Combination of talazoparib and enzalutamide in the treatment of metastatic castration-resistant prostate cancer

Abstract

This invention relates to talazoparib, or a pharmaceutically acceptable salt thereof, in combination with enzalutamide, or a pharmaceutically acceptable salt thereof, for the treatment of metastatic castration-resistant prostate cancer and methods of increasing overall survival thereof.

Description

[0001] PC073192A

[0002] - 1 -

[0003] COMBINATION OF TALAZOPARIB AND ENZALUTAMIDE IN THE TREATMENT OF METASTATIC CASTRATION-RESISTANT PROSTATE CANCER

[0004] Background

[0005] 5 Prostate cancer is the fifth most common cause of cancer-related death among men worldwide, with metastatic castration-resistant prostate cancer (mCRPC) being the most lethal form of the disease. The androgen receptor (AR) signaling axis, the principal driver of prostate cancer growth, has been targeted by castration and other systemic therapies. Initial treatment for advanced prostate cancer may involve reducing the amount of androgens produced by the body, primarily in the testes. This may be achieved surgically by removal of both testicles (bilateral orchiectomy) or through use of androgen deprivation therapies such as luteinizing hormone-releasing hormone (LHRH) agonist or antagonist drugs, which lower the native production of testosterone (sometimes called “chemical castration”). However, a proportion of tumors progress

[0006] 15 despite castrate levels of testosterone, at which point the disease is considered castration-resistant. Castration-resistant prostate cancer represents a lethal transition in the progression of prostate cancer, with most patients ultimately succumbing to the disease. In real-world practice, median overall survival of men with newly diagnosed mCRPC is <3 years, and nearly half of patients receive only one systemic treatment

[0007] 20 (Freedland SJ, et al. Real-world treatment patterns and overall survival among men with Metastatic Castration- Resistant Prostate Cancer (mCRPC) in the US Medicare population. Prostate Cancer Prostatic Dis 2024; 27: 327-33; George DJ, et al. Treatment patterns and outcomes in patients with metastatic castration-resistant prostate cancer in a real-world clinical practice setting in the United States. Clin Genitourin Cancer 2020; 18: 284-94; and Chowdhury S, Bjartell A, Lumen N, et al. Real-World Outcomes in First-Line Treatment of Metastatic Castration-Resistant Prostate Cancer: The Prostate Cancer Registry. Target Oncol 2020; 15: 301-15.

[0008] Anti-androgens are thought to suppress androgen activity by a number of different mechanisms. One example of an anti-androgen approved for the treatment of

[0009] 30 castration-resistant prostate cancer is abiraterone acetate (marketed as Zytiga™), a steroidal CY17A1 inhibitor. One specific class of anti-androgens are androgen receptor inhibitors, also known as androgen receptor signaling inhibitors or androgen receptor antagonists, which are thought to compete with endogenous ligands, androgens, for the androgen receptor. When an antagonist binds to an androgen receptor it is thought to induce a conformational change in the receptor itself that impedes transcription of key androgen regulated genes and therefore inhibits the biological effects of the androgens themselves, such as testosterone and dihydrotestosterone.

[0010] The compound, enzalutamide, which 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- sulfanylideneimidazolidin-1-yl}-2-fluoro- / \ / -methylbenzamide or also referred to as “RD162”’ and “MDV3100”) is a non-steroidal androgen receptor inhibitor, having the structure:

[0011] Enzalutamide, or a pharmaceutically acceptable salt thereof, is disclosed in PCT / US2006 / 011417, which published on 23rdNovember 2006 as WO 2006 / 124118, the contents of which are included herein by reference.

[0012] Enzalutamide (marketed as Xtandi®) is approved for the treatment of metastatic castration-resistant prostate cancer (“mCRPC”). However, for some subjects, their cancer will relapse or the subjects may develop therapeutic resistance. The mechanisms that underlie such resistance are, to date, not yet fully understood.

[0013] Poly (ADP-ribose) polymerase (PARP) engages in the naturally occurring process of deoxyribonucleic acid (DNA) repair in a cell. PARP inhibition has been shown to be an effective therapeutic strategy against tumors associated with mutations in double-strand DNA repair genes by inducing synthetic lethality (Sonnenblick, A., et al., Nat. Rev. Clin. Oncol, 2015, 12(1), 27-4). PARP inhibition is synthetically lethal in cells with homozygous deletions or deleterious alterations, or both, in DNA damage response (DDR) genes involved either directly or indirectly in homologous recombination repair (HRR) (Lord, CJ, et al., Science, 2017; 355: 1152-1158). Talazoparib is a potent, orally available PARP inhibitor, which is cytotoxic to human cancer cell lines harboring gene mutations that compromise deoxyribonucleic acid (DNA) repair, an effect referred to as synthetic lethality, and by trapping PARP protein on DNA thereby preventing DNA repair, replication, and transcription.

[0014] The compound, talazoparib, which is (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1- methyl-1 / 7-1 ,2,4-triazol-5-yl)-8,9-dihydro-2 / 7-pyrido[4,3,2-de]phthalazin-3(7 / - / )-one and (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1 / 7-1 ,2,4-triazol-5-yl)-2,7,8,9-tetrahydro- 3 / 7-pyrido[4,3,2-de]phthalazin-3-one (also referred to as “PF-06944076”, “MDV3800”, and “BMN673”) is a PARP inhibitor, having the structure:

[0015] Talazoparib

[0016] Talazoparib, and pharmaceutically acceptable salts thereof, including the tosylate salt, are disclosed in International Publication Nos. WO 2010 / 017055 and WO 2012 / 054698. Additional methods of preparing talazoparib, and pharmaceutically acceptable salts thereof, including the tosylate salt, are described in International Publication Nos. WO 2011 / 097602, WO 2015 / 069851 , and WO 2016 / 019125. Additional methods of treating cancer using talazoparib, and pharmaceutically acceptable salts thereof, including the tosylate salt, are disclosed in International Publication Nos. WO 2011 / 097334 and WO 2017 / 075091. Combination treatments using talazoparib, and pharmaceutically acceptable salts thereof, including the tosylate salt, are disclosed in International Publication Nos. WO2019 / 075032 and WO 2022 / 200982.

[0017] TALZENNA® (talazoparib) has been approved in several countries, including the United States, and in the European Union, and is approved or under review with anticipated approvals in other countries for the treatment of adult patients with deleterious or suspected deleterious gBRCAm HER2-negative locally advanced or metastatic breast cancer. Talazoparib has shown activity in metastatic castrationresistant prostate cancers with DDR alterations either directly or indirectly associated with HRR (de Bono et al., Lancet Oncol. 2021 Sep;22(9): 1250- 1264). Talazoparib in combination with enzalutamide has been approved in the United States for the treatment of adult patients with HRR gene-mutated mCRPC and in the European Union for the treatment of adult patients with mCRPC, with or without changes in specific HRR genes, who cannot receive chemotherapy. Talazoparib is under development for a variety of human cancers both as a single agent and in combination with other agents.

[0018] There remains a need for improved therapies for the treatment of cancers, particularly for the treatment of metastatic castration-resistant prostate cancer, the most advanced and aggressive stage of the disease. The combinations of the present invention are believed to have one or more advantages, such as an increase in overall survival, as compared to treatment of either therapeutic agent alone; increase in overall survival, as compared to a patient who has received enzalutamide, or a pharmaceutically acceptable salt thereof, and placebo; greater efficacy as compared to treatment with either therapeutic agent alone; potential to enable an improved dosing schedule; potential to overcome resistance mechanisms, and the like.

[0019] Summary

[0020] The present invention provides, in part, methods for administering talazoparib, or a pharmaceutically acceptable salt thereof, and enzalutamide, or a pharmaceutically acceptable salt thereof, in combination therapies, for increasing or prolonging overall survival in a subject having 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 in isolation as an aid in determining the scope of the claimed subject matter.

[0021] According to Embodiment 1 of the invention, there is provided a method of treating metastatic castration-resistant prostate cancer in a subject in need thereof, 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 the administration of the talazoparib, or a pharmaceutically acceptable salt thereof, and the administration of the enzalutamide, or a pharmaceutically acceptable salt thereof, prolongs overall survival in the subject, as compared to a standard of care therapy.

[0022] According to Embodiment 2 of the invention, there is provided a method of treating metastatic castration-resistant prostate cancer in a subject in need thereof, 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 the administration of the talazoparib, or a pharmaceutically acceptable salt thereof, and the administration of the enzalutamide, or a pharmaceutically acceptable salt thereof, prolongs overall survival in the subject, wherein the overall survival is a median of 45.8 months, as compared to a median of 37.0 months for a subject who has received enzalutamide, or a pharmaceutically acceptable salt thereof, and placebo.

[0023] Described below are embodiments of the invention, where for convenience Embodiment 1 and Embodiment 2 (E1 and E2) are identical to the embodiments provided above.

[0024] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

[0025] Detailed Description of the Invention

[0026] The present invention may be understood more readily by reference to the following detailed description of the embodiments of the invention and the Examples included herein. It is to be also understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting.

[0027] E1 A method of treating metastatic castration-resistant prostate cancer in a subject in need thereof, wherein the treatment prolongs overall survival in the subject, as compared to a standard of care therapy. E2 A method of treating metastatic castration-resistant prostate cancer in a subject in need thereof, wherein the treatment prolongs overall survival in the subject, as defined above.

[0028] E3 The method of embodiment 1, wherein the standard of care is: 1) abiraterone acetate and prednisone; 2) enzalutamide or a pharmaceutically acceptable salt thereof; or 3) docetaxel.

[0029] E4 A method of embodiment 2, wherein the median overall survival for the subject who has received the talazoparib, or a pharmaceutically acceptable salt thereof, and the enzalutamide, or a pharmaceutically acceptable salt thereof, is 45.8 months (95% confidence interval: [39.4 months, 50.8 months]), as compared to a median of 37.0 months (95% confidence interval: [34.1 months, 40.4 months]) for the subject who has received the enzalutamide, or a pharmaceutically acceptable salt thereof, and the placebo.

[0030] E5 A method of any one of embodiments 1 to 4, wherein the metastatic castrationresistant prostate cancer is metastatic castration-resistant prostate cancer with or without homologous recombination repair (HRR) gene mutations.

