Combination of taprazopalide and enzalocamide for treatment of metastatic castration-resistant prostate cancer

Abstract

The present invention relates to a combination of taprazopalide, or a pharmaceutically acceptable salt thereof, and enzalocamide, or a pharmaceutically acceptable salt thereof, for use in the treatment of metastatic castration resistant prostate cancer; and a method of extending its lifetime.

Description

Background Art

[0001] Prostate cancer is the second leading cause of cancer death in men. The androgen receptor (AR) signaling axis is the main driver of prostate cancer growth and has been targeted by castration and other systemic therapies. Initial treatment of advanced prostate cancer can involve reducing the amount of androgens produced by the body (primarily in the testes). This can be achieved surgically by removing both testicles (bilateral orchiectomy) or by using androgen deprivation therapies, such as luteinizing hormone-releasing hormone (LHRH) agonist or antagonist drugs, which can reduce the natural production of testosterone (sometimes referred to as "chemical castration"). However, despite testosterone being at castration levels, a portion of tumors still progress, at which point the disease is considered to be castration-resistant. Castration-resistant prostate cancer represents a fatal transition in the progression of prostate cancer, and most patients ultimately die from the disease.

[0002] Anti-androgens are thought to inhibit androgen activity through a variety of different mechanisms. An example of an anti-androgen approved for the treatment of castration-resistant prostate cancer is abiraterone acetate (sold as Zytiga TM ), which is a steroid CY17A1 inhibitor. A specific type of anti-androgen is an androgen receptor inhibitor, also known as an androgen receptor signaling inhibitor or androgen receptor antagonist, which is thought to compete with the endogenous ligand, i.e., androgen, for the androgen receptor. When the antagonist binds to the androgen receptor, it is thought to induce a conformational change in the receptor itself, thereby hindering the transcription of key androgen-regulated genes and thus inhibiting the biological actions of androgens themselves (such as testosterone and dihydrotestosterone).

[0003] The compound enzalutamide is 4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxo-1-imidazolidinyl]-2-fluoro-N-methyl-benzamide (also known as 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl}-2-fluoro-N-methylbenzamide, or also known as "RD162'" and "MDV3100"), which is a non-steroidal androgen receptor inhibitor and has the following structure:

[0004]

[0005] Enzalutamide or a pharmaceutically acceptable salt thereof is disclosed in PCT / US2006 / 011417, which was published as WO 2006 / 124118 on November 23, 2006, the content of which is incorporated herein by reference.

[0006] Enzalutamide (sold as ) is approved for the treatment of metastatic castration-resistant prostate cancer (“mCRPC”). However, for some subjects, their cancer will recur or the subjects may develop treatment resistance. To date, the mechanisms underlying such resistance have not been fully understood.

[0007] Poly(ADP-ribose) polymerase (PARP) is involved in the process of naturally occurring deoxyribonucleic acid (DNA) repair in cells. PARP inhibition has been shown to be an effective therapeutic strategy against tumors associated with mutations in double-stranded DNA repair genes by inducing synthetic lethality (Sonnenblick, A. et al., Nat. Rev. Clin. Oncol, 2015, 12(1), 27-4). Among DNA damage response (DDR) genes directly or indirectly involved in homologous recombination repair (HRR), PARP inhibition is synthetically lethal to cells with homozygous deletions or deleterious alterations or both (Lord, CJ et al., Science, 2017; 355:1152-1158).

[0008] Talazoparib is an effective orally administrable PARP inhibitor that is cytotoxic to human cancer cell lines carrying gene mutations that impair deoxyribonucleic acid (DNA) repair, such an effect being termed synthetic lethality, and thereby preventing DNA repair, replication, and transcription by trapping PARP protein on DNA.

[0009] The compound talazoparib is (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one and (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (also known as “PF-06944076”, “MDV3800”, and “BMN673”), which is a PARP inhibitor and has the following structure:

[0010]

[0011] Talazoparib and pharmaceutically acceptable salts thereof, including the tosylate salt, are disclosed in International Publications WO 2010 / 017055 and WO 2012 / 054698. Additional methods for preparing talazoparib and pharmaceutically acceptable salts thereof, including the tosylate salt, are described in International Publications WO 2011 / 097602, WO 2015 / 069851 and WO 2016 / 019125. Additional methods for treating cancer using talazoparib and pharmaceutically acceptable salts thereof, including the tosylate salt, are disclosed in International Publications WO 2011 / 097334 and WO 2017 / 075091. Combination therapies using talazoparib and pharmaceutically acceptable salts thereof, including the tosylate salt, are disclosed in International Publications WO2019 / 075032 and WO 2022 / 200982.

[0012] (Talazoparib) (0.25 mg and 1 mg capsules) has been approved in several countries including the United States and in the European Union, and is approved or under review (expected to be approved) in other countries for the treatment of adult patients with deleterious or suspected deleterious gBRCAm HER2-negative locally advanced or metastatic breast cancer. Additional capsule strengths of 0.5 mg and 0.75 mg have been approved in the United States. Talazoparib has shown activity in metastatic castration-resistant prostate cancer with DDR alterations directly or indirectly related to HRR (de Bono et al., Lancet Oncol. September 2021;22(9):1250-1264). Talazoparib is being investigated as a single agent and in combination with other agents for various human cancers.

[0013] There remains a need for improved therapies for the treatment of cancer, particularly for the treatment of metastatic castration-resistant prostate cancer. It is believed that the combinations of the present invention have one or more advantages such as, compared to treatment with either therapeutic agent alone, an increase in survival (including radiographic progression-free survival and overall survival); an increase in survival (including radiographic progression-free survival and overall survival) compared to patients who have received enzalutamide or a pharmaceutically acceptable salt thereof and placebo; greater efficacy compared to treatment with either therapeutic agent alone; the possibility of achieving an improved dosing schedule; the possibility of overcoming resistance mechanisms, etc. SUMMARY OF THE INVENTION

[0014] The present invention provides, in part, methods of administering talazoparib or a pharmaceutically acceptable salt thereof and enzalutamide or a pharmaceutically acceptable salt thereof in combination therapy for prolonging the survival of a subject with metastatic castration-resistant prostate cancer. This summary is provided to introduce a selection of concepts in a simplified form that are further described below in the detailed description. This summary is not intended to identify key features or essential features of the claimed subject matter nor is it intended to be used alone to aid in determining the scope of the claimed subject matter.

[0015] According to embodiment 1 of the present invention, there is provided a method of prolonging survival in a subject with metastatic castration-resistant prostate cancer, the method comprising: 1) orally administering to the subject talazoparib or a pharmaceutically acceptable salt thereof once daily; and 2) orally administering to the subject enzalutamide or a pharmaceutically acceptable salt thereof once daily.

[0016] According to embodiment 2 of the present invention, there is provided a method of treating metastatic castration-resistant prostate cancer in a subject in need thereof, the method comprising: 1) orally administering to the subject talazoparib or a pharmaceutically acceptable salt thereof once daily; and 2) orally administering to the subject enzalutamide or a pharmaceutically acceptable salt thereof once daily, wherein administering talazoparib or a pharmaceutically acceptable salt thereof and administering enzalutamide or a pharmaceutically acceptable salt thereof prolong the survival of the subject.

[0017] According to embodiment 3 of the present invention, there is provided a combination of talazoparib or a pharmaceutically acceptable salt thereof and enzalutamide or a pharmaceutically acceptable salt or solvate thereof for prolonging survival in a subject with metastatic castration-resistant prostate cancer, wherein talazoparib or a pharmaceutically acceptable salt thereof is orally administered to the subject once daily and enzalutamide or a pharmaceutically acceptable salt thereof is orally administered to the subject once daily.

[0018] According to embodiment 4 of the present invention, there is provided a combination of talazoparib or a pharmaceutically acceptable salt thereof and enzalutamide or a pharmaceutically acceptable salt or solvate thereof for treating a subject with metastatic castration-resistant prostate cancer, wherein talazoparib or a pharmaceutically acceptable salt thereof is orally administered to the subject once daily and enzalutamide or a pharmaceutically acceptable salt thereof is orally administered to the subject once daily, and further wherein administering talazoparib or a pharmaceutically acceptable salt thereof and administering enzalutamide or a pharmaceutically acceptable salt thereof prolong the survival of the subject.

[0019] Embodiments of the present invention are described below, where for convenience, embodiments 1, 2, 3, and 4 (E1, E2, E3, and E4) are consistent with the embodiments provided above.

[0020] It should be understood that the foregoing general description and the following detailed description are merely exemplary and explanatory and do not limit the claimed invention. Detailed Description

[0021] The present invention can be more readily understood by reference to the following detailed description of embodiments of the invention and the examples included therein. It should also be understood that the terms used herein are for the purpose of describing particular embodiments only and are not intended to be limiting.

[0022] E1 A method for prolonging survival in a subject with metastatic castration-resistant prostate cancer, as defined above.

[0023] E2 A method for treating metastatic castration-resistant prostate cancer in a subject in need thereof, wherein the treatment prolongs survival in the subject, as defined above.

[0024] E3 A combination for prolonging survival in a subject with metastatic castration-resistant prostate cancer, as defined above.

[0025] E4 A combination for treating a subject with metastatic castration-resistant prostate cancer, wherein administration of the combination prolongs survival in the subject, as defined above.

[0026] E5 A method or combination for use as described in any one of embodiments 1 to 4, wherein the metastatic castration-resistant prostate cancer is metastatic castration-resistant prostate cancer with or without a homologous recombination repair (HRR) gene mutation.

[0027] E6 A method or combination for use as described in any one of embodiments 1 to 5, wherein talazoparib or a pharmaceutically acceptable salt thereof and enzalutamide or a pharmaceutically acceptable salt thereof are administered simultaneously.

[0028] E7 A method or combination for use as described in any one of embodiments 1 to 6, wherein the subject has not received: 1) systemic cancer treatment for non-metastatic castration-resistant prostate cancer or metastatic castration-resistant prostate cancer; 2) treatment of prostate cancer with an androgen receptor signaling inhibitor, a PARP inhibitor, cyclophosphamide, or mitoxantrone; or 3) treatment with platinum-based chemotherapy within 6 months or any history of disease progression after receiving platinum-based therapy within 6 months.

[0029] E8 A method or combination for use as described in embodiment 7, wherein the subject has not received systemic cancer treatment for non-metastatic castration-resistant prostate cancer or metastatic castration-resistant prostate cancer.

[0030] E9 The method according to embodiment 7 or the combination for the use, wherein the subject has not been treated with an androgen receptor signaling inhibitor, a PARP inhibitor, cyclophosphamide or mitoxantrone for prostate cancer.

[0031] E10 The method according to embodiment 7 or the combination for the use, wherein the subject has not been treated with an androgen receptor signaling inhibitor.

[0032] E11 The method according to any one of embodiments 7, 9 or 10 or the combination for the use, wherein the androgen receptor signaling inhibitor is a second-generation androgen receptor inhibitor.

[0033] E12 The method according to embodiment 11 or the combination for the use, wherein the second-generation androgen receptor inhibitor is enzalutamide, apalutamide, darolutamide or abiraterone acetate.

[0034] E13 The method according to embodiment 12 or the combination for the use, wherein the second-generation androgen receptor inhibitor is enzalutamide, apalutamide or darolutamide.

[0035] E14 The method according to embodiment 7 or the combination for the use, wherein the subject has not received platinum-based chemotherapy within 6 months or any history of disease progression of platinum-based therapy within 6 months.

[0036] E15 The method according to any one of embodiments 1 to 14 or the combination for the use, wherein the subject is receiving a gonadotropin-releasing hormone analogue concomitantly or has undergone bilateral orchiectomy.

[0037] E16 The method according to embodiment 15 or the combination for the use, wherein the subject additionally receives a gonadotropin-releasing hormone analogue.

[0038] E17 The method according to embodiment 15 or 16 or the combination for the use, wherein the gonadotropin-releasing hormone analogue is a gonadotropin-releasing hormone agonist.

[0039] E18 The method according to embodiment 15 or 16 or the combination for the use, wherein the gonadotropin-releasing hormone analogue is a gonadotropin-releasing hormone antagonist.

[0040] E19 The method according to embodiment 15 or the combination for the use, wherein the subject has undergone bilateral orchiectomy.

