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

Abstract

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

Description

[Technical Field]

[0001] [Background technology]

[0002] Prostate cancer is the second leading cause of cancer death in men. The androgen receptor (AR) signaling axis, a major driver of prostate cancer growth, is targeted by castration and other systemic therapies. Initial treatment of advanced prostate cancer may require reducing the amount of androgens produced by the body, primarily in the testicles. This can be achieved by surgically removing both testicles (bilateral orchiectomy) or by using androgen deprivation therapy (sometimes called "chemical castration"), such as luteinizing hormone-releasing hormone (LHRH) agonist or antagonist drugs, which reduce natural production of testosterone. However, if a proportion of tumors progress despite castrated levels of testosterone, at that point the disease is deemed castration-resistant. Castration-resistant prostate cancer represents a fatal transition in prostate cancer progression, and the majority of patients ultimately succumb to the disease.

[0003] Antiandrogens are thought to suppress androgen activity through several different mechanisms. One example of an antiandrogen approved for treating castration-resistant prostate cancer is abiraterone acetate (marketed as Zytiga®), a steroidal CY17A1 inhibitor. One specific class of antiandrogens is androgen receptor inhibitors, also known as androgen receptor signaling inhibitors or androgen receptor antagonists, which are thought to antagonize the endogenous ligand androgen for the androgen receptor. When antagonists bind to the androgen receptor, they induce conformational changes in the receptor itself, which interfere with the transcription of important androgen-regulated genes, and thus inhibit the biological effects of androgens themselves, such as testosterone and dihydrotestosterone.

[0004] The compound enzalutamide, 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-N-methylbenzamide, or referred to as "RD162'" and "MDV3100"), is a nonsteroidal androgen receptor inhibitor having the structure:

[0005] [ka] It has.

[0006] Enzalutamide, or a pharmaceutically acceptable salt thereof, is disclosed in PCT / US2006 / 011417, published as WO2006 / 124118 on November 23, 2006, the contents of which are incorporated herein by reference.

[0007] Enzalutamide (marketed as Xtandi®) is approved for treating metastatic castration-resistant prostate cancer ("mCRPC"). However, in some subjects, their cancer may recur or the subject may develop treatment resistance. To date, the mechanisms underlying such resistance are not yet fully understood.

[0008] Poly(ADP-ribose) polymerase (PARP) is involved in the naturally occurring process of deoxyribonucleic acid (DNA) repair in cells. PARP inhibition has been shown to be an effective therapeutic strategy for tumors associated with mutations in double-stranded DNA repair genes by inducing synthetic lethality (Sonnenblick, A. et al., Nat Rev Clin Oncol., 2015.12(1), 27-4). PARP inhibition is synthetic lethal in cells harboring homozygous deletions or deleterious alterations, or both, in DNA damage response (DDR) genes directly or indirectly involved in homologous recombination repair (HRR) (Lord, CJ et al., Science, 2017;355:1152-1158).

[0009] Talazoparib is a potent, orally available PARP inhibitor that is cytotoxic (an effect termed synthetic lethality) to human cancer cell lines harboring genetic mutations that impair deoxyribonucleic acid (DNA) repair, preventing DNA repair, replication, and transcription by trapping PARP proteins on DNA.

[0010] The compounds talazoparib (also referred to as "PF-06944076," "MDV3800," and "BMN673"), which are (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one and (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one, have the structures

[0011] [ka] It is a PARP inhibitor with

[0012] Talazoparib and its pharmaceutically acceptable salts, including the tosylate salt, are disclosed in International Publications WO2010 / 017055 and WO2012 / 054698. Additional methods for preparing talazoparib and its pharmaceutically acceptable salts, including the tosylate salt, are described in International Publications WO2011 / 097602, WO2015 / 069851, and WO2016 / 019125. Additional methods for treating cancer using talazoparib and its pharmaceutically acceptable salts, including the tosylate salt, are disclosed in International Publications WO2011 / 097334 and WO2017 / 075091. Combination treatments using talazoparib and its pharmaceutically acceptable salts, including the tosylate salt, are disclosed in International Publications WO2019 / 075032 and WO2022 / 200982.

