such as a docetaxel-based or cabazitaxel-based chemotherapy regimen.

[27] The method according to

[21] , wherein the prostate cancer is refractory prostate cancer.

[0017]

[28] The method according to any one of [1] to [5] and [7] to

[27] , further comprising administering to the subject one or more agents selected from hydrocortisone, prednisone, prednisolone, methylprednisolone, and dexamethasone.

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

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

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

[29] , further comprising administering to the subject a first-generation androgen receptor antagonist, e.g., proxartamide, bicalutamide, flutamide, nilutamide, or topirutamide.

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

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

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

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

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

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

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

[33] , further comprising administering to the subject an immunotherapeutic agent, such as administering 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).

[0018]

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

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

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

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

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

[36] , further comprising administering to the subject a bone protective agent (e.g., denosumab, zolendronic acid), and characterized in that the subject is suffering from prostate cancer with bone metastasis (e.g., CRPC).

[38] Subjects were treated with 1) an anti-IL23 targeted monoclonal antibody, e.g., tildrakizumab; 2) selenium, such as sodium selenite; 3) an EZH2 inhibitor, e.g., CPI-1205, GSK2816126, or tazemetostat; 4) a CDK4 / 6 inhibitor, e.g., palbociclib, ribociclib, or abemaciclib; 6) a bromodomain and extra-terminal 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 PI3 The method of any one of [1] to

[37] , further comprising administering to the subject a therapeutic agent selected from the group consisting of a CYP17A1 inhibitor, such as AZD-8186, buparisib, or dactolisib, 10) a further non-steroidal CYP17A1 inhibitor, such as seviteronel, 11) an antiprogestogen, such as onapristone, 12) navitoclax, 13) an HSP90 inhibitor, such as onarespib (AT13387), 14) an HSP27 inhibitor, such as OGX-427, 15) a 5-alpha reductase inhibitor, such as dutasteride, 16) metformin, 17) AMG-386, 18) dextromethorphan, 20) theophylline, 21) hydroxychloroquine, and 22) lenalidomide.

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

[38] , further comprising administering to the subject one or more kinase regulators 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 IkappaB kinase 1 (IKK1) inhibitor, a PIM-1 regulator, a Lemur tyrosine kinase 2 (LMTK2) regulator, a Lyn inhibitor, an Aurora A inhibitor, an ANPK (A nuclear protein kinase) inhibitor, an extracellular signal-regulated kinase (ERK) regulator, a c-jun N-terminal kinase (JNK) regulator, a Big MAP kinase (BMK) regulator, a p38 mitogen-activated protein kinase (MAPK) regulator, and combinations thereof.

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

[39] , wherein the subject is chemotherapy-naïve or hormone therapy-naïve prior to administration of the pharmaceutical composition.

[0019]

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

[40] , wherein administration of the pharmaceutical composition provides the subject with an effective amount of abiraterone to achieve a sustained reduction in serum testosterone levels to about 50 ng / dL or less, if the subject is a non-castrated subject, or about 1 ng / dL or less, if the subject is a castrated subject, within 15 days of the initial administration of the abiraterone prodrug.

[42] A method of lowering serum testosterone levels in a subject in need thereof, comprising parenterally administering to the subject a pharmaceutical composition comprising an abiraterone prodrug (e.g., an abiraterone lipophilic ester), whereby the administration provides an amount of abiraterone effective to achieve a sustained reduction in serum testosterone levels to about 50 ng / dL or less, if the subject is a non-castrated subject, or to about 1 ng / dL or less, if the subject is a castrated subject, within 15 days of the initial administration of the abiraterone prodrug.

[43] The method according to

[42] , wherein the subject is a non-castrated subject.

[44] The method of

[42] or

[43] , wherein the subject is not treated with an amount of a gonadotropin releasing hormone antagonist and / or agonist effective to reduce the subject's serum testosterone level.

[45] The method of

[42] or

[43] , wherein the subject is not treated with a drug selected from buserelin, leuprolide, deslorelin, fertirelin, histrelin, gonadorelin, resilient, goserelin, nafarelin, perforelin, and triptorelin.

[46] The method of

[42] ,

[43] , or

[45] , wherein the subject is not being treated with a drug selected from abarelix, cetrorelix, degarelix, ganirelix, elagolix, linzagolixa, and relugolix.

[47] The method of any one of

[42] to

[46] , wherein the subject is sensitive or otherwise intolerant to gonadotropin releasing hormone antagonists and / or agonists.

[0020]

[48] ​​The method according to any one of

[42] to

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

[49] The method according to any one of

[42] to

[48] , wherein the pharmaceutical composition comprises an abiraterone prodrug and a pharma- ceutically acceptable carrier.

[50] The method of

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

[51] The method of

[50] , 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.

[52] The method of

[50] or

[51] , 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 seed oil, and soybean oil, and the further pharma- ceutically acceptable solvent, if present, comprises benzyl alcohol, benzyl benzoate, or a combination thereof.

[53] The method according to any one of

[49] to

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

[0021]

[54] The method of any one of

[42] to

[53] , wherein the pharmaceutical composition contains, per milliliter, (a) 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) of the basic form of abiraterone decanoate; (b) about 50 mg to about 150 mg (e.g., about 75 mg, about 100 mg, or about 125 mg) of benzyl alcohol; (c) about 100 mg to about 300 mg (e.g., about 100 mg, about 150 mg, about 200 mg, or about 250 mg) of benzyl benzoate; and (d) an appropriate amount of corn oil per milliliter.

[55] The method according to any one of

[42] to

[54] , wherein the pharmaceutical composition has a viscosity of less than 0.1 Pa*s, for example, about 0.05 Pa*s or less.

[56] The method according to any one of

[42] to

[55] , 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 a glide force of about 2 to 15 N when measured using a 23 G, 1.5 inch needle, and / or a glide force of about 30 to 150 N when measured using a 27 G, 1.5 inch needle.

[57] Pharmaceutical compositions are described in U.S.P. <788> and / or <789> The method according to any one of

[42] to

[56] , characterized in that the particle size 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, as measured according to the above.

[58] Pharmaceutical compositions are described in U.S.P. <85> The method according to any one of

[42] to

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

[59] The method according to any one of

[42] to

[58] , wherein the subject has a sex hormone-dependent cancer or an androgen receptor-driven cancer.

[60] The method according to any one of

[42] to

[59] , wherein the subject has androgen receptor-positive salivary duct carcinoma or androgen receptor-positive glioblastoma multiforme.

[61] The method according to any one of

[42] to

[59] , wherein the subject has prostate cancer.

[62] The method of

[61] , wherein the prostate cancer is localized prostate cancer, e.g., high-risk localized prostate cancer.

[0022]

[63] The method according to any one of

[42] to

[62] , wherein the subject has not undergone prostatectomy.

[64] The method of any one of

[42] to

[63] , wherein the subject is further treated with radiation therapy.

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

[64] , wherein the pharmaceutical composition is administered via intramuscular injection, intradermal injection, or subcutaneous injection.

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

[65] , wherein the pharmaceutical composition is administered to the subject once a week or once every few weeks.

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

[66] , wherein the pharmaceutical composition is administered to the subject once a month or once every few months, for example once every two months or once every three months.

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

[67] , wherein the pharmaceutical composition is administered to the subject with or without food.

[69] Administration of abiraterone to a patient with a pulmonary circulation disorder is associated with: (a) a plasma concentration of abiraterone greater than 1.0 ng / ml for a period of at least 2 weeks following a single dose; (b) a single-dose or steady-state C of abiraterone of about 5 ng / ml to about 300 ng / ml. maxor (c) a method according to any one of [1] to

[68] , which results in both (a) and (b).

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

[69] , wherein the subject has hepatic impairment, such as moderate to severe hepatic impairment (Child-Poo class B or C), prior to administration of the abiraterone prodrug.

[0023]

[71] The pharmaceutical composition comprises, per milliliter, (a) abiraterone decanoate in a basic form in an amount of about 100 mg to about 300 mg (e.g., about 100 mg, about 120 mg, about 150 mg, about 180 mg, about 200 mg, or about 250 mg); (b) benzyl alcohol in an amount of about 50 mg to about 150 mg (e.g., about 75 mg, about 100 mg, or about 125 mg); (c) benzyl benzoate in an amount of about 100 mg to about 300 mg (e.g., about 100 mg, about 150 mg, about 200 mg, or about 250 mg); and (d) corn oil in an amount appropriate for each milliliter, wherein the abiraterone decanoate has the structure: [ka]

[72] The pharmaceutical composition of

[71] , comprising, per milliliter: (a) abiraterone decanoate in a basic form in an amount of about 180 mg; (b) benzyl alcohol in an amount of about 50 mg to about 150 mg (e.g., about 75 mg, about 100 mg, or about 125 mg); (c) benzyl benzoate in an amount of about 100 mg to about 300 mg (e.g., about 100 mg, about 150 mg, about 200 mg, or about 250 mg); and (d) corn oil in an amount appropriate for each milliliter.

[73] The pharmaceutical composition of

[71] , comprising, per milliliter: (a) abiraterone decanoate in a basic form in an amount of about 200 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 appropriate for each milliliter.

[74] The pharmaceutical composition according to any one of

[71] to

[73] , 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).

[75] The pharmaceutical composition according to any one of

[71] to

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

[0024]

[76] The pharmaceutical composition according to any one of

[71] to

[75] , characterized in that the abiraterone decanoate has less than 1% by weight (e.g., less than 0.5% by weight, such as less than 0.3% by weight, less than 0.2% by weight, or less than 0.1% by weight) of ethyl prasterone decanoate having the following formula: [ka]

[77] The pharmaceutical composition according to any one of

[71] to

[75] and

[98] , wherein abiraterone decanoate does not contain a detectable amount of ethyl prasterone decanoate.

[78] The pharmaceutical composition according to any one of

[71] to

[77] and

[98] , characterized in that the pharmaceutical composition has a viscosity of less than 0.1 Pa*s, for example, about 0.05 Pa*s or less.

[79] The pharmaceutical composition according to any one of

[71] to

[78] and

[98] , characterized in that 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 a glide force of about 2 to 15 N when measured using a 23 G, 1.5 inch needle, and / or a glide force of about 30 to 150 N when measured using a 27 G, 1.5 inch needle.

[80] Pharmaceutical compositions are described in U.S.P. <788> and / or <789> The pharmaceutical composition according to any one of

[71] to

[79] and

[98] , characterized in having not more than 1,000 particles having a size of 10 μm or more and not more than 300 particles having a size of 25 μm or more, as measured according to

[81] Pharmaceutical compositions are described in U.S.P. <85> The pharmaceutical composition according to any one of

[71] to

[80] and

[98] , characterized in that it has a bacterial endotoxin content of less than 100 EU / ml, for example less than 25 EU / ml, measured according to the method of the present invention.

[0025]

[82] A substantially pure abiraterone decanoate, characterized in that it has a palladium content of less than 50 ppm, wherein the abiraterone decanoate has the following structure: [ka]

[83] The substantially pure abiraterone decanoate of

[82] , having a palladium content of less than 10 ppm.

[84] The substantially pure abiraterone decanoate of

[82] or

[83] , characterized in that it has a purity of at least 95% by weight, preferably at least 98%, e.g., about 98.5%, about 99%, about 99.5% or more.

[0026]

[85] The substantially pure abiraterone decanoate according to any one of

[82] to

[84] , characterized in that it has less than 1% by weight (e.g., less than 0.5% by weight, such as less than 0.3% by weight, less than 0.2% by weight, or less than 0.1% by weight) of ethyl prasterone decanoate having the following formula: [ka]

[86] A substantially pure abiraterone decanoate according to any one of

[82] to

[85] , which is in a crystalline form, for example, crystalline form A of any one of

[0108] to

[0113] .

[87] A substantially pure abiraterone decanoate according to any one of

[82] to

[86] , which meets the specifications set forth in Table D.

[88] A method for preparing a pharmaceutical composition comprising: a) mixing substantially pure abiraterone decanoate of any one of

[82] -

[87] with a pharma- ceutically acceptable carrier (e.g., any of those described herein) to form a mixture; and, optionally, b) sterilizing the mixture formed in a).

[89] The method of

[88] , wherein the pharma- ceutically acceptable carrier comprises a pharma- ceutically acceptable oil (e.g., any of those described herein), and optionally a pharma- ceutically acceptable solvent (e.g., any of those described herein).

[0027]

[90] The method of

[89] , wherein the pharma- ceutically acceptable oil comprises vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, or soybean oil.

[91] The method of

[89] or

[90] , wherein the optional pharma- ceutically acceptable solvent comprises benzyl alcohol and / or benzyl benzoate.

[92] The method according to any one of

[88] to

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

[93] The method according to any one of

[88] to

[92] , wherein abiraterone decanoate is present at a concentration of about 50 mg / mL to about 300 mg / mL.

[94] The method of any one of

[88] to

[93] , wherein the pharmaceutical composition comprises, per milliliter, (a) substantially pure abiraterone decanoate in basic form in an amount of about 100 mg to about 300 mg (e.g., about 100 mg, about 120 mg, about 150 mg, about 180 mg, about 200 mg, or about 250 mg); (b) benzyl alcohol in an amount of about 50 mg to about 150 mg (e.g., about 75 mg, about 100 mg, or about 125 mg); (c) benzyl benzoate in an amount of about 100 mg to about 300 mg (e.g., about 100 mg, about 150 mg, about 200 mg, or about 250 mg); and (d) corn oil in an amount appropriate for each milliliter.

[95] The method of any one of

[88] to

[93] , wherein the pharmaceutical composition comprises, per milliliter: (a) substantially pure abiraterone decanoate in basic form in an amount of about 180 mg; (b) benzyl alcohol in an amount of about 50 mg to about 150 mg (e.g., about 75 mg, about 100 mg, or about 125 mg); (c) benzyl benzoate in an amount of about 100 mg to about 300 mg (e.g., about 100 mg, about 150 mg, about 200 mg, or about 250 mg); and (d) corn oil in an amount appropriate for each milliliter.

[96] The method of any one of

[88] to

[93] , wherein the pharmaceutical composition comprises, per milliliter: (a) substantially pure abiraterone decanoate in basic form in an amount of about 200 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 appropriate for each milliliter.

[97] The method according to any one of

[88] to

[96] , wherein the pharmaceutical composition comprises benzyl alcohol and benzyl benzoate, and 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).

[98] A pharmaceutical composition produced by a method according to any one of

[88] to

[97] .

[99] The pharmaceutical composition is a method according to any one of [1] to

[70] , selected from any one of

[71] to

[81] and

[98] .

[0028]

[0100] 1. A method for preparing crystalline form A of abiraterone decanoate, the method comprising: a) dissolving abiraterone decanoate in a first solvent to form a first solution; b) adding activated charcoal to the first solution; c) removing the activated charcoal to form a second solution; and d) crystallizing abiraterone decanoate from the first solution to form crystalline form A of abiraterone decanoate, wherein abiraterone decanoate has the following structure: [ka]

[0101] The method of claim 0100, wherein the crystallization step d) comprises cooling the second solution, reducing the amount of the first solvent, and / or adding a poor solvent in which abiraterone decanoate has a lower solubility than the first solvent.

[0102] The method of any one of claims 1 to 5, wherein the first solvent is selected from acetone, dioxane, 1-propanol, methyl tert-butyl ether, isopropyl ether, t-butanol, chloroform, ethyl acetate, nitromethane, dimethylacetamide, tetrahydrofuran, dimethylformamide, diethyl ether, 2-butanol, isopropyl acetate, ethanol, methanol, toluene, acetonitrile, heptane, 2-propanol, 2-butanone, 2-methyltetrahydrofuran, a combination of methanol and tetrahydrofuran, a combination of methanol and chloroform, a combination of acetonitrile and t-butanol, and a combination of acetonitrile and 2-propanol.

[0103] The method according to claim 1, wherein the first solvent is selected from ethyl acetate, ter-butanol, chloroform, isopropyl ether, tetrahydrofuran, 2-propanol, acetonitrile, 2-butanone, heptane, toluene, and methanol, and the crystallization step d) comprises cooling the second solution and / or reducing the amount of the first solvent.

[0104] The method according to

[0100] or

[0101] , wherein the first solvent is acetone.

[0105] The method according to any one of

[0101] to

[0104] , wherein the poor solvent is water.

[0029]

[0106] The method according to any one of

[0101] to

[0105] , wherein the volume ratio of the poor solvent to the first solvent in the second solution is in the range of about 1:50 to about 1:10.

[0107] The method of

[0100] , which is substantially the same as the process described in Example 1B of the present specification.

[0108] Crystalline form A of abiraterone decanoate, prepared by any one of the methods described in

[0100] to

[0107] , which is substantially free of form B and form C of abiraterone decanoate, for example, detectable amounts of form B and form C by XRPD.

[0109] Crystalline form A of abiraterone decanoate described in

[0108] , which is substantially pure.

[0110] Crystalline form A of abiraterone decanoate according to

[0108] or

[0109] , characterized in that it has a palladium content of less than 50 ppm, such as less than 10 ppm.

[0111] Crystalline form A of abiraterone decanoate described in any one of

[0108] to

[0110] , characterized in that it has a purity of at least 95% by weight, preferably at least 98%, for example, about 98.5%, about 99%, about 99.5% or more.

[0030]

[0112] Crystalline form A of abiraterone decanoate ethyl described in any one of

[0108] to

[0111] , characterized in that it has less than 1 wt% (e.g., less than 0.5 wt%, such as less than 0.3 wt%, less than 0.2 wt%, or less than 0.1 wt%) of ethyl prasterone decanoate having the following formula: [ka]

[0113] Crystalline form A of abiraterone decanoate described in any one of

[0108] to

[0112] , which meets the specifications set forth in Table D.

[0114] A pharmaceutical composition comprising crystalline form A of abiraterone decanoate.

[0115] A pharmaceutical composition comprising crystalline form B of abiraterone decanoate.

[0116] A pharmaceutical composition comprising crystalline form C of abiraterone decanoate.

[0031]

[0013] Embodiments of the present disclosure may fulfill a long-standing need in the field of sex hormone dependent diseases and oncology, including the treatment of sex hormone dependent or androgen receptor driven cancers, e.g., prostate cancer. Embodiments of the present disclosure may also fulfill a long-standing need in the field of treatment of syndromes resulting from androgen excess and / or syndromes resulting from glucocorticoid excess, such as hypercortisolism. Embodiments of the present disclosure may overcome major shortcomings and deficiencies of prior art formulations of abiraterone acetate (including commercially available oral formulations) by providing a long-acting, sustained release depot-based parenteral formulation of an abiraterone prodrug, methods of making the same, methods of treatment using the same, and kits for convenient administration of the formulations to patients in need of treatment for various diseases, including prostate cancer.

[0032] The features have been outlined more broadly in order to provide a better understanding of the details set forth below, and to provide a better understanding of the present contribution to the art. It will be appreciated that additional features 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.

[0033] In this regard, before describing at least one embodiment in detail, it is to be understood that the invention is not limited in its application to the details and arrangements of construction set forth in the following description or illustrated in the following drawings. The invention is capable of other embodiments and of being practiced or carried out in various ways. Moreover, it is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting.

[0034] Thus, those skilled in the art will appreciate that the concepts underlying the present disclosure may be readily utilized as a basis for the design of other formulations, methods, systems, kits, and compositions for carrying out the several purposes of the present disclosure, and it is therefore important that equivalent structures within the scope of the present disclosure are included in the present disclosure.

[0035] The accompanying drawings are included to provide a further understanding, and are incorporated in and constitute a part of this specification, illustrating several embodiments and, together with the description, explaining the principles thereof. [Brief description of the drawings]

[0036] [Figure 1] 1 depicts biochemical pathways showing the effect of CYP17A1 inhibition on the synthesis of androgens, estrogens, glucocorticoids, progesterone, and mineralocorticoids. [Figure 2A] 1 depicts a representative X-ray powder diffraction (XRPD) spectrum of the solid form of abiraterone decanoate (alternatively abbreviated herein as "AbiDec") prepared in Example 1A, designated as Form A. [Figure 2B] 1 shows a representative differential scanning calorimetry (DSC) spectrum of the abiraterone decanoate solid form prepared in Example 1A, designated as Form A. [Figure 2C] 1 shows a representative thermogravimetric analysis (TGA) of the abiraterone decanoate solid form prepared in Example 1A, designated as Form A. [Figure 2D] 1 depicts a representative XRPD spectrum of abiraterone decanoate form B. [Figure 2E] 1 shows a representative DSC spectrum of abiraterone decanoate form B. [Figure 2F] 1 shows a representative TGA of abiraterone decanoate form B. [Figure 2G] 1 depicts a representative XRPD spectrum of abiraterone decanoate form C. [Figure 2H] 1 shows a representative DSC spectrum of abiraterone decanoate form C. [Figure 2I] 1 shows a representative TGA of abiraterone decanoate form C. [Diagram 3] A representative analysis of a batch of high purity abiraterone decanoate is shown. [Figure 4A] Figure 1 shows time profile data of mean plasma concentrations of abiraterone following a single oral dose of abiraterone acetate (5 mg / kg, 15 mg / kg, and 45 mg / kg) on ​​day 29 and a single IM injection of abiraterone decanoate (10 mg / kg, 30 mg / kg, and 100 mg / kg) on ​​day 43 in chemically castrated, sexually mature male cynomolgus monkeys. [Figure 4B] FIG. 1 shows time profile data of mean plasma concentrations of abiraterone following a single IM injection of abiraterone decanoate (10 mg / kg, 30 mg / kg, and 100 mg / kg) in chemically castrated, sexually mature male cynomolgus monkeys up to 98 days post-injection. [Figure 5A] Figure 1 shows time profile data of dihydrotestosterone levels (labeled DHT in figure) following a single IM injection of abiraterone decanoate (10 mg / kg, 30 mg / kg, and 100 mg / kg) in chemically castrated, sexually mature male cynomolgus monkeys up to 98 days post-injection. Dexamethasone (Dex) and methylprednisolone acetate (MethPred) were also administered according to the schedules shown in Example 3. [Figure 5B] Figure 1 shows time profile data of testosterone levels (labeled T in figure) following a single IM injection of abiraterone decanoate (10 mg / kg, 30 mg / kg, and 100 mg / kg) in chemically castrated, sexually mature male cynomolgus monkeys up to 98 days post-injection. Dexamethasone (Dex) and methylprednisolone acetate (MethPred) were also administered according to the schedules shown in Example 3. [Figure 5C]Figure 1 shows time profile data of cortisol levels (labeled Cort in figure) following a single IM injection of abiraterone decanoate (10 mg / kg, 30 mg / kg, and 100 mg / kg) in chemically castrated, sexually mature male cynomolgus monkeys up to 98 days post-injection. Dexamethasone (Dex) and methylprednisolone acetate (MethPred) were also administered according to the schedules shown in Example 3. [Figure 5D] Figure 1 shows time profile data of progesterone levels (labeled Prog in the figure) following a single IM injection of abiraterone decanoate (10 mg / kg, 30 mg / kg, and 100 mg / kg) in chemically castrated, sexually mature male cynomolgus monkeys up to 70 days post-injection. Dexamethasone (Dex) and methylprednisolone acetate (MethPred) were also administered according to the schedules shown in Example 3. [Figure 6A] Figure 1 shows time course profile data for serum androgen levels (dehydroepiandrosterone, androstenedione, testosterone, or dihydrotestosterone) following IM injections of vehicle or abiraterone decanoate (20 mg / kg, 60 mg / kg, and 200 mg / kg) in sexually mature male cynomolgus monkeys with intact gonads up to 85 days after the first injection. Note: Day 0 in the figure indicates samples collected on day -1 of the study: andro = androstenedione, DHEA = dehydroepiandrosterone, DHT = dihydrotestosterone, T = testosterone. [Figure 6B] Figure 1 shows time profile data of serum cortisol and progesterone levels following IM injections of vehicle or abiraterone decanoate (20 mg / kg, 60 mg / kg, and 200 mg / kg) once every two weeks in sexually mature male cynomolgus monkeys up to 85 days after the first injection. Note: Day 0 in the figure indicates samples collected on day -1 of the study: cort=cortisol, prog=progesterone. [Figure 6C]Figure 1 shows time course profile data of serum cortisol and progesterone levels following IM injections of vehicle or abiraterone decanoate (20 mg / kg, 60 mg / kg, and 200 mg / kg) in sexually mature male cynomolgus monkeys with intact gonads, up to 85 days after the first injection. Note: Day 0 in the figure indicates samples collected on day -1 of the study: 17OHP=17OH-progesterone, aldo=aldosterone, cortico=corticosterone, DOC=deoxycorticosterone. [Figure 7A] FIG. 1 shows time profile data of mean plasma concentrations of abiraterone following a single IM injection of abiraterone decanoate (90 mg / kg) in rats, strain CD® [Crl:CD® (SD)], up to 168 hours post-dose. [Figure 7B] FIG. 1 shows time profile data of mean plasma concentrations of abiraterone decanoate following a single IM injection of abiraterone decanoate (90 mg / kg) in rats, strain CD® [Crl:CD® (SD)], up to 168 hours post-dose. [Figure 7C] FIG. 1 shows time profile data of mean serum androstenedione (labeled Andro) levels up to 168 hours post-dose following a single IV injection of abiraterone (1.1 mg / kg) or abiraterone decanoate (1.6 mg / kg), or a single IM injection of vehicle or abiraterone decanoate (90 mg / kg) in rats, strain CD® [Crl:CD® (SD)]. [Figure 7D] FIG. 1 shows time profile data for mean serum progesterone (labeled Prog in figure) levels following a single IV injection of abiraterone (1.1 mg / kg) or abiraterone decanoate (1.6 mg / kg), or a single IM injection of vehicle or abiraterone decanoate (90 mg / kg) in rats, strain CD® [Crl:CD® (SD)], up to 168 hours post-dose. [Figure 7E]FIG. 1 shows time profile data of mean serum testosterone (labeled T in figure) levels following a single IV injection of abiraterone (1.1 mg / kg) or abiraterone decanoate (1.6 mg / kg), or a single IM injection of vehicle or abiraterone decanoate (90 mg / kg) in rats, strain CD® [Crl:CD® (SD)], for up to 168 hours post-dose. [Figure 7F] FIG. 1 shows time profile data of mean serum cortisol (Figure label Prog) levels following a single IV injection of abiraterone (1.1 mg / kg) or abiraterone decanoate (1.6 mg / kg), or a single IM injection of vehicle or abiraterone decanoate (90 mg / kg) in rats, strain CD® [Crl:CD® (SD)], up to 168 hours post-dose. [Figure 7G] FIG. 1 shows time profile data of mean serum testosterone (labeled T in figure) levels following a single IV injection of abiraterone (1.1 mg / kg) in rats, strain CD® [Crl:CD® (SD)], up to 168 hours post-dose. [Figure 7H] FIG. 1 shows time profile data of mean serum testosterone (labeled T in figure) levels following a single IM injection of abiraterone (90 mg / kg) in rats, strain CD® [Crl:CD® (SD)], up to 168 hours post-dose. [Figure 8A] FIG. 1 shows plasma and tissue exposure to abiraterone, expressed as AUC end, up to 168 hours post-dose following a single IV injection of abiraterone (1.1 mg / kg) or abiraterone decanoate (1.6 mg / kg) or a single IM injection of abiraterone decanoate (90 mg / kg) in rats, strain CD® [Crl:CD® (SD)]. [Figure 8B]FIG. 1 shows plasma and tissue exposure to abiraterone, expressed as AUC end, up to 168 hours post-dose following a single IV injection of abiraterone decanoate (1.6 mg / kg) or a single IM injection of abiraterone decanoate (90 mg / kg) in rats, strain CD® [Crl:CD® (SD)]. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0037] In a broad aspect, the present disclosure relates to novel methods for regulating serum steroid hormone levels in a subject in need of such regulation, and novel methods for treating or preventing diseases or disorders associated with such steroid hormones, as well as abiraterone prodrugs and formulations useful therein.Embodiments of the present disclosure are based in part on the fact that abiraterone prodrugs can be administered to a subject at a dosing frequency of once a week or once every few weeks to achieve sustained inhibition of CYP17A1 activity.Embodiments of the present disclosure are also based in part on the unexpected discovery that administering an abiraterone prodrug to a subject can achieve sustained reduction in serum androgen levels without the need to castrate the subject or administering to the subject an amount of another drug effective to reduce serum androgen levels.