[0031] E6 A method of any one of embodiments 1 to 5, wherein the talazoparib, or pharmaceutically acceptable salt thereof, and the enzalutamide, or a pharmaceutically acceptable salt thereof, are administered concurrently.

[0032] E7 A method of 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 with an androgen receptor signaling inhibitor, a PARP inhibitor, cyclophosphamide, or mitoxantrone for prostate cancer; or 3) treatment with platinum-based chemotherapy within 6 months or any history of disease progression on platinum-based therapy within 6 months. E8 A method of embodiment 7, wherein the subject has not received systemic cancer treatment for non-metastatic castration-resistant prostate cancer or metastatic castration-resistant prostate cancer.

[0033] E9 A method of embodiment 7, wherein the subject has not been treated with an androgen receptor signalling inhibitor, a PARP inhibitor, cyclophosphamide, or mitoxantrone for prostate cancer.

[0034] E10 A method of embodiment 7, wherein the subject has not been treated with an androgen receptor signaling inhibitor.

[0035] E11 A method of any one of embodiments 7, 9 or 10, wherein the androgen receptor signaling inhibitor is a second-generation androgen receptor inhibitor.

[0036] E12 A method of embodiment 11, wherein the second-generation androgen receptor inhibitor is enzalutamide, apalutamide, darolutamide, or aberatirone acetate.

[0037] E13 A method of embodiment 12, wherein the second-generation androgen receptor inhibitor is enzalutamide, apalutamide, or darolutamide.

[0038] E14 A method of embodiment 7, wherein the subject has not received treatment with platinum-based chemotherapy within 6 months or any history of disease progression on platinum-based therapy within 6 months.

[0039] E15 A method of any one of embodiments 1 to 14, wherein the subject is receiving a gonadotropin releasing hormone analog concurrently or has had a bilateral orchiectomy.

[0040] E16 A method of embodiment 15, wherein the subject is additionally receiving a gonadotropin releasing hormone analog.

[0041] E17 A method of embodiment 15 or 16, wherein the gonadotropin releasing hormone analog is a gonadotropin releasing hormone agonist. E18 A method of embodiment 15 or 16, wherein the gonadotropin releasing hormone analog is a gonadotropin releasing hormone antagonist.

[0042] E19 A method of embodiment 15, wherein the subject has had a bilateral orchiectomy.

[0043] E20 A method of any one of embodiments 1 to 19, wherein the subject has progressive disease as defined by 1 or more of the following: 1) prostate specific antigen progression defined by a minimum of 2 rising prostate specific antigen values from 3 consecutive assessments with an interval of at least 7 days between assessments; 2) soft tissue disease progression as defined by RECIST 1.1.; and 3) bone disease progression defined by Prostate Cancer Clinical Trials Working Group 3 with 2 or more new metastatic bone lesions on a whole body radionuclide bone scan.

[0044] E21 A method of any one of embodiments 1 to 20, wherein the subject has an Eastern Cooperative Oncology Group (ECOG) performance status < 1.

[0045] E22 A method of any one of embodiments 1 to 21 , wherein the subject is unselected for DNA damage response (DDR) mutation status.

[0046] E23 A method of any one of embodiments 1 to 22, wherein the talazoparib, or pharmaceutically acceptable salt thereof, is administered at a dosage equivalent to about 0.1 mg, about 0.25 mg, about 0.35 mg or about 0.5 mg once daily of talazoparib free base.

[0047] E24 A method of embodiment 23, wherein the talazoparib, or pharmaceutically acceptable salt thereof, is administered at a dosage equivalent to about 0.1 mg once daily of talazoparib free base. E25 A method of embodiment 23, wherein the talazoparib, or pharmaceutically acceptable salt thereof, is administered at a dosage equivalent to about 0.25 mg once daily of talazoparib free base.

[0048] E26 A method of embodiment 23, wherein the talazoparib, or pharmaceutically acceptable salt thereof, is administered at a dosage equivalent to about 0.35 mg once daily of talazoparib free base.

[0049] E27 A method of embodiment 26, wherein the subject has moderate renal impairment.

[0050] E28 A method of embodiment 23, wherein the talazoparib, or pharmaceutically acceptable salt thereof, is administered at a dosage equivalent to about 0.5 mg once daily of talazoparib free base.

[0051] E29 A method of any one of embodiments 1 to 28, wherein the talazoparib, or pharmaceutically acceptable salt thereof, is talazoparib tosylate.

[0052] E30 A method of any one of embodiments 1 to 29, wherein the enzalutamide, or pharmaceutically acceptable salt thereof, is administered at a dosage equivalent to about 160 mg once daily of enzalutamide free base.

[0053] E31 A method of embodiment 30, wherein the dosage of enzalutamide, or a pharmaceutically acceptable salt thereof, is reduced, if enzalutamide, or a pharmaceutically acceptable salt thereof, is dosed concomitantly with a strong CYP2C8 inhibitor.

[0054] E32 A method of embodiment 30, wherein the dose of enzalutamide, or a pharmaceutically acceptable salt thereof, is reduced to 80 mg once daily.

[0055] E33 A method of embodiment 30, wherein the dose of enzalutamide, or a pharmaceutically acceptable salt thereof, is increased if the enzalutamide is dosed concomitantly with a CYP3A4 inducer. E34 A method of embodiment 30, wherein the dose of enzalutamide, or a pharmaceutically acceptable salt thereof, is increased to 240 mg daily.

[0056] E35 A method of any one of embodiments 1 to 34, wherein the enzalutamide, or a pharmaceutically acceptable salt thereof, is a free base.

[0057] E36 A method of any one of embodiments 1 to 35, wherein the method comprises administering a further anti-cancer agent.

[0058] E37 A method of embodiment 36, wherein the further anti-cancer agent is selected from the group consisting of an anti-tumor agent, an anti-angiogenesis agent, a signal transduction inhibitor, and an antiproliferative agent.

[0059] E38 A method of any of the proceeding embodiments, wherein the subject is a human.

[0060] E39 A method of embodiment 38, wherein the human is an adult.

[0061] Each of the embodiments described herein may be combined with any other embodiment(s) described herein not inconsistent with the embodiment(s) with which it is combined.

[0062] Definitions

[0063] Unless otherwise defined herein, scientific and technical terms used in connection with the present invention have the meanings that are commonly understood by those of ordinary skill in the art.

[0064] The invention described herein suitably may be practiced in the absence of any element(s) not specifically disclosed herein.

[0065] As used herein, the singular form "a", "an", and "the" include plural references unless indicated otherwise. For example, "a" substituent includes one or more substituents. As used herein, the term “about” when used to modify a numerically defined parameter (e.g., the dose of a talazoparib, or a pharmaceutically acceptable salt thereof) means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter. For example, a dose of about 5 mg means 5 mg ± 10%, i.e. , it may vary between 4.5 mg and 5.5 mg.

[0066] As used herein, terms, including, but not limited to, “agent”, “composition, “compound”, “drug”, “medicine” and “therapeutic agent” may be used interchangeably to refer to compounds included in the methods and uses of the present invention, such as an anti-androgen, androgen receptor signaling inhibitors, androgen deprivation therapy, talazoparib, and enzalutamide.

[0067] For purposes of the present invention, “DDR mutation(s)”, “DDR alteration(s)”, ‘”HRR mutation(s)”, “HRR alteration(s)”, and “HRR gene alteration(s)” refer to alterations / mutations in genes involved directly or indirectly in homologous recombination repair (HRR). Though not as scientifically robust as the phrase “DNA damage response”, is commonly understood that “DDR” may also be referred to as “DNA damage repair” or “DNA repair”. “DDR-deficient” , “HRR-deficient” and “HRR gene-mutated” refer to gene mutations associated with deficiencies in deoxyriboneclueic acid (DNA) damage repair. A “DDR-deficient patient population”, an “HRR-deficient patient population” or an “HRR gene-mutated patient population” is a patient population with gene mutations associated with deficiencies in deoxyriboneclueic acid (DNA) damage repair. DDR is a network of pathways which have evolved to repair damaged DNA. These include mismatch repair, base excision repair, and homologous recombination repair (HRR) among others. HRR is particularly important in maintaining genomic integrity given its high fidelity in repairing doublestrand DNA breaks. Inhibition of PARP results in accumulation of single-strand DNA breaks and in DNA stress due to PARP trapping, which ultimately culminates in doublestrand DNA breaks. Hence, PARP inhibitors are selectively lethal to cancer cells deficient in HRR - this is an example of synthetic lethality, a mechanism whereby deficiency in function of one gene or gene product has little effect alone but is toxic in combination with deficiency in function 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. A deficiency in homologous recombination repair may be determined using next generation sequencing (NGS). As used herein, “systemic therapy” for mCRPC are drugs or therapeutic agents used to manage mCRPC. The medicines or drugs are referred to as systemic therapies because they circulate throughout the body to attack cancer cells wherever they may be located in the body.

[0068] Anti-androgens

[0069] As used herein, the terms “anti-androgen” and “anti-androgens” refer to compounds which prevent androgens, for example testosterone and dihydrotestosterone (DHT) and the like, from mediating their biological effects in the body. Anti-androgens may act by one or more of the following hormonal mechanisms of action such as blocking and I or inhibiting and I or modulating the androgen receptor (AR); inhibiting androgen production; suppressing androgen production; degrading the AR, inhibiting nuclear translocation, inhibiting binding of the AR to nuclear DNA, and the like. Anti-androgens include, but are not limited to, steroidal androgen receptor inhibitors (for example, cyproterone acetate, spironolactone, megestrol acetate, chlormadinone acetate, oxendolone, and osaterone acetate), non-steroidal androgen receptor inhibitors (for example, enzalutamide, bicalutamide, nilutamide, flutamide, topilutamide, apalutamide and darolutamide), androgen synthesis inhibitors, androgen receptor degraders and the like. Anti-androgens include androgen receptor inhibitors, androgen receptor signaling inhibitors, and androgen receptor pathway inhibitors (ARPIs), terms which are used interchangeably. Androgen receptor inhibitors may be determined by methods known to those of skilled in the art, for example using in vitro assays and I or cellular ligand binding assays and I or gene expression assays such as those disclosed in Tran C., et al., Science, 2009, 324, 787-790. First generation androgen receptor signaling inhibitors include bicalutamide, nilutamide, or flutamide.