[0013] TALZENNA® (talazoparib) (0.25 mg and 1 mg capsules) is approved in multiple countries, including the United States and the European Union, and is approved or expected to be approved in other countries for the treatment of adult patients with deleterious or suspected deleterious gBRCAm HER2-negative locally advanced or metastatic breast cancer. Additional capsule strengths of 0.5 mg and 0.75 mg are approved in the United States. Talazoparib has demonstrated activity in metastatic castration-resistant prostate cancer with DDR alterations directly or indirectly linked to HRR (de Bono et al., Lancet Oncol. 2021 Sep;22(9):1250-1264). Talazoparib is in development for a variety of human cancers, both as a single agent and in combination with other agents. Summary of the Invention [Problem to be solved by the invention]

[0014] There is still a need for the improved treatment of cancer, especially for treating metastatic castration-resistant prostate cancer.The combination of the present invention is believed to have one or more advantages, such as, when compared with the treatment of any single therapeutic agent, increase in survival, including progression-free survival by imaging and overall survival; when compared with the patients who are administered Enzalutamide or its pharmaceutically acceptable salt and placebo, increase in survival, including progression-free survival by imaging and overall survival; when compared with the treatment of any single therapeutic agent, higher efficacy; the possibility of enabling improved dosing schedule; the possibility of overcoming resistance mechanism and the like. [Means for solving the problem]

[0015] 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 therapy to increase survival in subjects with metastatic castration-resistant prostate cancer. This Summary is provided to introduce, in a simplified form, a selection of concepts 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 solely as an aid in determining the scope of the claimed subject matter.

[0016] In embodiment 1 of the present invention, there is provided a method of increasing survival in a subject with 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.

[0017] In embodiment 2 of the present invention, there is provided a method of treating metastatic castration-resistant prostate cancer in a subject in need thereof, comprising: 1) orally administering talazoparib, or a pharmaceutically acceptable salt thereof, to the subject once daily; and 2) orally administering enzalutamide, or a pharmaceutically acceptable salt thereof, to the subject once daily, wherein the administration of talazoparib, or a pharmaceutically acceptable salt thereof, and the administration of enzalutamide, or a pharmaceutically acceptable salt thereof, increases survival in the subject.

[0018] In embodiment 3 of the present invention, there is provided a combination of talazoparib, or a pharmaceutically acceptable salt thereof, and enzalutamide, or a pharmaceutically acceptable salt or solvate thereof, for use in increasing survival in a subject with metastatic castration-resistant prostate cancer, wherein the talazoparib, or a pharmaceutically acceptable salt thereof, is administered orally to the subject once daily, and the enzalutamide, or a pharmaceutically acceptable salt thereof, is administered orally to the subject once daily.

[0019] In embodiment 4 of the present invention, there is provided a combination of talazoparib, or a pharmaceutically acceptable salt thereof, and enzalutamide, or a pharmaceutically acceptable salt or solvate thereof, for use in treating a subject with metastatic castration-resistant prostate cancer, wherein the talazoparib, or a pharmaceutically acceptable salt thereof, is orally administered to the subject once daily, and the enzalutamide, or a pharmaceutically acceptable salt thereof, is orally administered to the subject once daily, and wherein said administration of the talazoparib, or a pharmaceutically acceptable salt thereof, and said administration of the enzalutamide, or a pharmaceutically acceptable salt thereof, increases survival in the subject.

[0020] Embodiments of the present invention are described below, where, for convenience, embodiments 1, 2, 3, and 4 (E1, E2, E3, and E4) are identical to the embodiments presented above.

[0021] 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. DETAILED DESCRIPTION OF THE INVENTION

[0022] The present invention may be understood more readily by reference to the following detailed description of embodiments of the invention and the examples included herein. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0023] E1 A method of increasing survival in a subject with metastatic castration-resistant prostate cancer as defined above.

[0024] E2 A method of treating metastatic castration-resistant prostate cancer in a subject in need thereof, wherein said treatment increases survival in said subject as defined above.