[0038] As further detailed herein and described in part in U.S. Pat. No. 10,792,292 B2 and U.S. Provisional Application No. 63 / 073,502, the methods herein provide the following benefits: reduced associated side effects; rapid and sustained reduction in serum testosterone; no need for castration; reduced or no liver toxicity compared to methods using oral abiraterone acetate formulations; improved bioavailability; elimination of the food effects associated with oral abiraterone acetate formulations; reduced dosage burden; improved patient compliance; reduced dosing frequency; sustained stable blood levels of active drug; max The present invention may be advantageous over existing methods in many aspects, including but not limited to, reducing

[0039] 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 associated with such steroids, such as sex hormone dependent or androgen receptor driven cancers, and / or abiraterone prodrugs and formulations useful therein.

[0040] Treatment method In some embodiments, the disclosure provides a method of treating a disease or disorder described herein in a subject in need thereof. The method typically involves parenterally administering to a subject, such as a non-castrated subject, a pharmaceutical composition comprising a therapeutically effective amount of an abiraterone prodrug (e.g., an abiraterone lipophilic ester), which can be effective to inhibit CYP17A1 and modulate various steroid hormone levels in the subject, such as androgens, estrogens, glucocorticoids, progesterone, and mineralocorticoids.

[0041] The methods herein are advantageous in many aspects over methods using oral abiraterone acetate. For example, compared to oral abiraterone acetate formulations, parenterally administering the pharmaceutical compositions herein can provide improved bioavailability, elimination of food effects, reduced dosage burden, reduced dosing frequency, and sustained effective plasma levels of abiraterone, e.g., daily C 100-1500 mg / dose observed with oral administration of abiraterone acetate for at least 1 week, typically at least 2 weeks, and up to 10 weeks or more after administration of an abiraterone prodrug formulation. minIt can provide sustained plasma exposure above levels of CYP17A1. As detailed herein, administering an abiraterone prodrug can achieve sustained inhibition of CYP17A1 (see also U.S. Patent No. 10,792,292B2 and U.S. Provisional Patent Application No. 63 / 073,502). In particular, as shown in Example 3 of the present disclosure, a single administration of a representative abiraterone prodrug, abiraterone decanoate, at doses of 10 mg / kg, 30 mg / kg, or 100 mg / kg to chemically castrated monkeys resulted in sustained inhibition of CYP17A1, as evidenced by sustained elevation of progesterone levels and reductions in cortisol, dihydrotestosterone, and testosterone levels, for up to 70 days. It was also found that sustained PD effects were observed even after the plasma concentration of abiraterone in the 10 mg / kg dose group had fallen to less than 1 ng / mL. Without wishing to be bound by theory, these observed prolonged PD effects may be due in part to the slow and tight binding of CYP17A1 by abiraterone, which may effectively achieve irreversible inhibition of CYP17A1 (see, e.g., Cheong EJY, et al. J. Pharmacol. Exp. Ther. 374:438-451 (2020)). Thus, abiraterone prodrugs and abiraterone prodrug formulations may be advantageously used for inhibiting CYP17A1 activity, reducing glucocorticoid levels, such as cortisol levels, reducing sex hormone levels, such as androgen and / or estrogen levels, and / or treating diseases associated with high glucocorticoid levels, such as cortisol levels, and / or treating diseases resulting from high sex hormone levels, such as androgen and / or estrogen levels.

[0042] As also detailed in the Examples section herein, the present disclosure unexpectedly shows that administration of abiraterone prodrugs can also result in sustained reductions in testosterone in subjects within days after the first administration of the prodrug, without the need for castration or another drug effective in reducing testosterone levels. Specifically, intramuscular administration of abiraterone decanoate to non-castrated monkeys at several doses (20, 60, or 200 mg / kg / dose) administered every two weeks achieved sustained reductions in serum androgen levels, including testosterone, androstenedione, dehydroepiandrosterone, and dihydrotestosterone, within 15 days after the first administration. The same sustained reduction was also observed in another study in rats, where a single intramuscular dose of abiraterone decanoate was found to achieve sustained reductions in testosterone for up to 168 hours (last test time point). Without wishing to be bound by theory, it is believed that intramuscular administration of the abiraterone prodrug resulted in both sustained effective plasma levels of abiraterone as well as favorable tissue distribution of abiraterone and the abiraterone prodrug, such as to the testes, which may contribute to the observed effects on serum steroids that are not achieved by oral abiraterone acetate formulations (e.g., Zytiga®). Because the methods herein do not rely on castration to achieve desired testosterone levels, it is advantageous to use the methods herein to treat at least subjects who do not wish to be castrated and / or who are sensitive or otherwise intolerant to gonadal testosterone suppressants.

[0043] The present disclosure further demonstrates that administering an abiraterone prodrug was generally well tolerated, e.g., no liver toxicity was observed from intramuscular administration of abiraterone decanoate at the doses tested. Thus, the methods herein can also advantageously treat subjects suffering from liver impairment, such as moderate to severe liver impairment (Child-Poo class B or C), prior to administration of an abiraterone prodrug.

[0044] Thus, in some embodiments, the disclosure provides a method of treating a disease or disorder described herein in a non-castrated subject in need of such treatment, the method comprising parenterally administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising an abiraterone prodrug (e.g., an abiraterone lipophilic ester). As used herein, "castration," "castrated," and similar terms should be understood to encompass all forms of castration, including surgical and chemical castration.

[0045] In some embodiments, the disclosure provides a method of treating a disease or disorder described herein in a subject in need thereof, the method comprising parenterally administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising an abiraterone prodrug (e.g., an abiraterone lipophilic ester), wherein the subject suffers from moderate to severe liver impairment (Child-Pugh class B or C) prior to administration of the abiraterone prodrug.

[0046] Typically, in the methods herein, another drug effective to reduce serum and / or gonadal testosterone levels is not administered to the subject simultaneously with administration of the abiraterone prodrug during treatment with the abiraterone prodrug or would otherwise interfere with treatment with the abiraterone prodrug. For example, in some embodiments, the subject is not treated with a gonadal testosterone suppressant other than the administered abiraterone prodrug in an amount effective to reduce the subject's serum testosterone level. In some embodiments, the subject is not treated with a gonadotropin releasing hormone antagonist and / or agonist in an amount effective to reduce the subject's serum testosterone level. In some embodiments, the subject is not treated with any gonadal testosterone suppressant other than the administered abiraterone prodrug. In some embodiments, the subject is not treated with any gonadotropin releasing hormone antagonist and / or agonist. In some embodiments, the subject is not being treated with a drug selected from buserelin, leuprolide, deslorelin, fertirelin, histrelin, gonadorelin, resilelin, goserelin, nafarelin, peforelin, and triptorelin. In some embodiments, the subject is not being treated with a drug selected from abarelix, cetrorelix, degarelix, ganirelix, elagolix, linzagolixa, and relugolix. In some embodiments, the subject may be sensitive to gonadotropin releasing hormone antagonists and / or agonists or may otherwise be intolerant to agonists.

[0047] 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 not desired. For example, glucocorticoids may be contraindicated for subjects who may have an underlying disease such as diabetes. In some embodiments, the methods may also be characterized in that the subject is not being treated with glucocorticoid replacement therapy. In some embodiments, the subject is not treated with an agent selected from hydrocortisone, prednisone, prednisolone, methylprednisolone, and dexamethasone. In some embodiments, the methods herein may include administering a mineralocorticoid receptor antagonist, such as eplerenone, to the subject. For example, in any of the embodiments herein in which glucocorticoid replacement therapy is not desired and / or is not administered, the methods may include administering a mineralocorticoid receptor antagonist, such as eplerenone, to the subject.

[0048] Various diseases or disorders are suitable for treatment by the methods herein. For example, in some embodiments, the disease or disorder may be a sex hormone-dependent benign or malignant disease, an androgen receptor-driven cancer, a syndrome resulting from androgen excess, and a syndrome resulting from glucocorticoid excess. In some embodiments, the hormone-dependent benign or malignant disease may be an androgen-dependent and estrogen-dependent disease, such as an androgen- or estrogen-dependent cancer. In some embodiments, the sex hormone-dependent benign or malignant disease may be prostate cancer or breast cancer. In some embodiments, the sex hormone-dependent benign or malignant disease is CRPC or CSPC. In some embodiments, the sex hormone-dependent benign or malignant disease is metastatic CRPC or metastatic CSPC. In some embodiments, the sex hormone-dependent benign or malignant disease may also be ovarian cancer, bladder cancer, hepatocellular carcinoma, or lung cancer. For example, various non-neoplastic syndromes resulting from androgen excess and / or glucocorticoid excess, such as hypercortisolism, including syndromes resulting from androgen excess, such as endometriosis, polycystic ovary syndrome, classical or non-classical congenital adrenal hyperplasia, precocious puberty, hirsutism, and / or syndromes resulting from cortisol excess, such as Cushing's syndrome and Cushing's disease, can also be treated by the methods herein.

[0049] 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 can be androgen receptor-positive salivary duct cancer or androgen receptor-positive glioblastoma multiforme. In some embodiments, the sex hormone-dependent or androgen receptor-driven cancer is prostate cancer (e.g., any of those described herein). Prostate cancer suitable for treatment by the method herein is not particularly limited, and includes, but is not limited to, any prostate cancer in which abiraterone or its derivatives (e.g., abiraterone acetate) have been approved for sale (e.g., in the United States or Europe) or in which abiraterone or its derivatives (e.g., abiraterone acetate) are in or after clinical trials, such as trials registered on the website clinicaltrials.gov at the time of filing this application. For example, in some embodiments, the prostate cancer may be primary / localized prostate cancer (newly diagnosed or early stage), advanced prostate cancer (e.g., post-castration, such as recurrent prostate cancer, locally advanced prostate cancer), 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 patient suffering from prostate cancer is characterized by an increased amount of prostate-specific antigen, e.g., 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 metastatic CRPC (mCRPC) and the control is an asymptomatic or mildly symptomatic control after failure of androgen deprivation therapy with no demonstrated clinical need for chemotherapy.In some embodiments, the prostate cancer is metastatic CRPC (mCRPC) and the subject's disease progresses on or after a taxane-based chemotherapy regimen, such as a docetaxel-based or cabazitaxel-based chemotherapy regimen. In some embodiments, the prostate cancer is refractory prostate cancer. As used herein and unless otherwise specified, the phrase "refractory prostate cancer" refers to prostate cancer that does not respond to anti-cancer therapy or does not respond adequately to anti-cancer therapy. Refractory prostate cancer may also include recurrent or relapsing prostate cancer. As used herein and unless otherwise specified, the phrase "relapsing prostate cancer" refers to prostate cancer that once responded to anti-cancer therapy but has become unresponsive or does not respond adequately to such therapy. As used herein and unless otherwise specified, the phrase "recurrent (or recurrent) prostate cancer" refers to prostate cancer that has recurred after a patient was previously diagnosed with prostate cancer and treated, or was previously diagnosed as not having cancer.

[0050] In some embodiments, the method herein is for treating breast cancer.The breast cancer suitable for treatment by the method herein is not particularly limited.For example, in some embodiments, breast cancer may 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.

[0051] In some embodiments, the disease or disorder is associated with 21 hydroxylase deficiency and can be treated by the methods herein.

[0052] In some embodiments, the methods herein can be used to treat a control, such as an uncastrated subject, having cancer, such as prostate cancer, breast cancer, adrenal cancer, leukemia, lymphoma, myeloma, Waldenstrom's macroglobulinemia, monoclonal gammopathy, benign monoclonal gammopathy, heavy chain disease, bone and connective tissue 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, penile cancer, oral cancer, skin cancer, kidney cancer, Wilms' tumor, and bladder cancer.

[0053] In some embodiments, the methods herein may include treating the subject with one or more additional therapies. For example, in some embodiments, the subject further receives radiation therapy. In some embodiments, the methods include combination therapy for treating prostate cancer and further comprising administering to the subject one or more additional therapeutic agents, for example, as described herein below in the section entitled Combination Treatment for Prostate Cancer. Non-limiting examples of useful additional therapies also include any of those described in

[28] -

[39] in the Summary section of this specification.

[0054] Subjects suitable for treatment by the methods herein are not particularly limited, and include subjects at various stages of disease or treatment and other characteristics. For example, in any of the embodiments described herein, unless specified or otherwise contradictory, the subject may be a non-castrated subject. In some embodiments, the methods herein may also administer a pharmaceutical composition comprising an abiraterone prodrug to a subject, regardless of whether the subject is castrated or not. In some embodiments, the subject has not undergone a prostatectomy. In some embodiments, the subject may be characterized as suffering from liver damage, such as moderate to severe liver damage (Child-Poo class B or C), prior to administration of the abiraterone prodrug. In some embodiments, the subject may be characterized as sensitive or otherwise intolerant to gonadotropin releasing hormone antagonists and / or agonists. In some embodiments, the subject may be characterized as being chemotherapy-naïve or hormone therapy-naïve prior to administration of the pharmaceutical compositions herein. However, in some embodiments, the patient may be treated with chemotherapy or hormone therapy prior to administration of the pharmaceutical compositions herein. For example, in some embodiments, the subject may have a disease or disorder (e.g., prostate cancer) that has progressed during or after chemotherapy, such as a taxane-based chemotherapy regimen, e.g., a docetaxel-based or cabazitaxel-based chemotherapy regimen, and / or hormone therapy. In any of the embodiments described herein, unless directly contradicted, the subject may be a human subject.

[0055] Suitable pharmaceutical compositions and abiraterone prodrugs for the methods herein include, but are not limited to, any of those described herein, such as the decanoic acid abiraterone formulations described herein, for example, any of those described in the Abstract Section of the present specification, such as

[71] -

[81] and

[98] , as well as any of the abiraterone prodrug and abiraterone prodrug formulations described in U.S. Patent No. 10,792,292 B2 and U.S. Provisional Application No. 63 / 073,502. Typically, a pharmaceutical composition suitable for the methods herein is a long-acting parenteral formulation comprising an abiraterone prodrug. In some embodiments, the long-acting parenteral formulation can be formulated to deliver therapeutically 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 weeks, or 8 weeks or more) in a subject after a single administration. In some embodiments, the therapeutically effective plasma concentration of abiraterone may be 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 also be about 0.5 ng / ml or greater. In some embodiments, the therapeutically effective plasma concentration of abiraterone may also be about 0.1 ng / ml or greater. In some embodiments, the pharmaceutical composition is administered to a subject to produce a PK profile as described herein, e.g., (a) a plasma concentration of abiraterone of greater than 1.0 ng / ml over a period of at least two weeks from a single dose; (b) a C of about 5 ng / ml to about 300 ng / ml from a single dose or at steady state. max or (c) both (a) and (b), and so forth.

[0056] The route of administration and dosage 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 subject via intramuscular injection, intradermal injection, or subcutaneous injection. For example, in some specific embodiments, the pharmaceutical composition is administered to the 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 subject has eaten or not, and thus, in some embodiments, the abiraterone prodrug or abiraterone prodrug formulation of the present disclosure can be administered to the subject regardless of whether or not the subject has eaten. In other words, it does not matter whether the patient is postprandial or fasting. This eliminates the limitation associated with the currently marketed Zytiga® formulation, which states that the drug "must be taken on an empty stomach, at least 1 hour before a meal or 2 hours after a meal, with water." Thus, among other advantages, the methods herein can improve patient compliance.

[0057] The dose and frequency of the methods herein are also not particularly limited and include any of those described herein. Generally, the pharmaceutical composition is administered to the subject once a week or once every few weeks. For example, in some embodiments, the methods herein include administering the abiraterone prodrug or abiraterone prodrug formulation herein at a dosing frequency ranging from once a week to once every few months. In some embodiments, the pharmaceutical composition is administered to the subject once a month or once every few months, for example, once every two months or once every three months. As described herein, a single administration of a representative abiraterone prodrug, abiraterone decanoate, at a dose of 10 mg / kg, 30 mg / kg, or 100 mg / kg resulted in sustained CYP17A1 inhibition in chemically castrated monkeys for up to 70 days or more. This result supports the less frequent dosing schedules described herein. In some specific embodiments, the methods herein include administering an abiraterone prodrug or abiraterone prodrug formulation herein at a dosing frequency ranging from once a month to once every several months, e.g., once a month, once every two months, once every three months, or even less frequent dosing. The dosage of the abiraterone prodrug herein (e.g., abiraterone decanoate) for each administration can typically vary from 0.5 mg / kg to 200 mg / kg of the subject's body weight, e.g., about 0.5 mg 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 of values ​​recited). In some embodiments, the administration results in: (a) a plasma concentration of abiraterone of greater than 1.0 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 5 ng / ml to about 300 ng / ml. maxor (c) both (a) and (b). In some embodiments, the administration may also result in a concentration of abiraterone in a tissue of the subject that is at least 10-fold higher than the plasma concentration of abiraterone at day 7 after administration (i.e., 168 hours from the time of administration), the tissue being selected from liver, lung, testis, inguinal lymph, iliac lymph, adrenal gland, and prostate.

[0058] In some embodiments, specifically in the methods of treating prostate cancer herein, the dosage and frequency of administration of an abiraterone prodrug herein (e.g., abiraterone decanoate) can be adjusted such that the 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 subject, or to about 1 ng / dL or less in a castrated subject, within 15 days (e.g., within 7 days, between 7 and 15 days, etc.) of the first administration of the abiraterone prodrug. For example, in some embodiments, the dosage 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 subject, or to about 1 ng / dL or less in a castrated subject, as measured 15 days after the first administration of the abiraterone prodrug. In some embodiments, the administration 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 subject, or about 1 ng / dL or less in a castrated subject, within 15 days (e.g., within 7 days, between 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 the administration 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, between 7-15 days, etc.) of the first administration of the abiraterone prodrug.For example, in some embodiments, the administration provides an amount of abiraterone effective to reduce serum testosterone levels by 50% or more, preferably 75% or more, from baseline, as measured 15 days after the first administration of the abiraterone prodrug. In some embodiments, the administration provides an amount of abiraterone effective to achieve a sustained reduction in 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 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 subject, or about 1 ng / dL or less in a castrated subject, or 50% or less compared to baseline, for a sustained period of time that 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, and at high doses of 200 mg / kg / dose, serum testosterone levels can be reduced by 75% or more for at least 85 days.

[0059] How to Lower Steroid Hormone Levels Some embodiments of the present disclosure are directed to methods of lowering serum steroid hormone levels in a subject in need thereof.

[0060] In some specific embodiments, the disclosure provides a method of reducing serum testosterone levels in a subject in need thereof, the method comprising parenterally administering to the subject a pharmaceutical composition comprising an abiraterone prodrug (e.g., an abiraterone lipophilic ester). Typically, the 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 subject, or to about 1 ng / dL or less in a castrated subject, within 15 days (e.g., within 7 days, 7-15 days, etc.) of the first administration of the abiraterone prodrug, particularly when the subject is characterized as having prostate cancer. For example, in some embodiments, the dosage 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 subject, or to about 1 ng / dL or less in a castrated subject, as measured 15 days after the first administration of the abiraterone prodrug. In some embodiments, the administration 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 subject, or about 1 ng / dL or less in a castrated subject, within 15 days (e.g., within 7 days, between 7-15 days, etc.) of the first administration of the abiraterone prodrug. Typically, the administration 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, between 7-15 days, etc.) of the first administration of the abiraterone prodrug.For example, in some embodiments, the administration provides an amount of abiraterone effective to reduce serum testosterone levels by 50% or more, preferably 75% or more, from baseline, as measured 15 days after the first administration of the abiraterone prodrug. In some embodiments, the administration provides an amount of abiraterone effective to achieve a sustained reduction in 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.

[0061] Suitable subjects to be treated by the methods herein for reducing serum testosterone levels are not particularly limited. For example, in some embodiments, the subject may be a non-castrated subject. In some embodiments, the methods herein may also administer a pharmaceutical composition comprising an abiraterone prodrug to a subject, regardless of whether the subject is castrated or not. Typically, in the methods herein, another drug effective to reduce serum and / or gonadal testosterone levels is not administered to the subject simultaneously with administration of the abiraterone prodrug during treatment with the abiraterone prodrug, or would otherwise interfere with treatment with the abiraterone prodrug. For example, in some embodiments, the subject is not treated with an amount of a gonadal testosterone suppressant other than the administered abiraterone prodrug that is effective to reduce the subject's serum testosterone level. In some embodiments, the subject is not treated with an amount of a gonadotropin releasing hormone antagonist and / or agonist that is effective to reduce the subject's serum testosterone level. In some embodiments, the subject is not treated with any gonadal testosterone suppressant other than the administered abiraterone prodrug. In some embodiments, the subject is not treated with any gonadotropin releasing hormone antagonist and / or agonist. In some embodiments, the subject is not treated with a drug selected from buserelin, leuprolide, deslorelin, fertirelin, histrelin, gonadorelin, resilelin, goserelin, nafarelin, peforelin, and triptorelin. In some embodiments, the subject is not treated with a drug selected from abarelix, cetrorelix, degarelix, ganirelix, elagolix, linzagolixa, and relugolix. In some embodiments, the subject may be sensitive to gonadotropin releasing hormone antagonists and / or agonists or may otherwise be intolerant to agonists.

[0062] A subject who needs to reduce testosterone typically suffers from one or more diseases or disorders that are mediated or associated with androgens. For example, in some embodiments, the subject is characterized as having a sex hormone-dependent cancer or an androgen receptor-driven cancer, such as any of the cancers described herein. In some embodiments, the subject is characterized as having androgen receptor-positive salivary duct cancer, or androgen receptor-positive glioblastoma multiforme. In some embodiments, the subject is characterized as having prostate cancer (e.g., any of those described herein). In some embodiments, the prostate cancer is localized prostate cancer, such as high-risk localized prostate cancer. In some embodiments, the subject has not undergone a prostatectomy. In some embodiments, the subject is further treated with radiation therapy.

[0063] Suitable pharmaceutical compositions and abiraterone prodrugs for the methods herein for reducing serum testosterone levels include, but are not limited to, any of those described herein, such as the abiraterone decanoate formulations described herein, for example, any of those described in the Summary section of the present specification, such as at

[71] -

[81] and

[98] , as well as any of the abiraterone prodrug and biraterone prodrug formulations described in U.S. Patent No. 10,792,292 B2 and U.S. Provisional Application No. 63 / 073,502. 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 weeks, or 8 weeks or more) after a single administration to reduce serum testosterone levels (e.g., to about 50 ng / dL or less in a non-castrated subject, or to about 1 ng / dL or less in a castrated subject, or by 50% or more compared to baseline). In some embodiments, the effective plasma concentration of abiraterone can be 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 also be about 0.1 ng / ml or more. In some embodiments, the pharmaceutical composition, when administered to a subject, provides: (a) a plasma concentration of abiraterone of greater than 1.0 ng / ml for a period of at least two weeks following a single dose; (b) a single dose or steady-state C of abiraterone of about 5 ng / ml to about 300 ng / ml. max or (c) can be formulated to provide both (a) and (b).