[0041] E20 The method according to any one of embodiments 1 to 19 or the combination for the use, wherein the subject has a progressive disease defined by one or more of the following: 1) Prostate-specific antigen progression, which is defined by prostate-specific antigen values that increase in at least 2 of 3 consecutive evaluations, wherein the interval between each evaluation is at least 7 days; 2) Soft tissue disease progression, which is defined by RECIST 1.1; and 3) Bone disease progression, which is defined by the Prostate Cancer Clinical Trials Working Group 3, wherein 2 or more new metastatic bone lesions are present on a whole-body radionuclide bone scan.

[0042] E21 The method according to any one of embodiments 1 to 20 or the combination for the use, wherein the subject has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤1.

[0043] E22 The method according to any one of embodiments 1 to 21 or the combination for the use, wherein the subject is not selected based on the DNA damage response (DDR) mutation status.

[0044] E23 The method according to any one of embodiments 1 to 22 or the combination for the use, wherein the survival period is the radiographic progression-free survival period.

[0045] E24 The method according to embodiment 23 or the combination for the use, wherein the radiographic progression-free survival period is prolonged compared to a subject who has received enzalutamide or a pharmaceutically acceptable salt thereof and a placebo.

[0046] E25 The method according to embodiment 23 or the combination for the use, wherein the radiographic progression-free survival period is prolonged compared to a subject who has received enzalutamide or a pharmaceutically acceptable salt thereof.

[0047] E26 The method according to any one of embodiments 1 to 22 or the combination for the use, wherein the survival period is the overall survival period.

[0048] E27 The method according to embodiment 26 or the combination for the use, wherein the overall survival period is prolonged compared to a subject who has received enzalutamide or a pharmaceutically acceptable salt thereof and a placebo.

[0049] E28 The method according to embodiment 26 or the combination for the use, wherein the overall survival period is prolonged compared to a subject who has received enzalutamide or a pharmaceutically acceptable salt thereof.

[0050] E29 The method according to any one of embodiments 1 to 22, or the combination for the said use, wherein the risk of disease progression or death during the survival period is significantly reduced as compared with the subjects who have received enzalutamide or its pharmaceutically acceptable salt and placebo.

[0051] E30 The method according to any one of embodiments 1 to 22, or the combination for the said use, wherein the risk of disease progression or death during the survival period is significantly reduced as compared with the subjects who have received enzalutamide or its pharmaceutically acceptable salt.

[0052] E31 The method according to embodiment 29, or the combination for the said use, wherein the risk of disease progression or death is significantly reduced by 37% as compared with the subjects who have received enzalutamide or its pharmaceutically acceptable salt and placebo.

[0053] E32 The method according to embodiment 29, or the combination for the said use, wherein the risk of disease progression or death is significantly reduced by at least 37% as compared with the subjects who have received enzalutamide or its pharmaceutically acceptable salt and placebo.

[0054] E33 The method according to embodiment 30, or the combination for the said use, wherein the risk of disease progression or death is significantly reduced by 37% as compared with the subjects who have received enzalutamide or its pharmaceutically acceptable salt.

[0055] E34 The method according to embodiment 30, or the combination for the said use, wherein the risk of disease progression or death is significantly reduced by at least 37% as compared with the subjects who have received enzalutamide or its pharmaceutically acceptable salt.

[0056] E35 The method according to any one of embodiments 1 to 34, or the combination for the said use, wherein talazoparib or its pharmaceutically acceptable salt is administered at a dose equivalent to about 0.1 mg, about 0.25 mg, about 0.35 mg or about 0.5 mg of talazoparib free base once a day.

[0057] E36 The method according to embodiment 35, or the combination for the said use, wherein talazoparib or its pharmaceutically acceptable salt is administered at a dose equivalent to about 0.1 mg of talazoparib free base once a day.

[0058] E37 The method according to embodiment 35, or the combination for the said use, wherein talazoparib or its pharmaceutically acceptable salt is administered at a dose equivalent to about 0.25 mg of talazoparib free base once a day.

[0059] E38 A method as in embodiment 35 or a combination for said use, wherein talazoparib or a pharmaceutically acceptable salt thereof is administered at a dose equivalent to about 0.35 mg of talazoparib free base once daily.

[0060] E39 A method as in embodiment 38 or a combination for said use, wherein the subject has moderate renal impairment.

[0061] E40 A method as in embodiment 35 or a combination for said use, wherein talazoparib or a pharmaceutically acceptable salt thereof is administered at a dose equivalent to about 0.5 mg of talazoparib free base once daily.

[0062] E41 A method as in any one of embodiments 1 to 40 or a combination for said use, wherein talazoparib or a pharmaceutically acceptable salt thereof is talazoparib tosylate.

[0063] E42 A method as in any one of embodiments 1 to 41 or a combination for said use, wherein enzalutamide or a pharmaceutically acceptable salt thereof is administered at a dose equivalent to about 160 mg of enzalutamide free base once daily.

[0064] E43 A method as in embodiment 42 or a combination for said use, wherein if enzalutamide or a pharmaceutically acceptable salt thereof is co-administered with a strong CYP2C8 inhibitor, the dose of enzalutamide or a pharmaceutically acceptable salt thereof is reduced.

[0065] E44 A method as in embodiment 42 or a combination for said use, wherein the dose of enzalutamide or a pharmaceutically acceptable salt thereof is reduced to 80 mg once daily.

[0066] E45 A method as in embodiment 42 or a combination for said use, wherein if enzalutamide is co-administered with a CYP3A4 inducer, the dose of enzalutamide or a pharmaceutically acceptable salt thereof is increased.

[0067] E46 A method as in embodiment 42 or a combination for said use, wherein the dose of enzalutamide or a pharmaceutically acceptable salt thereof is increased to 240 mg daily.

[0068] E47 A method as in any one of embodiments 1 to 46 or a combination for said use, wherein enzalutamide or a pharmaceutically acceptable salt thereof is the free base.

[0069] E48 A method as in any one of embodiments 1 to 47 or a combination for said use, wherein the method comprises administering another anti-cancer agent.

[0070] E49 The method as in embodiment 48 or the combination for the use, wherein the other anti-cancer agent is selected from the group consisting of: anti-tumor agents, anti-angiogenic agents, signal transduction inhibitors, and anti-proliferative agents.

[0071] E50 The method as in any one of the foregoing embodiments or the combination for the use, wherein the subject is a human.

[0072] E51 The method as in embodiment 50 or the combination for the use, wherein the human is an adult.

[0073] Each embodiment described herein can be combined with any other embodiment(s) described herein, provided there is no contradiction between the any other embodiment(s) and the one or more embodiments with which it is combined.

[0074] Definition

[0075] Unless otherwise defined herein, scientific and technical terms used in connection with the present invention have the meanings commonly understood by those of ordinary skill in the art.

[0076] The inventions described herein can suitably be practiced in the absence of any element(s) not specifically disclosed herein.

[0077] As used herein, unless otherwise indicated, the singular forms "a / an" and "the" include plural referents. For example, "a" substituent includes one or more substituents.

[0078] As used herein, the term "about", when used to modify a parameter defined numerically (such as the dose of talazoparib or a pharmaceutically acceptable salt thereof), means that the parameter can vary up to 10% downward or upward relative to the specified value of the parameter. For example, a dose of about 5 mg means 5 mg ± 10%, i.e., it can vary between 4.5 mg and 5.5 mg.

[0079] As used herein, terms including but not limited to "(pharmacological) agent", "composition", "compound", "drug", "medicine", and "therapeutic agent" can be used interchangeably to refer to compounds included in the methods and uses of the present invention, such as anti-androgens, androgen receptor signaling inhibitors, androgen deprivation therapy, talazoparib, and enzalutamide.

[0080] For the purposes of the present invention, “(one or more) DDR mutations”, “(one or more) DDR alterations”, “(one or more) HRR mutations”, “(one or more) HRR alterations” and “(one or more) HRR gene alterations” refer to alterations / mutations in genes that are directly or indirectly involved in homologous recombination repair (HRR). Although not as scientifically based as the phrase “DNA damage response”, it should generally be understood that “DDR” can also be referred to as “DNA damage repair” or “DNA repair”. “DDR-deficient” refers to a gene mutation associated with a defect in deoxyribonucleic acid (DNA) damage repair. “DDR-deficient patient population” or “HRR-deficient patient population” is a population of patients having a gene mutation associated with a defect in deoxyribonucleic acid (DNA) damage repair. DDR is a network of pathways that have evolved to repair damaged DNA. These include mismatch repair, base excision repair, and homologous recombination repair (HRR), among others. Given the high fidelity of HRR in repairing double-strand DNA breaks, HRR is particularly important for maintaining genomic integrity. Inhibition of PARP results in the accumulation of single-strand DNA breaks and DNA stress due to PARP trapping, ultimately leading to double-strand DNA breaks. Thus, PARP inhibitors are selectively lethal to cancer cells that are defective in HRR, which is an example of synthetic lethality, a mechanism in which the functional defect of a single gene or gene product has little effect but is toxic when combined with the functional defect of a second gene or gene product. DDR-HRR genes include, but are not limited to, ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, and RAD51C. Defects in homologous recombination repair can be assayed using next-generation sequencing (NGS).

[0081] For the purposes of the present invention, “radiography” and “imaging-based” can be used interchangeably. For example, “radiography” progression is the same as “imaging-based” progression; radiographic PFS is the same as imaging-based PFS (ibPFS); and rPFS is the same as ibPFS.

[0082] As used herein, “systemic therapy” for mCRPC is a drug or therapeutic agent used to control mCRPC. Drugs or pharmaceuticals are referred to as systemic therapies because they circulate throughout the body to attack cancer cells located anywhere in the body.

[0083] Anti-androgen

[0084] As used herein, the term "anti-androgen / anti-androgens" refers to compounds that prevent androgens, such as testosterone and dihydrotestosterone (DHT) and their analogs, from mediating their biological effects in the body. Anti-androgens can act through one or more of the following hormonal mechanisms: blocking and / or inhibiting and / or regulating the androgen receptor (AR); inhibiting androgen production; inhibiting androgen production; degrading AR, inhibiting nuclear translocation, inhibiting the binding of AR to nuclear DNA; etc. Anti-androgens include, but are not limited to, steroid androgen receptor inhibitors (such as cyproterone acetate, spironolactone, megestrol acetate, chlormadinone acetate, oxendolone, and osaterone acetate), non-steroid androgen receptor inhibitors (such as enzalutamide, bicalutamide, nilutamide, flutamide, topilutamide, apalutamide, and darolutamide), androgen synthesis inhibitors, androgen receptor degraders, etc. Anti-androgens include androgen receptor inhibitors or androgen receptor signaling inhibitors, and these terms can be used interchangeably. Androgen receptor inhibitors can be determined by methods known to those skilled in the art, such as using in vitro assays and / or cell ligand binding assays and / or gene expression assays, such as those disclosed in Tran C. et al., Science, 2009, 324, 787-790.

[0085] First-generation androgen receptor signaling inhibitors include bicalutamide, nilutamide, or flutamide.

[0086] Second-generation androgen receptor signaling inhibitors include enzalutamide, apalutamide, and darolutamide.

[0087] Another second-generation androgen receptor signaling inhibitor is abiraterone or a pharmaceutically acceptable salt or solvate thereof, such as abiraterone acetate (sold as Zytiga TM ), which is a steroid CY17A1 inhibitor disclosed in U.S. Patent No. US 5,604,213, which was published on February 18, 1997, the content of which is incorporated herein by reference. This second-generation AR inhibitor blocks androgen biosynthesis.

[0088] An example of an androgen receptor inhibitor is N-desmethyl enzalutamide:

[0089]

[0090] or a pharmaceutically acceptable salt or solvate thereof, also known as 4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]-2-fluorobenzamide; or MII; which is disclosed in PCT / US2010 / 025283, which was published as WO 2010 / 099238 on September 2, 2010, the content of which is incorporated herein by reference.

[0091] Examples of androgen receptor inhibitors are apalutamide (sold as )

[0092]

[0093] or a pharmaceutically acceptable salt or solvate thereof, also known as ARN-509; or 4-{7-[6-cyano-5-(trifluoromethyl)pyridin-3-yl]-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl}-2-fluoro-N-methylbenzamide; which is disclosed in PCT / US2007 / 007485, which was published as WO 2007 / 126765 on November 8, 2007, the content of which is incorporated herein by reference. In one embodiment, the androgen receptor inhibitor useful in the present invention is a pharmacologically active metabolite of apalutamide or a pharmaceutically acceptable salt or solvate thereof.