[0025] E3 A combination as defined above for use in increasing survival in a subject with metastatic castration-resistant prostate cancer.

[0026] E4 A combination for use in treating a subject having metastatic castration-resistant prostate cancer in a subject, wherein administration of said combination increases survival in said subject, as defined above.

[0027] E5 5. The method or combination for use according to any one of embodiments 1 to 4, wherein said metastatic castration-resistant prostate cancer is metastatic castration-resistant prostate cancer with or without homologous recombination repair (HRR) gene mutation.

[0028] E6 The method or combination for use of any one of embodiments 1 to 5, wherein the talazoparib, or a pharmaceutically acceptable salt thereof, and the enzalutamide, or a pharmaceutically acceptable salt thereof, are administered simultaneously.

[0029] E7 The method or combination for use 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 has no history of disease progression during platinum-based therapy within 6 months.

[0030] E8 The method or combination for use according to embodiment 7, wherein the subject has not received systemic cancer treatment for non-metastatic castration-resistant prostate cancer or metastatic castration-resistant prostate cancer.

[0031] E9 8. The method or combination for use of embodiment 7, wherein the subject has not been treated with an androgen receptor signaling inhibitor, a PARP inhibitor, cyclophosphamide, or mitoxantrone for prostate cancer.

[0032] E10 8. The method or combination for use according to embodiment 7, wherein the subject has not been treated with an androgen receptor signaling inhibitor.

[0033] E11 The method or combination for use according to any one of embodiments 7, 9 or 10, wherein said androgen receptor signaling inhibitor is a second generation androgen receptor inhibitor.

[0034] E12 The method or combination for use of embodiment 11, wherein said second-generation androgen receptor inhibitor is enzalutamide, apalutamide, darolutamide, or abiraterone acetate.

[0035] E13 The method or combination for use according to embodiment 12, wherein said second-generation androgen receptor inhibitor is enzalutamide, apalutamide, or darolutamide.

[0036] E14 The method or combination for use of embodiment 7, wherein the subject has not been treated with platinum-based chemotherapy within 6 months or has no history of disease progression during platinum-based therapy within 6 months.

[0037] E15 15. The method or combination for use according to any one of embodiments 1 to 14, wherein the subject is concurrently receiving a gonadotropin-releasing hormone analogue or has undergone bilateral orchiectomy.

[0038] E16 16. The method or combination for use according to embodiment 15, wherein the subject is additionally administered a gonadotropin-releasing hormone analogue.

[0039] E17 The method or combination for use according to embodiment 15 or 16, wherein said gonadotropin-releasing hormone analogue is a gonadotropin-releasing hormone agonist.

[0040] E18 17. The method or combination for use according to embodiment 15 or 16, wherein said gonadotropin-releasing hormone analogue is a gonadotropin-releasing hormone antagonist.

[0041] E19 The method or combination for use according to embodiment 15, wherein the subject has undergone bilateral orchiectomy.

[0042] E20 20. The method or combination for use of any one of embodiments 1 to 19, wherein the subject has progressive disease as defined by one or more of the following: 1) prostate-specific antigen progression as defined by rising prostate-specific antigen levels on at least two of three consecutive assessments with at least seven days between assessments; 2) soft tissue disease progression as defined by RECIST 1.1; and 3) bone disease progression as defined by Prostate Cancer Clinical Trials Working Group 3 with two or more new metastatic bone lesions on a whole-body radionuclide bone scan.

[0043] E21 21. The method or combination for use according to any one of embodiments 1 to 20, wherein the subject has an Eastern Cooperative Oncology Group (ECOG) performance status of ≦1.

[0044] E22 22. The method or combination for use according to any one of embodiments 1 to 21, wherein said subject has not been selected for DNA damage response (DDR) mutation status.

[0045] E23 23. The method or combination for use according to any one of embodiments 1 to 22, wherein survival is progression-free survival by imaging.

[0046] E24 The method or combination for use of embodiment 23, wherein the method or combination for use increases radiographic progression-free survival when compared to subjects receiving enzalutamide, or a pharmaceutically acceptable salt thereof, and a placebo.