[0070] Second-generation androgen receptor signaling inhibitors include enzalutamide, apalutamide and darolutamide.

[0071] A further second-generation androgen receptor signaling inhibitor is abiraterone, or a pharmaceutically acceptable salt or solvate thereof, such as abiraterone acetate (marketed as Zytiga™), a steroidal CY17A1 inhibitor which is disclosed in US Patent No. US 5,604,213 which published on 18thFebruary 1997, the contents of which are incorporated herein by reference. This second-generation AR inhibitor prevents androgen biosynthesis.

[0072] An example of an androgen receptor inhibitor is N-desmethyl enzalutamide: 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 MH; which is disclosed in PCT / US2010 / 025283, which published on 2ndSeptember 2010 as WO 2010 / 099238, the contents of which are included herein by reference.

[0073] An example of an androgen receptor inhibitor is apalutamide (marketed as ERLEADA®): or a pharmaceutically acceptable salt or solvate thereof, also known as ARN-509; or 4- {7-[6-cyano-5-(trifluoromethyl)pyridine-3-yl]-8-oxo-6-thioxo-5,7-diazaspiro[3,4]octan- 5yl}-2-fluoro-N-methylbenzamide; which is disclosed in PCT / US2007 / 007485, which published on 8thNovember 2007 as WO 2007 / 126765, the contents of which are included 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.

[0074] An example of an androgen receptor inhibitor is darolutamide (marketed as NUBEQA®): or a pharmaceutically acceptable salt or solvate thereof, also known as N-[(2S)-1-[3-(3- chloro-4-cyanophenyl)-1 H-pyrazol-1-yl]propan-2-yl]-5-(1-hydroxyethyl)-1 H-pyrazole-3- carboxamide which is disclosed in PCT / F 12010 / 000065, which published on 5thMay 2011 as WO 2011 / 051540, the contents of which are included herein by reference.

[0075] An example of an androgen receptor inhibitor is bicalutamide: or a pharmaceutically acceptable salt or solvate thereof, marketed as Casodex®, which is disclosed in US Patent No., US 4,636,505, published on 13thJanuary 1987, the contents of which are included herein by reference.

[0076] An example of an androgen receptor inhibitor is nilutamide (marketed as Nilandron®), or a pharmaceutically acceptable salt or solvate thereof.

[0077] An example of an androgen receptor inhibitor is flutamide (marketed as Eulexin®), or a pharmaceutically acceptable salt or solvate thereof.

[0078] Unless indicated otherwise, all references herein to the anti-androgens and androgen receptor inhibitors includes references to salts, solvates, hydrates and complexes thereof, and to solvates, hydrates and complexes of salts thereof, including polymorphs, stereoisomers, and isotopically labeled versions thereof.

[0079] Androgen Deprivation Therapy

[0080] Androgen deprivation therapy, also called ADT, uses surgery or medicines to lower the levels of androgens made by the testicles.

[0081] An example of surgical ADT is bilateral orchiectomy.

[0082] Examples of medicinal ADT include a luteinizing hormone-releasing hormone (LHRH) agonist, a LHRH antagonist, a gonadotropin releasing hormone (GnRH) agonist and a GnRH antagonist. Other examples of medicinal androgen deprivation therapy include leuprolide (also known as leuprorelin, for example Lupron or Eligardor Viadur and the like); buserelin (for example Suprefact); gonadorelin; goserelin (for example Zoladex); histrelin (for example Vantas); nafarelin; triptorelin (for example Trelstar); deslorelin; fertirelin; abarelix (for example Plenaxis); cetrorelix; degarelix (for example Firmagon); ganirelix; ozarelix; elagolix (for example Orilissa); relugolix; and linzagolix.

[0083] Salts

[0084] Salts encompassed within the term “pharmaceutically acceptable salts” refer to the compounds of this invention which are generally prepared by reacting the free base or free acid with a suitable organic or inorganic acid, or a suitable organic or inorganic base, respectively, to provide a salt of the compound of the invention that is suitable for administration to a subject or patient.

[0085] Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include, but are not limited to, acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, 1 ,5- naphathalenedisulfonic acid and xinofoate salts.

[0086] Suitable base salts are formed from bases which form non-toxic salts. Examples include, but are not limited to aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

[0087] Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts.

[0088] For a review on 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. Administration and Dosing

[0089] As used herein, the terms, “subject” and “patient,” are used interchangeably, to refer to any animal, including mammals. Mammals according to the invention include canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, humans and the like. In an embodiment, humans are suitable subjects. In an embodiment, a “subject” or “patient” is an adult human.

[0090] A “subject” or “patient” according to the combination of this invention may have imaging performed while receiving therapy to evaluate their response to treatment. Response criteria, specifically Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), are standardized and may be used at different time points to classify response into the categories, such as complete response (CR), partial response (PR), stable disease (SD), or disease progression. At the trial level, categorical responses for all patients are summated into image-based trial endpoints.

[0091] A “subject” or “patient” according to the combination of this invention may have: 1) histologically or cytologically confirmed adenocarcinoma of the prostate without small cell or signet cell features; 2) asymptomatic or mildly symptomatic metastatic castrationresistant prostate cancer; 3) DNA damage repair (DDR) deficiency as assessed centrally by a next-generation sequencing (NGS) biomarker mutation panel that contains DDR genes likely to sensitize to PARP inhibition; 4) surgically or medically castrated, with serum testosterone < 50 ng / dL (< 1 .73 nmol / L) at screening; 5) ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) agonist or antagonist for patients who have not undergone bilateral orchiectomy; 6) metastatic disease in bone documented on bone scan or in soft tissue documented on CT / MRI scan; 7) progressive disease at study entry in the setting of medical or surgical castration as defined by one or more of the following three criteria: i) prostate specific antigen (PSA) progression defined by a minimum of two rising PSA values from 3 assessments with an interval of at least 7 days between assessments; ii) soft tissue disease progression as defined by RECIST 1.1 ; and iii) bone disease progression defined by Prostate Cancer Clinical Trials Working Group 3 (PCWG3) with 2 or more new metastatic bone lesions on a whole body radionuclide bone scan; 8) ongoing bisphosphonate or denosumab use; 9) Eastern Cooperative Oncology Group (ECOG) performance status < 1 ; and 10) life expectancy > 12 months as assessed by the investigator. A “subject” or “patient” according to the combination of this invention may be unselected for DNA damage response (DDR) mutation status or, interchangeably, unselected for HRR gene alteration status. “Unselected for DDR mutation status” and “unselected for HRR gene alteration status” mean that the subject is not selected for treatment based on DDR mutation status or HRR gene alteration status. In other words, all subjects having metastatic castration-resistant prostate cancer are eligible for treatment with the combination of the invention regardless of DDR mutation status or HRR gene alteration status.

[0092] As used herein, the term “cancer” refers to or describes the physiological condition in a patient of subject that 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” as it relates to cancer, includes but is not limited to, a cancer that has spread from the place in which it started to other parts of the body, a recurrence from the original primary cancer after remission, and a second primary cancer that is a new primary cancer in a subject with a history of previous cancer of different type from latter one. Those skilled in the art will be able to recognize and diagnose metastatic cancer in a patient.

[0093] "Treat" or "treating" a metastatic cancer, such as mCRPC, as used herein means to administer a combination therapy according to the present invention to a subject or patient having a cancer, or diagnosed with a cancer, to achieve at least one positive therapeutic effect, such as, for example, reduced number of cancer cells, reduced tumor size, reduced rate of cancer cell infiltration into peripheral organs, or reduced rate of tumor metastasis or tumor growth, reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment" or “therapy,” as used herein, unless otherwise indicated, refers to the act of treating as "treating" is defined immediately above. For the purposes of this invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: reducing the proliferation of (or destroying) neoplastic or cancerous cell; inhibiting metastasis or neoplastic cells; shrinking or decreasing the size of tumor; remission of the cancer; decreasing symptoms resulting from the cancer; increasing the quality of life of those suffering from the cancer; decreasing the dose of other medications required to treat the cancer; delaying the progression the cancer; curing the cancer; overcoming one or more resistance mechanisms of the cancer; and I or prolonging survival of patients the cancer. Positive therapeutic effects in cancer may be measured in a number of ways (see, for example, W. A. Weber, J. Nucl. Med. 50:1S-10S (2009)).

[0094] The treatment achieved by a combination of the invention is increasing overall survival (OS) in the subject. OS is a clinically meaningful endpoint for measuring an increase in survival for patients treated with the combination of the present invention. OS is the length of time from either the date of diagnosis or the start of treatment for a disease, such as cancer, that patients diagnosed with the disease are still alive. In a clinical trial, measuring the OS is a way to see how well a new treatment works. For purposes of the clinical trial described here, For purposes of the clinical trial described here, OS refers to the time from the date of randomization to death due to any cause.

[0095] An “amount” for use and for treating a subject refers to an amount that provides, in single or multiple doses, alone, or in combination with one or more other agents, a detectable response of any duration of time (transient, medium or long term), a desired outcome in or an objective or subjective benefit to a subject of any measurable or detectable degree or for any duration of time (e.g., for hours, days, months, years, in remission or cured). Such amounts typically are effective to ameliorate a disease, or one, multiple or all adverse effects I symptoms, consequences or complications of the disease, to a measurable extent, although reducing or inhibiting a progression or worsening of the disease, or providing stability (i.e., not 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, effective for producing a desired therapeutic effect upon administration to a subject, for example, to stem the growth, or result in the shrinkage, of a cancerous tumor. In reference to the treatment of cancer, a therapeutically effective amount refers to that amount which has the effect of (1) reducing the size of the tumor, (2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis emergence, (3) inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth or tumor invasiveness, and / or (4) relieving to some extent (or, preferably, eliminating) one or more signs or symptoms associated with the cancer. Therapeutic or pharmacological effectiveness of the doses and administration regimens may 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 may be measured as prolongation of the time before disease progression.

[0096] As used herein, “ameliorate” refers to any reduction in the extent, severity, frequency, and / or likelihood of a symptom or clinical sign characteristic of a particular disease. “Symptom” refers to any subjective evidence of disease or of a subject's condition.