[0094] Examples of androgen receptor inhibitors are darolutamide (sold as )

[0095]

[0096] or a pharmaceutically acceptable salt or solvate thereof, also known as N-[(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl]-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide, which is disclosed in PCT / FI2010 / 000065, which was published as WO 2011 / 051540 on May 5, 2011, the content of which is incorporated herein by reference.

[0097] Examples of androgen receptor inhibitors are bicalutamide:

[0098]

[0099] or a pharmaceutically acceptable salt or solvate thereof, sold as Sales, which are disclosed in U.S. Patent No. US4,636,505, which was published on January 13, 1987, the content of which is incorporated herein by reference.

[0100] Examples of androgen receptor inhibitors are nilutamide (sold as ) or a pharmaceutically acceptable salt or solvate thereof.

[0101] Examples of androgen receptor inhibitors are flutamide (sold as ) or a pharmaceutically acceptable salt or solvate thereof.

[0102] Unless otherwise indicated, all references herein to antiandrogens and androgen receptor inhibitors include references to their salts, solvates, hydrates and complexes, as well as solvates, hydrates and complexes of their salts, including their polymorphs, stereoisomers and isotopically labeled forms.

[0103] Androgen deprivation therapy

[0104] Androgen deprivation therapy, also known as ADT, uses surgery or medications to lower the levels of androgens produced by the testicles.

[0105] An example of surgical ADT is bilateral orchiectomy.

[0106] Examples of medical ADT include luteinizing hormone-releasing hormone (LHRH) agonists, LHRH antagonists, gonadotropin-releasing hormone (GnRH) agonists and GnRH antagonists.

[0107] Other examples of pharmaceutical androgen deprivation therapies include leuprolide (also known as leuprorelin, such as Lupron or Eligardor Viadur, etc.); buserelin (such as Suprefact); gonadorelin; goserelin (such as Zoladex); histrelin (such as Vantas); nafarelin; triptorelin (such as Trelstar); deslorelin; fertirelin; abarelix (such as Plenaxis); cetrorelix; degarelix (such as Firmagon); ganirelix; ozarelix; elagolix (such as Orilissa); relugolix; and linzagolix.

[0108] Salt

[0109] The salts included within the term "pharmaceutically acceptable salts" refer to the compounds of the present invention, which are generally prepared by reacting the free base or free acid with a suitable organic acid or inorganic acid or a suitable organic base or inorganic base, respectively, to provide salts of the compounds of the present invention suitable for administration to a subject or patient.

[0110] Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include, but are not limited to, acetate / acetic acid salt, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclohexanesulfamate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthalenedicarboxylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / monohydrogenphosphate / dihydrogenphosphate, pyroglutamate, glucarate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, 1,5-naphthalenedisulfonic acid, and xinofoate.

[0111] Suitable base salts are formed from bases that form non-toxic salts. Examples include, but are not limited to, aluminum salts, arginine salts, N,N-dibenzylethylenediamine (benzathine) salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycine salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, potassium salts, sodium salts, tromethamine salts, and zinc salts.

[0112] Hemisalts of acids and bases can also be formed, such as hemisulfates and hemicalcium salts.

[0113] For a review of suitable salts, see Paulekun, G.S. et al., Trends in Active Pharmaceutical Ingredient Salt Selection Based on Analysis of the Orange Book Database, J. Med. Chem. 2007; 50(26), 6665-6672.

[0114] Administration and dosing

[0115] As used herein, the terms "subject" and "patient" are used interchangeably to refer to any animal, including mammals. Mammals according to the invention include dogs, cats, cows, goats, horses, sheep, pigs, rodents, lagomorphs, primates, humans, etc. In one embodiment, humans are suitable subjects. In one embodiment, the "subject" or "patient" is an adult.

[0116] The "subjects" and "patients" of the combination according to the invention can be imaged during therapy to evaluate their response to treatment. Efficacy criteria, particularly Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), are standardized and can be used at different time points to classify responses such as complete response (CR), partial response (PR), stable disease (SD), or disease progression. At the trial level, the category responses of all patients are aggregated into an imaging-based trial endpoint.

[0117] "Subjects" or "patients" of the combination according to the present invention may have: 1) adenocarcinoma of the prostate histologically or cytologically confirmed not to have small cell or signet ring cell features; 2) asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer; 3) DNA damage repair (DDR) defects, as centrally evaluated by next-generation sequencing (NGS) biomarker mutanome, which contains DDR genes potentially sensitive to PARP inhibition; 4) castration, either surgically or pharmacologically, with serum testosterone ≤ 50 ng / dL (≤ 1.73 nmol / L) at screening; 5) for patients not undergoing bilateral orchiectomy, androgen deprivation therapy with gonadotropin-releasing hormone (GnRH) agonist or antagonist; 6) metastatic disease in bone recorded on bone scan or in soft tissue recorded on CT / MRI scan; 7) in the case of medical or surgical castration, progressive disease at the time of entry into the study, defined by one or more of the following three criteria: i) prostate-specific antigen (PSA) progression, defined by PSA values rising in at least two of three assessments, with an interval of at least 7 days between assessments; ii) soft tissue disease progression, defined by RECIST 1.1; and iii) bone disease progression, defined by Prostate Cancer Clinical Trials Working Group 3 (PCWG3), with the appearance of 2 or more new metastatic bone lesions on whole-body radionuclide bone scan; 8) being on bisphosphonate or denosumab; 9) Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1; and 10) life expectancy ≥ 12 months as evaluated by the investigator.

[0118] "Subjects" and "patients" of the combination according to the present invention may not be selected for DNA damage response (DDR) mutation status, or interchangeably, may not be selected for HRR gene change status. "Not selected for DDR mutation status" and "not selected for HRR gene change status" mean that subjects are not selected for treatment based on DDR mutation status or HRR gene change status. In other words, regardless of DDR mutation status or HRR gene change status, all subjects with metastatic castration-resistant prostate cancer are suitable for treatment with the combination of the present invention.

[0119] As used herein, the term "cancer" refers to or describes a physiological disorder in a subject's patient, which is typically characterized by unregulated cell growth. "Cancer" refers to any malignant and / or invasive growth or tumor caused by abnormal cell growth. The term "metastatic", when related to cancer, includes, but is not limited to, cancer that has spread from its site of origin to other parts of the body, recurrence of an initial primary cancer after remission, and a second primary cancer, which is a new primary cancer in a subject with a history of a previous cancer and of a different type from the previous cancer. Those skilled in the art will be able to identify and diagnose metastatic cancer in a patient.

[0120] As used herein, "treat / treating" metastatic cancer such as mCRPC refers to administering to a subject or patient having or diagnosed with cancer the combination therapy according to the present invention to achieve at least one positive therapeutic effect such as reducing the number of cancer cells; reducing tumor size; decreasing the rate of cancer cell infiltration into surrounding organs; or decreasing the rate of tumor metastasis or tumor growth; reversing, alleviating, inhibiting the progression of a disease or disorder to which such terms apply or preventing the disease or disorder or one or more symptoms of such disease or disorder. Unless otherwise indicated, as used herein, the term "treatment" or "therapy" refers to the treatment act of "treating" as just defined above. For the purposes of the present invention, beneficial or desired clinical outcomes include, but are not limited to, one or more of the following: reducing (or destroying) the proliferation of neoplastic or cancerous cells; inhibiting cancer metastasis or neoplastic cells; shrinking or reducing tumor size; alleviating cancer; reducing the symptoms caused by cancer; improving the quality of life of a patient having cancer; reducing the dosage of other medications required to treat cancer; delaying the progression of cancer; curing cancer; overcoming one or more resistance mechanisms of cancer; and / or prolonging the survival of a cancer patient. Positive therapeutic effects in cancer can be measured in a variety of ways (see, e.g., W.A. Weber, J. Nucl. Med. 50:1S-10S (2009)).

[0121] In one embodiment, the treatment achieved by the combination of the present invention is prolonging the survival of a subject.

[0122] In one embodiment, the extension of survival is measured by any of the following: progression-free survival (PFS), radiographic PFS (rPFS), and overall survival (OS). PFS, rPFS, and OS are clinically meaningful endpoints for measuring the extension of survival of patients treated with the combination therapy of the present invention. PFS is the length of time during and after treating a disease such as cancer that a patient lives with the disease without the disease getting worse. OS is the length of time that a patient diagnosed with a disease such as cancer lives from the date of diagnosis or the start of treating the disease. In clinical trials, measuring PFS and OS is a way to observe how a new treatment works. For the purposes of the clinical trials described herein, rPFS refers to the time from the date of randomization to the first objective evidence of radiographic progression in soft tissue as determined by Blinded Independent Central Review (BICR) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) or in bone as determined according to Prostate Cancer Clinical Trials Working Group (PCWG3) guidelines (after subsequent confirmation) or death, whichever occurs first. For the purposes of the clinical trials described herein, OS refers to the time from the date of randomization to death from any cause.

[0123] In one embodiment, the progression-free survival is extended compared to subjects who have received enzalutamide or a pharmaceutically acceptable salt thereof and a placebo. In one embodiment, the progression-free survival is extended compared to subjects who have received enzalutamide or a pharmaceutically acceptable salt thereof and a placebo. For the purposes of the present invention, treatment with a placebo means that a patient with metastatic castration-resistant prostate cancer is not treated with talazoparib.

[0124] In one embodiment, the radiographic progression-free survival is extended compared to subjects who have received enzalutamide or a pharmaceutically acceptable salt thereof and a placebo. In one embodiment, the radiographic progression-free survival is extended compared to subjects who have received enzalutamide or a pharmaceutically acceptable salt thereof and a placebo. For the purposes of the present invention, treatment with a placebo means that a patient with metastatic castration-resistant prostate cancer is not treated with talazoparib.

[0125] "Amount" for use and for treating a subject means an amount that, in the form of a single or multiple doses, alone or in combination with one or more other agents, causes a detectable response, any measurable or detectable degree, or any desired outcome or objective or subjective benefit of any duration (brief, moderate or long term) in a subject, such as for hours, days, months, years, remission or cure. Such an amount typically effectively improves the disease or one, more or all of the side effects / symptoms, consequences or complications of the disease to a measurable degree, although reducing or inhibiting the progression or worsening of the disease or providing a stable (i.e., non-worsening) state of the disease is considered a satisfactory outcome. The term "therapeutically effective amount" also means an amount of an agent, alone or in combination with one or more other agents, that is capable of effectively producing a desired therapeutic effect, such as preventing the growth of a cancerous tumor or causing a cancerous tumor to shrink, after administration to a subject. With respect to the treatment of cancer, a therapeutically effective amount means an amount having the following effects: (1) reducing the size of the tumor, (2) inhibiting (i.e., slowing to some extent, preferably halting) the appearance of tumor metastasis, (3) inhibiting (i.e., slowing to some extent, preferably halting) tumor growth or tumor invasion to some extent, and / or (4) alleviating (or preferably eliminating) one or more cancer-related signs or symptoms to some extent. The therapeutic or pharmacological effectiveness of a dose and administration regimen can also be characterized as the ability to induce, enhance, maintain or prolong disease control and / or overall survival in patients with these specific tumors, which can be measured by an increase in the time before the appearance of disease progression.

[0126] As used herein, the term "improve" means any reduction in the degree, severity, incidence and / or likelihood of the symptoms or clinical sign characteristics of a particular disease. A "symptom" means any subjective evidence of a disease or a subject's condition.

[0127] In one embodiment, the amount or daily dose of talazoparib or a pharmaceutically acceptable salt thereof, and preferably its tosylate salt, to be administered to a subject is equivalent to about 0.1 mg to about 1 mg of talazoparib free base once daily. In one embodiment, talazoparib or a pharmaceutically acceptable salt thereof, and preferably its tosylate salt, is administered at a daily dose equivalent to about 0.1 mg of talazoparib free base once daily; to about 0.25 mg of talazoparib free base once daily; to about 0.35 mg of talazoparib free base once daily; to about 0.5 mg of talazoparib free base once daily; to about 0.75 mg of talazoparib free base once daily; or to about 1 mg of talazoparib free base once daily. In one embodiment, talazoparib or a pharmaceutically acceptable salt thereof, and preferably its tosylate salt, is administered at a daily dose equivalent to about 0.1 mg of talazoparib free base once daily; to about 0.25 mg of talazoparib free base once daily; about 0.35 mg of talazoparib free base once daily; or to about 0.5 mg of talazoparib free base once daily. In one embodiment, talazoparib or a pharmaceutically acceptable salt thereof, and preferably its tosylate salt, is administered at a daily dose equivalent to about 0.1 mg of talazoparib free base once daily. In one embodiment, talazoparib or a pharmaceutically acceptable salt thereof, and preferably its tosylate salt, is administered at a daily dose equivalent to about 0.25 mg of talazoparib free base once daily. In one embodiment, talazoparib or a pharmaceutically acceptable salt thereof, and preferably its tosylate salt, is administered at a daily dose equivalent to about 0.35 mg of talazoparib free base once daily. In one embodiment, talazoparib or a pharmaceutically acceptable salt thereof, and preferably its tosylate salt, is administered at a daily dose equivalent to about 0.5 mg of talazoparib free base once daily. In one embodiment, talazoparib or a pharmaceutically acceptable salt thereof, and preferably its tosylate salt, is administered at a daily dose equivalent to about 0.75 mg of talazoparib free base once daily. In one embodiment, talazoparib or a pharmaceutically acceptable salt thereof, and preferably its tosylate salt, is administered at a daily dose equivalent to about 1 mg of talazoparib free base once daily.