[0064] The route of administration and dosage 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 subject via intramuscular injection, intradermal injection, or subcutaneous injection. For example, in some particular embodiments, the pharmaceutical composition is administered to the subject via intramuscular injection. Generally, the pharmaceutical composition is administered to the subject once a week or once every few weeks. For example, in some embodiments, the pharmaceutical composition is administered to the subject once a month or once a month or more, for example, once every two months or once every three months.

[0065] In some embodiments, the disclosure provides a method of inhibiting CYP17A1 activity, such as inhibiting 17α-hydroxylase activity and 17,20-lyase activity, the method comprising administering any of the disclosed abiraterone prodrugs or abiraterone prodrug formulations to a subject in need of inhibition of CYP17A1 activity. In some embodiments, the subject is a non-castrated subject. In some embodiments, the patient suffers from a sex hormone-dependent benign or malignant disease, e.g., as described herein. In some embodiments, the patient suffers from a syndrome due to androgen excess and / or a syndrome due to glucocorticoid excess, such as hypercortisolism, e.g., as described herein. In some embodiments, the subject suffers from a sex hormone-dependent or androgen receptor-driven cancer, e.g., as described herein. Suitable pharmaceutical compositions, subjects, dosage regimens, and routes of administration for the methods include any of those described herein in any combination, such as any of those described in connection with the methods set forth in the Summary section of this specification.

[0066] In some embodiments, the disclosure provides a method of reducing glucocorticoid (e.g., cortisol) levels in a patient in need thereof, the method comprising administering to the patient any of the disclosed abiraterone prodrugs or abiraterone prodrug formulations. In some embodiments, the subject is a non-castrated subject. In some embodiments, the patient is suffering from a syndrome resulting from glucocorticoid excess, such as hypercortisolism, as described herein, such as Cushing's syndrome or Cushing's disease. Suitable pharmaceutical compositions, subjects, dosage regimens, and routes of administration for the methods include any of those described herein in any combination, such as any of those described in connection with the methods set forth in the Summary section of this specification.

[0067] In some embodiments, the disclosure provides a method of reducing androgen (e.g., testosterone and / or dihydrotestosterone) and / or estrogen levels in a patient in need thereof, the method comprising administering to the patient any of the disclosed abiraterone prodrugs or abiraterone prodrug formulations. In some embodiments, the subject is a non-castrated subject. In some embodiments, the subject is suffering from an androgen receptor-driven cancer. In some embodiments, the subject is suffering 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 subject is suffering from an androgen and / or estrogen-related cancer, such as suffering from prostate cancer or breast cancer. In some embodiments, the subject is suffering from a sex hormone-dependent cancer as described herein. Suitable pharmaceutical compositions, subjects, dosage regimens, and routes of administration for the methods include any of those described herein in any combination, such as any of those described in connection with the methods set forth in the Summary section of this specification.

[0068] Abiraterone Prodrugs and Formulations Various abiraterone prodrugs and abiraterone prodrug formulations are also provided herein, which can be used in the methods herein. For example, in some embodiments, the abiraterone drug can be an abiraterone lipophilic ester, such as an acetate, propionate, butanoate, (vaterate) pentanoate, isocaproate, buciclate, cyclohexanecarboxylate, phenylpropionate, caproate (hexanoate), enanthate (heptanoate), cypionate, octanoate, noncanoate, decanoate, undecanoate, dodecanoate, tridecanoate, tetradecanoate, pentadecanoate, or hexadecanoate of abiraterone. Other suitable abiraterone prodrugs include any of those described in U.S. Pat. No. 10,792,292 B2 and U.S. Provisional Application No. 63 / 073,502, the contents of each of which are incorporated herein by reference in their entirety.

[0069] In any of the embodiments described herein, unless specified or otherwise contradicted, the abiraterone prodrug may be abiraterone decanoate, or a pharma- ceutically acceptable salt thereof. [ka]

[0070] 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.

[0071] 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 oil, e.g., an injectable pharma- ceutical acceptable oil, including a plant-derived oil or a synthetic mono- or diglyceride of a fatty acid. In some embodiments, the pharma- ceutical acceptable oil may be a natural oil, a synthetic oil, or a semi-synthetic oil, such as fractionated coconut oil, and a medium-chain triglyceride, such as that 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 and / or medium-chain fatty acid, which may be independently polyunsaturated, monounsaturated, or saturated. As will be appreciated by those skilled in the art, medium chain fatty acids contain 6-12 carbons, such as caproic acid, caprylic acid, capric acid, lauric acid, etc., and short chain fatty acids typically have fewer 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 oils, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, and soybean oil. In some particular embodiments, the pharmaceutically acceptable carrier may comprise corn oil, which contains triglycerides whose fatty acid components are primarily linoleic acid, oleic acid, palmitic acid, and stearic acid.

[0072] In some embodiments, in addition to the pharma- ceutically acceptable oil, the pharma- ceutical carrier may further include a pharma- ceutical acceptable solvent (or a co-solvent if the oil counts as a solvent), such as an alcohol, an ester, or an acid. In some embodiments, the pharma- ceutical 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 acceptable solvent may be benzyl alcohol and / or benzyl benzoate. In some embodiments, the pharma- ceutical acceptable solvent may be benzyl alcohol. In some embodiments, the pharma- ceutical acceptable solvent may be a combination of benzyl alcohol and benzyl benzoate. The combination of benzyl alcohol and benzyl benzoate can significantly increase the solubility of abiraterone decanoate in the pharma- ceutical acceptable oil.

[0073] In some embodiments, the pharma- ceutically acceptable carrier can 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 seed oil, tea seed 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.

[0074] Exemplary Formulations Comprising Abiraterone Decanoate In some particular embodiments, the pharmaceutical composition comprises abiraterone decanoate having the formula: [ka] or a pharma- ceutically acceptable salt thereof and a pharma- ceutically 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, the abiraterone decanoate may be in a substantially pure form as described herein. For example, the pharmaceutical composition can be prepared by mixing substantially pure abiraterone decanoate with a pharma- ceutically 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., crystalline form A) with a pharma- ceutically acceptable carrier and optional other ingredients.

[0075] Abiraterone decanoate is typically prepared in a form of high purity suitable for, for example, pharmaceutical use. In some embodiments, the present disclosure provides a substantially pure form of abiraterone decanoate, for example, having a purity of more than 80%, preferably more than 90% (e.g., more than 95%, more than 97%, more than 98%, more than 99%, more than 99.5%) by weight, HPLC area, or both. In some embodiments, abiraterone decanoate can be characterized by a purity of about 95%, about 97%, about 99%, about 99.5%, about 99.9% by weight and / or HPLC area, or any range of values ​​specified. For example, in some embodiments, abiraterone decanoate can be characterized by a purity of about 95%, about 97%, about 99%, about 99.5%, about 99.9% by weight, or any range of values ​​specified. 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 may be in solid form (e.g., a crystalline form described herein, preferably crystalline form A, an amorphous form, or a combination thereof), or in solution, suspension, or another form. For the avoidance of doubt, the abiraterone prodrug formulations comprising substantially pure abiraterone decanoate and one or more other ingredients herein should be understood to be mixtures of substantially pure abiraterone decanoate as described herein with one or more other ingredients; for example, such formulations may be obtained directly or indirectly by 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.

[0076] 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, the benzyl alcohol is present in an amount of about 5-10% by volume, the benzyl benzoate is present in an amount of about 10-20% by volume, and the corn oil is present in an amount of about 70-85% by volume, with the sum of the benzyl alcohol, benzyl benzoate, and corn oil being 100%.

[0077] 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 of values ​​recited. 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.

[0078] In some embodiments, the pharmaceutical composition comprises abiraterone decanoate in its basic 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 comprises, per milliliter, (a) abiraterone decanoate in a basic form in an amount of about 100 mg to about 300 mg (e.g., about 100 mg, about 120 mg, about 150 mg, about 180 mg, about 200 mg, or about 250 mg); (b) benzyl alcohol in an amount of about 50 mg to about 150 mg (e.g., about 75 mg, about 100 mg, or about 125 mg); (c) benzyl benzoate in an amount of about 100 mg to about 300 mg (e.g., about 100 mg, about 150 mg, about 200 mg, or about 250 mg); and (d) corn oil in an amount appropriate for each milliliter. In some embodiments, the weight ratio of benzyl alcohol to 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).

[0079] Exemplary Formulations Comprising Substantially Pure Abiraterone Decanoate In some particular embodiments, the pharmaceutical composition comprises a substantially pure abiraterone decanoate having the formula: [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises substantially pure abiraterone decanoate in a basic form dispersed or dissolved in a pharmaceutically acceptable carrier. In some embodiments, the substantially pure abiraterone decanoate has a purity of at least 95% by weight, preferably at least 98%, for example, about 98.5%, about 99%, about 99.5% or more. In some embodiments, the substantially pure abiraterone decanoate may be characterized by a purity of about 95%, about 97%, about 99%, about 99.5%, about 99.9% by weight and / or by HPLC area, or any range of values ​​specified. In some embodiments, the substantially pure abiraterone decanoate may be characterized by a purity of about 95%, about 97%, about 99%, about 99.5%, about 99.9% by weight, or any range of values ​​specified. In some embodiments, the substantially pure 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. Abiraterone is typically synthesized in a palladium-catalyzed cross-coupling reaction step. Thus, available abiraterone generally has undesirable levels of palladium residuals, which may be carried into the crude abiraterone decanoate product. As described herein, the present disclosure shows that it is possible to reduce the palladium content of abiraterone decanoate in Example 1B to less than 5 ppm, in particular less than 3.7 ppm, by using a process of recrystallization with 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 comprises ethyl prasterone decanoate having the formula: [ka] Typically, when present, substantially pure abiraterone decanoate contains ethyl prasterone decanoate in an amount of less than 2% by weight, such as less than 1% by weight, less than 0.5% by weight, such as less than 0.3% by weight, less than 0.2% by weight, or less than 0.1% by weight.

[0080] The amount of ethyl prasterone decanoate can be readily determined by HPLC methods as described herein. In some embodiments, substantially pure abiraterone decanoate may also be free of detectable amounts of ethyl prasterone decanoate. High purity abiraterone starting material is readily available commercially. In the cross-coupling reaction to introduce the 3-pyridyl group in abiraterone, [ka] The abiraterone starting material obtained from a process using may contain small amounts of impurities that can ultimately be converted to ethylprasterone. In some embodiments, substantially pure abiraterone decanoate is an abiraterone starting material having 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 as described herein. For example, in some embodiments, the substantially pure abiraterone decanoate may be crystalline form A, which may be characterized by an X-ray power diffraction (XRPD) spectrum having one or more of the following peaks (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9); a differential scanning calorimetry (DSC) pattern having an endothermic peak at 4.6, 6.9, 8.7, 17.5, 18.3, 18.6, 19.1, 19.6, and 20.8 degrees 2θ, ±0.2°, with an onset temperature of about 69.0° C.; or a combination thereof. In some embodiments, crystalline form A can be characterized by an XRPD spectrum substantially the same as that shown in Figure 2A, e.g., the XRPD spectrum exhibits peaks at each diffraction angle (angle 2Θ, ±0.2°) corresponding to the peaks shown in Figure 2A, regardless of their relative intensities. In some embodiments, crystalline form A can be characterized by a DSC spectrum substantially the same as that shown in Figure 2B.

[0081] In some embodiments, the present disclosure also provides a method for preparing abiraterone decanoate crystalline form A. In some embodiments, the method may include recrystallizing abiraterone decanoate in a suitable solvent, such as acetone and water. In a typical method, abiraterone decanoate may first be dissolved in a first solvent, such as acetone, at room temperature or under heating (such as about 40° C.) to form a solution, which may then be cooled to form a suspension, which may then be optionally subsequently diluted with a second solvent, such as water (typically a poor solvent in which abiraterone decanoate has low solubility), and stirred for a period of time (such as about 12 hours) to form a crystalline form. The amount, concentration, etc. of the solvent may be adjusted by one skilled in the art in view of the present disclosure. An exemplary procedure is also shown in Example 1A.

[0082] In some embodiments, the disclosure also provides a method of preparing crystalline form A of abiraterone decanoate, the method comprising: a) dissolving abiraterone decanoate in a first solvent to form a first solution; b) adding activated charcoal to the first solution; c) removing the activated charcoal to form a second solution; and d) crystallizing abiraterone decanoate from the second solution to form crystalline form A of abiraterone decanoate, wherein abiraterone decanoate has the following structure: [ka]

[0083] Typically, the crystallization step d) comprises cooling the second solution, reducing the amount of the first solvent, and / or adding an antisolvent in which abiraterone decanoate has a lower solubility than the first solvent. For example, in some embodiments, the crystallization step d) comprises cooling the second solution, for example from about 40° C. to room temperature. In some embodiments, the crystallization step d) comprises cooling the second solution and reducing the amount of the first solvent. In some embodiments, the crystallization step d) comprises reducing the amount of the first solvent and adding an antisolvent in which abiraterone decanoate has a lower solubility than the first solvent. In some embodiments, the crystallization step d) comprises cooling the second solution, reducing the amount of the first solvent, and adding an antisolvent in which abiraterone decanoate has a lower solubility than the first solvent.

[0084] A variety of solvents may be suitable as the first solvent. For example, in some embodiments, the first solvent is selected from acetone, dioxane, 1-propanol, methyl tert-butyl ether, isopropyl ether, t-butanol, chloroform, ethyl acetate, nitromethane, dimethylacetamide, tetrahydrofuran, dimethylformamide, diethyl ether, 2-butanol, isopropyl acetate, ethanol, methanol, toluene, acetonitrile, heptane, 2-propanol, 2-butanone, 2-methyltetrahydrofuran, a combination of methanol and tetrahydrofuran, a combination of methanol and chloroform, a combination of acetonitrile and t-butanol, and a combination of acetonitrile and 2-propanol. In some embodiments, the first solvent is selected from those selected from ethyl acetate, tert-butanol, chloroform, isopropyl ether, tetrahydrofuran, 2-propanol, acetonitrile, 2-butanone, heptane, toluene, and methanol, and the crystallization step d) comprises cooling the second solution and / or reducing the amount of the first solvent.

[0085] In some preferred embodiments, the first solvent may be acetone.

[0086] In some preferred embodiments, the poor solvent may be water.

[0087] In some preferred embodiments, the crystallization step d) comprises adding an anti-solvent in which abiraterone decanoate has a lower solubility than the first solvent, hi some embodiments, the first solvent is acetone and the anti-solvent is water.

[0088] When a poor solvent is used, the volume ratio of the poor solvent to the first solvent in the second solution is typically in the range of about 1:50 to about 1:10, e.g., about 1:50, about 1:30, about 1:20, about 1:10, or any range therebetween.

[0089] The amount of solvent, concentration, etc. can be adjusted by one skilled in the art in view of the present disclosure. An exemplary procedure is also shown in Example 1B. In some embodiments, the method for preparing crystalline form A of abiraterone decanoate can be substantially the same as the procedure shown in Example 1B.

[0090] Crystalline form A of abiraterone decanoate prepared by any of the methods herein is also a novel composition of the disclosure. Typically, crystal form A of abiraterone decanoate prepared according to any of the methods herein can be characterized as being substantially free of forms B and C of abiraterone decanoate, e.g., forms B and C in detectable amounts by XRPD. Typically, crystal form A of abiraterone decanoate prepared according to any of the methods herein can be characterized as being substantially pure, e.g., crystal form A has a palladium content of less than 50 ppm, e.g., less than 10 ppm; (2) a purity of at least 95% by weight, preferably at least 98%, e.g., about 98.5%, about 99%, about 99.5% or more; (3) less than 1% (e.g., less than 0.5%, e.g., less than 0.3%, less than 0.2%, or less than 0.1%) of ethyl prasterone decanoate having the formula: [ka] (4) It may be characterized as conforming to the specifications set forth in Table D, or as having any combination thereof.

[0091] In some embodiments, the present disclosure also provides crystalline form B of abiraterone decanoate. In some embodiments, crystalline form B can be characterized by an X-ray power diffraction (XRPD) spectrum having one or more of the following peaks (e.g., 1, 2, 3, 4, 5, 6, or 7); a differential scanning calorimetry (DSC) pattern having two endothermic peaks at 4.4, 6.6, 14.8, 16.4, 18.1, 21.6, and 22.2 degrees 2θ, ±0.2°, with onset temperatures at about 60.6° C. and about 64.9° C., respectively, or a combination thereof. In some embodiments, crystalline form B can be characterized by an XRPD spectrum substantially the same as that shown in FIG. 2D, e.g., the XRPD spectrum exhibits peaks at each diffraction angle (angle 2θ, ±0.2°) corresponding to the peaks shown in FIG. 2D, regardless of their relative intensities. In some embodiments, crystalline form B can be characterized by a DSC spectrum substantially the same as that shown in FIG. 2E. Crystalline form B can typically be prepared by dissolving abiraterone decanoate in a suitable solvent, such as methanol, ethanol, ethyl acetate, dimethylacetamide (DMA), methyl tert-butyl ether, 2-propanol, or heptane, to form a solution, and cooling the solution, such as to about -10°C to about -20°C, to form the crystalline form. An exemplary procedure is provided in Example 1C herein.

[0092] In some embodiments, the present disclosure also provides crystalline form C of abiraterone decanoate. In some embodiments, crystalline form C can be characterized by an X-ray power diffraction (XRPD) spectrum having one or more of the following peaks: a differential scanning calorimetry (DSC) pattern having two endothermic peaks at 4.9, 6.3, 14.5, and 15.3, degrees 2θ, ±0.2°, with onset temperatures at about 58.7° C. and about 66.6° C., respectively, or a combination thereof. In some embodiments, crystalline form C can be characterized by an XRPD spectrum substantially the same as that shown in FIG. 2G, e.g., the XRPD spectrum exhibits peaks at each diffraction angle (angles 2θ, ±0.2°) corresponding to the peaks shown in FIG. 2G, regardless of their relative intensities. In some embodiments, crystalline form C can be characterized by a DSC spectrum substantially the same as that shown in FIG. 2H. Crystalline form C can typically be prepared by dissolving abiraterone decanoate in a suitable solvent, such as a 1:1 mixture of ethanol and 2-butanone, and reducing the amount of solvent, such as by evaporation, to form the crystalline form. An exemplary procedure is shown in Example 1C herein.

[0093] The pharmaceutical compositions herein comprising abiraterone decanoate are typically solutions of abiraterone decanoate in a suitable solvent as described herein. Typically, the solutions can be prepared by dissolving one or more of the solid forms of abiraterone decanoate, such as crystalline forms A, B, and / or C, in a suitable solvent. However, in some embodiments, the present disclosure also provides pharmaceutical compositions comprising one or more of the solid forms of abiraterone decanoate. For example, in some embodiments, the pharmaceutical composition may comprise crystalline form A as described herein. In some embodiments, the pharmaceutical composition may comprise crystalline form B as described herein. In some embodiments, the pharmaceutical composition may comprise crystalline form C as described herein.

[0094] In some embodiments, the pharmaceutical composition comprises substantially pure abiraterone decanoate in basic form dispersed or dissolved in a pharma- ceutically acceptable carrier comprising a pharma- ceutically acceptable oil (e.g., as described herein), and optionally an additional 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 additional 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 seed oil, tea seed oil, and soybean oil, and the additional 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.

[0095] In some specific embodiments, the pharmaceutical composition comprises substantially pure abiraterone decanoate in its basic form 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 basic form dissolved in corn oil, benzyl alcohol, and benzyl benzoate. In some embodiments, the pharmaceutical composition comprises: (a) substantially pure abiraterone decanoate in its basic form 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 of values ​​recited, such as about 100 mg / ml to about 300 mg / ml); (b) benzyl alcohol in an amount of about 50 mg to about 150 mg / mL; (c) benzyl benzoate in an amount of about 100 mg to about 300 mg / mL; and (d) a pharma- ceutically acceptable oil (e.g., as described herein), e.g., corn oil, in an amount appropriate to the volume of the pharmaceutical composition. In some particular embodiments, the pharmaceutical composition comprises, per milliliter, (a) substantially pure abiraterone decanoate in its basic form in an amount of about 100 mg to about 300 mg (e.g., about 100 mg, about 120 mg / ml, about 150 mg / ml, about 180 mg / ml, about 200 mg / ml, 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) corn oil in an amount appropriate for each milliliter. In some embodiments, the weight ratio of benzyl alcohol to benzoate in the pharmaceutical composition is in the range of 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.

[0096] Pharmaceutical compositions comprising substantially pure abiraterone decanoate are typically formulated for parenteral administration. For example, in some embodiments, the pharmaceutical composition is formulated for parenteral injection, such as intramuscular, intradermal, or subcutaneous injection, with, for example, a desired viscosity, glide force, particulate count, endotoxins, etc. In some embodiments, the pharmaceutical composition has: (1) a viscosity of less than 0.1 Pa*s, e.g., about 0.05 Pa*s or less; (2) a glide force of about 1-10 N when measured with a 21 G, 1.5 inch needle, and / or a glide force of about 2-15 N when measured with a 23 gauge (or 23 G), 1.5 inch needle, and / or a glide force of about 30-150 N when measured with a 27 G, 1.5 inch needle; (3) a USP <788> and / or <789> (4) Not more than 1,000 particles 10 μm or greater in size and not more than 300 particles 25 μm or greater in size, as measured in accordance with 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 bacterial endotoxin, as measured according to USP method 14. Methods for measuring viscosity and glide force are known in the art and are exemplified herein in Example 2. Glide force measurements can be performed using a 5 mL fill for a 5 mL syringe or a 2 mL fill for a 3 mL syringe. The USP method referenced herein <788> , <789> and <85> It should be understood that the current version of the method as known to those skilled in the art.

[0097] In any of the embodiments described herein, unless otherwise specified or clearly contradicted by context, a pharmaceutical composition comprising abiraterone decanoate (which may also be referred to as an abiraterone prodrug formulation) may be any pharmaceutical composition comprising substantially pure abiraterone decanoate as described herein.

[0098] Abiraterone decanoate is typically included in the pharmaceutical composition in an amount therapeutically effective to treat a disease or disorder described herein, such as prostate cancer. 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 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 subject having a sex hormone dependent benign or malignant disease, an androgen receptor driven cancer, a syndrome resulting from androgen excess, and / or a syndrome resulting from glucocorticoid excess, such as hypercortisolism. 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 subject having a sex hormone dependent benign or malignant disease, an androgen receptor driven cancer, a syndrome due to androgen excess, and / or a syndrome due to glucocorticoid excess, such as hypercortisolism. 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 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 subject having a sex hormone dependent benign or malignant disease, an androgen receptor driven cancer, a syndrome due to androgen excess, and / or a syndrome due to glucocorticoid excess, such as hypercortisolism.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 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 subject having a sex hormone dependent benign or malignant disease, an androgen receptor driven cancer, a syndrome due to androgen excess, and / or a syndrome due to glucocorticoid excess, such as hypercortisolism.

[0099] 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, comprising a pharma- ceutically acceptable oil and a pharma-ceutically acceptable solvent, wherein abiraterone decanoate is in its basic form and is present 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 1000 mg / ml, about 250 mg / ml, about 300 mg / ml, about 400 mg / ml, about 500 mg / ml, about 150 mg / ml, about 200 mg / ml, about 35 ...500 mg / ml, about 500 mg / ml, about g / ml, or any range of values ​​recited, e.g., the pharmaceutical composition, which is a unit formulation, is formulated for parenteral injection, such as intramuscular, intradermal, or subcutaneous injection, e.g., the pharmaceutical composition, which is a unit formulation, comprises an amount of abiraterone decanoate ranging from 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 of values ​​recited. In some embodiments, the pharmaceutical composition may be a unit formulation. Typically, one or more (e.g., one) of the unit formulations may be administered to a patient in need thereof, depending on the dosage. The pharma- ceutically acceptable oil in the pharmaceutical composition, e.g., a unit formulation, may be any of those described herein. For example, in some embodiments, the pharma-ceutically acceptable oil is an injectable pharma-ceutically acceptable oil, including oils derived from plants or synthetic mono- or diglycerides of fatty acids. In some embodiments, the pharma- ceutically acceptable oil may be a natural oil, a synthetic oil, or a semi-synthetic oil, such as fractionated coconut oil and medium chain triglycerides, such as those sold under the trademark Miglyol. In some embodiments, the pharma-ceutically acceptable oil may comprise a triglyceride derived from a fatty acid. In some embodiments, the pharma-ceutically acceptable oil may comprise a triglyceride derived from a long and / or medium chain fatty acid, 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 seed oil, tea seed oil, and soybean oil.In some specific embodiments, the pharma- ceutically acceptable oil can include corn oil, which contains triglycerides whose fatty acid components are primarily linoleic, oleic, palmitic, and stearic acids. Also, the pharma- ceutically acceptable solvent in the pharmaceutical composition, e.g., unit dosage form, includes any of those described herein. In some embodiments, the pharma- ceutically acceptable solvent (or co-solvent if oil counts as a solvent), such as 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- ceutical acceptable solvent may be benzyl alcohol and / or benzyl benzoate. In some embodiments, the pharmaceutical composition, e.g., unit dosage form, includes abiraterone decanoate, a pharma- ceutically acceptable oil (e.g., as described herein), benzyl alcohol, and benzyl benzoate. In some embodiments, the pharma- ceutical composition 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, with the total amounts of benzyl alcohol, benzyl benzoate, and corn oil being 100%. In some embodiments, abiraterone decanoate is in a substantially pure form as described herein.In some particular embodiments, the pharmaceutical composition has a concentration of (a) 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 of values ​​recited, e.g., about 100 mg / ml to about 30 (b) abiraterone decanoate, such as the substantially pure abiraterone decanoate herein in its base form, in a concentration of from about 50 mg to about 150 mg / mL; (c) benzyl alcohol in an amount of from about 100 mg to about 300 mg / mL; and (d) a pharma- ceutical composition comprising a pharmaceutical composition comprising: (a) a terpenic acid salt, such as terpenic acid salt, in an amount of from about 100 mg to about 300 mg / mL; (b) abiraterone decanoate, such as the substantially pure abiraterone decanoate herein in its base form, in a concentration of from about 50 mg to about 150 mg / mL; (c) benzyl benzoate in an amount of from about 100 mg to about 300 mg / mL; and (d) a pharma- ceutically acceptable oil (e.g., as described herein), specifically, for example, corn oil 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 as described herein in a basic 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 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) corn oil in an amount appropriate for each milliliter. In some embodiments, the weight ratio of benzyl alcohol to benzoate in the pharmaceutical composition ranges from about 2:1 to about 1:5 (e.g., from about 1:1 to 1:3, e.g., about 1:2). In some particular 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.