[0097] In one embodiment, the amount or daily dosage of talazoparib, or a pharmaceutically acceptable salt thereof, and preferably a tosylate thereof, to be administered to a subject is equivalent to about 0.1 mg to about 1 mg once daily of talazoparib free base. In an embodiment, talazoparib or a pharmaceutically acceptable salt thereof, and preferably a tosylate thereof, is administered at a daily dosage equivalent to about 0.1 mg once daily of talazoparib free base; to about 0.25 mg once daily of talazoparib free base; to about 0.35 mg once daily of talazoparib free base; to about 0.5 mg once daily of talazoparib free base; to about 0.75 mg once daily of talazoparib free base; or to about 1 mg once daily of talazoparib free base. In an embodiment, talazoparib or a pharmaceutically acceptable salt thereof, and preferably a tosylate thereof, is administered at a daily dosage equivalent to about 0.1 mg once daily of talazoparib free base; to about 0.25 mg once daily of talazoparib free base; to about 0.35 mg once daily of talazoparib free base; or to about 0.5 mg once daily of talazoparib free base. In an embodiment, talazoparib or a pharmaceutically acceptable salt thereof and preferably a tosylate thereof, is administered at a daily dosage equivalent to about 0.1 mg once daily of talazoparib free base. In an embodiment, talazoparib or a pharmaceutically acceptable salt thereof and preferably a tosylate thereof, is administered at a daily dosage equivalent to about 0.25 mg once daily of talazoparib free base. In an embodiment, talazoparib or a pharmaceutically acceptable salt thereof and preferably a tosylate thereof, is administered at a daily dosage equivalent to about 0.35 mg once daily of talazoparib free base. In an embodiment, talazoparib or a pharmaceutically acceptable salt thereof and preferably a tosylate thereof, is administered at a daily dosage equivalent to about 0.5 mg once daily of talazoparib free base. In an embodiment, talazoparib or a pharmaceutically acceptable salt thereof and preferably a tosylate thereof, is administered at a daily dosage equivalent to about 0.75 mg once daily of talazoparib free base. In an embodiment, talazoparib or a pharmaceutically acceptable salt thereof and preferably a tosylate thereof, is administered at a daily dosage equivalent to about 1 mg once daily of talazoparib free base.

[0098] In one embodiment, the amount or daily dosage of talazoparib, or a pharmaceutically acceptable salt thereof, and preferably a tosylate thereof, to be administered to a subject is about 0.1 mg to about 1 mg once daily of talazoparib free base or equivalent. In an embodiment, talazoparib or a pharmaceutically acceptable salt thereof, and preferably a tosylate thereof, is administered at a daily dosage of about 0.1 mg once daily of talazoparib free base or equivalent; to about 0.25 mg once daily of talazoparib free base or equivalent; to about 0.35 mg once daily of talazoparib free base or equivalent; to about 0.5 mg once daily of talazoparib free base or equivalent; to about 0.75 mg once daily of talazoparib free base or equivalent; or to about 1 mg once daily of talazoparib free base or equivalent. In an embodiment, talazoparib or a pharmaceutically acceptable salt thereof, and preferably a tosylate thereof, is administered at a daily dosage of about 0.1 mg once daily of talazoparib free base or equivalent; to about 0.25 mg once daily of talazoparib free base or equivalent; to about 0.35 mg once daily of talazoparib free base or equivalent; or to about 0.5 mg once daily of talazoparib free base or equivalent. In an embodiment, talazoparib or a pharmaceutically acceptable salt thereof and preferably a tosylate thereof, is administered at a daily dosage of about 0.1 mg once daily of talazoparib free base or equivalent. In an embodiment, talazoparib or a pharmaceutically acceptable salt thereof and preferably a tosylate thereof, is administered at a daily dosage of about 0.25 mg once daily of talazoparib free base or equivalent. In an embodiment, talazoparib or a pharmaceutically acceptable salt thereof and preferably a tosylate thereof, is administered at a daily dosage of about 0.35 mg once daily of talazoparib free base or equivalent. In an embodiment, talazoparib or a pharmaceutically acceptable salt thereof and preferably a tosylate thereof, is administered at a daily dosage of about 0.5 mg once daily of talazoparib free base or equivalent. In an embodiment, talazoparib or a pharmaceutically acceptable salt thereof and preferably a tosylate thereof, is administered at a daily dosage of about 0.75 mg once daily of talazoparib free base or equivalent. In an embodiment, talazoparib or a pharmaceutically acceptable salt thereof and preferably a tosylate thereof, is administered at a daily dosage of about 1 mg once daily of talazoparib free base or equivalent. Dosage amounts provided herein refer to the dose of the free base form of talazoparib, or are calculated as the free base equivalent of an administered talazoparib salt form. For example, a dosage or amount of talazoparib, such as 0.25, 0.35 mg or 0.5 mg refers to the free base equivalent.

[0099] In one embodiment, enzalutamide is dosed in accordance with the XTANDI® US approved label with a daily dose of 160 mg once daily. Dosage adjustments of enzalutamide, in accordance with full XTANDI® prescribing information may be readily determined by one of ordinary skill in the art, such as if the enzalutamide is to be dosed in concomitantly with a strong CYP2C8 inhibitor then the dose of enzalutamide should be reduced in accordance with the full prescribing information, such as to 80 mg once daily; or alternatively if the enzalutamide is to be dosed concomitantly with a CYP3A4 inducer then the dose of enzalutamide should be increased in accordance with the full prescribing information, such as to 240 mg daily.

[0100] In a preferred embodiment, enzalutamide, or a pharmaceutically acceptable salt thereof, is administered at a daily dosage of about 160 mg once daily. Dosage amounts provided herein refer to the dose of the free base form of enzalutamide, or are calculated as the free base equivalent of an administered enzalutamide salt form. For example, a dosage or amount of enzalutamide, such as 160 mg, refers to the free base or equivalent.

[0101] The recommended dose of talazoparib is 0.5 mg administered orally once daily in combination with enzalutamide 160 mg orally once daily, until disease progression or unacceptable toxicity occurs. This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. To manage adverse reactions, consider interruption of treatment with or without dose reduction based on severity and clinical presentation. The 0.35 mg, 0.25 mg and 0.1 mg capsules are available for dose reduction.

[0102] 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 enzalutamide 160 mg 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 enzalutamide 160 mg orally once daily. For patients with mCRPC, reduce the talazoparib dose to 0.35 mg once daily in combination with enzalutamide 160 mg orally once daily when coadministered with certain P-gp inhibitors, such as itraconazole, amiodarone, carvedilol, clarithromycin, itraconazole, and verapamil. When the P-gp inhibitor is discontinued, increase the talazoparib dose (after 3-5 half-lives of the P-gp inhibitor) to the dose used prior to the initiation of the P-gp inhibitor.

[0103] The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the bloodstream directly from the mouth.

[0104] In a preferred embodiment, the daily dose of talazoparib, or a pharmaceutically acceptable salt thereof, is administered orally.

[0105] In a preferred embodiment, the daily dose of enzalutamide, or a pharmaceutically acceptable salt thereof, is administered orally.

[0106] Talazoparib, or a pharmaceutically acceptable salt, may be present in a pharmaceutical composition which includes a pharmaceutically acceptable excipient. "Pharmaceutically acceptable excipient" refers to a component that may be included in the compositions described herein, is physiologically suitable for pharmaceutical use, and causes no significant adverse effects nor therapeutic effects to a subject. The term ’excipient’ is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0107] The amount of talazoparib, or a pharmaceutically acceptable salt, in the pharmaceutical compositions may be any amounts disclosed herein.

[0108] The compounds of the method, use or combination of the present invention may be formulated prior to administration. The formulation will preferably be adapted to the particular mode of administration. These compounds may be formulated with pharmaceutically acceptable excipients as known in the art and administered in a wide variety of dosage forms as known in the art. Dosage unit 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 nonaqueous oral solutions and suspensions, packaged in containers adapted for subdivision into individual doses.

[0109] In another embodiment, the dosage of a compound or pharmaceutical composition described herein may vary within the range depending upon the dosage form employed and the route of administration utilized. In another embodiment, an amount of a compound or pharmaceutical composition described herein administered to a subject may be dependent upon factors known to a skilled artisan, including bioactivity and bioavailability of the compound (e.g., half-life and stability of the compound in the body), chemical properties of the compound (e.g., molecular weight, hydrophobility and solubility), route and frequency of administration, and the like. Further, it will be understood that the specific dose of a pharmaceutical composition comprising a compound as disclosed herein may depend on a variety of factors including physical condition of the subject (e.g., age, gender, weight), and medical history of the subject (e.g., medications being taken, health condition other diseases or disorders). The precise dose of a pharmaceutical composition administered to a subject may be determined by methods known to a skilled artisan such as a pharmacologist, or an anesthesiologist.

[0110] Repetition of the administration or dosing regimens may be conducted as necessary to achieve the desired reduction or diminution of cancer cells. A “continuous dosing schedule”, as used herein, is an administration or dosing regimen without dose interruptions, e.g., without days off treatment. Repetition of 28-day treatment cycles without dose interruptions between the treatment cycles is an example of a continuous dosing schedule. In an embodiment, the compounds of the combination of the present invention may be administered in a continuous dosing schedule. In an embodiment, the compounds of the combination of the present invention may be administered concurrently in a continuous dosing schedule.

[0111] Therapeutic Methods and Uses

[0112] The methods and combination therapies of the present invention are useful for treating mCRPC. The methods and combination therapies of the present invention are useful for treating mCRPC with or without DDR mutations or HRR gene alterations.

[0113] “Standard of care” therapy is a treatment that is considered the most appropriate for a patient's condition, based on current medical and psychological practices. “First- line therapy” is the initial treatment given to a patient with cancer. Standard of care for first-line therapy in the treatment of mCRPC currently includes abiraterone acetate + prednisone, enzalutamide and docetaxel. One of skill in the art would be able to recognize and identify a standard of care for first-line therapy in the treatment of mCRPC.

[0114] In one embodiment, the disclosure provides a method of increasing overall survival in a subject having metastatic castration-resistant prostate cancer, 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.