[0128] In one embodiment, the amount or daily dose of talazoparib or a pharmaceutically acceptable salt thereof, and preferably its tosylate salt, to be administered to a subject is about 0.1 mg to about 1 mg of talazoparib free base or equivalent once daily. In one embodiment, talazoparib or a pharmaceutically acceptable salt thereof, and preferably its tosylate salt, is administered at a daily dose of about 0.1 mg of talazoparib free base or equivalent once daily; to about 0.25 mg of talazoparib free base or equivalent once daily; to about 0.35 mg of talazoparib free base or equivalent once daily; to about 0.5 mg of talazoparib free base or equivalent once daily; to about 0.75 mg of talazoparib free base or equivalent once daily; or to about 1 mg of talazoparib free base or equivalent once daily. In one embodiment, talazoparib or a pharmaceutically acceptable salt thereof, and preferably its tosylate salt, is administered at a daily dose of about 0.1 mg of talazoparib free base or equivalent once daily; to about 0.25 mg of talazoparib free base or equivalent once daily; to about 0.35 mg of talazoparib free base or equivalent once daily; or to about 0.5 mg of talazoparib free base or equivalent once daily. In one embodiment, talazoparib or a pharmaceutically acceptable salt thereof, and preferably its tosylate salt, is administered at a daily dose of about 0.1 mg of talazoparib free base or equivalent once daily. In one embodiment, talazoparib or a pharmaceutically acceptable salt thereof, and preferably its tosylate salt, is administered at a daily dose of about 0.25 mg of talazoparib free base or equivalent once daily. In one embodiment, talazoparib or a pharmaceutically acceptable salt thereof, and preferably its tosylate salt, is administered at a daily dose of about 0.35 mg of talazoparib free base or equivalent once daily. In one embodiment, talazoparib or a pharmaceutically acceptable salt thereof, and preferably its tosylate salt, is administered at a daily dose of about 0.5 mg of talazoparib free base or equivalent once daily. In one embodiment, talazoparib or a pharmaceutically acceptable salt thereof, and preferably its tosylate salt, is administered at a daily dose of about 0.75 mg of talazoparib free base or equivalent once daily. In one embodiment, talazoparib or a pharmaceutically acceptable salt thereof, and preferably its tosylate salt, is administered at a daily dose of about 1 mg of talazoparib free base or equivalent once daily.

[0129] The doses provided herein refer to the dose of talazoparib in free base form, or calculated as the free base equivalent in the form of the talazoparib salt administered. For example, a dose or amount of talazoparib, such as 0.25, 0.35 mg or 0.5 mg, refers to the free base equivalent.

[0130] In one embodiment, enzalutamide is according to The US-approved label administers the drug at a daily dose of 160 mg once daily. A person of ordinary skill in the art can easily determine the dose adjustment of enzalutamide based on the complete prescription information. For example, if enzalutamide is to be co-administered with a strong CYP2C8 inhibitor, the dose of enzalutamide should be reduced according to the complete prescription information, such as reduced to 80 mg once daily; or, if enzalutamide is to be co-administered with a CYP3A4 inducer, the dose of enzalutamide should be increased according to the complete prescription information, such as increased to 240 mg daily.

[0131] In a preferred embodiment, enzalutamide or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 160 mg once daily. The dose amounts provided herein refer to the dose of enzalutamide in free base form, or calculated as the free base equivalent in the form of the enzalutamide salt administered. For example, the dose or amount of enzalutamide, such as 160 mg, refers to the free base or its equivalent.

[0132] The recommended dose of talazoparib is 0.5 mg orally once daily, in combination with 160 mg enzalutamide orally once daily, until disease progression or unacceptable toxicity occurs. The dosing regimen can be adjusted to provide an optimal therapeutic response. For example, the dose can be proportionally reduced or increased as indicated by the exigencies of the treatment situation. To control adverse reactions, interruption of treatment with or without dose reduction is considered based on severity and clinical manifestation. 0.35 mg, 0.25 mg, and 0.1 mg capsules can be used for dose reduction.

[0133] For patients with mCRPC and moderate renal impairment (CLcr 30 - 59 mL / min), the recommended dose of talazoparib is 0.35 mg once daily in combination with 160 mg enzalutamide orally once daily. For patients with severe renal impairment (CLcr 15 - 29 mL / min), the recommended dose of talazoparib is 0.25 mg once daily in combination with 160 mg enzalutamide orally once daily.

[0134] For patients with mCRPC, when co-administered with certain P-gp inhibitors, such as itraconazole, amiodarone, carvedilol, clarithromycin, itraconazole, and verapamil, the talazoparib dose is reduced to 0.35 mg once daily, in combination with 160 mg enzalutamide orally once daily. When the P-gp inhibitor is discontinued, the talazoparib dose (3 to 5 half-lives after the P-gp inhibitor) is increased to the dose used before the initiation of the P-gp inhibitor.

[0135] The compounds of the present invention can be administered orally. Oral administration can involve swallowing such that the compound enters the gastrointestinal tract, or can be buccal or sublingual administration such that the compound enters the bloodstream directly from the mouth.

[0136] In a preferred embodiment, the daily dose of talazoparib or a pharmaceutically acceptable salt thereof is administered orally.

[0137] In a preferred embodiment, the daily dose of enzalutamide or a pharmaceutically acceptable salt thereof is administered orally.

[0138] Talazoparib or a pharmaceutically acceptable salt can be present in a pharmaceutical composition comprising a pharmaceutically acceptable excipient. "Pharmaceutically acceptable excipient" refers to a component that can be included in the compositions described herein, is physiologically suitable for pharmaceutical use, and does not cause significant adverse effects and therapeutic effects to the subject. The term "excipient" is used herein to describe any component other than the compound(s) of the present invention. The choice of excipient will depend to a large extent on factors such as the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0139] The amount of talazoparib or a pharmaceutically acceptable salt in the pharmaceutical composition can be any amount disclosed herein.

[0140] The compounds of the methods, uses, or combinations of the present invention can be formulated prior to administration. The formulation will preferably be suitable for the particular mode of administration. These compounds can be formulated with pharmaceutically acceptable excipients known in the art and administered in various dosage forms known in the art. Unit dosage forms or pharmaceutical compositions suitable for oral administration include, but are not limited to, tablets; capsules, such as gelatin capsules; pills; powders; granules; aqueous and non-aqueous oral solutions and suspensions, which are packaged in containers suitable for subdivision into individual doses.

[0141] In another embodiment, depending on the dosage form used and the route of administration employed, the dosage of the compounds or pharmaceutical compositions described herein can vary within a range. In another embodiment, the amount of the compounds or pharmaceutical compositions described herein administered to a subject can depend on factors known to those of skill in the art, including the biological activity and bioavailability of the compound (such as the half-life and stability of the compound in vivo), the chemical characteristics of the compound (such as molecular weight, hydrophobicity, and solubility), the route and frequency of use, etc. In addition, it will be understood that the specific dosage of a pharmaceutical composition comprising a compound as disclosed herein can depend on a variety of factors, including the physical condition of the subject (such as age, gender, weight) and the medical history of the subject (such as medications taken, health status, other diseases or disorders). The precise dosage of the pharmaceutical composition administered to a subject can be determined by methods known to those of skill in the art, such as pharmacologists or anesthesiologists.

[0142] Administration or dosing regimens can be repeated as needed to achieve the desired reduction or attenuation of cancer cells. As used herein, a "continuous dosing schedule" is an administration or dosing regimen without a dosage interruption (such as no days of treatment cessation). Repeating a 28-day treatment cycle with no dosage interruption between treatment cycles is an example of a continuous dosing schedule. In one embodiment, the compounds of the combination of the present invention can be administered according to a continuous dosing schedule. In one embodiment, the compounds of the combination of the present invention can be administered simultaneously according to a continuous dosing schedule.

[0143] Methods of treatment and uses

[0144] The methods and combination therapies of the present invention can be used to treat mCRPC. The methods and combination therapies of the present invention can be used to treat mCRPC in the presence or absence of DDR mutations or HRR gene alterations.

[0145] In one embodiment, the present disclosure provides a method of prolonging the survival of a subject with metastatic castration-resistant prostate cancer, the method comprising: 1) orally administering to the subject talazoparib or a pharmaceutically acceptable salt thereof once daily, and 2) orally administering to the subject enzalutamide or a pharmaceutically acceptable salt thereof once daily.

[0146] In one embodiment, the present disclosure provides a method of prolonging the survival of a subject with metastatic castration-resistant prostate cancer, the method comprising: 1) orally administering to the subject a combination of talazoparib or a pharmaceutically acceptable salt thereof and 2) orally administering to the subject enzalutamide or a pharmaceutically acceptable salt thereof once daily.

[0147] In one embodiment, the present disclosure provides a method for treating metastatic castration-resistant prostate cancer in a subject in need thereof, the method comprising: 1) orally administering talazoparib or a pharmaceutically acceptable salt thereof to the subject once daily; and 2) orally administering enzalutamide or a pharmaceutically acceptable salt thereof to the subject once daily, wherein administering talazoparib or a pharmaceutically acceptable salt thereof and administering enzalutamide or a pharmaceutically acceptable salt thereof prolong the survival of the subject.

[0148] In one embodiment, the present invention provides a method for treating metastatic castration-resistant prostate cancer in a subject in need thereof, the method comprising: 1) orally administering talazoparib or a pharmaceutically acceptable salt thereof to the subject once daily in combination with 2) orally administering enzalutamide or a pharmaceutically acceptable salt thereof to the subject once daily, wherein the combination prolongs the survival of the subject.

[0149] Unless otherwise indicated, as used herein, the term "combination" means a combination of agents administered at a time close enough to affect the treatment of the subject. The combinations of the present invention can be administered simultaneously (i.e., synchronously) or sequentially. Examples of "combination" include, but are not limited to, "administering simultaneously", "co-administering", "synchronously administering", "sequentially administering", and "administering concurrently". The combinations of the present invention can be co-administered in the same formulation. The combinations of the present invention can be administered simultaneously (i.e., synchronously) in separate formulations. The combinations of the present invention can be administered sequentially, i.e., talazoparib is administered first, followed by enzalutamide after a specific period (such as one hour); or enzalutamide is administered first, followed by talazoparib after a specific period (such as one hour). The combinations of the present invention are preferably administered simultaneously.

[0150] In one embodiment, the present invention provides a combination of talazoparib or a pharmaceutically acceptable salt thereof and enzalutamide or a pharmaceutically acceptable salt or solvate thereof for prolonging overall survival in the treatment of metastatic castration-resistant prostate cancer in a subject.

[0151] In another aspect, the present invention relates to the use of talazoparib or a pharmaceutically acceptable salt thereof and enzalutamide or a pharmaceutically acceptable salt thereof for the preparation of a medicament for prolonging overall survival in the treatment of metastatic castration-resistant prostate cancer in a subject.

[0152] In one embodiment, a combination therapy is administered to a subject who has not received: 1) a prior systemic cancer treatment for non-metastatic castration-resistant prostate cancer or metastatic castration-resistant prostate cancer; 2) a prior treatment of prostate cancer with an androgen receptor signaling inhibitor, a PARP inhibitor, cyclophosphamide, or mitoxantrone; or 3) any history of disease progression within 6 months of the last administration of a prior treatment with platinum-based chemotherapy or within 6 months of receiving the last administration of a platinum-based therapy.