[0100] In some embodiments, the disclosure provides exemplary abiraterone decanoate formulations as shown in Table C. All numerical values ​​in the table should be understood to be preceded by the term "about." The concentrations of abiraterone decanoate are expressed in mg of abiraterone decanoate per ml of final formulation, which may be a solution or suspension. The amounts of oil (primary solvent) and co-solvent (benzyl alcohol and / or benzyl benzoate) in the table are 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 as described herein, such as corn oil. Optional additional ingredients are not shown in Table C.

[0101] [Table 1]

[0102] The pharmaceutical compositions or unit dosage forms herein can 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 subject having a sex hormone dependent benign or malignant disease, an androgen receptor driven cancer, a syndrome resulting from androgen excess, and / or a syndrome resulting from glucocorticoid excess, such as hypercortisolism. In some embodiments, the method comprises reacting abiraterone decanoate having the formula: [ka] and mixing (e.g., dissolving or suspending) in a pharma- ceutically acceptable carrier to form a mixture (e.g., 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., a solution or suspension). 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., crystalline Form A) in a pharma-ceutically acceptable carrier. In some embodiments, the mixing (e.g., dissolving or suspending) may comprise mixing (e.g., dissolving or suspending) a substantially pure abiraterone decanoate described herein in a pharma-ceutically acceptable carrier. Suitable pharma-ceutically acceptable carriers and amounts, amounts of abiraterone decanoate, and concentrations of abiraterone decanoate 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 seed oil, tea seed oil, or soybean oil, the pharma- ceutically acceptable solvent comprises benzyl alcohol and / or benzyl benzoate, and the abiraterone decanoate is present at a concentration of about 50 mg / mL to about 300 mg / mL, e.g., about 100 mg / mL to about 300 mg / mL.

[0103] 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 U.S. Provisional Application No. 63 / 073,502. For example, in some embodiments, the pharmaceutical composition may include an abiraterone prodrug of Formula I, or a pharma- ceutically acceptable salt thereof: [ka] In the formula, R 1 But R 10 , OR10 , or NHR 10 and R 10 But, 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.

[0104] In some preferred embodiments, R 10 is C 7-30 As used herein, unless expressly stated to be substituted, alkyl is to be understood to be unsubstituted. However, alkyl may be either straight or branched. In some embodiments, R 10 is a linear C 7-30 In some embodiments, R 10 is a branched chain C 7-30 In some embodiments, R 10 is a linear C 7-16 alkyl, e.g., R 10 is a compound of the formula -(CH 2 ) n -CH 3 where n is an integer between 6 and 15 (e.g., between 6 and 12, such as 6, 7, 8, 9, 10, 11, or 12). 10 is a branched chain C 7-16 It may be alkyl.

[0105] In some embodiments, R 10 may also be alkyl substituted with cycloalkyl. Typically, in such embodiments, R 10has a total of 5 to 16 carbons, in other words, the total number of carbons in the alkyl and cycloalkyl portions is 5 to 16. Cycloalkyls are typically unsubstituted. However, in some embodiments, cycloalkyls may contain, for example, one or two lower alkyls (e.g., C 1-4 In some embodiments, R 10 Typically, C 3-6 In some embodiments, R is an alkyl substituted with cycloalkyl. 10 is C 3-6 A linear alkyl substituted with a cycloalkyl, e.g., R 10 is a compound of the formula -(CH 2 ) 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 10 is a compound of the formula -(CH 2 ) n -Cy, where n is 1 or 2, and Cy is cyclopentyl or cyclohexyl. 10 Also, C 3-6 Branched alkyl substituted with cycloalkyl (e.g., branched C 2-6 As used herein, branched C2 alkyl can be a 1,1-disubstituted ethyl group, such as CH(CH 3 )-Cy.

[0106] In some embodiments, R 10 may also be alkyl substituted with phenyl. Typically, in such embodiments, R 10 has a total of 7 to 16 carbons, in other words, the total number of carbons in the alkyl and phenyl portions is 5 to 16. In some embodiments, R 10 is a straight chain alkyl substituted with phenyl, e.g., R 10 is a compound of the formula -(CH 2 )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 a compound of the formula -(CH 2 ) n -Cy, where n is 1 or 2 and Cy is phenyl. In some embodiments, R 10 Also includes branched alkyl substituted with phenyl (e.g., branched C 2-6 ). Phenyl is typically unsubstituted. However, in some embodiments, phenyl may be substituted with, for example, one or two lower alkyls (e.g., C 1-4 alkyl).

[0107] In some embodiments, R 10 may be cycloalkyl optionally substituted with one or more alkyl. In such embodiments, R 10 Typically, R has a total of 5 to 16 carbons, in other words, the total number of carbons in the cycloalkyl and its optional substituents is 5 to 16. In some embodiments, R 10 is unsubstituted or C 1-4 Alkyl-substituted C 3-6 In some particular embodiments, R 10 teeth, [ka] It could be.

[0108] In some embodiments, R 10 may be a branched C5 or C6 alkyl. In some embodiments, R 10 teeth, [ka] Other branched chain C5 or C6 alkyls are also suitable.

[0109] In some embodiments, R 10is C 7-30 Alkenyl or C 7-30 It may be an unsaturated aliphatic group such as alkynyl.

[0110] 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 in formula I 1 is C 7-16 For example, alkyl may be -(CH 2 ) n -CH 3 where n is an integer between 6 and 12 (e.g., 6, 7, 8, 9, 10, 11, or 12). 1 is a compound of the formula -(CH 2 ) n -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. 1 teeth, [ka] In some particular embodiments, R of formula I can be 1 teeth, [ka] It can be. R 1 Other suitable groups of R are as defined herein. 10 Includes any of the following.

[0111] In some embodiments, R in formula I 1 Also, OR 10 or NHR 10 R may be 10 is defined herein.

[0112] Typically, the compound of formula I may be present in the formulation, for example in a non-aqueous formulation, in a basic form. However, in some embodiments, pharma- ceutically acceptable salts of the compound of formula I are also useful. Unless specifically referred to as a salt form or inconsistent with the context, the compound of formula I may be in its basic form in the abiraterone prodrug formulations described herein. In some embodiments, the compound of formula I may be in substantially pure form.

[0113] Abiraterone Prodrug Formulations In some embodiments, the pharmaceutical composition comprising the abiraterone prodrug may be an abiraterone prodrug formulation according to any of those described in U.S. Patent No. 10,792,292 B2 and U.S. Provisional Application No. 63 / 073,502 that may be used in the methods herein. Typically, the abiraterone prodrug is formulated as a parenteral formulation, such as an intramuscular, intradermal, or subcutaneous formulation, and in some embodiments, may be formulated to deliver therapeutically effective plasma concentrations 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, such as up to 10 weeks or more.

[0114] Various abiraterone prodrugs, such as abiraterone esters, carbamates, carbonates, etc., are suitable for the compositions and methods of the present disclosure. In some embodiments, the pharmaceutical composition comprises 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. The pharmaceutical composition typically comprises 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 the US Food and Drug Administration's Center for Drug Evaluation and Research on inactive ingredients present in FDA-approved drugs. In some embodiments, the pharmaceutically acceptable carrier may be a carrier approved for use by the FDA for intramuscular, intradermal, or subcutaneous drugs, e.g., one that is listed in the FDA's inactive ingredients database. In some embodiments, the pharmaceutically acceptable carrier may be any suitable non-aqueous solvent suitable for injection, as described 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 seed oil, tea seed oil, or soybean oil. In some embodiments, the pharmaceutically acceptable oil may be an oil that is suitable as a vehicle for injection (e.g., as described herein), e.g., one that meets the criteria as described in the corresponding monographs of the United States Pharmacopeia. In some embodiments, the pharmaceutically acceptable oil may be a plant-derived oil that is suitable as a vehicle for injection.In some embodiments, the pharma- ceutically acceptable oil may be a synthetic oil suitable as a solvent for injection, such as a synthetic mono- or diglyceride of fatty acid, e.g., liquid, remains a clear liquid when cooled to 10° C., and has an iodine value of 140 or less. In some embodiments, the pharma-ceutically acceptable oil may be a natural oil, a synthetic oil, or a semi-synthetic oil, such as fractionated coconut oil and a medium chain triglyceride, such as 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 and / or medium chain fatty acids, 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 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 of the recited ranges of values).

[0115] In some embodiments, pharmaceutical compositions suitable for use in the methods herein may comprise a compound of formula II, or a pharma- ceutically acceptable salt thereof. [ka] R in the formula 2is defined herein. In some embodiments, the pharmaceutical composition can be formulated for intramuscular, intradermal, or subcutaneous injection. In some embodiments, the compound of formula II 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 of the ranges of values ​​recited). 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 seed oil, tea seed 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.

[0116] Various groups are represented by R in formula II. 2 In some embodiments, R 2 may be selected such that the compound of formula II is an ester, carbamate, or carbonate of abiraterone. 2 is R 20 , OR 20 or NHR 20 And R 20 is C 1-30 Alkyl;C 2-30 Alkenyl; C 2-30 and is selected from 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.

[0117] In some preferred embodiments, R 20 is C 1-16In some embodiments, R 20 is a linear C 1-16 In some embodiments, R 20 is a branched chain 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 a compound of the formula -(CH 2 ) n -CH 3 where n is an integer between 0 and 12 (e.g., between 6 and 12, such as 6, 7, 8, 9, 10, 11, or 12).

[0118] In some embodiments, R 20 may also be alkyl substituted with cycloalkyl. Typically, in such embodiments, R 20 has a total of 4 to 30, e.g., a total of 5 to 16 carbons (in other words, the total number of carbons in the alkyl and cycloalkyl portions is 5 to 16). Cycloalkyls are typically unsubstituted. However, in some embodiments, cycloalkyls can have, for example, one or two lower alkyls (e.g., C 1-4 In some embodiments, R 20 Typically, C 3-6 In some embodiments, R is an alkyl substituted with cycloalkyl. 20 is C 3-6 A linear alkyl substituted with a cycloalkyl, e.g., R 20 is a compound of the formula -(CH 2 ) 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 20 is a compound of the formula -(CH 2 ) n -Cy, where n is 1 or 2, and Cy is cyclopentyl or cyclohexyl. 20 Also, C 3-6 Branched alkyl substituted with cycloalkyl (e.g., branched C 2-6 ) may be.

[0119] In some embodiments, R 20 may also be alkyl substituted with phenyl. Typically, in such embodiments, R 20 has a total of 7 to 30 carbons, e.g., a total of 7 to 16 carbons (i.e., the total number of carbons in the alkyl and phenyl portions is 7 to 16). 20 is a straight chain alkyl substituted with phenyl, e.g., R 20 is a compound of the formula -(CH 2 ) 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 a compound of the formula -(CH 2 ) n -Cy, where n is 1 or 2 and Cy is phenyl. In some embodiments, R 20 Also includes branched alkyl substituted with phenyl (e.g., branched C 2-6 ). Phenyl is typically unsubstituted. However, in some embodiments, phenyl may be substituted with, for example, one or two lower alkyls (e.g., C 1-4 alkyl).

[0120] In some embodiments, R 20 may be cycloalkyl optionally substituted with one or more alkyl. In such embodiments, R 20Typically, R has a total of 3 to 30 carbons, such as a total of 5 to 16 carbons (in other words, the total number of carbons in the cycloalkyl and its optional substituents is 5 to 16). 20 is unsubstituted or C 1-4 Alkyl-substituted C 3-6 In some particular embodiments, R 20 teeth, [ka] It could be.

[0121] In some embodiments, R 20 is C 2-30 Alkenyl or C 2-30 It may be an unsaturated aliphatic group such as alkynyl.

[0122] 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 in formula II 2 is C 1-16 For example, alkyl may be -(CH 2 ) n -CH 3 where n is an integer from 0 to 12. In some embodiments, R in Formula II 2 is a compound of the formula -(CH 2 ) n -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] It can be. R2 Other suitable groups of R are as defined herein. 20 In some embodiments, the abiraterone ester may be an acetate, propionate, butanoate, (vaterate) pentanoate, isocaproate, bucclate, 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 may be abiraterone acetate, abiraterone propionate, and abiraterone decanoate. In some particular embodiments, the abiraterone ester may be abiraterone pentanoate, abiraterone hexanoate, abiraterone heptanoate, abiraterone decanoate, abiraterone isocaproate, or abiraterone cypionate.

[0123] In some embodiments, R in formula II 2 Also, OR 20 or NHR 20 R may be 20 is defined herein.

[0124] Typically, the compound of formula II may be present in the formulation, for example in a non-aqueous formulation, in a basic form. However, in some embodiments, pharma- ceutically acceptable salts of the compound of formula II are also useful. Unless specifically referred to as a salt form or inconsistent with the context, the compound of formula II may be in its basic form in the abiraterone prodrug formulations described herein. In some embodiments, the compound of formula II may be in a substantially pure form.

[0125] 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 composition is formulated for parenteral injection, such as intramuscular, intradermal, or subcutaneous injection, with, for example, a desired viscosity, glide force, particulate count, endotoxins, and the like. In some embodiments, the pharmaceutical composition has (1) a viscosity of less than 0.1 Pa*s, e.g., 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 a glide force of about 2-15 N when measured using a 23 gauge (or 23 G), 1.5 inch needle, and / or a glide force of about 30-150 N when measured using a 27 G, 1.5 inch needle; (3) a viscosity of about 0.01 Pa*s when measured using a 21 G, 1.5 inch needle; <788> and / or <789> (4) Not more than 1,000 particles 10 μm or greater in size and not more than 300 particles 25 μm or greater in size, as measured in accordance with 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, bacterial endotoxins, as measured according to the USP method. Methods for measuring viscosity and glide force are known in the art and are exemplified herein in Example 1. <788> , <789> and <85> It should be understood that the current version of the method as known to those skilled in the art.

[0126] 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 a higher concentration of abiraterone in plasma for a longer period of time when compared to an aqueous solution or suspension. For example, as detailed herein, IM injection of aqueous suspension and vegetable oil solution of abiraterone acetate prodrug was evaluated in rats. Surprisingly, it was determined that the vegetable oil solution (not the aqueous suspension) of abiraterone acetate prodrug provided the highest plasma levels and the longest exposure of active abiraterone. Thus, in some embodiments, the abiraterone prodrug formulation 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 solvent suitable for injection, as described in the United States Pharmacopeia. In some embodiments, the pharma- ceutically acceptable carrier may be a pharma- ceutically acceptable oil, such as vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, or soybean oil. In some embodiments, the pharma- ceutically acceptable oil may be an oil (e.g., as described herein) that is suitable as a vehicle for injection, e.g., meets the criteria as described in the corresponding monographs of the United States Pharmacopeia. In some embodiments, the pharma- ceutically acceptable oil may be a plant-derived oil that is suitable as a vehicle for injection. In some embodiments, the pharma- ceutically acceptable oil may be a synthetic oil that is suitable as a vehicle for injection, e.g., a synthetic monoglyceride or diglyceride of fatty acids that is liquid, remains a clear liquid when cooled to 10° C., and has an iodine value of 140 or less. In some embodiments, the pharma- ceutically acceptable oil may be a natural oil, a synthetic oil, or a semi-synthetic oil, such as fractionated coconut oil and medium chain triglycerides, such as those sold under the trademark Miglyol. In some embodiments, 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 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 oil approved for use by the FDA for intramuscular, intradermal, or subcutaneous drugs, such as those listed in the FDA inactive ingredients database. 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.

[0127] 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. It has been determined that the additives / co-solvents benzyl alcohol and benzyl benzoate not only increase the solubility of the prodrug, but also reduce the viscosity and / or glide force of the solution (see U.S. Patent No. 10,792,292 B2), thereby providing a more concentrated solution that is easier to inject through gauge needles acceptable for IM injection (e.g., 20-27 gauge, such as 22-25 gauge). The co-solvent may be selected based on its ability to reduce the viscosity of the solvent to allow injection through a suitable needle or cannula. Benzyl alcohol as an additive in IM or subcutaneous injections 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, may be included at a level (e.g., about 0-50%, e.g., 10%) that does not cause irritation (i.e., minimal or tolerable irritation) at the injection site.

[0128] 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, such as corn oil, castor oil, sesame oil, peanut oil, cottonseed oil, and / or Miglyol 812. Additionally, it was unexpectedly found that a representative abiraterone prodrug (abiraterone decanoate) formulation containing oil (70% corn oil) and benzyl alcohol (10%) and benzyl benzoate (20%) achieved higher abiraterone plasma exposures in monkeys when compared to a formulation containing substantially the same concentration of abiraterone decanoate but without benzyl benzoate, i.e., 90% corn oil and 10% benzyl alcohol, administered in the same amount.

[0129] The solubility of the abiraterone ester may be affected by the addition of a co-solvent to the vegetable oil solvent. In some embodiments, the abiraterone ester is completely dissolved within the composition, while in other embodiments, the abiraterone ester is partially dispersed within the composition. In one embodiment, the abiraterone ester is completely dissolved in the solvent.

[0130] Abiraterone prodrug formulations may also contain pharma- ceutically acceptable preservatives, polymers, antioxidants, antimicrobial agents, chelating agents, and other excipients, including, but not limited to, citric acid, dextrose, ascorbic acid, benzalkonium chloride, benzoic acid, betadex sodium sulfobutylether, calcium chloride, sodium carbomethoxycellulose, chlorobutanol, creatine, croscarmellose, dibasic potassium phosphate, docusate sodium, sodium edetate, glycerin, sodium hyaluronate, hydroxypropyl betadex, lactic acid, lactose, lecithin, maleic acid, mannitol, meglumine, methylcellulose, methylparaben, microcrystalline cellulose, miripitium chloride ... chloride), monothioglycerol, 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.

[0131] Abiraterone prodrug formulations may be sterilized by methods known to those of skill in the art (e.g., gamma irradiation, micron filtration, and autoclaving).

[0132] Long-acting release of abiraterone The abiraterone prodrugs and abiraterone prodrug formulations of the present disclosure (e.g., formulations containing a compound of Formula I or II as described herein) are typically formulated to provide a long-acting release form of abiraterone, preferably as a parenteral formulation, such as an intramuscular, intradermal, or subcutaneous formulation, to a subject in need thereof, e.g., having a sex hormone dependent benign or malignant disease, an androgen receptor driven cancer, a syndrome resulting from androgen excess, and / or a syndrome resulting from glucocorticoid excess, such as hypercortisolism. In some embodiments, the abiraterone prodrugs and abiraterone prodrug formulations of the present disclosure (e.g., formulations containing a compound of Formula I or II as described herein) can be formulated to deliver therapeutic range plasma levels of abiraterone for extended periods 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 to a subject with a hormone-dependent benign or malignant disease, androgen receptor-driven cancer, syndrome resulting from androgen excess, and / or syndrome resulting from glucocorticoid excess, such as hypercortisolism. 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.

[0133] Unit preparation In some embodiments, the abiraterone prodrugs and abiraterone prodrug formulations of the present disclosure (e.g., formulations containing a compound of Formula I or II as described herein) can be formulated as unit formulations. In some embodiments, the unit formulations may contain a sufficient amount of the corresponding respective prodrugs such that, after a single administration (e.g., intramuscular injection) to a subject having, for example, a sex hormone-dependent benign or malignant disease (e.g., metastatic CRPC or metastatic CSPC), an androgen receptor-driven cancer, a syndrome resulting from androgen excess, and / or a syndrome resulting from glucocorticoid excess, such as hypercortisolism, the unit formulation provides a therapeutic range plasma concentration of abiraterone in the 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 formulation is a parenteral formulation, such as an intramuscular, intradermal, or subcutaneous formulation. In some embodiments, the unit formulation is a non-aqueous solution or suspension. In some embodiments, the unit formulation comprises an abiraterone prodrug (a compound of formula I or II) dissolved or suspended in a pharmaceutically acceptable oil, e.g., a vegetable oil, such as castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, or soybean oil. In some embodiments, two or more different pharmaceutically acceptable oils may be used in the unit formulation. In some embodiments, the unit formulation may further comprise a pharmaceutically acceptable solvent, e.g., an alcohol, ester, and / or acid, such as benzyl alcohol, benzyl benzoate, or a combination thereof. Other ingredients suitable for the unit formulation include those described herein.

[0134] The abiraterone prodrug (e.g., a compound of formula I or II) is typically present in the unit formulation 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 of values ​​recited). The amount of abiraterone prodrug in the unit dosage form may 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 amount of abiraterone prodrug may range from about 50 mg to about 2000 mg, which, when expressed as abiraterone equivalents, may typically range from about 25 mg to about 1750 mg. In some embodiments, the amount of abiraterone prodrug may be higher, such as in the range of about 50 mg to about 5000 mg. In some embodiments, to achieve a lower dosing frequency, 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 intended user. Typically, the unit dosage form is formulated to have a viscosity suitable for parenteral injection, such as intramuscular, intradermal, or subcutaneous injection.

[0135] In some embodiments, the unit dosage form can be formulated to obtain a certain pharmacokinetic (PK) profile, for example, a PK profile that has a substantially flat curve after an initial rise period. Typically, after administration of the unit dosage form to a patient, the plasma concentration of abiraterone in the patient may rise for the first few hours to several weeks (e.g., 5 days or 1 week) after administration, and then gradually plateau (see, for example, Figures 2-4). In some embodiments, after this initial rise period, the plasma concentration of abiraterone in the patient may plateau and remain substantially constant for an extended period of time, for example, for 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.

[0136] In some embodiments, the unit formulation is suitable for administration once a month (or once every several months, e.g., once every two months or once every three months), such that after a single administration (e.g., intramuscularly) to a patient in need thereof, the unit formulation achieves a PK profile characterized by one or more of the following (a)-(f): (a) the unit formulation provides a therapeutically effective plasma concentration of abiraterone in the subject for at least 4 weeks, e.g., up to 6 weeks, or up to 8 weeks, or up to 10 weeks or more; (b) a C of a single administration of abiraterone of about 5 ng / ml to about 300 ng / ml (e.g., about 50 ng / ml to about 100 ng / ml, about 10 ng / ml to about 100 ng / ml, or about 15 ng / ml to about 160 ng / ml); max (c) no food effect; (d) C of abiraterone observed at steady state when administered orally at 1000 mg Zytiga® once daily without food. max At least 30% lower C of a single dose of abiraterone compared to max (e) a C of a single dose of abiraterone of about 1 ng / ml to about 8 ng / ml, or greater than about 8 ng / ml, 28 days after administration. 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. The absence of food effect should generally be understood to mean that no significant differences in PK are observed when the unit dosage form is administered to patients without regard to food, e.g., in some embodiments, the absence of food effect means that the C max and AUC are substantially the same (e.g., 80% to 125%). maxis the C achieved after a single dose in treatment-naïve patients (generally meaning patients who have not received any abiraterone medication for at least 3 days, e.g., at least 1 week, prior to dosing and have no observable abiraterone in plasma prior to dosing). max As used herein, the C min By "minimum concentration" is meant the minimum concentration observed on a given day following a single dose in untreated patients, for example, 28 days after administration.

[0137] In some embodiments, the unit dosage form is suitable for administration once per month (or once per month or more, e.g., once per two months or once per three months), such that when the unit dosage form is administered once per month (or once per month or more, e.g., once per two months or once per three months) to a subject in need thereof, the unit dosage form achieves the following: (a) a steady-state C of abiraterone of about 5 ng / ml to about 300 ng / ml (e.g., about 50 ng / ml to about 100 ng / ml, about 10 ng / ml to about 100 ng / ml, or about 15 ng / ml to about 160 ng / ml); max (b) no food effect; (c) C of abiraterone observed at steady state when administered orally at 1000 mg Zytiga® once daily without food. max At least 30% lower steady-state C of abiraterone compared to max (d) a steady-state C of abiraterone of about 1 ng / ml to about 8 ng / ml, or greater than about 8 ng / ml; min and (g) the plasma concentration of abiraterone remains substantially constant for at least one week, e.g., for one to three weeks, one to ten weeks, or two to eight weeks, following each administration. As used herein, steady-state C max or C min is typically observed after several doses in a patient and steady state is reached. max or C min It should be understood that.