[0047] E25 The method or combination for use according to embodiment 23, wherein the imaging-based progression-free survival is increased when compared to subjects receiving enzalutamide, or a pharmaceutically acceptable salt thereof.

[0048] E26 23. The method or combination for use according to any one of embodiments 1 to 22, wherein survival is overall survival.

[0049] E27 27. The method or combination for use according to embodiment 26, wherein overall survival is increased when compared to subjects receiving enzalutamide, or a pharmaceutically acceptable salt thereof, and a placebo.

[0050] E28 27. The method or combination for use according to embodiment 26, wherein overall survival is increased when compared to subjects receiving enzalutamide, or a pharmaceutically acceptable salt thereof.

[0051] E29 23. The method or combination for use of any one of embodiments 1 to 22, wherein survival is at a significantly reduced risk of disease progression or death when compared to subjects receiving enzalutamide, or a pharmaceutically acceptable salt thereof, and a placebo.

[0052] E30 23. The method or combination for use of any one of embodiments 1 to 22, wherein survival is at a significantly reduced risk of disease progression or death when compared to subjects receiving enzalutamide, or a pharmaceutically acceptable salt thereof.

[0053] E31 The method or combination for use according to embodiment 29, wherein said significantly reduced risk of disease progression or death is a 37% reduction when compared to subjects receiving enzalutamide, or a pharmaceutically acceptable salt thereof, and a placebo.

[0054] E32 The method or combination for use according to embodiment 29, wherein said significantly reduced risk of disease progression or death is a reduction of at least 37% when compared to subjects receiving enzalutamide, or a pharmaceutically acceptable salt thereof, and a placebo.

[0055] E33 The method or combination for use according to embodiment 30, wherein said significantly reduced risk of disease progression or death is a 37% reduction compared to subjects receiving enzalutamide, or a pharmaceutically acceptable salt thereof.

[0056] E34 The method or combination for use according to embodiment 30, wherein said significantly reduced risk of disease progression or death is a reduction of at least 37% when compared to a subject receiving enzalutamide, or a pharmaceutically acceptable salt thereof.

[0057] E35 The method or combination for use of any one of embodiments 1 to 34, wherein the talazoparib, or a 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 of talazoparib free base once daily.

[0058] E36 The method or combination for use of embodiment 35, wherein said talazoparib, or a pharmaceutically acceptable salt thereof, is administered in a dosage equivalent to about 0.1 mg of talazoparib free base once daily.

[0059] E37 The method or combination for use according to embodiment 35, wherein said talazoparib, or a pharmaceutically acceptable salt thereof, is administered in a dosage equivalent to about 0.25 mg of talazoparib free base once daily.

[0060] E38 The method or combination for use according to embodiment 35, wherein said talazoparib, or a pharmaceutically acceptable salt thereof, is administered in a dosage equivalent to about 0.35 mg of talazoparib free base once daily.

[0061] E39 The method or combination for use according to embodiment 38, wherein the subject has moderate renal impairment.

[0062] E40 The method or combination for use according to embodiment 35, wherein said talazoparib, or a pharmaceutically acceptable salt thereof, is administered in a dosage equivalent to about 0.5 mg of talazoparib free base once daily.

[0063] E41 The method or combination for use according to any one of embodiments 1 to 40, wherein said talazoparib, or a pharmaceutically acceptable salt thereof, is talazoparib tosylate.

[0064] E42 The method or combination for use according to any one of embodiments 1 to 41, wherein the enzalutamide, or a pharmaceutically acceptable salt thereof, is administered at a dosage equivalent to about 160 mg of enzalutamide free base once daily.

[0065] E43 The method or combination for use according to embodiment 42, wherein the dosage of enzalutamide, or a pharmaceutically acceptable salt thereof, is reduced when enzalutamide, or a pharmaceutically acceptable salt thereof, is administered concomitantly with a strong CYP2C8 inhibitor.