[0115] In one embodiment, the disclosure provides a method of increasing overall survival in a subject having metastatic castration-resistant prostate cancer, comprising 1) orally administering to the subject talazoparib, or a pharmaceutically acceptable salt thereof, once daily, in combination with 2) orally administering to the subject enzalutamide, or a pharmaceutically acceptable salt thereof, once daily.

[0116] In one embodiment, the disclosure provides a method of treating metastatic castration-resistant prostate cancer in a subject in need thereof, 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 the administration of the talazoparib, or a pharmaceutically acceptable salt thereof, and the admistration of the enzalutamide, or a pharmaceutically acceptable salt thereof, increases overall survival in the subject.

[0117] In one embodiment, the disclosure provides a method of treating metastatic castration-resistant prostate cancer in a subject in need thereof, comprising: 1) orally administering to the subject talazoparib, or a pharmaceutically acceptable salt thereof, once daily, in combination with 2) orally administering to the subject enzalutamide, or a pharmaceutically acceptable salt thereof, once daily, wherein the combination increases overall survival in the subject.

[0118] The term “combination”, as used herein, unless otherwise indicated, means a combination of agents that is administered closely enough in time to affect treatment of the subject. The combination of the invention may be administered concurrently (i.e., simultaneously) or sequentially. Examples of “in combination” include, but are not limited to, “concurrent administration,” “co-administration,” “simultaneous administration,” “sequential administration” and “administered simultaneously”. The combination of the invention may be co-administered in the same formulation. The combination of the invention may be administered concurrently- (i.e., simultaneously) in separate formulations. The combination of the invention may be administered sequentially, i.e., talazoparib is administered first, followed by enzalutamide after a specific duration of time, such as one hour; or enzalutamide is administered first, followed by talazoparib after a specific duration of time, such as one hour. The combination of the invention is preferably administered concurrently.

[0119] In one embodiment, the disclosure provides a combination of talazoparib, or a pharmaceutically acceptable salt thereof, and enzalutamide, or a pharmaceutically acceptable salt or solvate thereof, for use in increasing overall survival in the treatment of metastatic castration-resistant prostate cancer in a subject.

[0120] In another aspect, this invention relates to the use of talazoparib, or a pharmaceutically acceptable salt thereof, and enzalutamide, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for increasing overall survival in the treatment of metastatic castration-resistant prostate cancer in a subject.

[0121] In one embodiment, the combination therapy is administered to a subject that has not received: 1) prior systemic cancer treatment for non-metastatic castrationresistant prostate cancer or metastatic castration-resistant prostate cancer; 2) prior treatment with an androgen receptor signaling inhibitor, a PARP inhibitor, cyclophosphamide, or mitoxantrone for prostate cancer; or 3) prior treatment with platinum-based chemotherapy within 6 months from the last dose or any history of disease progression on platinum-based therapy within 6 months from the last dose.

[0122] In one embodiment, the combination therapy is administered to a subject who has not received: 1) systemic cancer treatment for non-metastatic castration-resistant prostate cancer or metastatic castration-resistant prostate cancer; 2) treatment with an androgen receptor signaling inhibitor, a PARP inhibitor, cyclophosphamide, or mitoxantrone for prostate cancer; or 3) treatment with platinum-based chemotherapy within 6 months from the last dose or any history of disease progression on platinumbased therapy within 6 months from the last dose.

[0123] Further Therapeutic Agents In one embodiment, the methods and combination therapies of the present invention may additionally comprise administering a further anti-cancer agent, such as an anti-tumor agent, an anti-angiogenesis agent, a signal transduction inhibitor and an antiproliferative agent. In some such embodiments, the anti-tumor agent is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, antihormones, androgen deprivation therapy and anti-androgens.

[0124] In one embodiment, the methods and combination therapies of the present invention may additionally comprise administering a further active agent, wherein the further active agent is androgen deprivation therapy.

[0125] 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 GnRH antagonist.

[0126] In one embodiment, the androgen deprivation therapy is a GnRH agonist or GnRH antagonist.

[0127] In one embodiment, the androgen deprivation therapy is a GnRH agonist.

[0128] In one embodiment, the androgen deprivation therapy is a GnRH antagonist.

[0129] In one embodiment, the androgen deprivation therapy is a LHRH agonist or

[0130] LHRH antagonist.

[0131] In one embodiment, the androgen deprivation therapy is a LHRH agonist.

[0132] In one embodiment, the androgen deprivation therapy is a LHRH antagonist.

[0133] In one embodiment, the androgen deprivation therapy is selected from the group consisting of leuprolide (also known as leuprorelin, for example Lupron or Eligardor Viadur and the like); buserelin (for example Suprefact); gonadorelin; goserelin (for example Zoladex); histrelin (for example Vantas); nafarelin; triptorelin (for example Trelstar); deslorelin; fertirelin; abarelix (for example Plenaxis); cetrorelix; degarelix (for example Firmagon); ganirelix; ozarelix; elagolix (for example Orilissa); relugolix; and linzagolix.

[0134] In one embodiment, the androgen deprivation therapy is selected from the group consisting of leuprolide; buserelin gonadorelin; goserelin; histrelin; nafarelin; triptorelin; deslorelin; fertirelin; abarelix; cetrorelix; degarelix; ganirelix; ozarelix; elagolix; relugolix; and linzagolix. In one embodiment, the androgen deprivation therapy is selected from the group consisting of leuprolide, goserelin and degaralix.

[0135] In one embodiment, the androgen deprivation therapy is leuprolide. In some embodiments the leuprolide is administered intramuscularly at a dose of about 7.5 mg every month, or about 22.5 mg every three months, or about 30 mg every four months.

[0136] In one embodiment, the androgen deprivation therapy is leuprolide. In some embodiments the leuprolide is administered subcutaneously at a dose of about 7.5 mg every 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.

[0137] In one embodiment, the androgen deprivation therapy is goserelin. In some embodiments the goserelin is administered subcutaneously at a dose of about 3.6 mg every month, or about 10.8 mg every three months.

[0138] In one embodiment, the androgen deprivation therapy is degarelix. In some embodiments the degarelix is administered intramuscularly at an initial dose of about 240 mg, which initial dose may be optionally divided into several smaller doses, for example 2 doses of about 120 mg, followed by a maintenance dose of about 80 mg every month.

[0139] In one embodiment of the methods and combination therapies of the present invention, the regimen includes a further active agent, wherein the further active agent is etoposide. In some embodiments, the etoposide is administered intravenously in accordance with the approved label, for example at a dose of from 50 to 100 mg / m2once a day on days 1 to 5; or from 5 to 100 mg / m2once a day on days 1 , 3 and 5. In one example etoposide may be administered at a dose from 80 to 120 mg / m2, on days 1 , 2 and 3 of each 21 -day cycle for 1 , 2, 3, 4, 5 or 6 cycles.

[0140] EXAMPLE

[0141] A Randomized, Double-Blind, Placebo-Controlled Phase 3 Efficacy and Safety Study of Talazoparib in Combination with Enzalutamide in Patients with mCRPC,TALAPRO-2

[0142] Study Objectives and Endpoints

[0143] Primary Objective: To evaluate the effect of talazoparib in combination with enzalutamide compared with placebo in combination with enzalutamide on BICR-assessed rPFS

[0144] To evaluate the effect of talazoparib in combination with enzalutamide compared with placebo in combination with enzalutamide on OS

[0145] To evaluate safety / toxicity profile of talazoparib and enzalutamide when administered in combination

[0146] Study Design

[0147] This was an international, Phase 3, randomized, double-blind, two-part study for mCRPC patients, TALAPRO-2 (NCT03395197).

[0148] Part 1 was open-label and non-randomized and evaluated the safety, tolerability, and pharmacokinetic (PK) of talazoparib (Tala) in combination with enzalutamide (Enza). Nineteen mCRPC patients were enrolled to establish the appropriate starting dose of talazoparib in combination with enzalutamide for Part 2. The starting dose in Part 2 was talazoparib / placebo 0.5 mg / day (mg QD) in combination with enzalutamide 160 mg / day. Patients with moderate renal impairment at screening had a reduced talazoparib / placebo starting dose of 0.35 mg / day.

[0149] Part 2 was randomized, double-blind, and placebo-controlled and evaluated the efficacy and safety of talazoparib in combination with enzalutamide compared with placebo in combination with enzalutamide. Patients were randomized 1 :1 to receive either talazoparib or matching placebo in combination with open-label enzalutamide. Randomization was stratified by prior novel hormonal therapy or taxane-based chemotherapy, e.g., abiraterone, orteronel, or docetaxel for castration-sensitive prostate cancer (yes / no) and DDR mutational status, also referred to as, homologous recombination repair gene alteration status (deficient versus non deficient / unknown).

[0150] Genomic screening to identify alterations in DDR genes was optional for patients in Part 1 , but it was required for randomization in Part 2. Mutational status was determined by testing for the presence of mutations in defined DDR genes likely to sensitize to PARP inhibition using next generation sequencing (NGS) based gene panel test (FoundationOne® and / or FoundationOneLiquid® CDx). Study treatment (including enzalutamide) continued until radiographic progression was determined by (BICR) (Part 2) or local review (Part 1) unless in the opinion of the investigator the patient was still deriving benefit at this time, or an adverse event leading to permanent discontinuation, or patient decision to discontinue treatment, or death.

[0151] There were two patient cohorts in Part 2: unselected, (cohort 1, all-comers cohort) and selected for gene alterations involved in deoxyribonucleic acid (DNA) damage repair (DDR) (cohort 2, the DDR-deficient cohort). After enrollment into Cohort 1 was complete on 17 September 2020, patient enrollment in Cohort 2 continued until 20 January 2022.

[0152] The results from the final analysis of overall survival (OS) in the all-comers cohort unselected for HRR gene alterations, e.g, patients with and without tumor HRR gene alterations, in Part 2 of the study are provided in this Example.

[0153] Inclusion Criteria:

[0154] 1. Histologically or cytologically confirmed adenocarcinoma of the prostate without small cell or signet cell features.

[0155] 2. Asymptomatic or mildly symptomatic metastatic castration resistant prostate cancer (mCRPC) (score on BPI-SF Question #3 must be < 4).