[0138] In some embodiments, the unit formulation may be packaged in a container such as a vial or an ampoule. In some embodiments, the unit formulation may be included in a kit with a syringe, such as a prefilled or disposable syringe. Other packages and / or containers known to those skilled in the art are also useful. In some embodiments, kits are also provided that include a plurality of the unit formulations described herein. In some embodiments, the kit may further include a syringe. Typically, one or more (e.g., one) unit formulations are used to meet a desired single dose. In some embodiments, the present disclosure provides abiraterone prodrug formulations that allow for multiple single-use. In some embodiments, the present disclosure also provides abiraterone prodrug formulations that can be divided into multiple unit formulations.

[0139] Exemplary Specific Formulations In some embodiments, the present disclosure also provides some specific abiraterone prodrug formulations, which in some embodiments may be unit formulations or multiple unit formulations. For example, the following tables (Tables A and B) show some representative abiraterone ester prodrug formulations in an oil-based solvent. All numerical values ​​in the tables should be understood as being preceded by the term "about". The concentration of abiraterone prodrug is expressed in mg of abiraterone prodrug per ml of 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 as 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, e.g., Table B). A suitable co-solvent is benzyl alcohol. An 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 also described herein.

[0140] [Table 2]

[0141] In some embodiments, the disclosure provides an abiraterone prodrug formulation comprising an abiraterone prodrug and a pharma- ceutically acceptable carrier, including pharma- ceutically acceptable oils (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 a medium chain triglyceride, 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 seed oil, tea seed oil, and soybean oil. In some embodiments, the disclosure provides certain exemplary formulations shown in Table B.

[0142] [Table 3]

[0143] 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 of x% oil and y% co-solvent (e.g., 90% corn oil and 10% benzyl alcohol) at a particular concentration. In such expressions, x% and y% should be understood to be based on volume percentages, regardless of whether they are followed by "v / v," unless otherwise stated or clearly contrary to the context.

[0144] Combination treatment In some embodiments, the method 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 the subject, either simultaneously or sequentially, through the same or different routes of administration. In some embodiments, the other drugs or agents may be steroids, such as prednisone, prednisolone, and / or methylprednisolone. In some embodiments, the other drugs or agents may be chemotherapy drugs, such as paclitaxel, mitoxantrone, and / or docetaxel. Although not typically administered in the methods herein, in some embodiments of the methods herein, the other drugs or agents may be GnRH agonists, such as leuprolide, deslorelin, goserelin, or triptorelin, e.g., leuprolide acetate (e.g., long-acting IM injectable formulations). In some embodiments, the other agent or drug may be a glucocorticoid, including but not limited to seocalcitol, bicalutamide, flutamide, hydrocortisone, prednisone, prednisolone, or dexamethasone. The amount of the other drug or drug administered can vary and typically will be an amount effective, alone or in combination with an abiraterone prodrug or abiraterone prodrug formulation of the present disclosure, to treat the corresponding disease or disorder (e.g., prostate cancer).

[0145] 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.

[0146] For example, suitable anticancer drugs include acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, amsacrine, anagrelide, anastrozole, ancestim, bexarotene, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, daclizumab, dexrazoxane, dilazep, docosanol, doxifluridine, bromocriptine, carmustine, cytarabine, and diclofenac. , edelfosine, edrecolomab, eflonitine, emitefur, exemestane, exisulind, 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, mastoprolol aztreonam, 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 Suitable antiandrogens include, but are not limited to, bicalutamide, flutamide, vinorelbine ...Suitable differentiation agents include, but are not limited to, 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; phenylbutyrate; and nonsteroidal anti-inflammatory agents.Antineoplastic agents, including but not limited to tubulin interactors, topoisomerase inhibitors and inhibitors, acitretin, alstonine, amonafide, amfetinil, amsacrine, anikomycin, antineoplaston, aphidicolin glycinate, asparaginase, baccharin, batracillin, benflurone, benzotript, bromophosphamide, caracemide, carmethizole hydrochloride, chlorsulfaquinoxalone, clanfenur, claviridinone, clinathol, claderm, cytarabine, saphenol, squalene ... Itocytoin, dacarbazine, datelipitinium, dihematoporphyrin ether, dihydrolenperone, dinaline, distamycin, docetaxel, elipravine, elliptinium acetate, epothilone, ergotamine, etoposide, etretinate, ferretinide, gallium nitrate, genquadaphnine, hexadecylphosphocholine, homoharringtonine, hydroxyurea, irmofosine, isoglutamine, isotretinoin, leukoregulin, lonidamine, mervalone, merocyanine derivatives, methylanilinoacridine , minactivin, mitonafide, mitoxantrone, mopidamole, motretinide, N-(retinoyl)amino acids, N-acylated dehydroalanine, nafazatrom, nocodazole derivatives, octreotide, oxanosine, paclitaxel, pancratistatin, pazeriptin, piroxantrone, polyhematoporphyrin, polyprenic acid, probimane, procarbazine, proglumide, razoxane, reteriptin, spatol, spirocyclopropane derivatives, spirogermanium, stripoldinone, Superoxide dismutase, teniposide, thaliblastine, tocotrienol, topotecan, ukrainian, vinblastine sulfate, vincristine, vindesine, binestramide, vinorelbine, vintriptol, vinzolidine, and withanolides, kinase inhibitors including p38 inhibitors and CDK inhibitors, TNF inhibitors, metallomatrix proteinase inhibitors (MMPs), COX-2 inhibitors including celecoxib, rofecoxib, parecoxib, valdecoxib, and etoricoxib, SOD mimetics, or alpha. v β 3Suitable antimetabolic agents may be selected from, but are not limited to, 5-FU-fibrinogen, acantifolic acid, aminothiadiazole, brequinar sodium, carmofur, cyclopentylcytosine, cytarabine stearate phosphate, cytarabine complex, desaguanine, 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 uricitin. Suitable alkylating agents may be selected from, but are not limited to, aldophosphamide analogs, altretamine, anaxylon, bestravcil, budotitane, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, ciplatate, diphenylspiromustine, diplatinum cytostatic, ermustine, estramustine sodium phosphate, fotemustine, hepsulfam, ifosfamide, iproplatin, lomustine, mafosfamide, mitolactol, oxaliplatin, prednimustine, ranimustine, semustine, spiromustine, tauromustine, temozolomide, teroxylon, tetraplatin, and trimelamol.Suitable antibiotic agents include aclarubicin, actinomycin D, actinoplanon, adriamycin, aeroprisinin derivatives, amrubicin, anthracyclines, azinomycin A, viscaverin, bleomycin sulfate, bryostatin-1, calicheamicin, chromoximycin, dactinomycin, daunorubicin, ditricarubicin B, dexamethasone, doxorubicin, doxorubicin-fibrinogen, elsamycin-A, epirubicin, erbstatin, esorubicin, esperamicin-A1, esperamicin-A1b, fostriecin, glidobactin, gregatin-A, glomerulonephritis ... The steroids may be selected from, but are not limited to, corticosteroids such as lincamycin, herbimycin, hydrocortisone, idarubicin, iludin, kazusamycin, kesarilodin, menogaril, mitomycin, neoenactin, oxalicin, oxaunomycin, peplomycin, pyratin, pirarubicin, polosuramycin, prednisone, prednisolone, pirindanaicin A, rapamycin, rhizoxin, rodorubicin, sivanomycin, siwenmycin, solangicin-A, sparsomycin, tallysomycin, terpentesin, thorazine, triclozaline A, and zorubicin. Non-limiting examples of suitable steroids include hydrocortisone, prednisone, prednisolone, or dexamethasone.

[0147] Combination Treatment of Prostate Cancer Prostate cancer treatment often includes multiple therapies, such as, for example, radiation therapy, surgery, androgen deprivation therapy, hormone therapy, chemotherapy, immunotherapy, and various combination formulations. A search of the website clinicaltrials.gov displays over 250 clinical trials with abiraterone / abiraterone acetate listed as an intervention agent, with the majority of such trials including combination therapy to treat prostate cancer. As discussed herein, compared to oral abiraterone acetate formulations, the abiraterone prodrugs herein can provide improved bioavailability, elimination of food effects, reduced dosage burden, reduced dosing frequency, and sustained effective plasma levels of abiraterone, as well as sustained elevated progesterone levels for up to 70 days or more after administration of the abiraterone prodrug formulation, as well as prolonged CYP17A1 inhibition with reduced cortisol, dihydrotestosterone, and testosterone levels. In view of their superior pharmacokinetic and / or pharmacodynamic profiles, the abiraterone prodrugs herein can be advantageously used in various combination therapies to replace or supplement oral administration of abiraterone acetate.

[0148] Further, the present disclosure shows that administering an abiraterone prodrug to a subject can achieve a sustained reduction in serum androgen levels without the need to castrate the subject or administering to the subject an amount of another drug effective to reduce serum androgen levels. Thus, in any of the embodiments described herein, unless otherwise specified or clearly contrary to context, the methods herein may include combination treatments in which the subject is not treated with a gonadal testosterone suppressant other than an abiraterone prodrug administered in an amount effective to reduce serum testosterone levels in the subject. For example, in some embodiments, the methods herein may include combination treatments in which the subject is not treated with any GnRH antagonists or antagonists.

[0149] 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 subject in need thereof, e.g., a non-castrated subject, comprising administering to the subject a therapeutically effective amount of an abiraterone prodrug (e.g., abiraterone decanoate) or abiraterone prodrug formulation herein and one or more additional therapeutic agents. The one or more additional therapeutic agents can be administered to the patient simultaneously or sequentially in any order with the administration of the abiraterone prodrug or abiraterone prodrug formulation herein, via the same or different administration route. In some embodiments, the method herein comprises treating the patient with radiation therapy or surgery. In some embodiments, the method includes administering to the patient one or more other agents selected from anti-cancer agents, hormone ablation agents, anti-androgenic 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 patient one or more other agents selected from chemotherapeutic agents, hormone replacement agents, or hormone ablation agents. In some embodiments, the method includes treating the patient 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 limited thereto. In some embodiments, the combination therapies described below can also be used in the treatment of other diseases or disorders described herein, such as other cancers described herein.

[0150] In many particular embodiments, the combination therapy typically includes administering a glucocorticoid to the patient. For example, in some embodiments, the method includes administering one or more agents selected from hydrocortisone, prednisone, prednisolone, methylprednisolone, and dexamethasone to the patient. 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 for subjects who may have an underlying disease such as diabetes. In some embodiments, the method may also be characterized in that the subject is not treated with glucocorticoid replacement therapy. In some embodiments, the subject is not treated with an agent selected from hydrocortisone, prednisone, prednisolone, methylprednisolone, and dexamethasone. In some embodiments, the method may include administering a mineralocorticoid receptor antagonist, such as eplerenone, to the subject. For example, in any of the embodiments herein where glucocorticoid replacement therapy is not desired and / or is not administered, the methods may include administering a mineralocorticoid receptor antagonist, such as eplerenone, to the subject.

[0151] Combination therapy for the methods herein may also include, but typically does not include, androgen deprivation therapy, such as through administration of a gonadotropin releasing hormone (GnRH) analog to the subject. If included, GnRH analogs suitable for combination therapy include, but are not limited to, both GnRH agonists and GnRH antagonists. For example, in some embodiments, the method may include administering to the patient a gonadotropin releasing hormone (GnRH) agonist, such as buserelin, leuprolide, deslorelin, fertirelin, histrelin, gonadorelin, resilelin, goserelin, nafarelin, peforelin, or triptorelin, and / or a GnRH antagonist, such as abarelix, cetrorelix, degarelix, ganirelix, elagolix, linzagolixa, or relugolix. In some embodiments, the subject is not administered any of the GnRH agonists and GnRH antagonists described herein.

[0152] Inhibition of androgen receptor activity In some embodiments, the combination therapy includes treating the patient to reduce androgen receptor (AR) activity, such as with an AR antagonist, or downregulating or inhibiting AR activity.

[0153] In some embodiments, the method may include administering an androgen receptor (AR) antagonist to the patient. 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)), as well as third generation AR antagonists, such as N-terminal domain inhibitors. In some embodiments, the method includes administering to the 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 subject a second generation androgen receptor antagonist, including, but not limited to, for example, apalutamide, darolutamide, or enzalutamide. In some embodiments, the method includes administering to the patient apalutamide. In some embodiments, the method includes administering to the patient enzalutamide. In some embodiments, the method includes administering a third generation androgen receptor antagonist, such as an N-terminal domain inhibitor, to the patient. N-terminal domain inhibitors are known in the art. Non-limiting useful examples include any of those described in U.S. Patent Application 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 may be administered, which may be selected from a first, second, and third AR antagonist, alone or in any combination.

[0154] In addition to agents that directly target androgen receptor, other methods and / or agents that modulate androgen receptor activity, 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 the patient one or more upstream kinase regulators, 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&Cancer 4(9-10):342-359(2013). In some embodiments, the method comprises administering to the 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 IkappaB kinase 1 (IKK1) inhibitor, a PIM-1 modulator, a Lemur tyrosine kinase 2 (LMTK2) modulator, a Lyn inhibitor, an Aurora A inhibitor, an ANPK (A 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 include, but are not limited to, any of the known small molecule drugs, polypeptides including antibodies, such as monoclonal antibodies or antigen-binding fragments thereof, RNA or DNA based drugs, etc.

[0155] In some embodiments, the combination therapy may include administering to the patient a drug that downregulates AR or inhibits AR activity in another way.Without wishing to be bound by theory, AR activity may be affected at the genome and / or transcription level of AR itself, or at the genome and / or transcription level of the upstream target of AR and the downstream target regulated by AR that play a role in regulating AR activity, by using various molecules that interfere with transcription and / or translation (e.g., RNA silencing agents (e.g., antisense, siRNA, shRNA, microRNA), ribozyme and DNAzyme), or at the protein level, by using, for example, antagonists, enzymes that cleave polypeptides, small molecules that interfere with the activity of proteins (e.g., competitive ligands), etc.

[0156] 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 (e.g., RNA interference (RNAi), transcriptional gene silencing (TGS), post-transcriptional gene silencing (PTGS), quelling, co-suppression, and translational suppression) mediated by RNA molecules, which results in the inhibition or "silencing" of the expression of corresponding protein-coding genes.RNA silencing has been observed in many types of organisms, such as plants, animals, and fungi.

[0157] 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 through a post-transcriptional silencing mechanism. RNA silencing agents include non-coding RNA molecules, such as RNA duplexes that include paired strands, as well as precursor RNAs that can generate such small non-coding RNAs. Exemplary RNA silencing agents include double-stranded RNAs (dsRNAs), such as small interfering RNAs (siRNAs), 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 linked to form a hairpin or stem-loop structure (e.g., shRNA or sh-RNA). Thus, as described, the RNA silencing agent of some embodiments of the present disclosure may also be a short hairpin RNA (shRNA).

[0158] It will be understood that the RNA silencing agents of some embodiments of the present disclosure need not be limited to molecules containing only RNA, but further include chemically modified nucleotides and non-nucleotides.

[0159] In some embodiments, the RNA silencing agents provided herein may be functionally related to a cell-penetrating peptide. As used herein, a "cell-penetrating peptide" is a peptide that contains a short amino acid sequence (about 12-30 residues) or functional motif that confers energy-independent (i.e., non-endocytic) translocation properties associated with transport of a membrane-permeable complex across the plasma and / or nuclear membrane of a cell.

[0160] According to another embodiment, the RNA silencing agent may 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 of about 19-28 nucleotides in length that regulate gene expression. miRNAs are found in a wide range of organisms and have been shown to be involved in development, homeostasis, and 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).

[0161] Downregulation of AR or inhibition of AR activity can also be achieved by gene editing of target gene (such as AR or suitable upstream and downstream target of AR as described herein). Gene editing can be carried out, for example, using clustered regularly interspaced short palindromic repeats CRISPR-CAS9 system. CRISPR-CAS9 system has been described in the literature, and may include, for example, CAS9 and guide RNA. Other gene editing techniques have also been described in the literature, and they can also be used.

[0162] Another agent capable of downregulating a target (e.g., AR or suitable upstream and downstream targets of AR as described herein) is a DNAzyme molecule capable of specifically cleaving a 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, Proc. Natl. Acad. Sci. USA 1997;943:4262). A general model of DNAzymes (the "10-23" model) has been proposed so far. The "10-23" DNAzyme has a catalytic region of 15 deoxyribonucleotides flanked by two substrate recognition domains, each of 7-9 deoxyribonucleotides. This type of DNAzyme can effectively cleave its substrate RNA at the purine:pyrimidine junction. (Santoro et al.,Khachigian,Curr.Opin.Mol.Ther.2002;4:119-121.)

[0163] 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 with the mRNA transcript encoding the target.

[0164] Another agent capable of downregulating a target (such as AR or suitable upstream and downstream targets of AR as described herein) is a ribozyme molecule capable of specifically cleaving an mRNA transcript encoding the target. Ribozymes are increasingly being used for sequence-specific inhibition of gene expression by cleavage of the mRNA encoding the protein of interest. (Welch et al., Curr. Opin. Biotechnol. 1998;9:486-96.)

[0165] Another agent capable of downregulating a target (e.g., AR or suitable upstream and downstream targets of AR as described herein) 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.

[0166] Another agent that may be used in line 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 target activation and / or substrate binding.

[0167] Another agent that can be used in accordance with some embodiments of the present disclosure to downregulate AR or inhibit AR activity is an androgen receptor degradation inducer, such as those based on proteolysis-inducing chimeric molecule (PROTAC) technology. See, for example, Kregel, S. et al. Neoplasia 22(2):111-119(2020).

[0168] Another agent that can be used in accordance with some embodiments of the present disclosure to downregulate a target (such as AR or suitable upstream and downstream targets of AR as described herein) is to suppress or downregulate the transcriptional activity of the target, more specifically the activation of 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 transcription interfering 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 that can inhibit or interfere with such activity, and any of the agents exemplified herein. For example, certain AR antagonists, such as first-generation AR antagonists (e.g., bicalutamide), are known to inhibit AR transcription activity by inhibiting the nuclear translocation of AR.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).

[0169] In some embodiments, the combination therapy may include administering one or more chemotherapeutic agents to the patient. Suitable chemotherapeutic agents include any known in the art. In some embodiments, the method includes administering a taxane-based chemotherapeutic agent (e.g., docetaxel, cabazitaxel, paclitaxel, etc.) and / or a platinum-based chemotherapeutic agent (e.g., cisplatin, carboplatin, oxaliplatin, etc.) to the patient.

[0170] In some embodiments, the combination therapy may include treating the patient with radiation therapy. Suitable radiation therapies include any known in the art. In some embodiments, the method includes treating the patient with stereotactic body radiation therapy or neutron radiation.

[0171] In some embodiments, the combination therapy may include treating the patient with radium-223, for example, Xofigo (radium-223 dichloride) infusions.

[0172] In some embodiments, the combination therapy may include administering one or more immunotherapeutic agents to the patient. Suitable immunotherapies include any known in the art. In some embodiments, the method includes administering Sipuleucel-T to the subject. In some embodiments, the method includes administering an immune checkpoint inhibitor to the 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 patient. In some embodiments, the method includes administering an anti-CTLA-4 antibody, such as ipilimumab, to the patient.

[0173] In some embodiments, the combination therapy may include administering to the subject a bispecific T cell engager (BiTE) therapy, such as blinatumomab or solitomab.

[0174] In some embodiments, the combination therapy may comprise administering one or more poly ADP ribose polymerase (PARP) inhibitors to the patient. In some embodiments, the patient with prostate cancer also suffers from DNA repair defects. In some embodiments, the patient with prostate cancer does not suffer from DNA repair defects. Suitable PARP inhibitors include any of those known in the art. For example, in some embodiments, the method comprises administering to the patient a PARP inhibitor selected from niraparib, rucaparib, olaparib, talazoparib, veliparib and fluzoparib.

[0175] In some embodiments, the combination therapy may include administering one or more kinase inhibitors to the patient. In some embodiments, the patient is characterized by having abnormal levels of the corresponding kinase. In some embodiments, the kinase inhibitor can reduce the activity of the androgen receptor or is beneficial in treating cancer. Suitable kinase inhibitors include any known in the art. For example, in some embodiments, the method includes administering to the patient a kinase inhibitor selected from sunitinib, dasatinib, cabozantinib, erdafitinib, dovitinib, capivasertib, onvansertib, ipatasertib, afuresertib, alisertib, apitolisib, and opaganib.

[0176] In some embodiments, the combination therapy may include administering one or more bone protective agents to the patient. In such embodiments, the 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 patient a bone protective agent selected from denosumab and zolendronic acid.

[0177] In some embodiments, the combination therapy may include administering to the patient one or more additional agents useful for the treatment of prostate cancer, either alone or in combination with an abiraterone drug, such as an abiraterone prodrug herein. Such additional agents are not limited. For example, in some embodiments, the methods include the use of: 1) an anti-IL23 targeted monoclonal antibody, e.g., tildrakizumab; 2) selenium, such as sodium selenite; 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 extra terminal domain (BET) inhibitor, e.g., CCS1477, INCB057643, allobresib, ZEN-3694, or molybresib (GSK525762); 7) an anti-CD105 antibody, e.g., TRC105 or carotuximab; 8) niclosamide; 9) an A2A receptor antagonist, e.g., AZD10247, AZD10247, or AZD10247. 4635; 10) a phosphoinositide 3 kinase (PI3K) inhibitor, e.g., AZD-8186, buparisib, or dactolisib; 11) an additional 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 alpha 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 the 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 IkappaB kinase 1 (IKK1) inhibitor, a PIM-1 modulator, a Lemur tyrosine kinase 2 (LMTK2) modulator, a Lyn inhibitor, an Aurora A inhibitor, an ANPK (A 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. In some embodiments, cell therapy, such as T cell mediated cell therapy including central memory T cells, may be part of a combination therapy.

[0178] 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 CYP17, including but not limited to galeterone, abiraterone, abiraterone acetate; 4) docetaxel. 4) Microtubule inhibitors, including but not limited to cefotaxime, paclitaxel, and cabazitaxel (XRP-6258); 5) PD-1 or PD-L1 modulators, including but not limited to pembrolizumab, durvalumab, nivolumab, and atezolizumab; 6) Gonadotropin-releasing hormone agonists, including but not limited to cyproterone acetate and leuprolide; 7) Finasteride, dutasteride, turosteride, bexlosteride, izonsteride, FCE28260, and SKF105,111. , 5α-reductase inhibitors; 8) Vascular endothelial growth factor inhibitors, including but not limited to bevacizumab (Avastin); 9) Histone deacetylase inhibitors, including but not limited to OSU-HDAC42; 10) Integrin α-v-β3 inhibitors, including but not limited to VITAXIN; 11) Receptor tyrosine kinase inhibitors, including but not limited to sunitumib; 12) Phospholipase inhibitors, including but not limited to alpelisib, bupallisib, and idealisib; nositide 3 kinase inhibitors; 13) anaplastic lymphoma kinase (ALK) inhibitors, including but not limited to crizotinib and alectinib; 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 degradation inducers, including but not limited to ARV-330 and ARV-110;18) androgen receptor DNA binding domain inhibitors, including but not limited to VPC-14449; 19) bromodomain and extra-terminal motif (BET) inhibitors, including but not limited to BI-894999, GSK525762, 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 salts thereof; 22) nitric oxide; closamide; or related compositions thereof; 23) selective estrogen receptor modulators (SERMs), including but not limited to tamoxifen, raloxifene, toremifene, arzoxifene, bazedoxifene, pipindoxifene, lasofoxifene, enclomiphene; 24) selective estrogen receptor modulators, including but not limited to fulvestrant, ZB716, OP-1074, elaquestrant, AZD9496, GDC0810, GDC0927, GW5638, GW7604. 25) aromitase inhibitors, including but not limited to anastrozole, exemestane, letrozole; 26) selective progesterone receptor modulators (SPRMs), including but not limited to mifepristone, lonaprison, onapristone, asoprisnil, lonaprisnil, ulipristal, telapristone; 27) mifepristone, COR108297, The present invention may include administering to the patient one or more agents selected from the following: glucocorticoid receptor inhibitors, including but not limited to COR125281, ORIC-101, and PT150; 28) CDK4 / 6 inhibitors, including but not limited to palbociclib, abemaciclib, and ribociclib; 29) HER2 receptor antagonists, including but not limited to trastuzumab and neratinib; and 30) mammalian target of rapamycin (mTOR) inhibitors, including but not limited to everolimus and temsirolimus.

[0179] 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 glucocorticoids such as hydrocortisone, prednisone, prednisolone, methylprednisolone and dexamethasone, the combination therapy may typically 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 agent to the patient. In some embodiments, the combination therapy may include administering a GnRH agonist and a radiation therapy agent to the patient. In some embodiments, the combination therapy may include administering to the patient a GnRH agonist, a chemotherapeutic agent, and a radiotherapy agent. In some embodiments, the combination therapy may include administering to the patient an androgen receptor antagonist (e.g., a first, second, and / or third generation AR antagonist), a GnRH agonist, and optionally a radiotherapy agent, a chemotherapeutic agent, indomethacin, or a 5-alpha reductase inhibitor. In some embodiments, the combination therapy may include administering to the patient an androgen receptor antagonist (e.g., a first, second, and / or third generation AR antagonist) and a radiotherapy agent. In some embodiments, the combination therapy may include administering to the patient an androgen receptor antagonist (e.g., a first, second, and / or third generation AR antagonist) and a chemotherapeutic agent. In some embodiments, the combination therapy may include administering to the patient 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 not limiting, and other combinations of additional therapies described herein are possible. However, in preferred embodiments, the combination therapy does not include administration of a GnRH agonist, a GnRH antagonist, androgen deprivation therapy to the subject, and / or does not include castration of the subject.

[0180] In any of the combination therapies described herein, unless otherwise specified or clearly contradicted by context, 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 therapeutic agents.