[0066] E44 The method or combination for use according to embodiment 42, wherein the dose of enzalutamide, or a pharmaceutically acceptable salt thereof, is reduced to 80 mg once daily.

[0067] E45 The method or combination for use according to embodiment 42, wherein the dose of enzalutamide, or a pharmaceutically acceptable salt thereof, is increased when the enzalutamide is administered concomitantly with a CYP3A4 inducer.

[0068] E46 The method or combination for use according to embodiment 42, wherein the dose of enzalutamide, or a pharmaceutically acceptable salt thereof, is increased to 240 mg once daily.

[0069] E47 The method or combination for use according to any one of embodiments 1 to 46, wherein said enzalutamide, or a pharmaceutically acceptable salt thereof, is the free base.

[0070] E48 48. The method or combination for use according to any one of embodiments 1 to 47, comprising administering a further anti-cancer drug.

[0071] E49 49. The method or combination for use according to embodiment 48, wherein said additional anti-cancer agent is selected from the group consisting of an anti-tumor agent, an anti-angiogenic agent, a signal transduction inhibitor, and an anti-proliferative agent.

[0072] E50 10. The method or combination for use according to any preceding embodiment, wherein the subject is a human.

[0073] E51 The method or combination for use according to embodiment 50, wherein said human is an adult.

[0074] Each embodiment described herein may be combined with any other embodiment described herein that is not inconsistent with the embodiment with which it is combined.

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

[0076] The invention described herein may be suitably practiced in the absence of any element not specifically disclosed herein.

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

[0078] As used herein, the term "about," when used to modify a parameter defined by a numerical value (e.g., the dose of talazoparib, or a pharmaceutically acceptable salt thereof), means that the parameter can vary by 10% above or below the stated numerical value for that parameter. For example, a dose of about 5 mg means 5 mg ± 10%, i.e., can vary between 4.5 mg and 5.5 mg.

[0079] As used herein, terms including, but not limited to, "agent," "composition," "compound," "drug," "pharmaceutical agent," and "therapeutic agent" may be used interchangeably to refer to compounds included in the methods and uses of the present invention, such as antiandrogens, androgen receptor signaling inhibitors, androgen deprivation therapy, talazoparib, and enzalutamide.

[0080] For the purposes of the present invention, the terms "DDR mutation," "DDR modification," "HRR mutation," "HRR modification," and "HRR gene modification" refer to modifications / mutations in genes directly or indirectly involved in homologous recombination repair (HRR). While less scientifically robust than the term "DNA damage response," it is commonly understood that "DDR" can also be referred to as "DNA damage repair" or "DNA repair." "DDR deficiency" refers to a genetic mutation associated with a defect in deoxyribonucleic acid (DNA) damage repair. A "DDR-deficient patient population" or "HRR-deficient patient population" refers to a patient population with a genetic mutation associated with a defect in deoxyribonucleic acid (DNA) damage repair. DDR is a network of pathways that evolve to repair damaged DNA. These include mismatch repair, base excision repair, and homologous recombination repair (HRR), among others. HRR is particularly important in maintaining genome integrity given its high fidelity in repairing double-stranded DNA breaks. Inhibition of PARP leads to DNA stress due to the accumulation of single-stranded DNA breaks and PARP trapping, ultimately resulting in double-stranded DNA breaks. Therefore, PARP inhibitors are selectively lethal to cancer cells that lack HRR, which is an example of synthetic lethality, a mechanism in which the loss of function of one gene or gene product alone has little effect, but becomes toxic when combined with the loss of 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.Homology-directed recombination repair deficiency can be determined using next-generation sequencing (NGS).

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

[0082] As used herein, a "systemic therapy" for mCRPC is a drug or therapeutic agent used to manage mCRPC. Medicines or drugs are considered systemic therapies because whenever they can be placed in the body, they circulate throughout the body and attack cancer cells.