[0153] Additional therapeutic agents

[0154] In one embodiment, the methods and combination therapies of the invention may additionally comprise administering another anti-cancer agent, such as an anti-tumor agent, an anti-angiogenic agent, a signal transduction inhibitor, and an anti-proliferative agent. In some such embodiments, the anti-tumor agent is selected from the group consisting of: a mitotic inhibitor, an alkylating agent, an anti-metabolite, intercalating antibiotics, a growth factor inhibitor, radiation, a cell cycle inhibitor, an enzyme, a topoisomerase inhibitor, a biological response modifier, an antibody, a cytotoxic agent, an anti-hormone, androgen deprivation therapy, and an anti-androgen.

[0155] In one embodiment, the methods and combination therapies of the invention may additionally comprise administering another active agent, wherein the other active agent is androgen deprivation therapy.

[0156] In one embodiment, the androgen deprivation therapy is a luteinizing hormone-releasing hormone (LHRH) agonist, an LHRH antagonist, a gonadotropin-releasing hormone (GnRH) agonist, or a GnRH antagonist.

[0157] In one embodiment, the androgen deprivation therapy is a GnRH agonist or a GnRH antagonist.

[0158] In one embodiment, the androgen deprivation therapy is a GnRH agonist.

[0159] In one embodiment, the androgen deprivation therapy is a GnRH antagonist.

[0160] In one embodiment, the androgen deprivation therapy is an LHRH agonist or an LHRH antagonist.

[0161] In one embodiment, the androgen deprivation therapy is an LHRH agonist.

[0162] In one embodiment, the androgen deprivation therapy is an LHRH antagonist.

[0163] In one embodiment, androgen deprivation therapy is selected from the group consisting of: leuprorelin (also known as leuprolide, such as Lupron or Eligard or Viadur and its analogs); buserelin (such as Suprefact); gonadorelin; goserelin (such as Zoladex); histrelin (such as Vantas); nafarelin; triptorelin (such as Trelstar); deslorelin; futirelin; abarelix (such as Plenaxis); cetrorelix; degarelix (such as Firmagon); ganirelix; ozerelix; elagolix (such as Orilissa); relugolix; and linzagolix.

[0164] In one embodiment, androgen deprivation therapy is selected from the group consisting of: leuprorelin; buserelin; gonadorelin; goserelin; histrelin; nafarelin; triptorelin; deslorelin; futirelin; abarelix; cetrorelix; degarelix; ganirelix; ozerelix; elagolix; relugolix; and linzagolix.

[0165] In one embodiment, androgen deprivation therapy is selected from the group consisting of leuprorelin, goserelin, and degarelix.

[0166] In one embodiment, androgen deprivation therapy is leuprorelin. In some embodiments, leuprorelin is administered intramuscularly at a dose of about 7.5 mg per month, or about 22.5 mg every three months, or about 30 mg every four months.

[0167] In one embodiment, androgen deprivation therapy is leuprorelin. In some embodiments, leuprorelin is administered subcutaneously at a dose of about 7.5 mg per month, or about 22.5 mg every three months, or about 30 mg every four months, or about 45 mg every six months, or about 65 mg every 12 months.

[0168] In one embodiment, androgen deprivation therapy is goserelin. In some embodiments, goserelin is administered subcutaneously at a dose of about 3.6 mg per month or about 10.8 mg every three months.

[0169] In one embodiment, androgen deprivation therapy is degarelix. In some embodiments, degarelix is administered intramuscularly at an initial dose of about 240 mg, followed by a maintenance dose of about 80 mg per month, and the initial dose can optionally be divided into several smaller doses, such as 2 doses of about 120 mg.

[0170] In one embodiment of the methods and combination therapies of the present invention, the regimen includes another active agent, wherein the other active agent is etoposide. In some embodiments, etoposide is administered intravenously according to an approved label, for example, at a dose of 50 to 100 mg / m 2 per day on days 1 to 5; or at a dose of 5 to 100 mg / m 2 per day on days 1, 3, and 5. In one example, etoposide can be administered at a dose of 80 to 120 mg / m 2 per day on days 1, 2, and 3 of each 21-day cycle for 1, 2, 3, 4, 5, or 6 cycles.

[0171] Examples

[0172] Study Design

[0173] This is an international, phase 3, randomized, double-blind, two-part study, TALAPRO-2 (NCT03395197), in patients with mCRPC.

[0174] Part 1 is open-label and non-randomized and assesses the safety, tolerability, and pharmacokinetics (PK) of the combination of talazoparib (Tala) and enzalutamide (Enza). Nineteen mCRPC patients were recruited to determine the appropriate starting dose of the combination of talazoparib and enzalutamide in Part 2. The starting dose in Part 2 is the combination of talazoparib / placebo at 0.5 mg / day (mg QD) and enzalutamide at 160 mg / day. At screening, the starting dose of talazoparib / placebo in patients with moderate renal impairment was reduced to 0.35 mg / day.

[0175] Part 2 is randomized, double-blind, and placebo-controlled and evaluates the efficacy and safety of the combination of talazoparib and enzalutamide compared to the combination of placebo and enzalutamide. Patients were randomly assigned 1:1 to receive the combination of talazoparib or matching placebo and open-label enzalutamide. Randomization was stratified according to previous novel hormonal therapy or taxane-based chemotherapy, such as abiraterone, orteronel, or docetaxel, for castration-sensitive prostate cancer (yes / no) and DDR mutation status (also known as homologous recombination repair gene change status (deficient vs. non-deficient / unknown)). Stratification factors were designated by the investigator and recorded in the Interactive Web Response System (IWRS) prior to randomization and used for the stratified analysis of the primary efficacy endpoint. However, since the IWRS grouped non-deficient and unknown statuses together, a secondary stratified analysis based on the homologous recombination repair gene change status derived from the clinical database was also performed and used to identify the non-deficient subgroup.

[0176] In Part 1, genomic screening for identifying DDR gene alterations is optional for patients but required for randomization in Part 2. Using next-generation sequencing (NGS)-based gene panel testing, the mutation status is determined by testing for the presence of mutations in established DDR genes that may be sensitive to PARP inhibition. Prior to randomization, patients consented to provide solid tumor tissue (fresh or archived) and / or blood-based samples for prospective assessment of the status of DNA damage response genes (BRCA1, BRCA2, PALB2, ATM, ATR, CHEK2, FANCA, RAD51C, NBN, MLH1, MRE11A, CDK12) directly or indirectly involved in homologous recombination repair using and / or CDx. Among 805 enrolled patients, tumor tissue for directive stratification was available from 804 (99.9%) patients, and blood-based testing for circulating tumor DNA (ctDNA) was also performed in 114 (14.2%) patients. Only one patient was enrolled based on ctDNA results. For exploratory analysis, available blood-based samples (not collected in China) were retrospectively tested using CDx to determine the status of patients with unknown prospective assessment status.

[0177] Study treatment (including enzalutamide) was continued until radiographic / imaging-based progression was determined by the (BICR) (Part 2) or local review (Part 1) (unless, in the investigator's opinion, the patient was still benefiting at that time), or an adverse event leading to permanent discontinuation occurred, or the patient decided to discontinue treatment or died.

[0178] In Part 2, there are two patient cohorts: first, the all-comers cohort, and then the DDR-deficient cohort. Results for the all-comers cohort in Part 2 of the study who were not selected for HRR gene alterations are provided in this example, such as patients with or without tumor HRR gene alterations. The DDR-deficient cohort is still under investigation.

[0179] Inclusion criteria:

[0180] 1. Adenocarcinoma of the prostate, histologically or cytologically confirmed, without small cell or signet ring cell features.

[0181] 2. Asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer (mCRPC) (score on BPI-SF question #3 must be < 4).

[0182] 3. Enrollment in Part 2 only (optional in Part 1): Assessment of DDR mutation status.

[0183] 4. Consent to the collection of saliva samples for germline comparators (optional for patients in Part 1), unless prohibited by local regulations or an ethics committee decision.

[0184] 5. Castration, either surgically or pharmacologically, with a serum testosterone ≤ 50 ng / dL (≤ 1.73 nmol / L) at screening.

[0185] 6. Metastatic disease in bone as recorded on bone scan or in soft tissue as recorded on CT / MRI scan.

[0186] 7. In the case of medical or surgical castration, progressive disease at study entry, defined by one or more of the following 3 criteria (prostate-specific antigen only or imaging-based):

[0187] a. Prostate-specific antigen (PSA) progression, defined by PSA values that increase in at least 2 of 3 consecutive assessments, with an interval of at least 7 days between each assessment.

[0188] b. Soft tissue disease progression, defined by RECIST 1.1.

[0189] c. Bone disease progression, defined by Prostate Cancer Clinical Trials Working Group 3 (PCWG3), with the appearance of 2 or more new metastatic bone lesions on a whole-body radionuclide bone scan.

[0190] 8. Use of bisphosphonates or denosumab is allowed but not mandatory before Day 1 (Part 1) or randomization (Part 2).

[0191] 9. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.

[0192] 10. Life expectancy ≥ 12 months, as assessed by the investigator.

[0193] 11. Able to swallow the study drug and have no known intolerance to the study drug or excipients.

[0194] 12. Must consent to use a condom during sexual intercourse with a spouse from the time of the first dose of the study drug until 4 months after the last dose of study treatment. Must also consent to the use of an additional highly effective form of contraception by the female spouse with reproductive potential during sexual intercourse with a non-pregnant female spouse with reproductive potential from the time of the first dose of study treatment until 4 months after the last dose of study treatment.

[0195] 13. Must consent not to donate sperm from the time of the first dose of the study drug until 4 months after the last dose of the study drug.

[0196] 14. Evidence of a personal, signed, and dated informed consent document (and, where appropriate, a molecular pre-screening consent form) indicating that the patient [or legally acceptable representative / legal guardian] has been informed of all relevant aspects of the study.

[0197] 15. Willing and able to comply with the scheduled visits, treatment plan, laboratory tests, and other study procedures.

[0198] Exclusion criteria:

[0199] 1. Any prior systemic cancer treatment initiated in the non-metastatic CRPC and mCRPC disease states.

[0200] 2. Patients with evidence of metastasis limited to adenopathy below the aortic bifurcation.

[0201] 3. Prior treatment of prostate cancer with second-generation androgen receptor inhibitors (enzalutamide, apalutamide, and darolutamide), PARP inhibitors, cyclophosphamide, or mitoxantrone.

[0202] 4. Prior treatment with platinum-based chemotherapy within 6 months (from the last dose) before Day 1 (Part 1) or randomization (Part 2), or any history of disease progression within 6 months (from the last dose) after receiving platinum-based therapy.

[0203] 5. Not excluded if cytotoxic chemotherapy, biotherapy including sipuleucel T, or radionuclide therapy received in castration-sensitive prostate cancer was interrupted within 28 days before Day 1 (Part 1) or randomization (Part 2).

[0204] 6. In the castration-sensitive setting, prior docetaxel and abiraterone or autotaxol are not excluded.

[0205] 7. Treatment with any investigational agent within the 4 weeks before Day 1 (Part 1) or randomization (Part 2).

[0206] 8. Prior treatment with opioids for pain related to primary prostate cancer or metastases within the 28 days before Day 1 (Part 1) or randomization (Part 2).

[0207] 9. Currently using a potent P-gp inhibitor within 7 days before Day 1 (Part 1) or randomization (Part 2).

[0208] 10. Major surgery (as defined by the investigator) within 2 weeks before Day 1 (Part 1) or randomization (Part 2), or palliative local radiotherapy within 3 weeks before randomization (Part 2).

[0209] 11. Clinically significant cardiovascular disease.

[0210] 12. Presence of significant renal dysfunction defined by any of the following laboratory abnormalities:

[0211] a. Kidney: eGFR < 30 mL / min / 1.73 m2 according to the MDRD equation (available via www.mdrd.com).

[0212] 13. Patients enrolled only in Part 1: Moderate renal impairment (eGFR 30 - 59 mL / min / 1.73 m2) at screening.

[0213] 14. Presence of significant liver dysfunction defined by any of the following laboratory abnormalities at laboratory screening:

[0214] a. Total serum bilirubin > 1.5 times the upper limit of normal (ULN) (for patients with confirmed Gilbert syndrome or indirect bilirubin concentration indicating an extrahepatic source of elevation, > 3 times ULN).

[0215] b. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 times ULN (if liver dysfunction is due to liver metastases, > 5 times ULN).

[0216] c. Albumin < 2.8 g / dL.