[0156] 3. For enrollment into Part 2 only (optional in Part 1): assessment of DDR mutation status.

[0157] 4. Consent to a saliva sample collection for a germline comparator unless prohibited by local regulations or ethics committee decision (optional for patients in Part 1).

[0158] 5. Surgically or medically castrated, with serum testosterone < 50 ng / dL (< 1.73 nmol / L) at screening.

[0159] 6. Metastatic disease in bone documented on bone scan or in soft tissue documented on CT / MRI scan.

[0160] 7. Progressive disease at study entry in the setting of medical or surgical castration as defined by 1 or more of the following 3 criteria (prostate-specific antigen only or imaging-based): a. Prostate specific antigen (PSA) progression defined by a minimum of 2 rising PSA values from 3 consecutive assessments with an interval of at least 7 days between assessments. b. Soft tissue disease progression as defined by RECIST 1.1. c. Bone disease progression defined by Prostate Cancer Clinical Trials Working Group 3 (PCWG3) with 2 or more new metastatic bone lesions on a whole body radionuclide bone scan.

[0161] 8. Ongoing bisphosphonate or denosumab use prior to Day 1 (Part 1) or randomization (Part 2) is allowed but not mandatory.

[0162] 9. Eastern Cooperative Oncology Group (ECOG) performance status < 1.

[0163] 10. Life expectancy > 12 months as assessed by the investigator.

[0164] 11. Able to swallow the study drug and have no known intolerance to study drugs or excipients.

[0165] 12. Must agree to use a condom when having sex with a partner from the time of the first dose of study drug through 4 months after last dose of study treatment. Must also agree for female partner of childbearing potential to use an additional highly effective form of contraception from the time of the first dose of study treatment through 4 months after last dose of study treatment when having sex with a non pregnant female partner of childbearing potential.

[0166] 13. Must agree not to donate sperm from the first dose of study drug to 4 months after the last dose of study drug.

[0167] 14. Evidence of a personally signed and dated informed consent document (and molecular prescreening consent if appropriate) indicating that the patient [or a legally acceptable representative / legal guardian] has been informed of all pertinent aspects of the study.

[0168] 15. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

[0169] Exclusion Criteria:

[0170] 1. Any prior systemic cancer treatment initiated in in the non metastatic CRPC and mCRPC disease state.

[0171] 2. Patients whose only evidence of metastasis is adenopathy below the aortic bifurcation. 3. Prior treatment with second-generation androgen receptor inhibitors (enzalutamide, apalutamide, and darolutamide), a PARP inhibitor, cyclophosphamide, or mitoxantrone for prostate cancer.

[0172] 4. Prior treatment with platinum-based chemotherapy within 6 months (from the last dose) prior to Day 1 (Part 1) or randomization (Part 2), or any history of disease progression on platinum-based therapy within 6 months (from the last dose).

[0173] 5. Treatment with cytotoxic chemotherapy, biologic therapy including sipuleucel T, or radionuclide therapy received in the castration-sensitive prostate cancer is NOT exclusionary if discontinued in the 28 days prior to Day 1 (Part 1) or randomization (Part 2).

[0174] 6. Prior docetaxel and abiraterone or orteronel in the castration-sensitive setting was NOT exclusionary.

[0175] 7. Treatment with any investigational agent within 4 weeks before Day 1 (Part 1) or randomization (Part 2).

[0176] 8. Prior treatment with opioids for pain related to either primary prostate cancer or metastasis within 28 days prior to Day 1 (Part 1) or randomization (Part 2).

[0177] 9. Current use of potent P-gp inhibitors within 7 days prior to Day 1 (Part 1) or randomization (Part 2).

[0178] 10. Major surgery (as defined by the investigator) within 2 weeks before Day 1 (Part 1) or randomization (Part 2), or palliative localized radiation therapy within 3 weeks before randomization (Part 2).

[0179] 11. Clinically significant cardiovascular disease

[0180] 12. Significant renal dysfunction as defined by any of the following laboratory abnormalities: a. Renal: eGFR < 30 mL / min / 1.73 m2 by the MDRD equation (available via www.mdrd.com).

[0181] 13. Patients enrolled in Part 1 only: Moderate renal impairment (eGFR 30-59 mL / min / 1.73 m2) at screening.

[0182] 14. Significant hepatic dysfunction as defined by any of the following laboratory abnormalities on screening labs: a. Total serum bilirubin >1.5 times the upper limit of normal (ULN) (>3 x ULN for patients with documented Gilbert syndrome or for whom indirect bilirubin concentrations suggest an extrahepatic source of elevation). b. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 times ULN (>5 x ULN if liver function abnormalities are due to hepatic metastasis). c. Albumin <2.8 g / dL

[0183] 15. Absolute neutrophil count < 1500 / pL, platelets < 100,000 / pL, or hemoglobin < 9 g / dL (may not have received growth factors or blood transfusions within 14 days before obtaining the hematology values at screening).

[0184] 16. Known or suspected brain metastasis or active leptomeningeal disease.

[0185] 17. Symptomatic or impending spinal cord compression or cauda equina syndrome.

[0186] 18. Any history of myelodysplastic syndrome, acute myeloid leukemia, or prior malignancy except any of the following: a. Carcinoma in situ or non melanoma skin cancer b. Any prior malignancies >3 years before randomization with no subsequent evidence of recurrence or progression regardless of the stage. c. Stage 0 or Stage 1 cancer <3 years before randomization that has a remote probability of recurrence or progression in the opinion of the investigator

[0187] 19. Gastrointestinal disorder affecting absorption.

[0188] 20. Fertile male subjects who are unwilling or unable to use highly effective methods of contraception for the duration of the study and for 4 months after the last dose of investigational product.

[0189] 21. Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or patients who are Pfizer employees, including their family members, directly involved in the conduct of the study.

[0190] 22. Other acute or chronic medical (concurrent disease, infection, or comorbidity) or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that interferes with ability to participate in the study, may increase the risk associated with study participation or investigational product administration, or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study. 23. History of seizure or any condition that may predispose to seizure (eg, prior cortical stroke, significant brain trauma). Also, history of loss of consciousness or transient ischemic attack within 12 months of randomization (Part 2).

[0191] Statistical analysis (overview):

[0192] For overall survival (OS) in the all-comers cohort, two interim analyses and a final analysis were planned according to the study statistical analysis plan. An O’Brien- Fleming alpha-spending function was used to maintain the overall type I error at onesided 0.0125. OS results were not statistically significant at the two interim analyses at 58% and 75% information fraction, respectively.

[0193] This Example summarizes the top line results from the final analysis of OS in the all-comers cohort with a data cutoff on 03 September 2024. To achieve statistical significance at the final OS analysis, the one-sided p-value needed to be < 0.011 based on the pre-specified O’Brien-Fleming spending function.

[0194] Statistical analysis (overview):

[0195] Efficacy was analysed in the intention-to-treat population. Approximately 750 patients were to be enrolled in the unselected cohort. For the primary endpoint of rPFS and the key secondary endpoint of overall survival, alpha was split equally between the unselected cohort 1 and the HRR-deficient cohort 2 populations to maintain overall type I error for the study at one-sided 0 025, equivalent to two-sided 0 05. The one-sided alpha for the unselected population was controlled at 0 0125, which was equivalent to two-sided 0 025.

[0196] Sample size and power calculations were based on a stratified log-rank test and were performed using the software package East 6 (Cytel, Cambridge, MA, USA). For the primary comparison in the unselected population, 333 PFS events based on a Lan DeMets alpha-spending function would provide 85% power to detect an HR of 0 696 using a one-sided stratified log-rank test at a significance level of 0 0125. A prespecified interim futility analysis of rPFS was planned in the unselected population using the O’Brien-Fleming p-spending function when approximately 50% of the expected events (167 rPFS events) had occurred; the futility boundary was not crossed. Final analysis of rPFS in the unselected population was planned after approximately 333 rPFS events, together with the first interim analysis of overall survival (252 events, data cutoff Aug 16, 2022). A second interim analysis of overall survival in the unselected population was planned after approximately 75% of the total required events (330 events, data cutoff March 28, 2023). Final analysis of overall survival in the unselected population was planned at the same time as final analysis of overall survival in the HRR-deficient population after approximately 224 rPFS events in the HRR- deficient population. It was projected that approximately 438 deaths would have occurred in the unselected population at this time. Overall survival was tested in a hierarchical stepwise procedure to preserve the overall type I error. For the unselected population, 438 overall survival events would provide 77% power to detect an HR of 0 75 using a one-sided stratified log-rank test at a significance level of 0 0125 based on a three-look group sequential design with O’Brien-Fleming a-spending function. Other endpoints had no adjustment for multiplicity. At the time of the final analysis of overall survival, a descriptive update of rPFS and other secondary endpoints was planned to be provided.

[0197] Time-to-event endpoints were compared between treatment arms using a stratified log-rank test and the randomisation stratification factors. To achieve statistical significance at the final overall survival analysis, the one-sided p value needed to be <0 011 (two-sided <0 022) based on a group sequential design with O’Brien-Fleming spending function. HRs and associated two-sided 95% Cis were estimated by a stratified Cox proportional hazards model using the randomisation stratification factors, except for the subgroup analysis of overall survival by baseline characteristics, which used an unstratified Cox model with treatment as the only covariate due to the small number of patients in some of the subgroups. Median time-to-event endpoints were estimated by the Kaplan-Meier method, with 95% Cis based on the Brookmeyer- Crowley method. Missing or partial dates were imputed as specified per the statistical analysis plan. Other missing data were not imputed. All reported p values are two- sided. For exploratory subgroup analyses and descriptive updates of secondary, non- alpha-controlled endpoints, p values were nominal and descriptive and had no adjustment for multiplicity. SAS version 9.4 statistical software was used. Safety was analysed in all patients who received at least one study drug dose (safety population). Adverse events were coded to preferred term and system organ class using the Medical Dictionary for Regulatory Activities (MedDRA) and classified by severity using NCI-CTCAE version 4.03. Patient Population:

[0198] The primary population for evaluating efficacy endpoints as well as patient characteristics was the intent-to-treat (ITT) population. This population included all patients who were randomized, with treatment assignment designated according to the randomization, regardless of whether patients received study treatment.

[0199] 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.