[0181] 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 conjunction with a combination therapy. For example, the methods include administering to a patient a therapeutically effective amount of an abiraterone prodrug (e.g., abiraterone decanoate) or abiraterone prodrug formulation herein without one or more additional therapeutic agents described herein.

[0182] Usage / Dosage The abiraterone prodrugs and formulations of the present disclosure can generally provide a long-acting release profile of abiraterone to a target user, which can allow the target user to administer abiraterone less frequently, for example, once a week, once a month, once every two months, once every three months, or less frequently, thereby improving patient compliance and reducing medication burden.

[0183] In some embodiments, the methods herein may include a once-weekly or once-every-few-weeks dosing regimen. Typically, the dosing frequency can range from once a week to once every few 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 dose per 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 of values ​​recited) of abiraterone decanoate. In some embodiments, the dosage of the abiraterone prodrug per dose is from about 0.5 mg / kg to about 200 mg / kg of the subject's body weight (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 of values ​​recited). In some embodiments, the methods herein can include administering an abiraterone prodrug or abiraterone prodrug formulation of the present disclosure to a subject in need thereof once a week, or once more than once a week, e.g., once every two weeks, once a month, which administration results in a therapeutically effective plasma concentration of abiraterone in the subject (e.g., 0.5 ng / ml or more, 1 ng / ml or more, 8 ng / ml or more, or 8.4 ng / ml or more, as described herein) over an extended period of time, e.g., 1 week or more, 2 weeks or more, 3 weeks or more, 4 weeks or more, and up to 6 or 8 weeks or more, e.g., up to 10 weeks or more. In some embodiments, the administration results in a C of a single dose of abiraterone of about 5 ng / ml to about 300 ng / ml (e.g., about 50 ng / ml to about 100 ng / ml, about 10 ng / ml to about 100 ng / ml, or about 15 ng / ml to about 160 ng / ml). max In some embodiments, the administration can result in a steady-state C of abiraterone of about 5 ng / ml to about 300 ng / ml (e.g., about 50 ng / ml to about 100 ng / ml, about 10 ng / ml to about 100 ng / ml, or about 15 ng / ml to about 160 ng / ml). maxIn some embodiments, the administration can result in a C of a single dose of abiraterone of about 1 ng / ml to about 8 ng / ml, or greater than about 8 ng / ml, e.g., greater than 8.4 ng / ml, on days 1-7, 1-14, 1-21, 1-28, 1-70, or 7-70 after administration. min In some embodiments, the administration can result in a steady-state C of abiraterone of about 1 ng / ml to about 8 ng / ml, or greater than about 8 ng / ml, e.g., greater than 8.4 ng / ml. min may result.

[0184] Suitable abiraterone prodrugs for use in the once-weekly or once-every-weekly dosing regimen include those described herein. In some embodiments, the abiraterone prodrug may be a lipophilic ester of abiraterone described herein, such as acetate, propionate, butanoate, (butyrate)pentanoate, isocaproate, bucclate, cyclohexanecarboxylate, phenylpropionate, caproate (hexanoate), enanthate (heptanoate), cypionate, octanoate, noncanoate, decanoate, undecanoate, dodecanoate, tridecanoate, tetradecanoate, pentadecanoate, and hexadecanoate. In some preferred embodiments, the abiraterone prodrug may be a compound of formula I, such as, for example, where R 1 is C 7-16 Alkyl, for example -(CH 2 ) n -CH 3 where n is an integer from 6 to 12 (e.g., n is 6, 7, 8, 9, 10), or R 1 is a compound of the formula -(CH 2 ) n -Cy, where n is an integer from 1 to 6, and Cy is C 3-6For example, in more specific embodiments, n can be 1 or 2, and Cy is cyclopentyl, cyclohexyl, or phenyl, or R 1 teeth, [ka] or R 1 teeth, [ka] In some embodiments, the abiraterone prodrug may be a compound of formula II, wherein R 2 is C 1-16 Alkyl, for example, -(CH 2 ) n -CH 3 where n is an integer from 0 to 12, or R 2 is a compound of the formula -(CH 2 ) n -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, or R 2 teeth, [ka] In any of the embodiments described herein, unless otherwise specified or directly contradicted by context, the abiraterone prodrug may be abiraterone decanoate.

[0185] In some embodiments, monthly or monthly administration is preferred, for example, a frequency of administration ranging from once a month to once every few months, for example, once a month to once every two months, or once a month to once every three months. In such embodiments, the abiraterone prodrug must not only release abiraterone slowly, but also release abiraterone at sufficient plasma concentrations to be beneficial to the intended user. Monthly or monthly administration is typically parenteral, such as intramuscular, intradermal, or subcutaneous. In any of the embodiments herein, unless directly contradicted, administration may be intramuscular.

[0186] The abiraterone prodrug and abiraterone prodrug formulations of the present disclosure can be administered to a patient 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 Zytiga® formulations, simultaneously or sequentially in any order. In some embodiments, patients can use abiraterone prodrug and abiraterone prodrug formulations as a supplement to existing abiraterone therapy. Furthermore, administration herein is not limited to administration of 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 patient.

[0187] In some embodiments, prior to the monthly or monthly administration, the methods herein may include an initial treatment period of more frequent dosing, such as weekly or biweekly administration. The initial treatment period may include administering a different abiraterone drug, such as the same abiraterone prodrug or a different abiraterone prodrug. Typically, the initial treatment period may be used to achieve a plasma concentration of abiraterone of about 1 ng / ml to about 8 ng / ml or greater than about 8 ng / ml prior to the monthly or monthly administration described herein. However, in some embodiments, the methods herein do not include such an initial treatment period.

[0188] As discussed herein, the disclosed abiraterone prodrugs and abiraterone prodrug formulations have several advantages over the currently marketed Zytiga® product. For example, administration of the disclosed abiraterone prodrugs and abiraterone prodrug formulations to a subject typically results in a C max Decreased C of abiraterone observed at steady state when administered orally at 1000 mg Zytiga® once daily without food max (at least 30% lower compared to

[0189] Thus, in some embodiments, the present disclosure provides, for example, the C maxThe present invention provides a method of treating a subject having side effects associated with high abiraterone exposure, such as having side effects associated with high abiraterone exposure, comprising administering to the subject an abiraterone prodrug and abiraterone prodrug formulation of the present disclosure, which reduces side effects compared to administering 1000 mg of Zytiga® orally 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 Zytiga® prescribing information (see, e.g., February 2018 or June 2019 versions). In some embodiments, the disclosure provides methods of treating a subject whose metabolism is inhibited by abiraterone, e.g., who is also administered a substrate drug of CYP2D6 and / or CYP2C8, the methods comprising administering to the subject an abiraterone prodrug and abiraterone prodrug formulation of the disclosure, which administration reduces inhibition of metabolism of the drug compared to oral administration of 1000 mg of Zytiga® once daily without food. In some embodiments, the disclosure provides a method of treating a subject having or likely to have hypertension, hypokalemia, or fluid retention due to mineralocorticoid excess, the method comprising administering to the subject an abiraterone prodrug and abiraterone prodrug formulation of the disclosure, which reduces hypertension, hypokalemia, and fluid retention, or reduces the likelihood of having hypertension, hypokalemia, and fluid retention, as compared to administering 1000 mg of Zytiga® orally once daily without food. In some embodiments, the disclosure provides a method of treating a subject having or likely to have adrenal cortical insufficiency, the method comprising administering to the subject an abiraterone prodrug and abiraterone prodrug formulation of the disclosure, which reduces adrenal cortical insufficiency or the likelihood of having adrenal cortical insufficiency, as compared to administering 1000 mg of Zytiga® orally once daily without food.In some embodiments, the disclosure provides methods of treating a subject having severe or fatal liver toxicity after taking Zytiga®, the methods comprising administering to the subject an abiraterone prodrug and abiraterone prodrug formulation of the disclosure, whereby the administration reduces liver toxicity. Without wishing to be bound by theory, it is believed that administration of the disclosed abiraterone prodrugs and abiraterone prodrug formulations typically results in reduced, yet effective, exposure to abiraterone and thus may be beneficial to patients requiring lower doses of abiraterone, for example as described above. Suitable dosage regimens and routes of administration include those described herein.

[0190] Exemplary Methods of Using Abiraterone Decanoate In some specific embodiments, the present disclosure also provides a method of treating a sex hormone-dependent benign or malignant disease, an androgen receptor-driven cancer, a syndrome resulting from androgen excess, and / or a syndrome resulting from glucocorticoid excess, such as hypercortisolism, 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, such as

[71] -

[81] and

[98] of the Summary Section of the present specification) to a subject in need thereof, e.g., a non-castrated subject. 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 patient in need thereof regardless of food. In some embodiments, the subject is a non-castrated subject. In some embodiments, the methods herein can also administer a pharmaceutical composition comprising abiraterone decanoate to a subject, regardless of whether the subject is castrated or not. In addition, as shown herein, no liver toxicity was observed from intramuscular administration of abiraterone decanoate at the doses tested. Thus, the methods herein can also advantageously treat subjects suffering from liver damage, such as moderate to severe liver damage (Child-Poo class B or C), prior to administration of an abiraterone prodrug.

[0191] Sex hormone-dependent benign or malignant diseases that can be treated by the method include any of those described herein, such as sex hormone-dependent cancers. In some embodiments, the sex hormone-dependent benign or malignant disease may be selected from androgen-dependent diseases and estrogen-dependent diseases, such as androgen-dependent cancers 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, and the like. 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 disease is CRPC or CSPC. In some embodiments, the sex hormone-dependent benign or malignant disease is metastatic CRPC or metastatic CSPC. Syndromes resulting from androgen excess and / or syndromes resulting from glucocorticoid excess, such as hypercortisolism, that can be treated by the method include any of those described herein. In some embodiments, the method can be a method for treating a non-neoplastic syndrome in a subject resulting from androgen excess, such as endometriosis, polycystic ovary syndrome, congenital adrenal hyperplasia (e.g., classical or non-classical congenital adrenal hyperplasia), precocious puberty, hirsutism, etc. In some embodiments, the method can be a method for treating a syndrome resulting from glucocorticoid (e.g., cortisol) excess, such as Cushing's syndrome or Cushing's disease.

[0192] In some particular embodiments, the methods are for treating sex hormone dependent or androgen receptor driven cancers, such as prostate cancer (e.g., as described herein), androgen receptor positive salivary duct carcinoma, or androgen receptor positive glioblastoma multiforme.

[0193] The methods herein can be used in combination with one or more additional therapies for the corresponding 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, etc.) to the patient, either simultaneously or sequentially, via the same or different routes of administration. Non-limiting examples of useful additional treatments include any of those described in

[28] -

[39] in the Summary section of this specification.

[0194] Typically, in the methods herein, another drug effective to reduce serum and / or gonadal testosterone levels is not administered simultaneously with the administration of abiraterone decanoate during treatment with abiraterone decanoate or otherwise interferes with treatment with abiraterone decanoate. For example, in some embodiments, the subject is not treated with a gonadal testosterone suppressant other than abiraterone decanoate in an amount effective to reduce the subject's serum testosterone level. In some embodiments, the subject is not treated with a gonadotropin releasing hormone antagonist and / or agonist in an amount effective to reduce the subject's serum testosterone level. In some embodiments, the subject is not treated with a gonadal testosterone suppressant other than abiraterone decanoate. In some embodiments, the subject is not treated with any gonadotropin releasing hormone antagonist and / or agonist. In some embodiments, the subject is not being treated with a drug selected from buserelin, leuprolide, deslorelin, fertirelin, histrelin, gonadorelin, resilelin, goserelin, nafarelin, peforelin, and triptorelin. In some embodiments, the subject is not being treated with a drug selected from abarelix, cetrorelix, degarelix, ganirelix, elagolix, linzagolixa, and relugolix. In some embodiments, the subject may be sensitive to gonadotropin releasing hormone antagonists and / or agonists or may otherwise be intolerant to agonists.

[0195] As discussed herein, abiraterone is a 17α-hydroxylase / C17,20-lyase (CYP17) inhibitor that may result in decreased biosynthesis of androgens (e.g., testosterone), decreased glucocorticoids (e.g., cortisol), and mineralocorticoid excess (e.g., increased progesterone). Adrenal insufficiency is also known to be associated with abiraterone therapy, such as Zytiga®. Intramuscular administration of a pharmaceutical composition comprising abiraterone decanoate herein has been shown to inhibit CYP17A1 in vivo for an extended period of time, resulting in effective plasma levels of abiraterone, along with increased progesterone levels and decreased cortisol levels.

[0196] In some embodiments, the methods herein (e.g., treating prostate cancer or treating classical or non-classical congenital adrenal hyperplasia) can include administering to the patient an agent that counteracts the reduction in glucocorticoid(s) associated with administration of abiraterone decanoate as described herein. In some embodiments, the methods can include administering to a subject in need thereof an agent effective in treating one or more symptoms associated with adrenal insufficiency, such as acute stress, fatigue, etc. In some particular embodiments, the methods can include administering to the subject a steroid, such as a corticosteroid. In some embodiments, the methods can include administering to the patient a glucocorticoid. In some particular embodiments, the methods can also include administering to the patient prednisone, prednisolone, and / or methylprednisolone. In some particular embodiments, the methods can also include administering to the subject hydrocortisone, prednisone, prednisolone, methylprednisolone, and / or dexamethasone. In some embodiments, the method may also include administering to the patient an agent effective in treating cortisol deficiency, such as hydrocortisone, prednisone, prednisolone, methylprednisolone, and / or dexamethasone. In any such embodiment, the agents may be administered to the patient simultaneously or sequentially in any order via the same or different routes of administration. However, in some embodiments, glucocorticoid replacement therapy (e.g., administering a glucocorticoid such as hydrocortisone, prednisone, prednisolone, methylprednisolone, or dexamethasone) is not desirable. For example, glucocorticoids may be contraindicated for subjects who may have an underlying disease such as diabetes. In some embodiments, the method may also be characterized in that the subject is not being treated with glucocorticoid replacement therapy. In some embodiments, the 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 subject a mineralocorticoid receptor antagonist, such as eplerenone. For example, in any of the embodiments herein in which glucocorticoid replacement therapy is not desired and / or is not administered, the method may include administering to the subject a mineralocorticoid receptor antagonist, such as eplerenone. In some embodiments, the method is for treating prostate cancer and includes a combination therapy that further includes administering to the patient one or more additional therapeutic agents, for example, as described in the "Combination Therapies for Prostate Cancer" chapter herein. Non-limiting examples of useful additional treatments include any of those described in

[28] -

[39] in the Summary section of this specification.

[0197] In some embodiments, the methods herein may be characterized by a dosing frequency of once a week or less. 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 to the patient a pharmaceutical composition (e.g., a unit dosage form described herein) comprising abiraterone decanoate once a week, once every two weeks, once every three weeks, once a month, or once every few months, e.g., once every two months, or once every three months. In some embodiments, the methods include administering to the patient a pharmaceutical composition (e.g., a unit dosage form described herein) comprising abiraterone decanoate once every two weeks, once a month, or once every few months, e.g., once every two months, or once every three months. In some embodiments, the dosage is about 50 mg to about 5000 mg of abiraterone decanoate (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 of values ​​recited). In some embodiments, the dosage is about 0.5 mg / kg to about 200 mg / kg of the subject's body weight (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 of values ​​recited). In some embodiments, administration is via intramuscular injection. In some embodiments, administration of a single dose provides therapeutically effective plasma concentrations of abiraterone for a period of at least 1 week, such as at least 2 weeks, such as at least 3 weeks, at least 4 weeks, and up to 6 or 8 weeks or more, such as up to 10 weeks or more.In some embodiments, administration of a single dose results in a plasma concentration of abiraterone of greater than 1.0 ng / ml (e.g., about 1 ng / ml to about 8 ng / ml, or about 2 ng / ml or more, about 4 ng / ml or more, about 5 ng / ml or more, or 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, the administration results in a steady-state C of abiraterone of greater than 1.0 ng / ml (e.g., about 1 ng / ml to about 8 ng / ml, about 2 ng / ml or more, about 4 ng / ml or more, about 5 ng / ml or more, or about 8 ng / ml or more). min In some embodiments, the administration results in a single dose or steady state C of abiraterone of about 5 ng / ml to about 300 ng / ml, e.g., about 5 ng / ml, about 10 ng / ml, about 15 ng / ml, about 20 ng / ml, about 30 ng / ml, about 50 ng / ml, about 60 ng / ml, about 100 ng / ml, about 150 ng / ml, about 160 ng / ml, or any range of values ​​recited, e.g., about 10-30 ng / ml, about 20-60 ng / ml, about 15-160 ng / ml, or about 50-100 ng / ml. max In some embodiments, the administration may also result in a concentration of abiraterone in a tissue of the 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, iliac lymph, adrenal gland, and prostate. In some embodiments, the abiraterone decanoate formulation may be administered to a patient in need thereof as the sole source of abiraterone. However, in some embodiments, the abiraterone decanoate formulation may also be administered to a patient in need thereof as a supplement to another abiraterone therapy.

[0198] In some embodiments, specifically in the methods of treating prostate cancer herein, the dosage and frequency of abiraterone decanoate can be adjusted such that the 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 subject, or to about 1 ng / dL or less in a castrated subject, within 15 days (e.g., within 7 days, between 7 and 15 days, etc.) of the first administration of an abiraterone prodrug. For example, in some embodiments, the dosage 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 subject, or to about 1 ng / dL or less in a castrated subject, as measured 15 days after the first administration of the abiraterone prodrug. In some embodiments, the administration 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 subject, or about 1 ng / dL or less in a castrated subject, within 15 days (e.g., within 7 days, between 7-15 days, etc.) of the first administration of the abiraterone prodrug. In some embodiments, the dosage and frequency of abiraterone decanoate can be adjusted such that the administration 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, between 7-15 days, etc.) of the first administration of abiraterone decanoate. For example, in some embodiments, the administration provides an amount of abiraterone effective to reduce serum testosterone levels by 50% or more, preferably 75% or more, from baseline as measured 15 days after the first administration of abiraterone decanoate.In some embodiments, the administration provides an amount of abiraterone effective to achieve a sustained reduction in serum testosterone levels of 50% or more, 75% or more from baseline within 15 days (e.g., within 7 days, between 7 and 15 days, etc.) of the first administration of abiraterone decanoate.

[0199] In some specific examples, the disclosure provides a method of treating prostate cancer, the method comprising administering to a subject a dose of abiraterone decanoate of 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 of values ​​recited), and wherein each dose of abiraterone decanoate is about 0.5 mg / kg to about 200 mg / kg (e.g., about 0.5 mg / kg, about 1 mg / kg, or about 200 mg / kg) of the subject's body weight. , 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 of values ​​recited) once a week or once every few weeks, for example, once a month or once every few months, for example, once every two months or once every three months, via intramuscular, intradermal, or subcutaneous injection to a subject in need thereof. In some embodiments, abiraterone decanoate is administered via intramuscular injection. In some embodiments, the prostate cancer is CRPC or CSPC. In some embodiments, the prostate cancer is metastatic CRPC or metastatic CSPC. Suitable prostate cancers that can be treated by the method include any of those described herein. In some embodiments, the prostate cancer is localized prostate cancer. In some embodiments, the subject has not undergone a prostatectomy. In some embodiments, the method of treating prostate cancer includes combination therapy, further comprising administering to the patient one or more additional therapeutic agents, for example, as described in the "Combination Therapies for Prostate Cancer" section herein. For example, in some embodiments, the subject is treated with radiation therapy.

[0200] In some specific examples, the disclosure provides a method of treating prostate cancer, the method comprising administering to a subject a 50 mg to about 2000 mg dose of abiraterone decanoate (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 of values ​​recited), or a 50 mg to about 200 mg dose of abiraterone decanoate (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, or any range of values ​​recited), of the subject. The present invention includes administering a pharmaceutical composition (e.g., a unit dosage form described herein) comprising abiraterone decanoate as described herein (e.g., a substantially pure abiraterone decanoate as described herein) to a subject in need thereof, e.g., a non-castrated subject in need thereof, via intramuscular, intradermal, or subcutaneous injection at a dose of about 0 mg / kg, about 90 mg / kg, about 100 mg / kg, about 200 mg / kg, or any range of values ​​described therein, once a week or once every few weeks, e.g., once a month or once every few months, e.g., once every two months, once every three months. In some embodiments, the pharmaceutical composition is administered via intramuscular injection. In some embodiments, the prostate cancer is localized prostate cancer. In some embodiments, the prostate cancer is metastatic CRPC or metastatic CSPC. Suitable prostate cancers that can be treated by the present method include any of those described herein. In some embodiments, the prostate cancer is localized prostate cancer. In some embodiments, the subject has not undergone a prostatectomy. In some embodiments, the method of treating prostate cancer includes combination therapy further comprising administering to the patient one or more additional therapeutic agents, for example, as described in the "Combination Therapies for Prostate Cancer" section of this specification. For example, in some embodiments, the subject is treated with radiation therapy. Non-limiting examples of useful additional treatments also include any of those described in

[28] -

[39] in the Summary section of this specification.

[0201] In some specific examples, the disclosure provides a method of treating prostate cancer, the method comprising administering to a subject a 50 mg to about 5000 mg dose of abiraterone decanoate (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 of values ​​recited), or a 50 mg to about 200 mg dose of abiraterone decanoate (e.g., about 0.5 mg / kg, about 1 mg / kg, about 5 mg / kg, about The present invention includes administering a unit formulation described herein to a subject in need thereof, e.g., an uncastrated subject in need thereof, via intramuscular, intradermal, or subcutaneous injection at a dose of 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 of values ​​described) once a week or once every few weeks, e.g., once a month or once every few months, e.g., once every two months or once every three months. In some embodiments, the unit formulation is administered via intramuscular injection. In some embodiments, the prostate cancer is CRPC or CSPC. In some embodiments, the prostate cancer is metastatic CRPC or metastatic CSPC. Suitable prostate cancers that can be treated by the present method include any of those described herein. In some embodiments, the prostate cancer is localized prostate cancer. In some embodiments, the subject has not undergone a prostatectomy. In some embodiments, the method of treating prostate cancer includes combination therapy, further comprising administering to the patient one or more additional therapeutic agents, for example, as described in the "Combination Therapies for Prostate Cancer" section herein. For example, in some embodiments, the subject is treated with radiation therapy.

[0202] In some specific examples, the disclosure provides a method of treating prostate cancer, the method comprising administering to a subject a 50 mg to about 5000 mg dose of abiraterone decanoate (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 of values ​​recited), or a 50 mg to about 200 mg dose of abiraterone decanoate (e.g., about 0.5 mg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 20 mg / kg, or any range of values ​​recited), of the subject's body weight. The present invention includes administering abiraterone decanoate (e.g., a substantially pure abiraterone decanoate herein) to a subject in need thereof, e.g., an uncastrated subject in need thereof, via intramuscular, intradermal, or subcutaneous injection at a dose of about 100 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 of values ​​recited) once a week or once every few weeks, e.g., once a month or once every few months, e.g., once every two months or once every three months. In some embodiments, the abiraterone decanoate is administered via intramuscular injection. In some embodiments, the sex hormone-dependent or androgen receptor-driven cancer is androgen receptor-positive salivary duct cancer, or androgen receptor-positive glioblastoma multiforme. In some embodiments, the sex hormone-dependent or androgen receptor-driven cancer is prostate cancer as described herein.

[0203] In some specific examples, the disclosure provides a method of treating localized prostate cancer, the method comprising administering abiraterone decanoate at a dose of 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 of values ​​recited), or at a dose of 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, The method includes administering abiraterone decanoate (e.g., the substantially pure abiraterone decanoate herein) to a subject in need thereof via intramuscular, intradermal, or subcutaneous injection at 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 of values ​​recited), once a week or once every few weeks, for example once a month or once every few months, for example once every two months or once every three months, wherein the subject has not undergone a prostatectomy. In some embodiments, the abiraterone decanoate is administered via intramuscular injection. In some embodiments, the subject is treated with radiation therapy.

[0204] In some specific embodiments, the disclosure also provides a method of treating breast cancer in a subject in need thereof, e.g., an uncastrated subject in need thereof, comprising administering to a subject a dose of abiraterone decanoate of 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 of values ​​recited), and wherein each dose of abiraterone decanoate is about 0.5 mg / kg to about 200 mg / kg of the subject's body weight (e.g., about 0.5 mg / kg). The method includes administering to the subject a pharmaceutical composition comprising abiraterone decanoate as described herein (e.g., a unit dosage form as described herein) at 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 of values ​​recited) once a week or once every few weeks, for example once a month or once every few months, for example once every two months or once every three months, via intramuscular, intradermal, or subcutaneous injection. In some embodiments, the breast cancer may be molecular apocrine HER2-negative breast cancer, metastatic breast cancer, for example ER+ metastatic breast cancer, ER+ and HER2-negative breast cancer, AR+ triple-negative breast cancer, etc. In some embodiments, the method further includes administering an aromatase inhibitor, for example, exemestane, to the subject.

[0205] In some specific embodiments, the disclosure also provides a method of treating 21 hydroxylase deficiency in a subject in need thereof, e.g., a non-castrated subject, wherein each dose of abiraterone decanoate 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 of values ​​recited), and each dose of abiraterone decanoate is about 0.5 mg / kg to about 200 mg / kg of the subject's body weight (e.g., about 0.5 mg / kg to about 100 mg / kg). The present invention includes administering to a subject a pharmaceutical composition comprising abiraterone decanoate as described herein (e.g., a unit dosage form as described herein) at 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, 200 mg / kg, or any range of values ​​recited) via intramuscular, intradermal, or subcutaneous injection once a week or once every few weeks, e.g., once a month or once every few months, e.g., once every two months or once every three months.