[0217] 15. Absolute neutrophil count < 1500 / μL, platelets < 100,000 / μL or hemoglobin < 9 g / dL (growth factors or transfusions not received within 14 days prior to obtaining hematology values at screening).

[0218] 16. Known or suspected brain metastases or active leptomeningeal disease.

[0219] 17. Symptomatic or impending spinal cord compression or cauda equina syndrome.

[0220] 18. History of any myelodysplastic syndrome, acute myeloid leukemia or prior malignancy, except for any of the following:

[0221] a. Carcinoma in situ or non - melanoma skin cancer.

[0222] b. Any prior malignancy ≥ 3 years before randomization, regardless of stage, with no evidence of subsequent recurrence or progression.

[0223] c. Stage 0 or 1 cancer < 3 years before randomization, with a very low likelihood of recurrence or progression as determined by the investigator.

[0224] 19. Gastrointestinal disorders affecting absorption.

[0225] 20. Reproductive male subjects who are unwilling or unable to use highly effective contraceptive methods during the study period and for 4 months after the last dose of the study product.

[0226] 21. Investigators, site staff directly involved in conducting the study, and their family members, site staff supervised by the investigator in other ways, or Pfizer / Pfizer employee patients directly involved in conducting the study, including their family members.

[0227] 22. Other acute or chronic medical (comorbidities, infections or co - morbid conditions) or psychiatric conditions that interfere with the ability to participate in the study, may increase the risk associated with study participation or study product administration, or may interfere with the interpretation of study results and, in the judgment of the investigator, render the patient unfit to participate in this study, including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormalities.

[0228] 23. History of epilepsy or any condition predisposing to epilepsy (e.g., previous cortical stroke, significant head trauma). In addition, history of loss of consciousness or transient ischemic attack within 12 months of randomization (Part 2).

[0229] Statistical analysis:

[0230] Approximately 750 patients were enrolled in the overall participant cohort. For the primary comparison in the overall participant population, 333 ibPFS events (based on BICR) provided 85% power to detect a hazard ratio of 0.696 at a significance level of 0.0125 using a one - sided stratified log - rank test (to maintain the overall Type I error at or below one - sided 0.025, the α value for ibPFS by BICR was evenly divided between all participants [cohort 1] and the upcoming molecularly selected cohort 2; the one - sided α value for each cohort was 0.0125).

[0231] Overall survival was tested in a stratified step - down procedure only when ibPFS showed a statistically significant improvement to preserve the overall Type I error. Other endpoints were not adjusted for multiplicity.

[0232] The sample size and power calculations for ibPFS included the following assumptions: for the overall participant population, the median ibPFS for the placebo + enzalutamide group would be 16 months, and for the talazoparib + enzalutamide group would be 23 months; approximately 15% of the overall participant population would carry homologous recombination repair gene alterations.

[0233] The time-to-event endpoints were compared between treatment groups using the stratified log-rank test. Hazard ratios and associated 95% two-sided confidence intervals (CIs) were estimated by the Cox proportional hazards model. Median time-to-event endpoints were estimated by the Kaplan-Meier method and 95% CIs were based on the Brookmeyer-Crowley method. Missing or partial dates were imputed as per the protocol. No other missing data were imputed.

[0234] Patient population:

[0235] The primary population for evaluating efficacy endpoints and patient characteristics was the intention-to-treat (ITT) population. This population included all patients randomized, in whom treatment assignment was specified according to randomization, regardless of whether the patient received study treatment.

[0236] The safety analysis population consisted of all patients who received at least one dose of study treatment (talazoparib / placebo or enzalutamide) and was based on the actual treatment received. This population was the primary population for evaluating safety.

[0237] Between January 7, 2019 and September 17, 2020, a total of 805 patients were enrolled and randomized to the all-comers cohort (402 assigned to the talazoparib + enzalutamide group and 403 assigned to the placebo + enzalutamide group, intention-to-treat population). 398 patients in the talazoparib + enzalutamide group and 401 patients in the placebo + enzalutamide group received study treatment (all-comers safety population). Data cutoff was August 16, 2022.

[0238] The patient treatment period disposition is summarized in Table 1 below.

[0239] Table 1. Patient Disposition During the Study Treatment Period (Safety Population)

[0240]

[0241] *Two patients (one in each treatment group) who received enzalutamide but not talazoparib / placebo were excluded from these data.

[0242] **One patient was incorrectly reported as having discontinued due to death. The patient discontinued talazoparib and enzalutamide on the same day due to the same adverse event.

[0243] Baseline demographics / disease characteristics were well balanced. Representative data for the patients are shown in Table 2.

[0244] Table 2. Representative Data for the Study Participants

[0245]

[0246] Table 3 shows the baseline patient demographics and disease characteristics (intent-to-treat population of all participants), which were well balanced between treatment groups.

[0247] Table 3. Baseline patient demographics and disease characteristics (intent-to-treat population of all participants)

[0248]

[0249]

[0250] Values (%) unless otherwise indicated.

[0251] * American Indian, Alaska Native, Native Hawaiian, or other Pacific Islander.

[0252] ** Not reported for remaining patients.

[0253] *** All patients received docetaxel.

[0254] § The remaining two patients in each treatment group received olaparib.

[0255] The prospective “unknown” status of the homologous recombination repair gene alteration status mainly reflects technical failures in testing due to limitations in sample quality or purity.

[0256] ctDNA represents cell-free tumor DNA, ECOG represents Eastern Cooperative Oncology Group, IWRS represents Interactive Web Response System, and PSA represents prostate-specific antigen.

[0257] The biomarker status was prospectively known by tissue for 99.9% of patients. Among 805 patients, 804 had tissue available for prospective testing of homologous recombination repair gene status (1 patient had only ctDNA results). Table 4 shows the source of tumor DNA used for assessment and the baseline HRR gene status.

[0258] Table 4. Source of tumor DNA used for assessment and baseline homologous recombination repair gene status

[0259]

[0260] Values (%) unless otherwise indicated.

[0261] In the prospective test, homologous recombination repair gene alterations were not detected (non-deficient) in 426 (52.9%) patients, alterations were detected (deficient) in 167 (20.7%) patients, and 212 (26.3%) patients had unknown alteration status (Table 3). BRCA alterations were detected in 6.7% (n = 27) of the patients in the talazoparib + enzalutamide group and in 7.9% (n = 32) of the patients in the placebo + enzalutamide group. Table 5 includes an overview of homologous recombination repair gene alterations and shows that HRR gene alterations were well balanced between the treatment groups. Exploratory analyses, including retrospective ctDNA results to resolve the status of prospectively unknown patients, found that 547 (68.0%) patients were in the non-deficient alteration state, 214 (26.6%) patients were in the deficient state, and 44 (5.5%) patients were in the unknown state. Unless otherwise stated, all results are based on the IWRS.

[0262] Table 5. Overview of homologous recombination repair gene alterations (intention-to-treat population of all participants)

[0263]

[0264] Key efficacy results and supportive findings:

[0265] According to RECIST 1.1 and PCWG3, the primary endpoint was rPFS as assessed by BICR, also known as ibPFS by BICR. Based on data cut off on August 16, 2022, the number of events in the talazoparib + enzalutamide group was 151 / 402, and the number of events in the placebo + enzalutamide group was 191 / 403. For the talazoparib + enzalutamide group and the placebo + enzalutamide group, the median follow-up times for rPFS were 24.9 months and 24.6 months, respectively. The stratified hazard ratio for the primary endpoint observed (talazoparib + enzalutamide versus placebo + enzalutamide) was 0.627 (95% CI: [0.506, 0.777]; one-sided p-value < 0.0001; two-sided p-value < 0.0001), favoring talazoparib + enzalutamide. The median rPFS in the talazoparib + enzalutamide group was not estimable (NE) / not reached (NR) (95% CI: [27.5, NE / not reached]) months, compared with 21.9 months (95% CI: [16.6, 25.1]) in the placebo + enzalutamide group. Treatment with talazoparib plus enzalutamide resulted in a 37% reduction in the risk of imaging-based progression (blinded independent central assessment) or death compared with placebo plus enzalutamide.

[0266] The investigator-assessed rPFS was a secondary efficacy endpoint. The stratified hazard ratio for the secondary endpoint observed (talazoparib + enzalutamide vs placebo + enzalutamide) was 0.637 (95% CI: [0.501, 0.811]; one-sided p-value: 0.0001), favoring talazoparib + enzalutamide. The median rPFS in the talazoparib + enzalutamide group was NE (95% CI: [30.4, NE]) months, while the median rPFS in the placebo + enzalutamide group was 30.3 months (95% CI: [24.3, NE]).

[0267] OS was a key secondary endpoint for α-spending; however, the OS data were immature (31% maturity). Based on data as of August 16, 2022, the number of events in the talazoparib + enzalutamide group was 123 / 402, and the number of events in the placebo + enzalutamide group was 129 / 402. A total of 252 deaths were observed (123 [30.6%] deaths in talazoparib + enzalutamide vs 129 [32.0%] deaths in placebo + enzalutamide). Based on data as of August 16, 2022, the median follow-up time in the talazoparib + enzalutamide group was 28.0 months, and the median follow-up time in the placebo + enzalutamide group was 27.1 months. An interim analysis of OS was performed based on the pre-specified O'Brien-Fleming α-spending function. Based on 252 deaths, the stratified hazard ratio for OS observed (talazoparib + enzalutamide vs placebo + enzalutamide) was 0.888 (95% CI: [0.693, 1.138]; p = 0.35), favoring talazoparib + enzalutamide. The median OS in the talazoparib + enzalutamide group was 36.4 months (95% CI: [33.5, NE / Not reached]), and the median OS in the placebo + enzalutamide group was NE / Not reached (95% CI: [33.7, NE / Not reached]) months. The interim OS results did not cross the pre-specified O'Brien-Fleming efficacy boundary.

[0268] Based on data as of March 28, 2023, a total of 330 deaths were observed (156 [38.8%] deaths in talazoparib + enzalutamide, compared with 175 [43.25%] deaths in placebo + enzalutamide). The median follow-up time for the talazoparib + enzalutamide group was 35.8 months, and for the placebo + enzalutamide group was 34.6 months. The stratified hazard ratio for OS observed was 0.837 (95% CI: [0.674, 1.040]; one-sided P value: 0.00537), favoring talazoparib + enzalutamide. The median OS for the talazoparib + enzalutamide group was NE (95% CI: [37.3, NE]) and for the placebo + enzalutamide group was 38.2 months (95% CI: [34.1, 43.1]). The OS results did not cross the pre-specified O'Brien-Fleming efficacy boundary.

[0269] The objective response rate (ORR) was a secondary endpoint and was defined as the proportion of patients with a best overall confirmed soft tissue response of the CR or PR type among patients with measurable soft tissue disease at baseline as confirmed by BICR according to RECIST 1.1. The objective response rates evaluated by BICR were 61.7% (74 / 120 events; 95% CI: [52.4, 70.4]) in the talazoparib + enzalutamide group and 43.9% (58 / 132; 95% CI: [35.3, 52.8]) in the placebo + enzalutamide group. The difference in objective response rates between the two groups was 17.7% (95% CI: [5.6, 29.9]; one-sided nominal p value: 0.0025). In addition, the CR rates in the talazoparib + enzalutamide group and the placebo + enzalutamide group were 37.5% (45 / 120) and 18.2% (24 / 132), respectively. The higher complete response (CR) rate indicates a synergistic effect of talazoparib plus enzalutamide treatment.

[0270] PSA response was also a secondary endpoint and was defined as a decrease in PSA from baseline of at least 50% and confirmed by a second consecutive value at least 3 weeks later. Accordingly, the PSA response rate for the talazoparib + enzalutamide group was 83.6% (95% CI: [79.6, 87.1]), and for the placebo + enzalutamide group was 72.1% (95% CI: [67.4, 76.5]). The difference in PSA response was 11.5% (95% CI: [5.8, 17.2]; one-sided P value < 0.0001).

[0271] The time to PSA progression was a secondary endpoint and was defined as the time from randomization to the first PSA progression, which was defined as an increase of ≥25% and an absolute increase of ≥2 μg / L above the nadir. The stratified hazard ratio for the time to PSA progression (talazoparib + enzalutamide versus placebo + enzalutamide) was 0.715 (95% CI: [0.577, 0.886]; one-sided P value: 0.0010), favoring talazoparib + enzalutamide. The median time to PSA progression in the talazoparib + enzalutamide group was 26.7 months (95% CI: [21.2, 30.4]), and the median time to PSA progression in the placebo + enzalutamide group was 17.5 months (95% CI: [14.1, 20.8]). Treatment with talazoparib plus enzalutamide prolonged the time to PSA progression.