[0200] Between 07 January 2019 and 17 September 2020, a total of 805 patients randomized into the all-comers cohort (402 to the talazoparib + enzalutamide group and 403 to the placebo + enzalutamide group, intent-to-treat (ITT) population). 398 patients in the talazoparib + enzalutamide group and 401 patients in the placebo + enzalutamide group received study treatment (all-comers safety population). 1 patient in each of those groups was treated with enzalutamide only.

[0201] The patient treatment disposition is summarized in Table 1 below.

[0202] Table 1. Patient Disposition by Study Treatment (Safety Population)

[0203] *308 patients in the talazoparib plus enzalutamide arm discontinued treatment of both talazoparib and enzalutamide. 336 patients in the placebo plus enzalutamide arm discontinued treatment of both placebo and enzalutamide.

[0204] §Long-term follow-up began after safety follow-up and occurred every 8 weeks through week 25 and every 12 weeks thereafter until death, patient withdrawal of consent for follow-up, or study termination. Efficacy: Key Results & Supportive Findings:

[0205] OS was an alpha-protected key secondary endpoint. Patients last known to be alive were censored at the date of last contact. Based on a data cutoff on 03 September 2024, a total of 454 deaths were observed (211 [52.5%] deaths in the talazoparib + enzalutamide group versus 243 [60.3%] deaths in the placebo + enzalutamide group). Median follow-up time was 52.5 months (interquartile range (IQR) 48 6-56 0) for the talazoparib + enzalutamide group and 53.0 months for the placebo + enzalutamide group. The observed stratified hazard ratio for OS in the ITT population was 0.796 / 0.80 (95% Cl: [0.661 (0.66), 0.958(0.96)]; one-sided p-value: 0.0078, two-sided p=0.016) in favor of talazoparib + enzalutamide. Median OS was

[0206] 45.8 months (95% Cl: [39.4, 50.8]) for the talazoparib + enzalutamide group (number of events: 211 / number of patients: 402) and 37.0 months (95% Cl: [34.1 , 40.4]) for the placebo + enzalutamide group (number of events: 2431 number of patients: 403). The percentage of patients who were alive at 4 years was 48% in the talazoparib group and 38% in the control group. The final OS results crossed the efficacy boundary, and the OS improvement was statistically significant.

[0207] Consistent OS results were observed in the prespecified subgroups.

[0208] In prespecified exploratory subgroup analyses for the subgroup of DDR- deficient / HRR-deficient patients per interactive web response system (IWRS) within the all-comers cohort (n=169, 21%), the observed OS hazard ratio was 0.549 / 0.55 (95% Cl: [0.364(0.36), 0.826(0.83)]; one-sided nominal p-value: 0.0018, two-sided p=0.0035). Median OS was 45.8 months (95% Cl: [35.8, NE]) for the talazoparib + enzalutamide group (number of events: 40 1 number of patients: 85), which is 8.8 months longer than

[0209] 30.8 months (95% Cl: [26.1 , 38.8]) for the placebo + enzalutamide group (number of events: 561 number of patients: 84).

[0210] In prespecified exploratory subgroup analyses for the subgroup of DDR-non- deficient / HRR-non-deficient / unknown alteration status patients per IWRS (n=636, 79%), the observed OS hazard ratio was 0.878 / 0.88 (95% Cl: [0.713(0.71), 1.080(1.08)]; onesided nominal p-value: 0.1091 , two-sided p=0.22). Median OS was 45.5 months (95% Cl: [37.6, 50.8]) for the talazoparib + enzalutamide group (number of events: 171 / number of patients: 317) versus. 38.3 months (95% Cl: [34.7, 42.4]) for the placebo + enzalutamide group (number of events: 187 / number of patients: 319). In patients who received prior ARPI for castration-sensitive prostate cancer (n=50), the HR for overall survival was 0.79 (95% Cl 0.40-1 .55; two-sided p=0.49) and in patients who received prior docetaxel (n=180) the HR for overall survival 0.63 (95% Cl 0.42-0.94; two-sided p=0.024]).

[0211] In post-hoc analyses for the subgroup of non-DDR-mutant / HRR-non-deficient patients by both circulating tumor DNA (ctDNA) and tumor tissue within the all-comers cohort (“double negative”, n=314, 39%), the observed hazard ratio for OS was 0.782 / 0.78 (95% Cl: [0.582(0.58), 1.050(1.05)]; one-sided nominal p-value: 0.0504, two- sided p=0.10). Median OS was 46.6 months (95% Cl: [33, 54.1]) for the talazoparib + enzalutamide group (number of events: 82 1 number of patients: 154) and 37.4 months (95% Cl: [30, 40.9]) for the placebo + enzalutamide group (number of events: 991 number of patients: 160).

[0212] In post-hoc analyses for the subgroup of patients without BRCA gene alteractions, e.g., non-BRCA-mutant / non-BRCA-deficient patients, by both ctDNA and tumor tissue within the all-comers cohort (“double negative”, n=439, 55%), the observed hazard ratio for OS was 0.749 / 0.75 (95% Cl: [0.582(0.58), 0.963(0.96)]; one-sided nominal p-value: 0.0118, two-sided p=0.024). Median OS was 48.4 months (95% Cl: [37.2, 54.1]) for the talazoparib + enzalutamide group (number of events: 114 / number of patients: 219) and 37.1 months (95% Cl: [31.1 , 40.7]) for the placebo + enzalutamide group (number of events: 137 / number of patients: 220).

[0213] In addition, a descriptive update of the primary endpoint BICR-assessed rPFS was provided. Based on the data cutoff on 03 September 2024, the observed stratified hazard ratio for rPFS in the ITT population was 0.667 / 0.67 (95% Cl: [0.551(0.55), 0.807(0.81)]; one-sided p-value <0.0001 , two-sided p<0.0001) in favor of talazoparib + enzalutamide. Median rPFS was 33.1 months (95% Cl: [27.4, 39.0]) for the talazoparib + enzalutamide group (number of events: 2021 number of patients: 402), which was 13.6 months longer than 19.5 months (95% Cl: [16.6, 24.7]) for the placebo + enzalutamide group (number of events: 231 1 number of patients: 403). The updated rPFS results were consistent with the rPFS results reported in the primary analysis in 2022.

[0214] In patients who received prior ARPI for castration-sensitive prostate cancer (n=50), the HR for rPFS was 0.46 (95% Cl 0.22-0.96; two-sided p=0.034) and in patients who received prior docetaxel (n=180), the HR for rPFS was 0.57 (95% Cl 0.39-0.85; two-sided p=0.0050).

[0215] For the subgroup of DDR-deficient patients per IWRS within the all-comers cohort (n=169), the observed stratified hazard ratio for rPFS was 0.475 (95% Cl: [0.321, 0.705]; one-sided nominal p-value: <0.0001). Median rPFS was 27.7 months (95% Cl: [16.8, 38.4]) for the talazoparib + enzalutamide group versus 13.8 months (95% Cl: [10.9, 19.3]) for the placebo + enzalutamide group.

[0216] For the subgroup of DDR-non-deficient / unknown patients per IWRS (n=636), the observed stratified hazard ratio for rPFS was 0.739 (95% Cl: [0.595, 0.918]; one-sided nominal p-value: 0.0030). Median rPFS was 33.3 months (95% Cl: [27.9, 41.4]) for the talazoparib + enzalutamide group versus 22.4 months (95% Cl: [17.7, 28.0]) for the placebo + enzalutamide group.

[0217] In addition, for the subgroup of non-DDR-mutant patients by both circulating tumor DNA (ctDNA) and tumor tissue within the all-comers cohort (“double negative”, n=314), the observed stratified hazard ratio for rPFS was 0.757 (95% Cl: [0.553, 1.035]; one-sided nominal p-value: 0.0400). Median rPFS was 33.1 months (95% Cl: [24.7, 44.3]) for the talazoparib + enzalutamide group and 19.4 months (95% Cl: [16.4, 24.7]) for the placebo + enzalutamide group.

[0218] For the subgroup of non-BRCA-mutant patients by both ctDNA and tumor tissue within the all-comers cohort (“double negative”, n=439), the observed stratified hazard ratio for rPFS was 0.742 (95% Cl: [0.572, 0.963]; one-sided nominal p-value: 0.0123). Median rPFS was 30.2 months (95% Cl: [22.3, 38.4]) for the talazoparib + enzalutamide group and 19.4 months (95% Cl: [16.6, 26]) for the placebo + enzalutamide group.

[0219] Table 2 below shows forest plot data of OS by baseline characteristics in the unselected ITT population.

[0220] Table 2. Subgroup analysis of OS by baseline characteristics (unselected intention-to-treat population)

[0221] The overall hazard ratio for al patients was based on a Cox model stratified by the randomisation stratification factors. For all subgroups, the hazard ratio was based on an unstratified Cox model with treatment as the only covariate.

[0222] *with or without PSA progression. ** all received doxetaxel.

[0223] Safety

[0224] The median duration of talazoparib treatment was 86 weeks and the median duration of placebo was 70 weeks. The median duration of enzalutamide treatment was 97 weeks for the talazoparib + enzalutamide group and 72 weeks for the placebo + enzalutamide group. Median (IQR) duration of treatment was 19.7 months (8.8-44.6) for talazoparib and 22.4 months (9.9-47.8) for enzalutamide in the talazoparib group, and 16.1 months (6.5-34.1) for placebo and 16.6 months (6.7-35.9) for enzalutamide in the control group. Median (IQR) relative dose intensities in the talazoparib group were 81 .8% (64.9-100.0) for talazoparib and 99.6% (94.9-100.0) for enzalutamide.

[0225] Table 3. Dosing Exposure (Safety Population) The numbers of patients with treatment-emergent AEs and SAEs were summarized in Table 4. Treatment-emergent was defined as the period from the first dose of any study treatment to 28 days after the last dose of the last study treatment, or before any new antineoplastic therapy, whichever occurs first. Table 4. Treatment-emergent AEs (Safety Population)

[0226] Data are n (%). Shown are adverse events that occurred from the time of the first dose of study treatment through 28 days after permanent discontinuation of all study treatments or before initiation of a new antineoplastic or any investigational therapy, whichever occurs first. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.