[0083] antiandrogens As used herein, the terms "antiandrogen" and "antiandrogens" refer to compounds that prevent androgens, such as testosterone and dihydrotestosterone (DHT), and the like, from mediating their biological effects in the body.Antiandrogens can act through one or more of the following hormone mechanisms of action: blocking and / or inhibiting and / or regulating androgen receptor (AR); inhibiting androgen production; suppressing androgen production; degrading AR, inhibiting nuclear translocation, inhibiting the binding of AR to nuclear DNA, and the like. Antiandrogens include, but are not limited to, steroidal androgen receptor inhibitors (e.g., cyproterone acetate, spironolactone, megestrol acetate, chlormadinone acetate, oxendolone, and osaterone acetate), nonsteroidal androgen receptor inhibitors (e.g., enzalutamide, bicalutamide, nilutamide, flutamide, topirutamide, apalutamide, and darolutamide), androgen synthesis inhibitors, androgen receptor degraders, and the like. Antiandrogens include androgen receptor inhibitors or androgen receptor signaling inhibitors, and these terms are used interchangeably. Androgen receptor inhibitors can be determined by methods known to those skilled in the art, for example, using in vitro assays and / or cellular ligand binding assays and / or gene expression assays, such as those disclosed in Tran C. et al., Science, 2009, 324, 787-790.

[0084] First-generation androgen receptor signaling inhibitors include bicalutamide, nilutamide, or flutamide.

[0085] Second-generation androgen receptor signaling inhibitors include enzalutamide, apalutamide, and darolutamide.

[0086] Another second-generation androgen receptor signaling inhibitor is abiraterone, or a pharmaceutically acceptable salt or solvate thereof, such as abiraterone acetate (sold under the trademark Zytiga), a steroidal CY17A1 inhibitor disclosed in U.S. Patent No. 5,604,213, published February 18, 1997, the contents of which are incorporated herein by reference. This second-generation AR inhibitor prevents androgen biosynthesis.

[0087] An example of an androgen receptor inhibitor is N-desmethylenzalutamide, also known as 4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]-2-fluorobenzamide; or MII, which was disclosed in PCT / US2010 / 025283, published September 2, 2010, as WO 2010 / 099238, the contents of which are incorporated herein by reference.

[0088] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0089] An example of an androgen receptor inhibitor is ARN-509, disclosed in PCT / US2007 / 007485 published November 8, 2007 as WO 2007 / 126765, the contents of which are incorporated herein by reference; or apalutamide, also known as 4-{7-[6-cyano-5-(trifluoromethyl)pyridin-3-yl]-8-oxo-6-thioxo-5,7-diazaspiro[3,4]octan-5yl}-2-fluoro-N-methylbenzamide (commercially available as ERLEADA®):

[0090] [ka] or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, an androgen receptor inhibitor useful in the present invention is a pharmacologically active metabolite of apalutamide, or a pharmaceutically acceptable salt or solvate thereof.

[0091] An example of an androgen receptor inhibitor is darolutamide (commercially available as NUBEQA®), also known as N-[(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl]-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide, which was disclosed in PCT / FI2010 / 000065 published May 5, 2011 as WO 2011 / 051540, the contents of which are incorporated herein by reference.

[0092] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0093] An example of an androgen receptor inhibitor is bicalutamide, commercially available as Casodex®, disclosed in U.S. Patent No. 4,636,505, published January 13, 1987, the contents of which are incorporated herein by reference:

[0094] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0095] An example of an androgen receptor inhibitor is nilutamide (marketed as Nilandron®), or a pharmaceutically acceptable salt or solvate thereof.

[0096] An example of an androgen receptor inhibitor is flutamide (marketed as Eulexin®), or a pharmaceutically acceptable salt or solvate thereof.

[0097] Unless otherwise indicated, all references herein to antiandrogens and androgen receptor inhibitors include references to salts, solvates, hydrates and complexes thereof, and solvates, hydrates and complexes of salts thereof, including polymorphs, stereoisomers, and isotopically labeled versions thereof.

[0098] Androgen deprivation therapy Androgen deprivation therapy, also known as ADT, uses surgery or medications to reduce the levels of androgens made by the testicles.

[0099] An example of surgical ADT is bilateral orchiectomy.