[0272] Benefits of talazoparib plus enzalutamide were consistently observed in other secondary endpoints. As shown in Table 6, the time to PSA progression, use of subsequent cytotoxic chemotherapy, and use of subsequent anti-tumor therapy were all significantly prolonged in the talazoparib + enzalutamide group.

[0273] Table 6. Secondary Efficacy Endpoints (Intention-to-Treat Population of All Participants)

[0274]

[0275]

[0276] * Includes only patients with measurable disease at baseline according to blinded independent central review: talazoparib plus enzalutamide (N = 120); placebo plus enzalutamide (N = 132).

[0277] ** Includes only patients with confirmed complete or partial response: talazoparib plus enzalutamide (N = 74); placebo plus enzalutamide (N = 58).

[0278] *** Number of patients with baseline PSA value and at least one post-baseline PSA value: talazoparib plus enzalutamide (N = 396); placebo plus enzalutamide (N = 394).

[0279] **** Progression-free survival 2 (PFS2) based on investigator assessment (time from randomization to the date of progression of the first subsequent anti-tumor therapy or death from any cause, whichever occurs first).

[0280] Through prospective tumor tissue testing, talazoparib plus enzalutamide reduced the risk of progression or death in subgroups with homologous recombination repair deficiency, non-deficiency or unknown status, and non-deficiency status.

[0281] In subgroup analyses by homologous recombination repair gene alteration status, in patients with a defective status, the HR for ibPFS was 0.46 (95% CI, 0.30 - 0.70; P < 0.001), and in patients with a non - defective or unknown status, the HR for ibPFS was 0.70 (95% CI, 0.54 - 0.89; P = 0.004), favoring talazoparib plus enzalutamide compared with placebo plus enzalutamide. For patients with a defective status, based on 37 events among 85 patients in the talazoparib + enzalutamide group, the median ibPFS in the talazoparib + enzalutamide group was 27.9 months (95% CI: [16.6 - NE / NR]), compared with a median ibPFS of 16.4 months (95% CI: [10.9 - 24.6]) based on 49 events among 84 patients in the placebo + enzalutamide group. For patients with a non - defective or unknown status, based on 114 events among 317 patients in the talazoparib + enzalutamide group, the median ibPFS in the talazoparib + enzalutamide group was NR (95% CI: [27.5 - NE / NR]) months, compared with a median ibPFS of 22.5 months (95% CI: [19.1 - 30.5]) months based on 142 events among 319 patients in the placebo + enzalutamide group. Regardless of HRR status, a clinically meaningful reduction in the risk of progression or death was found.

[0282] In exploratory subgroup analyses of patients with only HRR non - defective status by prospective tumor tissue testing, talazoparib plus enzalutamide reduced the risk of imaging - based progression or death by 34% (HR 0.66; 95% CI, 0.49 - 0.91; P = 0.009) compared with placebo plus enzalutamide. For patients in whom HRR gene alterations were not detected by prospective tumor tissue testing, based on 70 events among 198 patients in the talazoparib + enzalutamide group, the median ibPFS per BICR in the talazoparib + enzalutamide group was NR (95% CI: [25.8 - NE / NR]) months, compared with a median ibPFS per BICR of 22.1 months (95% CI: [16.6 - NE / NR]) months based on 96 events among 214 patients in the placebo + enzalutamide group.

[0283] In the exploratory subgroup analysis, the risk of imaging-based progression or death was reduced by 77% (HR 0.23; 95% CI, 0.10 - 0.53; P < 0.001) in patients with tumors having BRCA alterations, and by 34% (HR 0.66; 95% CI, 0.39 - 1.12; P = 0.12) in those with non-BRCA homologous recombination repair gene alterations. Among patients without BRCA alterations or with unknown status, the risk was reduced by 31% (HR 0.69; 95% CI, 0.55 - 0.86; P = 0.001).

[0284] In addition, within the overall participant cohort, for DDR-deficient patients according to IWRS, the stratified hazard ratio of rPFS (talazoparib + enzalutamide vs placebo + enzalutamide) as assessed by BICR was 0.457 (95% CI; [0.297, 0.702]; one-sided P value: 0.0001), favoring talazoparib + enzalutamide. The median rPFS for the talazoparib + enzalutamide group was 27.9 (95% CI: [16.6, NE]) months, compared with a median rPFS of 16.4 months (95% CI: [10.9, 24.6]) for the placebo + enzalutamide group. Based on data as of March 28, 2023, within the overall participant cohort, for DDR-deficient patients according to IWRS, the stratified hazard ratio of OS was 0.569 (95% CI; [0.355, 0.912]; one-sided P value: 0.0088), favoring talazoparib + enzalutamide. The median OS for the talazoparib + enzalutamide group was 41.9 months (95% CI: [36.4, NE]), compared with a median OS of 31.1 months (95% CI: [26.1, NE]) for the placebo + enzalutamide group.

[0285] For DDR-non-defective / unknown patients according to IWRS, the stratified hazard ratio of rPFS evaluated by BICR (talazoparib + enzalutamide vs. placebo + enzalutamide) was 0.697 (95% CI: [0.544, 0.892]; P = 0.004), favoring talazoparib + enzalutamide. The median rPFS in the talazoparib + enzalutamide group was NE (95% CI: [27.5, NE]), compared with a median rPFS of 22.5 months (95% CI: [19.1, 30.5]) months in the placebo + enzalutamide group. Based on data as of March 28, 2023, for DDR-non-defective / unknown patients according to IWRS, the observed stratified hazard ratio of OS was 0.930 (95% CI: [0.729, 1.188]; one-sided P value: 0.2808), favoring talazoparib + enzalutamide. The median OS in the talazoparib + enzalutamide group was NE (95% CI: [37.0, NE]), compared with a median OS of 38.7 months (95% CI: [35.0, NE]) in the placebo + enzalutamide group.

[0286] In addition, for BRCA-mutated patients within the overall participant cohort, the observed stratified hazard ratio of OS was 0.558 (95% CI [0.263, 1.187]; one-sided P value: 0.0622), favoring talazoparib + enzalutamide. The median OS in the talazoparib + enzalutamide group was 41.9 months (95% CI: [24.9, NE]), while the median OS in the placebo + enzalutamide group was 26.1 months (95% CI: [15.2, NE]).

[0287] For non-BRCA-mutated DDR-defective patients within the overall participant cohort, the observed stratified hazard ratio of OS was 0.594 (95% CI: [0.322, 1.094]; one-sided P value: 0.0454), favoring the talazoparib + enzalutamide group, compared with 38.2 months (95% CI: [29.0, NE]) in the placebo + enzalutamide group.

[0288] For non-BRCA-mutated patients within the overall participant cohort, the observed stratified hazard ratio of OS was 0.874 (95% CI: [0.696, 1.097]; one-sided P value: 0.1225), favoring talazoparib + enzalutamide. The median OS in the talazoparib + enzalutamide group was NE (95% CI: [37.3, NE]), while the median OS in the placebo + enzalutamide group was 38.7 months (95% CI: [35.0, 45.3]).

[0289] The results of the secondary endpoints according to the defective or non-defective / unknown homologous recombination repair gene change status are in Table 7. An overview of the selected subsequent systemic therapies for prostate cancer is shown in Table 8.

[0290] Table 7. Overview of secondary efficacy results according to homologous recombination repair status (all participants intention-to-treat population)*

[0291]

[0292]

[0293] * Based on investigator-assessed PFS2 (time from randomization to the date of progression after the first subsequent anti-tumor therapy was recorded or death from any cause, whichever occurred first).

[0294] Table 8. Overview of the selected subsequent anti-tumor systemic therapies for prostate cancer (all participants safety population)

[0295]

[0296]

[0297] Data are n (%) unless otherwise indicated.

[0298] * Includes lutetium (177Lu) vipivotide tetraxetan, lutetium (Lu 177), and lutetium-177.

[0299] ** Includes radium, radium 223, and radium dichloride (Ra 223).

[0300] In Table 9, in the predefined subgroups, a consistent treatment effect of talazoparib plus enzalutamide was found. The HR for all patients was based on a Cox model stratified according to the randomization stratification factors. For all subgroups, the HR was based on an unstratified Cox model with treatment as the only covariate.

[0301] Table 9. Subgroup analysis of ibPFS by BICR

[0302]

[0303]

[0304]

[0305] * a Two patients who had previously received autotaxol were included in each treatment group.

[0306] As shown in Table 9, all enrolled patients (N = 805) had prospective tumor tissue HRR test results. Overall, baseline characteristics were relatively balanced between treatment groups and by HRR status; however, in the younger group (age < 65 years), there were more HRR+ (29.6%) patients than HRR− / unknown (19.3%) patients, and HRR+ patients had evidence of more aggressive disease. Treatment with talazoparib plus enzalutamide improved ORR and prolonged time to PSA progression, time to initiation of cytotoxic chemotherapy, and PFS2 compared to placebo plus enzalutamide, and benefits were seen in both HRR+ and HRR− / unknown subgroups.

[0307] The following Tables 10 and 11 show OS forest plot data by baseline characteristics and by DDR subgroup based on the following definitions: prospective tumor tissue and prospective ctDNA samples; prospective samples plus retrospective ctDNA samples; tumor tissue samples only; and retrospective ctDNA samples only.

[0308] Table 10. OS analysis of baseline subgroups

[0309]

[0310]

[0311] Table 11. OS analysis of DDR subgroups

[0312]

[0313] Safety:

[0314] A comprehensive safety analysis is ongoing. To date, the safety profile of the combination of talazoparib and enzalutamide for mCRPC is generally consistent with the known safety profiles of the individual drugs.

[0315] The safety population consisted of 799 patients treated with at least one dose of the study treatment agent; 398 patients were treated with talazoparib + enzalutamide and 401 patients were treated with placebo + enzalutamide.

[0316] In the talazoparib + enzalutamide group, the median treatment duration of talazoparib was 19.8 months and of enzalutamide was 22.2 months, and in placebo + enzalutamide, the median treatment duration of placebo was 16.1 months and of enzalutamide was 16.6 months. In the talazoparib + enzalutamide group, the median relative dose intensity of talazoparib was 83.5% and of enzalutamide was 100%.

[0317] The median treatment duration for talazoparib was 86 weeks and for placebo was 70 weeks. For the talazoparib + enzalutamide group, the median enzalutamide treatment duration was 97 weeks, and for the placebo + enzalutamide group, the median enzalutamide treatment duration was 72 weeks. See Table 12 below.

[0318] Table 12. Drug Exposure (Safety Population)

[0319]

[0320] The number of patients with treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) is summarized in Table 13. Treatment-emergent was defined as the time between the first dose of study treatment and 28 days after the last dose of the last study treatment or prior to any new anti-tumor therapy, whichever occurred first.

[0321] Table 13. Summary of Adverse Events (All Participant Safety Population)

[0322]

[0323] * Not considered treatment-related.

[0324] ** Two cases were considered treatment-related.

[0325] The most common treatment-emergent AEs of any grade (G) and causality experienced by ≥ 10% of patients in any group are summarized in Table 14 below and are presented in descending order of incidence of events in the talazoparib + enzalutamide group.

[0326] Table 14. TEAEs in ≥ 10% of Patients - All Causality (Safety Population)

[0327]

[0328] The most common SAEs observed in the study were anemia, which occurred in 55 (13.8%) patients in the talazoparib + enzalutamide group and 1 (0.2%) patient in the placebo + enzalutamide group; hematuria, which occurred in 10 (2.5%) patients in the talazoparib + enzalutamide group and 4 (1.0%) patients in the placebo + enzalutamide group; and urinary tract infection, which occurred in 9 (2.3%) patients in the talazoparib + enzalutamide group and 3 (0.7%) patients in the placebo + enzalutamide group. See Table 15 below.

[0329] Table 15. SAEs in ≥ 2% of Patients - All Causality (Safety Population)

[0330] Preferred items Talazoparib + enzalutamide (N = 398) Placebo + enzalutamide (N = 401) Anemia 55(13.8％) 1(0.2％) Hematuria 10(2.5％) 4(1.0％) Urinary tract infection 9(2.3％) 3(0.7％)

[0331] Accordingly, in the talazoparib + enzalutamide group, 14 (3.5%) deaths occurred within 28 days after the last dose of study treatment, and in the placebo + enzalutamide group, 20 (5.0%) deaths occurred within 28 days after the last dose.