[0227] *One was considered treatment-related and was attributed to disease progression. **Two were considered treatment-related, of which one was due to COVID-19.§lncludes permanent discontinuation, dose reduction, or dose interruption of talazoparib or placebo only plus permanent discontinuation, dose reduction, or dose interruption of both talazoparib or placebo and enzalutamide.

[0228] ^Includes permanent discontinuation, dose reduction, or dose interruption of enzalutamide only plus permanent discontinuation, dose reduction, or dose interruption of both talazoparib or placebo and enzalutamide.

[0229] The most frequent treatment-emergent AEs of any grade and causality experienced in >10% patients in either arm were summarized in Table 5 below and arranged in descending order based on the frequency of events in the talazoparib + enzalutamide group.

[0230] Table 5. TEAEs in >10% Patients - All Causalities (Safety Population)

[0231] #One additional patient had a missing or unknown grade.

[0232] The most frequent SAEs observed in the study were anemia, haematuria, urinary tract infection, and pulmonary embolism. For details see Table 6 below. Table 6. SAEs in >2% Patients - All Causalities (Safety Population)

[0233] The most common all-cause adverse events in the talazoparib group (>30% of patients) were anaemia, neutropenia, and fatigue, and the most common (>10% of patients) grade 3-4 adverse events were anaemia (195 [49%] of 398) and neutropenia (77 [19%] of 398) (Tables 3 and 4). Of note, there was a higher incidence of serious adverse events of grade 3 or higher in the talazoparib group (168 [42%] of 398) than in the placebo group (113 [28%] of 401). The median time to onset of grade 3 or 4 anaemia was unchanged from the primary analysis (3.3 months). After the occurrence of grade 3-4 anaemia, supportive care was implemented (168 [42%] of 398 received a packed red blood cell transfusion [median of two transfusions]) per investigator discretion, together with protocol-mandated dose reduction of talazoparib or placebo (if hemoglobin returned to >9 g / dL). Discontinuation of talazoparib due to adverse events occurred in 86 (22%) of 398 patients, with 34 (9%) of 398 discontinuing due to anaemia.

[0234] In the talazoparib group, post-hoc exposure-adjusted analysis showed that the rate of venous embolic and thrombotic events was unchanged with longer follow-up (2.4 per 100 participant-years), and there were no additional cases of myelodysplastic syndrome or acute myeloid leukaemia, besides the one instance of each previously reported. Deaths considered to be treatment-related occurred in one patient (documented as “disease progression”; <1%) in the talazoparib group and two patients (one of unknown cause and one due to COVID- 19; <1%) in the control group.

[0235] The safety profile of talazoparib plus enzalutamide remained consistent with the known safety profile of the combination from the primary analysis, as reflected in the labelling globally. No new safety signals were identified. Conclusion

[0236] The final OS analysis showed a statistically significant and clinically meaningful improvement in OS for the all-comers cohort, with progressive improvement in the hazard ratios from each of the preceding interim analyses. Furthermore, consistent OS results were observed in the pre-specified subgroup analyses and the median OS in all tested subgroups under treatment with talazoparib plus enzalutamide was similar to that observed in the ITT population. These results demonstrate that talazoparib in combination with enzalutamide would provide a safe and effective treatment option for mCRPC, with or without DDR gene mutations.

[0237] Talazoparib in combination with enzalutamide prolongs overall survival in the Phase 3 TALAPRO-2 trial. Results showed a statistically significant and clinically meaningful improvement in the final OS in all-comers unselected population (cohort 1), compared to enzalutamide alone.

[0238] In this final analysis of overall survival, after a median follow-up of 52.5 months, the risk of death was reduced by 20% and the median overall survival of 45.8 months was approximately 9 months longer with talazoparib plus enzalutamide than for the enzalutamide control. To date, the median overall survival with talazoparib plus enzalutamide is longer than those reported in trials for current standard-of-care treatments (including docetaxel, ARPIs, and PARP inhibitor plus ARPI combinations) in patients with mCRPC (Saad F, Clarke NW, Oya M, et al. Olaparib plus abiraterone versus placebo plus abiraterone in metastatic castration-resistant prostate cancer (PROpel): final prespecified overall survival results of a randomised, double-blind, phase 3 trial. Lancet Oncol 2023; 24: 1094-108; Chi KN, Sandhu S, Smith MR, et al. Niraparib plus abiraterone acetate with prednisone in patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations: second interim analysis of the randomized phase III MAGNITUDE trial. Ann Oncol 2023; 34: 772-82; Armstrong AJ, Lin P, Tombal B, et al. Five-year survival prediction and safety outcomes with enzalutamide in men with chemotherapy-naive metastatic castration-resistant prostate cancer from the PREVAIL trial. Eur Urol 2020; 78: 347-57; Morris MJ, et al. Randomized phase III study of enzalutamide compared with enzalutamide plus abiraterone for metastatic castration-resistant prostate cancer (Alliance A031201 Trial). J Clin Oncol 2023; 41 : 3352-62; Saad F, et al. Apalutamide plus abiraterone acetate and prednisone versus placebo plus abiraterone and prednisone in metastatic, castration-resistant prostate cancer (ACIS): a randomised, placebo-controlled, double-blind, multinational, phase 3 study. Lancet Oncol 2021 ; 22: 1541-59; Ryan CJ, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2015; 16: 152-60; Oudard S, et al. Cabazitaxel versus docetaxel as first-line therapy for patients with metastatic castrationresistant prostate cancer: a randomized phase III trial-FIRSTANA. J Clin Oncol 2017; 35: 3189-97) and is an important advance for patients with a lethal disease. This result is particularly notable given the comparison to an active control, enzalutamide.

[0239] Talazoparib is the first and only PARP inhibitor plus androgen receptor pathway inhibitor (ARPI) combination to demonstrate statistically significant and clinically meaningful improvement in overall survival (OS) in patients with metastatic castrationresistant prostate cancer (mCRPC). These data support talazoparib plus enzalutamide as a standard-of-care initial treatment for mCRPC.

[0240] All publications and patent applications cited in the specification are herein incorporated by reference in their entirety. Although the foregoing invention has been described in some detail by way of illustration and example, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Claims

What is claimed is:1 . A method of treating metastatic castration-resistant prostate cancer in a subject in need thereof, 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 the administration of the talazoparib, or a pharmaceutically acceptable salt thereof, and the administration of the enzalutamide, or a pharmaceutically acceptable salt thereof, prolongs overall survival in the subject, as compared to a standard of care therapy.

2. The method of claim 1 , wherein the standard of care is: 1) abiraterone acetate and prednisone; 2) enzalutamide or a pharmaceutically acceptable salt thereof; or 3) docetaxel.

3. A method of treating metastatic castration-resistant prostate cancer in a subject in need thereof, 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 the administration of the talazoparib, or a pharmaceutically acceptable salt thereof, and the administration of the enzalutamide, or a pharmaceutically acceptable salt thereof, prolongs overall survival in the subject, wherein the overall survival is a median of 45.8 months, as compared to a median of 37.0 months for a subject who has received enzalutamide, or a pharmaceutically acceptable salt thereof, and placebo.

4. The method of claim 3, wherein the median overall survival for the subject who has received the talazoparib, or a pharmaceutically acceptable salt thereof, and the enzalutamide, or a pharmaceutically acceptable salt thereof, is 45.8 months (95% confidence interval: [39.4 months, 50.8 months]), as compared to a median of 37.0 months (95% confidence interval: [34.1 months, 40.4 months]) for the subject who has received the enzalutamide, or a pharmaceutically acceptable salt thereof, and the placebo.

5. The method of any one of claims 1 to 4, wherein the metastatic castrationresistant prostate cancer is metastatic castration-resistant prostate cancer with or without homologous recombination repair (HRR) gene mutations.

6. The method of any one of claims 1 to 5, 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 with an androgen receptor signaling inhibitor, a PARP inhibitor, cyclophosphamide, or mitoxantrone for prostate cancer; or 3) treatment with platinum-based chemotherapy within 6 months or any history of disease progression on platinum-based therapy within 6 months.

7. The method of any one of claims 1 to 6, wherein the subject is additionally receiving a gonadotropin releasing hormone analog or has had a bilateral orchiectomy.

8. The method of claim 7, wherein the gonadotropin releasing hormone analog is a gonadotropin releasing hormone agonist or a gonadotropin releasing hormone antagonist.

9. The method of any one of claims 1 to 8, wherein the subject is unselected for DNA damage response (DDR) mutation status.

10. The method of any one of claims 1 to 9, wherein the talazoparib, or pharmaceutically acceptable salt thereof, is administered at a dosage equivalent to about 0.1 mg, about 0.25 mg, about 0.35 mg or about 0.5 mg once daily of talazoparib free base.

11. The method of claim 10, wherein the talazoparib, or pharmaceutically acceptable salt thereof, is administered at a dosage equivalent to about 0.35 mg once daily of talazoparib free base and further wherein the subject has moderate renal impairment.

12. The method of any one of claims 1 to 11, wherein the talazoparib, or pharmaceutically acceptable salt thereof, is talazoparib tosylate.

13. The method of any one of claims 1 to 12, wherein the enzalutamide, or pharmaceutically acceptable salt thereof, is administered at a dosage equivalent to about 160 mg once daily of enzalutamide free base.

14. The method of claim 13, wherein the dosage of enzalutamide, or a pharmaceutically acceptable salt thereof, is reduced, if enzalutamide, or a pharmaceutically acceptable salt thereof, is dosed concomitantly with a strong CYP2C8 inhibitor.

15. The method of claim 14, wherein the dose of enzalutamide, or a pharmaceutically acceptable salt thereof, is reduced to 80 mg once daily.

16. The method of claim 13, wherein the dose of enzalutamide, or a pharmaceutically acceptable salt thereof, is increased if the enzalutamide is dosed concomitantly with a CYP3A4 inducer.

17. The method of claim 16 wherein the dose of enzalutamide, or a pharmaceutically acceptable salt thereof, is increased to 240 mg daily.

18. The method of any one of claims 1 to 17, wherein the enzalutamide, or a pharmaceutically acceptable salt thereof, is a free base.

19. The method of any of the proceeding claims, wherein the subject is a human.

20. The method of claim 19, wherein the human is an adult.

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