[0100] Examples of pharmaceutical ADTs include luteinizing hormone-releasing hormone (LHRH) agonists, LHRH antagonists, gonadotropin-releasing hormone (GnRH) agonists and GnRH antagonists.

[0101] Other examples of pharmaceutical androgen deprivation therapy include leuprolide (also known as leuprorelin, e.g., Lupron or Eligardor Viadur, and the like); buserelin (e.g., Suprefact); gonadorelin; goserelin (e.g., Zoladex); histrelin (e.g., Vantas); nafarelin; triptorelin (e.g., Trelstar); deslorelin; fertirelin; abarelix (e.g., Plenaxis); cetrorelix; degarelix (e.g., Firmagon); ganirelix; ozalelix; elagolix (e.g., Orilissa); relugolix; and linzagolix.

[0102] salt Salts encompassed within the term "pharmaceutically acceptable salt" generally refer to compounds of the present invention 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 obtain a salt of a compound of the present invention suitable for administration to a subject or patient.

[0103] 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, hydrogensulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, These include lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, 1,5-naphthalenedisulfonate and xinofoate.

[0104] 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.

[0105] Hemisalts of acids and bases, such as hemisulfates and hemicalcium salts, may also be formed.

[0106] For a review of suitable salts, see Paulekun, GS 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.

[0107] Administration and Dosage As used herein, the terms "subject" and "patient" are used interchangeably to refer to any animal, including mammals. Mammals according to the present invention include dogs, cats, cows, goats, horses, sheep, pigs, rodents, rabbits, primates, humans, and the like. In one embodiment, humans are the preferred subject. In one embodiment, the "subject" or "patient" is an adult.

[0108] "Subjects" or "patients" of the combination of the present invention may undergo imaging during treatment to assess their response to treatment. Response criteria, specifically, Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), are standardized and can be used at various time points to categorize responses into categories, such as complete response (CR), partial response (PR), stable disease (SD), or disease progression. At the clinical trial level, categorical responses for all patients are counted toward the image-based clinical trial endpoint.

[0109] A "subject" or "patient" according to the combination of the present invention is defined as: 1) histologically or cytologically confirmed adenocarcinoma of the prostate without small cell or signet ring cell phenotype; 2) asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer; 3) DNA damage repair (DDR) deficiency as assessed centrally by a next-generation sequencing (NGS) biomarker mutation panel containing 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) not having undergone bilateral orchiectomy. 5) Ongoing androgen deprivation therapy with gonadotropin-releasing hormone (GnRH) agonists or antagonists in patients with metastatic disease; 6) Metastatic disease in bone as documented by bone scan or in soft tissue as documented by 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 rising PSA levels on at least two of three consecutive assessments with at least seven days between assessments; ii) RECIST 1.1. Soft tissue disease progression as defined by iii) bone disease progression as defined by the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) with two 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) may have a life expectancy ≧12 months as assessed by the investigator.

[0110] " Subject " or " patient " of the combination of the present invention may not be selected for DNA damage response (DDR) mutation status, or alternatively, may not be selected for HRR gene alteration status. " Not selected for DDR mutation status " and " not selected 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 with metastatic castration-resistant prostate cancer are eligible for treatment with the combination of the present invention, regardless of DDR mutation status or HRR gene alteration status.

[0111] As used herein, the term "cancer" refers to or describes a physiological condition in a subject that is typically characterized by uncontrolled cell proliferation.Cancer refers to any malignant and / or invasive growth or tumor resulting from abnormal cell proliferation.The term "metastatic" in relation to cancer includes, but is not limited to, cancer that has spread from the place where it began to other parts of the body, recurrence from the original primary cancer after remission, and second primary cancer, which is a new primary cancer in a subject with a history of a previous cancer of a different type from the later one.Those skilled in the art will be able to recognize and diagnose metastatic cancer in a patient.