[0206] In certain embodiments, the disclosure also provides methods of delivering abiraterone to a subject in need thereof, e.g., a non-castrated subject, wherein each dose of abiraterone decanoate 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 of values ​​recited), or each dose of abiraterone decanoate is about 0.5 mg / kg to about 200 mg / kg of the subject's body weight (e.g., about 0.5 mg / kg to about 100 mg / kg). The method comprises administering to the subject a pharmaceutical composition comprising abiraterone decanoate as described herein (e.g., a unit dosage form as described herein) at 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 of values ​​recited) once a week or once every few weeks, for example once a month or once every few months, for example once every two months or once every three months, via intramuscular, intradermal, or subcutaneous injection. In some embodiments, the pharmaceutical composition is administered via intramuscular injection. In some embodiments, the subject suffers from a hormone-dependent benign or malignant disease, an androgen receptor-driven cancer, a syndrome resulting from androgen excess, and / or a syndrome resulting from glucocorticoid excess, such as hypercortisolism, for example, as described herein.

[0207] In some specific embodiments, the disclosure also provides a method of inhibiting CYP17A1 activity in a subject in need thereof, e.g., a non-castrated subject, wherein each dose of abiraterone decanoate 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 of values ​​recited), or each dose of abiraterone decanoate is about 0.5 mg / kg to about 200 mg / kg of the subject's body weight (e.g., about 0.5 mg The present invention includes administering to a subject a pharmaceutical composition comprising abiraterone decanoate as described herein (e.g., a unit dosage form as described herein) via intramuscular, intradermal, or subcutaneous injection at a dose of 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 of values ​​recited) once a week or once every few weeks, for example once a month or once every few months, for example once every two months or once every three months. In some embodiments, the pharmaceutical composition is administered via intramuscular injection. In some embodiments, the patient suffers from a sex hormone-dependent benign or malignant disease, for example, as described herein. In some embodiments, the patient suffers from a syndrome resulting from androgen excess and / or a syndrome resulting from glucocorticoid excess, such as hypercortisolism, for example, as described herein.

[0208] In some specific embodiments, the disclosure also provides a method of reducing glucocorticoid (e.g., cortisol) levels in a subject in need thereof, e.g., a non-castrated subject, wherein each dose of abiraterone decanoate 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 of values ​​recited), or each dose of abiraterone decanoate is about 0.5 mg / kg to about 200 mg / kg of the subject's body weight (e.g., about 100 mg, about 150 mg, about 200 mg, about 5000 mg, or any range of values ​​recited), The method includes administering to a subject a pharmaceutical composition comprising abiraterone decanoate as described herein (e.g., a unit dosage form as described herein) via intramuscular, intradermal, or subcutaneous injection, for example, 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 of values ​​recited), once a week or once every few weeks, for example, once a month or once every few months, for example, once every two months or once every three months. In some embodiments, the pharmaceutical composition is administered via intramuscular injection. In some embodiments, the patient is suffering from hypercortisolism as described herein, such as Cushing's syndrome or Cushing's disease.

[0209] In some specific embodiments, the disclosure also provides methods of reducing androgen (e.g., testosterone and / or dihydrotestosterone) and / or estrogen levels in a subject in need thereof, e.g., a non-castrated subject, wherein each dose of abiraterone decanoate 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 of values ​​recited), or each dose of abiraterone decanoate is about 0.5 mg / kg of the subject's body weight. The method comprises administering to the subject a pharmaceutical composition comprising abiraterone decanoate as described herein (e.g., a unit dosage form as described herein) at a dose of 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 of values ​​recited), once a week or once every few weeks, e.g., once a month or once every few months, e.g., once every two months or once every three months, via intramuscular, intradermal, or subcutaneous injection. In some embodiments, the pharmaceutical composition is administered via intramuscular injection. In some embodiments, the 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, or hirsutism. In some embodiments, the subject has an androgen and / or estrogen associated cancer, such as having prostate cancer or breast cancer, hi some embodiments, the subject has an androgen receptor driven cancer, such as those described herein.

[0210] In some specific embodiments, the disclosure also provides a method of reducing serum testosterone levels in a subject in need thereof, e.g., a non-castrated subject, wherein each dose of abiraterone decanoate 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 of values ​​recited), and each dose of abiraterone decanoate is about 0.5 mg / kg to about 200 mg / kg of the subject's body weight (e.g., about 0.5 mg / kg to about 100 mg / kg). The method includes administering to a subject a pharmaceutical composition comprising abiraterone decanoate as described herein (e.g., a unit dosage form as described herein) at 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 of values ​​recited) via intramuscular, intradermal, or subcutaneous injection once a week or once every few weeks, e.g., once a month or once every few months, e.g., once every two months or once every three months. In some embodiments, the pharmaceutical composition is administered via intramuscular injection. In some embodiments, specifically when the subject is characterized as having prostate cancer, the 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 subject, or about 1 ng / dL or less in a castrated subject, within 15 days (e.g., within 7 days, between 7 and 15 days, etc.) of the first administration of abiraterone decanoate. For example, in some embodiments, the 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 subject, or to about 1 ng / dL or less in a castrated subject, as measured 15 days after the first administration of the abiraterone prodrug.In some embodiments, the administration 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 subject, or about 1 ng / dL or less in a castrated subject, within 15 days (e.g., within 7 days, between 7-15 days, etc.) of the first administration of abiraterone prodrug. In some embodiments, the administration 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, between 7-15 days, etc.) of the first administration of abiraterone decanoate. For example, in some embodiments, the administration provides an amount of abiraterone effective to reduce serum testosterone levels by 50% or more, preferably 75% or more, from baseline, as measured 15 days after the first administration of abiraterone decanoate. In some embodiments, the administration provides an amount of abiraterone effective to achieve a sustained reduction in serum testosterone levels by 50% or more, 75% or more, from baseline, within 15 days (e.g., within 7 days, 7-15 days, etc.) of the first administration of abiraterone decanoate. In some embodiments, the subject suffers from a sex hormone dependent cancer or an androgen receptor driven cancer, as described herein.

[0211] In any of the embodiments described herein, unless otherwise specified or contradictory, abiraterone decanoate is formulated in a pharmaceutical composition that contains, per milliliter, (a) abiraterone decanoate in its basic form in an amount of about 100 mg to about 300 mg (e.g., about 100 mg, about 120 mg, about 150 mg, about 180 mg, about 200 mg, or about 250 mg); (b) benzyl alcohol in an amount of about 50 mg to about 150 mg (e.g., about 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 appropriate for each milliliter. In some embodiments, the weight ratio of benzyl alcohol to 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). In some embodiments, the pharmaceutical composition has (1) a viscosity of less than 0.1 Pa*s, e.g., about 0.05 Pa*s or less; (2) a glide force of about 1-10 N when measured using a 21G (or 23G), 1.5 inch needle, and / or a glide force of about 2-15 N when measured using a 23 gauge (or 23G), 1.5 inch needle, and / or a glide force of about 30-150 N when measured using a 27G, 1.5 inch needle; (3) a viscosity of about 100-2000 g / ml, e.g., about 100-25 ... <788> and / or <789> (4) Not more than 1,000 particles 10 μm or greater in size and not more than 300 particles 25 μm or greater in size, 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, bacterial endotoxins, as measured according to the USP method. Methods for measuring viscosity and glide force are known in the art and are exemplified herein in Example 2. The USP method referred to herein <788> , <789> and <85> should be understood to be the current version of the method as known to those skilled in the art. In any of the embodiments described herein, unless otherwise specified or contradicted, abiraterone decanoate may be formulated in a pharmaceutical composition according to any of

[71] -

[81] and

[98] in the Summary section of this specification.In any of the embodiments described herein, unless specified or otherwise contradicted, abiraterone decanoate may be formulated in a pharmaceutical composition with ingredients on a per milliliter basis according to those set forth in Example 2 herein.

[0212] Formulations, methods and kits are provided herein for treating patients with sex hormone dependent benign or malignant diseases, such as prostate cancer. Methods are also provided for preparing formulations useful for treating subjects with sex hormone dependent benign or malignant diseases (e.g., prostate cancer), androgen receptor driven cancers, syndromes due to androgen excess and / or syndromes due to glucocorticoid excess, such as hypercortisolism. Reference numbers are given to details of representative embodiments, examples of which are shown in the accompanying drawings.

[0213] The term "subject", as used herein, refers to, but is not limited to, an animal or human who needs to undergo or can undergo chemotherapy for sex hormone-dependent benign or malignant diseases, such as androgen- or estrogen-dependent diseases (including prostate and breast cancer), androgen receptor-driven cancers, or an animal or human who needs to undergo or can undergo treatment for non-neoplastic syndromes resulting from androgen excess, such as endometriosis, polycystic ovary syndrome, congenital adrenal hyperplasia (e.g., classical or non-classical congenital adrenal hyperplasia), precocious puberty, hirsutism, and / or non-neoplastic syndromes resulting from glucocorticoid excess, such as hypercortisolism, such as Cushing's syndrome or Cushing's disease. In a preferred embodiment, the patient is a human subject.

[0214] The term "other drug or agent" as used herein means at least one other compound, formulation, molecule, biological agent, etc. that can enhance the efficacy of the formulation(s), reduce the undesirable side effect(s) of the formulation(s), or improve the treatment of a particular disease (e.g., when at least one other drug or agent is administered before, simultaneously with, and after at least one abiraterone prodrug formulation). Any suitable route of administration of such "other drug or agent" may be used, e.g., oral administration. Those skilled in the art of treating subjects with sex hormone-dependent benign or malignant diseases (e.g., androgen-dependent or estrogen-dependent diseases), androgen receptor-driven cancers, syndromes resulting from androgen excess syndromes and / or syndromes resulting from glucocorticoid excess, such as hypercortisolism, will recognize and understand how to select and use such "other drugs or agents" for the intended purpose(s).

[0215] The formulation may optionally be administered via a modified sustained release device or method. As used herein, the term "modified release" should be understood to encompass delayed release, extended or prolonged release, sustained release, or targeted release, and the like. For example, in some embodiments, the modified release device or method can further extend the release of the abiraterone of the prodrugs and formulations of the present disclosure. In some embodiments, the improved sustained release device or method may also include any device or method that can release a drug or product (e.g., a drug or biological agent) at a time later than immediately after its administration (and may include, for example, injection). A variety of modified release devices have been described (Stubbe et al., Pharm. Res. 21:1732, 2004) and may be applicable to the representative embodiments. Improved sustained release devices and methods can be recognized and utilized by those skilled in the art without undue experimentation after considering all criteria and exercising their best judgment on behalf of the patient.

[0216] The formulations and agents of the embodiments are administered in pharmacologically or physiologically acceptable and effective amounts, for example, to reduce or eliminate the presence of prostate tumor tissue and abnormal or malignant prostate cells in patients exhibiting prostate cancer. Similarly, the formulations and agents of the embodiments are administered in prophylactically or therapeutically effective amounts, either alone or in combination with other therapeutic agents or treatments (e.g., radiation therapy and surgery), with such amounts being understood as amounts that meet the intended prophylactic or therapeutic purpose and provide the benefit obtained from the administration of such formulations and agents.

[0217] The terms "effective amount", "effective dose" and "therapeutic range plasma concentration" as used herein refer to, but are not limited to, an amount, dose or concentration that can treat, delay, slow, inhibit or eliminate the onset, presence or progression of a disease, disorder or condition. For example, an "effective amount", "effective dose" or "therapeutic range plasma concentration" is an amount, dose or concentration that can reduce or eliminate the presence of prostate tumor tissue and abnormal or malignant prostate cells in a patient exhibiting prostate cancer, and thus cure (partially or completely) the disease or prevent the onset or further spread of a disease, disorder or condition. As a further example, an effective amount of a formulation refers to an amount that is administered alone or in combination with other therapeutic agents or treatments (e.g., radiation therapy and surgery) to clinically significantly reduce tumor burden. Those skilled in the art will understand when a clinically significant reduction in tumor burden (or improvement of sex hormone-dependent benign or malignant disease or another disease or syndrome described herein) occurs after administration of the formulation. An "effective amount," "effective dose," or "therapeutic plasma concentration" is an amount, dose, or concentration that does not cause significant harm to the patient, and in any event, it is understood that any adverse side effects outweigh the benefits. By way of example only, an effective amount or dose of an abiraterone prodrug formulation means an amount that can achieve a plasma concentration of at least 1 ng / ml, e.g., at least 1 ng / ml, at least 2 ng / ml, at least 4 ng / ml, or at least 8 ng / ml, of abiraterone in a subject following parenteral administration of the prodrug formulation, and the effective plasma concentration is achieved for at least 1 week, e.g., at least 2 weeks (e.g., 4, 6, 8 weeks or more) following administration.

[0218] In general, the dosage range of the administration of the formulation according to the present disclosure is that which produces the desired effect(s). The useful dosage varies according to the age, weight and health condition of the patient to be treated, the mode, route and schedule of administration, the response of the individual patient, and the type or stage of prostate cancer (or the severity of sex hormone-dependent benign or malignant disease or another syndrome or disease described herein) for which treatment with the formulation is sought. The dosage also varies according to the nature or severity of the primary tumor and other underlying pathologies, epidemiological pathologies, the combination with other active compounds, and the route of administration. In addition, the dosage is determined by the presence of adverse side effects, such as local hypersensitivity, systemic adverse effects, and immune resistance.

[0219] The effective dosage of the formulation (and other drug(s)) can be determined without the need for experimentation (e.g., pharmacokinetic studies) by those skilled in the art after considering all criteria and exercising their best judgment on behalf of the patient (and will in most cases be determined by the particular formulation utilized). The dosage will vary depending on the particular case, but in any case will be an amount sufficient to produce a clinical benefit or improvement in sex hormone-dependent benign or malignant diseases (e.g., prostate cancer), androgen receptor-driven cancers, syndromes due to androgen excess, and / or syndromes due to glucocorticoid excess, such as hypercortisolism.

[0220] The formulations and medicaments of the embodiments can be administered in combination with (or can include) one or more pharma- ceutically acceptable carriers, diluents, or excipients, if desired. Formulations, administration techniques, pharmaceutical compositions, methods for preparing pharmaceutical compositions, and pharma- ceutically acceptable carriers, diluents, and excipients are known in the art and described, for example, 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)), the disclosure of which is incorporated herein by reference. Those skilled in the art can use known physiologically acceptable sterile solutions for injection. To prepare a ready-to-use solution for parenteral injection or infusion, isotonic aqueous solutions, such as saline, phosphate buffered saline (PBS), or corresponding plasma protein solutions, are readily available. The formulation can be present as a lyophilized or dried preparation, for example as a kit of parts, and can be dissolved in a known injection solution immediately before use under sterile conditions. In addition, the formulation can include one or more acceptable carriers, such as solvents, dispersions, coatings, adjuvants, stabilizers, diluents, preservatives, antibacterial and antifungal agents, isotonicity agents, absorption modifiers, etc. "Diluents" can include water, saline, phosphate-buffered saline (PBS), dextrose, ethanol, glycerol, etc. Isotonicity agents can include sodium chloride, dextrose, mannitol, sorbitol, and lactose, etc. Stabilizers include albumin and alkali salts of ethylenediaminetetraacetic acid, etc.

[0221] Any suitable route of administration may be used to provide an effective amount / dose of the formulation and agent to a patient in accordance with exemplary embodiments. Suitable routes of administration can be readily determined without undue experimentation by those skilled in the art of pharmacology, immunology, medicine, oncology, and the like. However, it is expected that the formulations will primarily be suitable for parenteral administration, such as by IM, intradermal, or subcutaneous injection.

[0222] The abbreviations used herein have their conventional meaning within the chemical and biological arts.

[0223] Headings and subheadings are used for convenience and / or formal compliance only, are not intended to limit the subject art, and should not be referenced in connection with interpreting the description of the subject art. Features described under one heading or one subheading of the subject disclosure may be combined with features described under other headings or subheadings in various embodiments. Moreover, not all features under one heading or one subheading may be used together in an embodiment.

[0224] As used herein, the term "about" modifies the quantities associated with this disclosure and refers to variations in numerical quantities that may occur, for example, through routine testing and processing, through errors in such testing and processing, and through differences in manufacturing, supply, or purity of the components / materials used in this disclosure. As used herein, a particular value with "about" includes the particular value, such as about 10%, including 10%. Whether or not modified by the term "about," the claims include the equivalent of the recited quantity. In one embodiment, the term "about" means within 20% of the reported numerical value.

[0225] It is also to be understood that a particular embodiment that is a variable part of this specification may be the same as or different from another particular embodiment that uses the same identifier.

[0226] Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified by the Periodic Table of the Elements, CAS version, inside cover of Handbook of Chemistry and Physics, 75th Ed, and specific functional groups are generally defined as described therein. In addition, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley&Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987. This disclosure is not intended to be limited in any manner by the exemplary list of substituents described herein.

[0227] As used herein, the term "alkyl," used by itself or as part of another group, refers to a straight or branched chain saturated aliphatic hydrocarbon. In some embodiments, an alkyl contains 1 to 30 carbon atoms (i.e., C 1-30 Alkyl, or C 1 -C 30 alkyl) or contains a specified number of carbon atoms (i.e., C 1 C such as alkyl and ethyl 2 C such as alkyl, propyl or isopropyl 3 In one embodiment, the alkyl group may be a straight chain C 1-16In another embodiment, the alkyl group is a branched chain C 3-16 For the avoidance of doubt, when a range of carbon numbers is recited, it will be understood by one of ordinary skill in the art that the carbon number includes each individual integer within the range and subranges of such integers. For example, "C 7-16 " is C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 7-16 , C 7-15 , C 7-14 , C 7-13 , C 7-12 , C 7-11 , C 7-10 , C 7-9 , C 7-8 , C 8-16 , C 8-15 , C 8-14 , C 8-13 , C 8-12 , C 8-11 , C 8-10 , C 8-9 , C 9-16 , C 9-15 , C 9-14 , C 9-13 , C 9-12 , C 9-11 , C 9-10 , C 10-16 , C 10-15 , C 10-14 , C 10-13 , C 10-12 , C 10-11 , C 11-16 , C 11-15 , C 11-14 , C 11-13 , C 11-12 , C 12-16 , C 12-15 , C 12-14 , C 12-13 , C 13-16 , C 13-15 , C 13-14 , C 14-16 , C 14-15 , and C 15-16It should be understood that other ranges, such as "5 to 16 carbons," as described herein, are similar.

[0228] As used herein, the term "cycloalkyl" used by itself or as part of another group refers to cycloalkyl groups having 3 to 12 carbon atoms (i.e., C 3-12 Cycloalkyl refers to saturated and partially unsaturated (e.g., containing one or two double bonds) cyclic aliphatic hydrocarbons containing one to three rings having the specified number of carbon atoms. In one embodiment, a cycloalkyl group has two rings. In one embodiment, a cycloalkyl group has one ring. In another embodiment, a cycloalkyl group has C 3-8 In another embodiment, the cycloalkyl group is 3-6 Cycloalkyl groups. "Cycloalkyl" also includes ring systems in which a cycloalkyl ring is fused to one or more aryl or heteroaryl groups as described above, where the point of attachment is on the cycloalkyl ring, and in such instances, the number of carbons continues to refer to the number of carbons in the cycloalkyl ring system. Non-limiting exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclopentenyl, and cyclohexenyl.

[0229] As used herein, the term "alkenyl" by itself or as part of another group means a straight or branched chain aliphatic hydrocarbon containing one or more (e.g., 1, 2, or 3) carbon-to-carbon double bonds. In one embodiment, an alkenyl group is 2-16 It is an alkenyl group.

[0230] As used herein, the term "alkynyl" used by itself or as part of another group means a straight or branched chain aliphatic hydrocarbon containing one or more (e.g., 1, 2, or 3) carbon-to-carbon triple bonds. In one embodiment, an alkynyl has one carbon-carbon triple bond. In one embodiment, an alkynyl group is a C2-16 It is an alkynyl group.

[0231] As used herein, the term "abiraterone prodrug(s) of the present disclosure" refers to any of the compounds described herein of formula I or II, lipophilic esters of abiraterone prodrugs, isotopically labeled compound(s) thereof (e.g., deuterium-enriched compounds), possible stereoisomers thereof (including diastereoisomers, enantiomers, and racemic mixtures), tautomers thereof, conformers thereof, and / or pharma- ceutically acceptable salts thereof (e.g., acid addition salts such as HCl salts). Hydrates and solvates of the prodrugs of the present disclosure are considered compositions of the present disclosure, in which the prodrug(s) are associated with water or solvent, respectively. Some of the prodrugs of the present disclosure may also exist in various polymorphic or amorphous forms. The prodrugs described herein include compounds that readily undergo chemical changes under physiological conditions to provide active abiraterone. Additionally, the prodrugs may be converted by chemical or biochemical methods in an ex vivo environment. As used herein, the term "abiraterone prodrug formulation(s) of the present disclosure" refers to any pharmaceutical composition or formulation comprising any one or more of the abiraterone prodrugs of the present disclosure, e.g., any of the formulations prepared in Example 2. In any of the embodiments described herein, unless directly contradicted by context, the abiraterone prodrug of the present disclosure may be abiraterone decanoate. In any of the embodiments described herein, unless directly contradicted by context, the abiraterone prodrug formulation of the present disclosure may be any of the pharmaceutical compositions comprising abiraterone decanoate as described herein.

[0232] The abiraterone prodrugs of the present disclosure may be present in isotopically labeled or isotopically enriched forms containing one or more atoms having an atomic mass, or a mass number different from the atomic mass, or a mass number most commonly found in nature. The isotopes may be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, oxygen, and nitrogen include: 2 H, 3 H,13 C. 14 C. 15 N, and 18 Compounds containing other isotopes of these and / or other atoms are within the scope of the disclosure.

[0233] The solid and dashed wedge bonds represent the stereochemistry conventional in the art.

[0234] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claimed subject matter.

[0235] Example 1A. Large-Scale Preparation of Abiraterone Decanoate from Decanoic Acid [ka] To a suspension of abiraterone (381.9 g, 1.09 mol) in dichloromethane (3500 mL) was added triethylamine (165 g, 1.64 mol) and a catalytic amount of DMAP (13.35 g, 0.109 mol). Decanoic acid (225 g, 1.31 mol) as a solution in dichloromethane (500 mL) was added to the suspension followed by EDCI (293 g, 1.53 mol), then the reaction was stirred at 20-25 °C for 19 h.

[0236] Then, a 10 wt% aqueous solution of NaH 2 PO 4 (4000 mL) was added and the reaction was stirred for 20 min. The organic layer was separated and washed with 10 wt% NaH 2 PO 4 Extraction was performed with aqueous solution (2000 mL) and brine (2000 mL). The organic layer was solvent exchanged with acetonitrile (4750 mL) and concentrated to 3100 g while maintaining the bath temperature below 40° C. The suspension was diluted with acetonitrile (900 g). The solids were isolated by filtration to give 510 g of crude abiraterone decanoate.

[0237] 510 g of crude abiraterone decanoate was dissolved in acetone (4000 mL) at 40° C. The solution was filtered through filter paper. The filtrate was transferred to a 12 L 3-neck flask, diluted to 5100 g, and reheated to 40° C. to form a solution. The solution was slowly cooled to 20° C. to form a suspension. This was diluted with water (1020 mL) and stirred at room temperature overnight. The solids were filtered, the flask was rinsed with the filtrate, and transferred to a filter funnel. The wet cake was transferred to a drying tray and dried overnight at 40-45° C. in a vacuum oven to give 457.1 g (90% yield) as a white solid. The crystalline form of this solid is designated as Form A. 1 H NMR (CDCl 3 , 400MHz):d H 8.62 (d, 1H, J=1.9 Hz), 8.31 (dd, 1H, J = 4.9, 1.6 Hz), 7.64 (dt, 1H, J= 7.9, 1.9 Hz), 7.21 (ddd, 1H, J = 8.0, 4.9, 0.8 Hz), 6.01-5.97 (m, 1H), 5.44-5.40 (m, 1H), 4.68-4.58 (m, 1H), 2.39-2.23 (m, 3H), 2.27 (t, 2H, J = 7.6 Hz), 2.12-2.00 (m, 3H), 1.91-1.54 (m, 10H), 1.49 (dt, 1H, J = 11.9, 5.1 Hz), 1.35-1.23 (m, 12H), 1.20-1.07 (m, 2H), 1.08 (s, 3H), 1.05 (s, 3H), 0.88 (t, 3H, J = 6.8 Hz). Elemental analysis, theoretical (corrected for 0.055% moisture level): C, 81.0%, H, 9.8%, N, 2.8%; found: C, 81.1%, H, 10.2%, N, 2.8%. The differential scanning calorimeter (DSC) pattern of this solid shows an endothermic peak with an onset temperature of approximately 69.0 °C (see Figure 2B).

[0238] Using HPLC method, the abiraterone decanoate obtained in this example was found to have a purity of 99.7% by weight. For HPLC analysis, abiraterone decanoate samples were prepared in methanol at a concentration of 0.05 mg / mL (for assay analysis) or 5 mg / mL (for impurity analysis). The HPLC conditions were as follows: HPLC column: Halo C8 (2.7um, 100x3.0mm), injection volume: 5uL; column temperature: 40°C, sample temperature: ambient, detection: 210nm; mobile phase: 25mM ammonium acetate, pH 8.0 (MPA) and 95 / 5 acetonitrile / tetrahydrofuran (MPB); flow rate: 0.6ml / min; gradient: starting at 65 / 35 MPA / MPB, reaching 100% MPB in 35 minutes, maintaining 100% MPB until 40 minutes, returning to 65 / 35 MPA / MPB at 40.10 minutes, maintaining 65 / 35 MPA / MPB until the end of 45 minutes.