[0332] The most common treatment-emergent adverse events of all causalities in the talazoparib + enzalutamide and placebo + enzalutamide groups are shown in Table 16.

[0333] Table 16. Most common treatment-emergent adverse events of all causalities

[0334]

[0335] The most common adverse events of all causalities (≥30% of patients) in the talazoparib + enzalutamide group were anemia, neutropenia, and fatigue.

[0336] The most common non-hematological TEAEs were fatigue (33.7%; 4.0% G3), back pain (22.1%; 2.5% G3), and decreased appetite (21.6%; 1.3% G3).

[0337] The three most common hematological treatment-emergent adverse events of all causalities and related dose modifications were anemia, neutropenia, and thrombocytopenia. Details are provided in Table 17 below.

[0338] Table 17. Most common hematological adverse events of all causalities in the talazoparib + enzalutamide group

[0339]

[0340] a Cluster terms for anemia, neutropenia, and thrombocytopenia.

[0341] In the talazoparib + enzalutamide group, the most common grade 3 to 4 adverse events (≥10% of patients) were anemia (46.5%) and neutropenia (18.3%).

[0342] To ensure optimal dosing of talazoparib at the individual patient level, the protocol did not require dose modification of talazoparib until anemia was grade (G) ≥3. The median time to onset of the first G≥3 anemia was 3.3 months. After grade 3 to 4 anemia, the protocol required maintaining the dose and then reducing the dose of talazoparib. At baseline, 49.0% of patients had G1-2 anemia. According to the protocol, 43.2% of patients had anemia leading to dose reduction (with or without transfusion); 20.6% of patients had recurrent G3-4 anemia, and 8.3% of patients discontinued talazoparib due to anemia.

[0343] Compared with the placebo + enzalutamide group, there were more dose interruptions and reductions due to adverse events in the talazoparib + enzalutamide group (Table 13). Compared with 94 (23.4%) patients who discontinued placebo, 300 (75.4%) patients discontinued talazoparib due to adverse events. The dose of talazoparib was reduced due to adverse events in 223 (56.0%) patients, and the dose of placebo was reduced due to adverse events in 29 (7.2%) patients. The most common adverse events leading to dose reduction of talazoparib were anemia (179 [45.0%] patients), neutropenia (62 [15.6%]), thrombocytopenia (23 [5.8%]), and leukopenia (9 [2.3%]). The three most common adverse events leading to dose reduction of talazoparib were anemia (43.2%), neutropenia (15.1%), and thrombocytopenia (5.5%). 76 (19.1%) patients interrupted talazoparib, and 49 (12.2%) patients interrupted placebo due to adverse events. The most common adverse events leading to interruption of talazoparib were anemia (33 [8.3%]) and neutropenia (13 [3.3%]). The interruption rate of enzalutamide due to adverse events was 10.8% (talazoparib + enzalutamide group) compared with 11.0% (placebo + enzalutamide group).

[0344] Table 18. Overview of dose modifications due to adverse events (all participants safety population)

[0345]

[0346] 1 Including dose interruptions of talazoparib / placebo only plus interruptions of both talazoparib / placebo and enzalutamide

[0347] 2 Including dose interruptions of enzalutamide only plus interruptions of both talazoparib / placebo and enzalutamide

[0348] 3 Including dose reductions of talazoparib / placebo only plus reductions of both talazoparib / placebo and enzalutamide

[0349] 4 Including dose reductions of enzalutamide only plus dose reductions of both talazoparib / placebo and enzalutamide

[0350] 5 Including permanent interruptions of talazoparib / placebo only plus interruptions of both talazoparib / placebo and enzalutamide

[0351] 6 Including permanent discontinuation of enzalutamide only, discontinuation of both talazoparib / placebo and enzalutamide

[0352] Table 19. Overview of dose modifications and interruptions of talazoparib due to anemia, neutropenia, and thrombocytopenia (safety population)

[0353]

[0354] In the talazoparib + enzalutamide group, there was one case of myelodysplastic syndrome during the safety reporting period and one case of acute myeloid leukemia during the follow-up period (none in the placebo + enzalutamide group). Sixteen (4.0%) patients in the talazoparib + enzalutamide group reported venous thromboembolism and thrombotic events, including 10 (2.5%) patients with pulmonary embolism (9 patients ≥ grade 3), and 3 (0.7%) patients in the placebo + enzalutamide group reported venous thromboembolism and thrombotic events, all of which were ≥ grade 3 pulmonary embolism.

[0355] The safety profile of talazoparib plus enzalutamide was consistent with the individual profiles, and TEAE were generally managed by dose modification and supportive measures. Talazoparib 0.5 mg QD plus enzalutamide 160 mg QD could generally be managed by dose modification of talazoparib and / or standard supportive care. Anemia was the most common TEAE and led to discontinuation of talazoparib in 8.3% of patients. Table 20 shows an overview of supportive care measures for the treatment of anemia. G ≥ 3 hematological AEs typically occurred within 6 months of starting therapy and were transient, and the decrease in hemoglobin level was most obvious in the early stage of treatment, followed by a rebound in hemoglobin level.

[0356] Table 20. Overview of supportive care measures for the treatment of anemia (safety population)

[0357] Supportive care Talazoparib + enzalutamide (N = 398) Patients receiving at least 1 hematological supportive therapy 53(13.1) Erythropoiesis-stimulating agents* 33(8.3) Granulocyte-stimulating factors** 30(7.5) Platelet-stimulating factors*** 6(1.5)

[0358] All values are presented as n (%). The following medications were considered hematological supportive treatments and are included in the table:

[0359] * Epoetin alfa, darbepoetin alfa, epoetin theta, erythropoietin, human erythropoietin, epoetin zeta.

[0360] ** Filgrastim, lenograstim, lipegfilgrastim, granulocyte colony-stimulating factor, pegylated granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, filgrastim-sndz

[0361] *** Oprelvekin.

[0362] Patient-reported outcomes

[0363] Compared with the placebo + enzalutamide group (25 months [95% CI, 22.9 - 30.4], based on 146 events; HR 0.78 [95% CI, 0.62 - 0.99]; P = 0.04), the median time to a confirmed clinically meaningful deterioration in overall health status / quality of life ( GHS / QoL ) in the talazoparib + enzalutamide group, based on 138 events, was significantly longer (30.8 months [95% CI, 27 - 39.6]). As assessed by the European Organisation for Research and Treatment of Cancer cancer-specific global health status questionnaire (EORTC QLQ-C30), a confirmed clinically meaningful deterioration was defined as a decrease of ≥10 points from baseline and subsequent absence of observations of a decrease of <10 points from baseline. The combination of talazoparib and enzalutamide significantly prolonged the time to a confirmed clinically meaningful deterioration in GHS / QoL.

[0364] The overall estimated mean change in overall health status / quality of life was significantly better than that of placebo plus enzalutamide (-2.5; 95% CI, -4.6 - -0.5; P = 0.014).

[0365] Conclusion

[0366] The overall participant cohort met its primary endpoint. The combination of talazoparib and enzalutamide demonstrated clinical benefit in metastatic mCRPC. In mCRPC patients not selected for DDR status, the combination of talazoparib and enzalutamide statistically significantly prolonged rPFS when compared with the combination of placebo and enzalutamide. Robust, highly consistent efficacy was demonstrated in men with and without homologous recombination repair gene mutations. In the overall participant population and pre-specified subgroups, talazoparib plus enzalutamide led to clinically meaningful and statistically significant benefits compared with enzalutamide plus placebo. Benefits were consistently observed in secondary endpoints. In patients with measurable disease receiving talazoparib plus enzalutamide, the complete response rate was twice that of placebo plus enzalutamide. The results of the initial analysis of the overall participant population in the TALAPRO-2 trial support the use of talazoparib plus enzalutamide as first-line treatment in patients with metastatic castration-resistant prostate cancer not selected for homologous recombination repair gene alterations.

[0367] For patients with metastatic castration-resistant prostate cancer not selected molecularly, first-line talazoparib plus enzalutamide significantly reduced the risk of disease progression or death by 37% compared to placebo plus enzalutamide.

[0368] All publications and patent applications cited in this specification are hereby incorporated by reference in their entirety. Although the foregoing invention has been described in considerable detail by way of illustration and example, it will be apparent to those of ordinary skill in the art that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Claims

1. A method of treating metastatic castration-resistant prostate cancer in a subject in need thereof, the method comprising: 1) Administering talazoparib or a pharmaceutically acceptable salt thereof orally to the subject once daily; and 2) Administering enzalutamide or a pharmaceutically acceptable salt thereof orally to the subject once daily, wherein administering the talazoparib or a pharmaceutically acceptable salt thereof and administering the enzalutamide or a pharmaceutically acceptable salt thereof prolong the survival of the subject.

2. The method according to claim 1, wherein the metastatic castration-resistant prostate cancer is metastatic castration-resistant prostate cancer with or without a homologous recombination repair (HRR) gene mutation.

3. The method according to claim 1 or claim 2, wherein the subject has not received: 1) systemic cancer treatment for non-metastatic castration-resistant prostate cancer or metastatic castration-resistant prostate cancer; 2) treatment of prostate cancer with an androgen receptor signaling inhibitor, a PARP inhibitor, cyclophosphamide or mitoxantrone; or 3) treatment with platinum-based chemotherapy within 6 months or any history of disease progression after receiving platinum-based therapy within 6 months.

4. The method according to any one of claims 1 to 3, wherein the subject additionally receives a gonadotropin-releasing hormone analogue or has received bilateral orchiectomy.

5. The method according to claim 4, wherein the gonadotropin-releasing hormone analogue is a gonadotropin-releasing hormone agonist or a gonadotropin-releasing hormone antagonist.

6. The method according to any one of claims 1 to 5, wherein the subject is not selected based on the DNA damage response (DDR) mutation status.

7. The method according to any one of claims 1 to 6, wherein the survival is radiographic progression-free survival.

8. The method according to claim 7, wherein the radiographic progression-free survival is prolonged compared to a subject who has received enzalutamide or a pharmaceutically acceptable salt thereof and a placebo.

9. The method according to any one of claims 1 to 6, wherein the survival is overall survival.

10. The method according to claim 9, wherein the overall survival is prolonged compared to a subject who has received enzalutamide or a pharmaceutically acceptable salt thereof and a placebo.

11. The method according to any one of claims 1 to 6, wherein the risk of disease progression or death during survival is significantly reduced compared to a subject who has received enzalutamide or a pharmaceutically acceptable salt thereof and a placebo.

12. The method according to claim 11, wherein the risk of disease progression or death is significantly reduced by at least 37% compared to a subject who has received enzalutamide or a pharmaceutically acceptable salt thereof and a placebo.

13. The method according to any one of claims 1 to 12, wherein the talazoparib or a pharmaceutically acceptable salt thereof is administered at a dose equivalent to about 0.1 mg, about 0.25 mg, about 0.35 mg or about 0.5 mg of talazoparib free base once daily.

14. The method according to claim 13, wherein the talazoparib or a pharmaceutically acceptable salt thereof is administered at a dose equivalent to about 0.35 mg of talazoparib free base once daily, and further wherein the subject has moderate renal impairment.

15. The method according to any one of claims 1 to 14, wherein the talazoparib or a pharmaceutically acceptable salt thereof is talazoparib tosylate.

16. The method according to any one of claims 1 to 15, wherein the enzalutamide or a pharmaceutically acceptable salt thereof is administered at a dose equivalent to about 160 mg of enzalutamide free base once daily.

17. The method according to claim 16, wherein if the enzalutamide or a pharmaceutically acceptable salt thereof is co-administered with a potent CYP2C8 inhibitor, the dose of the enzalutamide or a pharmaceutically acceptable salt thereof is reduced.

18. The method according to claim 17, wherein the dose of the enzalutamide or a pharmaceutically acceptable salt thereof is reduced to 80 mg once daily.

19. The method according to claim 16, wherein if the enzalutamide is co-administered with a CYP3A4 inducer, the dose of the enzalutamide or a pharmaceutically acceptable salt thereof is increased.

20. The method according to claim 19, wherein the dose of the enzalutamide or a pharmaceutically acceptable salt thereof is increased to 240 mg daily.

21. The method according to any one of claims 1 to 20, wherein the enzalutamide or a pharmaceutically acceptable salt thereof is the free base.

22. The method according to any one of the preceding claims, wherein the subject is a human.

23. The method according to claim 22, wherein the human is an adult.

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