[0239] The white solid obtained in this example was also characterized by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). XRPD was performed on a Bruker D8 Discover·X-ray diffractometer equipped with a Θ-Θ vertical goniometer using a Vantec-500 as detector. Standard conditions: voltage 40 kV, current 40 mA, radiation: Cu, temperature: ambient temperature, X-ray source exit slit size: 0.5 mm pinhole, snout collimator: 0.5 mm, sample holder: polished quartz plate. Operating conditions: detector distance, 30 cm, chi integral range, 4-40 degrees 2θ, counting time, 120 sec / frame, number of frames: 3, theta 1 position, 4 degrees, theta 2 position, 4 degrees, frame width, 12, scan axis, interlocked. The software used was GADD software, General Area Detector Diffraction System, version 4.1.50; and DIFFRAC.EVA, version 4.0. DSC was performed on a TA Instruments Q2000 (Thermal Advantage V 5.0.0-qualified) with a sample size of 2-10 mg, a heating range of 25 °C-250 °C, and a heating rate of 10 °C / min. Representative XRPD and DSC spectra are shown in Figures 2A-2B. Thermogravimetric analysis (TGA) was also performed on this sample. TGA was performed on a TA Instruments TGA Q500 (Thermal Advantage V5.2.5-qualified) with a sample size of 5-20 mg, a heating range of 25 °C-150 °C, and a heating rate of 10 °C / min. A representative TGA trace is shown in Figure 2C.

[0240] Example 1B. Preparation of High Purity Abiraterone Decanoate This example illustrates a process for purifying abiraterone decanoate to remove residual palladium. The abiraterone decanoate used in this example was prepared using a procedure similar to that shown in Example 1A.

[0241] Crude abiraterone decanoate (7.17 kg) was dissolved in acetone (142 kg) at room temperature. Activated carbon (1.43 kg) was added and the resulting slurry was stirred at room temperature for 4 hours. The mixture was filtered to remove the activated carbon and the solid was washed with acetone (142 kg). The combined acetone filtrate was concentrated by vacuum distillation at 40° C. The concentrated filtrate, containing about 72 L of acetone, was then cooled to 20° C. and water (4.3 kg) was added slowly. The mixture was stirred at 20° C. for 12 hours and abiraterone decanoate was recovered by filtration. The product was washed with 1:1 acetone / water (7.2 kg) and dried under vacuum at 40° C. to obtain 5.524 kg of pure abiraterone decanoate (Form A). The analytical data is consistent with that described in Example 1A. A representative Certificate of Analysis for the resulting abiraterone decanoate is shown in Table D below. The purity of the resulting abiraterone decanoate was analyzed using HPLC Method 1, see Example 2 below for details.

[0242] [Table 4]

[0243] The crude abiraterone decanoate contained 130 ppm Pd. Simple recrystallization from acetone / water reduced the Pd level to 120 ppm. However, by using the process described in this example, the final abiraterone decanoate can be purified to have a Pd content of only 3.7 ppm.

[0244] Example 1C. Polymorph Screening for Abiraterone Decanoate Polymorph screening studies were also conducted on abiraterone decanoate. In addition to Form A, two other polymorphs of abiraterone decanoate were identified, namely, Form B and Form C, as shown in Example 1A.

[0245] Crystallization by cooling at -15°C: Approximately 30 mg of abiraterone decanoate was dissolved in a minimum volume of solvent. Samples were heated at 50°C for 1 hour if not completely dissolved. Samples were placed in the freezer and filtered after 2 days (if precipitate was visible). Results using this crystallization method are shown in Table E1 below.

[0246] [Table 5]

[0247] Evaporation from a binary 1:1 solvent mixture: Approximately 25 mg of abiraterone decanoate was dissolved in approximately 10 mL total volume of solvent. The sample was evaporated under a 1 psi nitrogen purge. Results using this crystallization method are shown below in Table E2.

[0248] [Table 6]

[0249] Anti-solvent addition: Approximately 25 mg of abiraterone decanoate was dissolved in 1-2 mL of solvent followed by the addition of 2-4 mL of anti-solvent. If a precipitate formed, the sample was filtered. Results using this crystallization method are shown in Table E3 below.

[0250] [Table 7]

[0251] Solvent Recrystallization from Single Solvents: Abiraterone decanoate was recrystallized using a variety of solvents. The scale of the recrystallization experiments ranged from approximately 2 to 10 mL. Saturated solutions were prepared by contacting and stirring excess abiraterone decanoate with various solvent systems at saturation temperature. If the solids did not completely dissolve in the solvent, the mother liquor was separated from the remaining solids by filtration. The mother liquor was then heated above the saturation temperature to dissolve any remaining solids. The temperature of each solution was then adjusted to the growth temperature and a controlled nitrogen shear flow was introduced to initiate solvent evaporation. The recrystallization conditions for the solvent system panel used during the study are summarized in Tables E4-E5. XRD analysis was performed.

[0252] [Table 8]

[0253] [Table 9]

[0254] Noncompetitive Slurry Experiments: Noncompetitive slurry experiments were performed by exposing Form A abiraterone decanoate to a solvent and stirring the resulting suspension at ambient temperature for one week. The solids were filtered and analyzed by XRD to determine the resulting form(s). Solvents used in this study include water, acetonitrile, isopropyl ether / acetonitrile (1:4), 2-butanol / water (1:1), 1-propanol / water (1:1), t-butanol / water (1:1), ethanol / water (1:1), THF / water (1:1), acetone / water (1:1), dioxane / water (1:1), 2-butanone / water (1:1), methanol, DMF / water (1:1), ethyl acetate / water (1:1), and heptane. Based on their X-ray scattering behavior, all noncompetitive slurry experiments did not result in any changes from the starting material.

[0255] A competition study was also performed. Competition slurry: Approximately 20 mg of abiraterone decanoate suspended in 1-2 mL of solvent. The sample was stirred for 3 days and filtered. The results of the competition study are shown in Table E6 below.

[0256] [Table 10]

[0257] Morphology Characterization: Solids produced from the solvent-based recrystallization panel were analyzed by powder XRD. To mitigate favorable particle effects, a two-dimensional detection system was used to collect all XRD screening data. The two-dimensional detector is integrated along concentric Debye cones to help reduce pattern variability. If bright spots appear in the conical rings, it indicates a strong favorable particle effect, which can result in considerable variability in the observed diffraction pattern, including changes in peak intensity. Some samples of abiraterone decanoate showed favorable particle effects based on the appearance of scattering behavior.

[0258] The results of this analysis revealed that the material exists as at least three primary polymorphs. The forms observed were designated as Forms A, B, and C.

[0259] After categorizing the data into different forms based on their diffraction behavior, each form was studied to determine whether other properties of the forms could be distinguished. Characterization of each form began with comparing the diffraction data representative of each form with the diffraction data of the other forms. This was typically followed by NMR, DSC, and TGA.

[0260] The initial material used in this study was Form A, which is consistent with the representative characterization data presented in Example 1A, see also summary Table E7 below.

[0261] Form B was obtained in various crystallization experiments, especially those carried out at low temperatures (-10 to -20 °C). The characteristic diffraction behavior of this form is shown in a representative XRPD spectrum, Figure 2D. 1 The H NMR spectrum shows no organic impurities and is consistent with the expected structure of ADEC. Representative DSC and TGA spectra of Form B are shown in Figures 2E and 2F.

[0262] Form C was obtained by evaporation from a 1:1 mixture of ethanol and 2-butanone. The characteristic diffraction behavior of this form is shown in a representative XRPD spectrum, FIG. 2G. Note that the diffractogram obtained for one "pure" Form C sample shows significant overlap with Form A at higher diffraction angles and may therefore contain some Form A. The 1H NMR spectrum of Form C shows no organic impurities and is consistent with the predicted structure of ADEC. Representative DSC and TGA spectra of Form C are shown in FIGS. 2H and 2I.

[0263] Table E7 below summarizes representative analyses for abiraterone decanoate forms A, B, and C. [Table 11]

[0264] Polymorph screen recrystallization experiments produced either Forms A, B, C, or a mixture of forms. Form A is expected to be the thermodynamically stable form under ambient conditions based on noncompetitive and competitive slurry experiments.

[0265] Example 2. Preparation of Abiraterone Decanoate Formulations Approximately half of the required amount of corn oil was added to a suitable container (approximately 1,750 ml). The required amount of benzyl alcohol (360 g) was weighed and added to the corn oil. The required amount of benzyl benzoate (720 g) was weighed and added to the corn oil. This mixture was mixed using a suitable mixer (e.g., shaft mixer) for a minimum of 10 minutes or until all of the benzyl alcohol and benzyl benzoate were dissolved. The appropriate amount of abiraterone decanoate (720 g) was weighed and added to the corn oil / benzyl alcohol / benzyl benzoate solution and mixed using a suitable mixer (e.g., shaft mixer) for a minimum of 30 minutes or until all of the abiraterone decanoate was dissolved. The resulting solution was then diluted to its final volume (3,600 ml) with corn oil to create a solution having the composition shown below.

[0266] [Table 12]

[0267] Drug Substance Analysis: The abiraterone decanoate used to prepare the aforementioned formulations was obtained by a process similar to that described in Example 1A, except that it did not include a recrystallization step. The abiraterone decanoate typically has a purity of 99% or greater by weight (as measured by HPLC). A typical batch of abiraterone decanoate using HPLC Method 1 has the quality shown in FIG. 3. Based thereon, the assigned purity of such an abiraterone decanoate batch is about 99.4% by weight, calculated by the following method: 100%-(HPLC impurities %+Karl Fischer moisture %+residual solvents %). The HPLC method used to measure the purity of abiraterone decanoate can be HPLC Method 1, where the separation is performed using an Advanced Materials Technology Halo C8 reversed phase column with dimensions of 3.0×100 mm and particle size of 2.7 μm. A linear gradient program (20 min) is used with a mobile phase consisting of 25 mM aqueous ammonium acetate buffer and a mixture of methanol and acetonitrile (see gradient profile in Table 1B below). Working standard and sample solutions are prepared in methanol diluent. Typical injection volumes are 5 μL and the detection wavelength is 210 nm.

[0268] [Table 13]

[0269] The final solution is then sterilized under sterile conditions by passing the solution through a 0.22 micron PVDF filter using a standard pumping system (e.g., peristaltic pump) into sterile vials (219 vials, 15 ml fill). The filled vials are sealed with rubber stoppers and then capped to ensure the integrity of the final product. The vial fill volume and size can be varied based on the dose to be manufactured.

[0270] Analytical method for abiraterone decanoate formulations A reversed-phase high performance liquid chromatography analytical method, HPLC Method 2, was used to assay, identify related substances, and identify abiraterone decanoate formulations by retention time. HPLC Method 2: Separation is performed using an XBridge Shield RP18 reversed-phase column with dimensions of 4.6 x 100 mm and particle size of 3.5 μm. A linear gradient program (25 min) is used with a mobile phase consisting of 40 mM aqueous ammonium bicarbonate buffer and a mixture of methanol and acetonitrile (see gradient profile in Table 1C below). Working standard and sample solutions are prepared in isopropyl alcohol diluent. Typical injection volume is 10 μL and detection wavelength is 254 nm.

[0271] [Table 14]

[0272] Glide Force Determination: Glide Force Measurement: The analytical method is performed using tensile and compression testing equipment (e.g., Lloyd press or equivalent) using a 250N load cell and Nexygen Plus material testing software. Two separate syringe / needle configurations (5mL Luer-Lok syringe configured with a 23 gauge (23G) 1.5 inch thin wall precision glide needle, and a 5mL Luer-Lok syringe configured with a 27 gauge (27G) 1.5 inch standard wall precision glide needle) were used for the analytical measurements. Glide force measurements were performed using a 5mL sample size and constant compression rate.

[0273] Viscosity: The analytical method is performed using a Malvern Kinexus Lab+ viscometer using rSpace Rheometry software. The following parameters were set for the pharmaceutical viscosity measurements: Bob Shape: C25 DIN with spline Cup shape: C25 DIN AL ·Analysis temperature: 20.0℃ Manual Gap: 1.0mm ·Shear rate: 50s -1 Test duration: 1 minute Sampling interval: 15 seconds

[0274] Particulates: The number of particles in a drug product is measured according to USP <788> and / or <789> Measured according to the current version of.

[0275] Bacterial Endotoxins: USP <85> Bacterial endotoxin testing was performed according to the current version of the .

[0276] Analysis results: The table below shows the results of the analysis using the method described above.

[0277] [Table 15]

[0278] The impurity with relative retention time 1.19 is [ka] It was determined that this was the case.

[0279] Following a similar procedure described above, an abiraterone decanoate formulation having an abiraterone decanoate concentration of about 180 mg / mL was also prepared using the abiraterone decanoate prepared according to Example 1B. The components of the 180 mg / mL formulation, per milliliter, include: abiraterone decanoate, about 180 mg / mL, benzyl alcohol, about 100 mg / mL, benzyl benzoate, about 200 mg / mL, and corn oil per mL.

[0280] The glide force of the 180 mg / mL abiraterone decanoate formulation (see formulation details above) was also tested using two separate syringe / needle configurations: a 5 mL Luer-Lok syringe configured with a 23 gauge (23G), 1.5 inch thin wall precision glide needle, and a 5 mL Luer-Lok syringe configured with a 21 gauge (21G), 1.5 inch standard wall precision glide needle. Glide force measurements were performed using a 5 mL sample size and constant compressibility. The average glide forces observed for the 180 mg / mL abiraterone decanoate formulation were: 3.2835 (for the 21G, 1.5 inch needle) and 6.7863 (for the 23G, 1.5 inch needle). Glide force measurements were also performed using a 2 mL fill of a 3 mL syringe. Under these settings, the average glide forces observed for the 180 mg / mL abiraterone decanoate formulation are: 1.0957 (for the 21 G, 1.5 inch needle) and 2.1481 (for the 23 G, 1.5 inch needle).

[0281] Both the 200 mg / mL and 180 mg / mL abiraterone decanoate formulations were found to be stable for at least three months of storage at 25° C. / 60% RH and 40° C. / 75% RH.

[0282] Example 3. PK / PD Study of Abiraterone Decanoate in Chemically Castrated Monkeys This study compares a single oral gavage dose of abiraterone acetate with a single intravenous injection dose of abiraterone decanoate in chemically castrated, sexually mature male cynomolgus monkeys.

[0283] The test substances used in this study are shown in Table 3A below. [Table 16]

[0284] The dosing schedule for this study will follow that shown in Table 3B below. [Table 17] The dosage levels for abiraterone acetate and decanoate are based on the prodrug and not the equivalent abiraterone dose, e.g., the dose of 10 mg / kg abiraterone decanoate shown in the table is expressed as an abiraterone equivalent dose of approximately 6.9 mg / kg.

[0285] PK results from a single IM abiraterone decanoate injection are shown in Figures 4A and 4B (plasma concentrations of abiraterone over time up to 98 days after IM injection) and in the tables below (Tables 4A-4C, based on a period up to 70 days after IM injection) for the 10 mg / kg, 30 mg / kg, and 100 mg / kg doses, respectively.

[0286] [Table 18]

[0287] [Table 19]

[0288] [Table 20]

[0289] The above PK results indicate that the bioavailability of abiraterone decanoate can be 100%. Also, a single intramuscular dose results in prolonged abiraterone plasma exposure of up to 98 days or more. For example, even at a dose of 10 mg / kg, abiraterone was measurable in plasma at day 70. For doses of 30 mg / kg and 100 mg / kg, respectively, the plasma concentrations of abiraterone at day 70 range from 1 ng / mL to 10 ng / mL.

[0290] Progesterone, cortisol, dihydrotestosterone, and testosterone levels were also analyzed in this study. As shown in Figures 5A, 5B, 5C, and 5D, all three doses achieved prolonged CYP17A1 inhibition for up to 70 days or more after a single dose IM injection, as evidenced by sustained elevation of progesterone levels and reduction of cortisol, dihydrotestosterone, and testosterone levels. The effect of administering dexamethasone and methylprednisolone acetate according to the schedule of this example is also shown in Figures 5A, 5B, 5C, and 5D.

[0291] The PK / PD profiles observed from a single intramuscular injection of abiraterone decanoate in this example further support a dosing frequency of once a month or once every several months, e.g., once every two or three months.

[0292] Example 4. A 13-Week Intramuscular Toxicity Study of Abiraterone Decanoate in Male Cynomolgus Monkeys with a 28-Day Recovery Period This example studies the potential toxicity of the test substance, abiraterone decanoate, when administered as an intramuscular injection once every two weeks for 13 weeks in male cynomolgus monkeys, and evaluates the potential reversibility of any findings. Additionally, the toxicokinetic properties (TK) of abiraterone decanoate and abiraterone, as well as serum hormone levels, and the effects of abiraterone decan...

Claims

1. A pharmaceutical composition for use in the treatment of sex hormone dependent cancer or androgen receptor driven cancer in an uncastrated subject, comprising: The pharmaceutical composition comprises abiraterone decanoate. 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier; the pharmaceutical composition is parenterally administered to the subject; The pharmaceutical composition, wherein the subject is not treated with an amount of a gonadotropin releasing hormone agonist and / or antagonist effective to decrease serum testosterone levels in the subject.

2. The pharmaceutical composition of claim 1 , wherein the subject is not being treated with glucocorticoid replacement therapy.

3. (i) The pharma- ceutical acceptable carrier comprises a pharma- ceutical acceptable oil, and optionally a further pharma- ceutical acceptable solvent, and optionally (a) 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; and / or (b) the pharmaceutically acceptable oil is selected from vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, and soybean oil, and the additional pharmaceutically acceptable solvent, if present, comprises benzyl alcohol, benzyl benzoate, or a combination thereof; and / or (ii) the pharma- ceutically acceptable carriers include corn oil, benzyl alcohol, and benzyl benzoate; The pharmaceutical composition according to claim 1 or 2. [0023] (i) the pharmaceutical composition comprises, per milliliter, (a) abiraterone decanoate in a basic form in an amount of about 100 mg to about 300 mg (e.g., about 100 mg, about 120 mg, about 150 mg, about 180 mg, about 200 mg, or about 250 mg); (b) benzyl alcohol in an amount of about 50 mg to about 150 mg (e.g., about 75 mg, about 100 mg, or about 125 mg); (c) benzyl benzoate in an amount of about 100 mg to about 300 mg (e.g., about 100 mg, about 150 mg, about 200 mg, or about 250 mg), and (d) corn oil in an amount appropriate for each milliliter; and / or (ii) the pharmaceutical composition is characterized by a viscosity of less than 0.1 Pa*s, e.g., about 0.05 Pa*s or less; and / or (iii) the pharmaceutical composition is characterized by having a glide force of about 1-10 N when measured using a 21 G, 1.5 inch needle, and / or a glide force of about 2-15 N when measured using a 23 G, 1.5 inch needle, and / or a glide force of about 30-150 N when measured using a 27 G, 1.5 inch needle; and / or (iv) the pharmaceutical composition is characterized in that it has no more than 1000 particles ≧10 μm in size and no more than 300 particles ≧25 μm in size, as measured according to USP <788> and / or <789>; and / or (v) the pharmaceutical composition is characterized in that it has less than 100 EU / ml, e.g., less than 25 EU / ml, bacterial endotoxins measured according to USP <85>; and / or (vi) the subject has not undergone a prostatectomy; The pharmaceutical composition according to any one of claims 1 to 3.

5. (i) the sex hormone dependent cancer or androgen receptor driven cancer is androgen receptor positive salivary duct carcinoma or androgen receptor positive glioblastoma multiforme; or (ii) the sex hormone dependent cancer or androgen receptor driven cancer is prostate cancer, and optionally (a) the prostate cancer is localized prostate cancer, e.g., high-risk localized prostate cancer, or (b) 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; or (c) the prostate cancer is newly diagnosed high-risk metastatic hormone-sensitive prostate cancer; or (d) the prostate cancer is metastatic CRPC (mCRPC) and the subject is an asymptomatic or mildly symptomatic subject after failure of androgen deprivation therapy with no demonstrated clinical need for chemotherapy; or (e) the prostate cancer is metastatic CRPC (mCRPC) and the subject's disease has progressed during or after a taxane-based chemotherapy regimen, such as a docetaxel-based or cabazitaxel-based chemotherapy regimen; or (f) the prostate cancer is refractory prostate cancer; The pharmaceutical composition according to any one of claims 1 to 4.

6. The pharmaceutical composition of any one of claims 1 or 3 to 5, wherein the subject is further administered one or more drugs selected from hydrocortisone, prednisone, prednisolone, methylprednisolone, and dexamethasone.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the subject is chemotherapy-naïve or hormone therapy-naïve prior to administration of the pharmaceutical composition.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the pharmaceutical composition is administered via intramuscular, intradermal, or subcutaneous injection. (i) the pharmaceutical composition is administered to the subject once a week or once every few weeks; and / or (ii) the pharmaceutical composition is administered to the subject once a month or once every few months, for example once every two months or once every three months; and / or (iii) the subject suffers from hepatic impairment, such as moderate to severe hepatic impairment (Child-Poo class B or C), prior to administration of the pharmaceutical composition; The pharmaceutical composition according to any one of claims 1 to 8.

10. 1. A pharmaceutical composition comprising, per milliliter, (a) abiraterone decanoate in its basic form in an amount of about 180 mg; (b) benzyl alcohol in an amount of 50 mg to 150 mg (e.g., about 75 mg, about 100 mg, or about 125 mg); (c) benzyl benzoate in an amount of 100 mg to 300 mg (e.g., about 100 mg, about 150 mg, about 200 mg, or about 250 mg); and (d) corn oil in an amount appropriate for each milliliter, wherein the abiraterone decanoate has the following structure: 【Chemistry 2】 1. A pharmaceutical composition comprising: (i) 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); and / or (ii) the abiraterone decanoate is substantially pure, e.g., characterized as having a purity of at least 95%, preferably at least 98%, e.g., about 98.5%, about 99%, about 99.5% or more by weight; and / or (iii) The abiraterone decanoate has the following formula: 【Chemistry 3】 or having less than 1 wt. % (e.g., less than 0.5 wt. %, such as less than 0.3 wt. %, less than 0.2 wt. %, or less than 0.1 wt. %) of ethyl prasterone decanoate having The abiraterone decanoate is characterized in that it does not have detectable amounts of ethyl prasterone decanoate; and / or (iv) the pharmaceutical composition is characterized by a viscosity of less than 0.1 Pa*s, e.g., about 0.05 Pa*s or less; and / or (v) the pharmaceutical composition is characterized by having a glide force of about 1-10 N when measured using a 21 G, 1.5 inch needle, and / or a glide force of about 2-15 N when measured using a 23 G, 1.5 inch needle, and / or a glide force of about 30-150 N when measured using a 27 G, 1.5 inch needle; and / or (vi) the pharmaceutical composition is characterized in that it has no more than 1000 particles ≧10 μm in size and no more than 300 particles ≧25 μm in size, as measured according to USP <788> and / or <789>; and / or (vii) the pharmaceutical composition is characterized in that it has less than 100 EU / ml, e.g. less than 25 EU / ml, bacterial endotoxins measured according to USP<85>; The pharmaceutical composition according to claim 10.

12. abiraterone decanoate having a palladium content of less than 50 ppm, the abiraterone decanoate having the following structure: 【Chemistry 4】 Abiraterone decanoate, (i) having a palladium content of less than 10 ppm; and / or (ii) characterized by a purity of at least 95% by weight, preferably at least 98%, e.g., about 98.5%, about 99%, about 99.5% or more; and / or (iii) a compound of the formula 【Chemistry 5】 and / or having less than 1 wt. % (e.g., less than 0.5 wt. %, such as less than 0.3 wt. %, less than 0.2 wt. %, or less than 0.1 wt. %) of ethyl prasterone decanoate having (iv) It is a crystalline form such as crystalline form A, B, C, etc.; 13. Abiraterone decanoate according to claim 12.

14. 14. A method for preparing a pharmaceutical composition comprising: a) mixing abiraterone decanoate of claim 12 or 13 in a pharma- ceutically acceptable carrier to form a mixture; and, optionally, b) sterilizing the mixture formed in a).

15. (i) The pharma- ceutical acceptable carrier comprises a pharma- ceutical acceptable oil, and optionally a pharma- ceutical acceptable solvent, and optionally the pharma- ceutically acceptable oil comprises vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, or soybean oil; and / or The optional pharma- ceutically acceptable solvent comprises benzyl alcohol or benzyl benzoate; and / or (ii) the pharma- ceutically acceptable carrier comprises corn oil, benzyl alcohol, and benzyl benzoate; and / or (iii) the abiraterone decanoate is present in a concentration of about 50 mg / mL to about 300 mg / mL; and / or (iv) the pharmaceutical composition contains, per milliliter, the abiraterone decanoate in its basic form in an amount of about 100 mg to about 300 mg (e.g., about 100 mg, about 120 mg, about 150 mg, about 180 mg, about 200 mg, or about 250 mg); 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); 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 an appropriate amount of corn oil per milliliter; or the abiraterone decanoate in its basic form in an amount of about 180 mg; 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); 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 corn oil in an amount appropriate for each milliliter; or the abiraterone decanoate in its basic form in an amount of about 200 mg; 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); 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 corn oil in an amount appropriate for each milliliter; and / or (v) the pharmaceutical composition comprises benzyl alcohol and benzyl benzoate, and 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); The method of claim 14.

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