[0112] "Treating" or "treating" metastatic cancer, such as mCRPC, as used herein, means administering a combination therapy according to the present invention to a subject or patient having or diagnosed with cancer to achieve at least one positive therapeutic effect, such as, for example, a reduction in the number of cancer cells, a reduction in tumor size, a decrease in the rate of cancer cell invasion into surrounding organs, or a decrease in the rate of tumor metastasis or tumor growth, or a reversal, alleviation, inhibition, or prevention of the progression of a disorder or condition to which such term applies, or one or more symptoms of such a disorder or condition. As "treating" is defined immediately above, the term "treatment" or "therapy," as used herein, refers to the act of treating, unless otherwise indicated. For purposes of the present invention, advantageous or desired clinical results include, but are not limited to, one or more of the following: reduction in the proliferation (or destruction) of neoplastic or cancerous cells; inhibition of metastatic or neoplastic cells; reduction or decrease in tumor size; remission of cancer; reduction of symptoms resulting from cancer; improvement in the quality of life of those suffering from cancer; reduction in the dose of other drugs required to treat cancer; delay in the progression of cancer; cure of cancer; overcoming one or more resistance mechanisms of cancer; and / or prolongation of survival of patients with cancer. Positive therapeutic effects in cancer can be measured in several ways (see, for example, W.A. Weber, J.Nucl.Med.50:1S-10S(2009)).

[0113] In one embodiment, the treatment achieved by the combination of the present invention is an increase in survival of a subject.

[0114] In one embodiment, increased survival is measured by any of the following: progression-free survival (PFS), radiological PFS (rPFS), and overall survival (OS). PFS, rPFS, and OS are clinically meaningful endpoints for measuring increased survival in patients treated with the combination of the present invention. PFS is the length of time during and after treatment for a disease, such as cancer, that a patient is alive with the disease but has not worsened. OS is the length of time from either the date of diagnosis or the start of treatment for a disease, such as cancer, that a patient diagnosed with the disease is still alive. In clinical trials, measuring PFS and OS is a way to see how well a new treatment is working. For purposes of the clinical trials described herein, rPFS refers to the time from the date of randomization to first objective evidence of radiological progression as assessed in soft tissue by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) or in bone (subsequent confirmation) by Blinded Independent Central Review (BICR) according to the Prostate Cancer Clinical Trials Working Group (PCWG3) guidelines, or death, whichever occurs first. For purposes of the clinical trials described herein, OS refers to the time from the date of randomization to death from any cause.

[0115] In one embodiment, progression-free survival is increased compared to subjects administered enzalutamide, or a pharmaceutically acceptable salt thereof, and a placebo. In one embodiment, progression-free survival is increased compared to subjects administered enzalutamide, or a pharmaceutically acceptable salt thereof, and a placebo. For purposes of this invention, placebo treatment means that patients with metastatic castration-resistant prostate cancer are not treated with talazoparib.

[0116] In one embodiment, imaging-based progression-free survival is increased compared to subjects administered enzalutamide, or a pharmaceutically acceptable salt thereof, and a placebo. In one embodiment, imaging-based progression-free survival is increased compared to subjects administered enzalutamide, or a pharmaceutically acceptable salt thereof, and a placebo. For purposes of this invention, placebo treatment means that patients with metastatic castration-resistant prostate cancer are not treated with talazoparib.

[0117] The term "amount" for use and for treating a subject refers to an amount, in single or multiple doses, that alone or in combination with one or more other drugs, produces a detectable response of any duration (temporary, medium-term, or long-term), a desired outcome in the subject, an objective or subjective benefit to the subject of any measurable or detectable degree, or for any duration (e.g., remission or cure over hours, days, months, or years). Such an amount is typically effective to measurably alleviate the disease, or one, several, or all adverse effects / symptoms, prognosis, or complications of the disease, although reducing or inhibiting the progression or worsening of the disease, or resulting in a stable (i.e., non-worsening) state of the disease, is also considered a satisfactory result. The term "therapeutically effective amount" also refers to an amount of drug that, when administered to a subject, alone or in combination with one or more other drugs, is effective to produce a desired therapeutic effect, for example, to stop or shrink the growth of a cancerous tumor. With respect to the treatment of cancer, a therapeutically effective amount refers to an amount that has the effect of (1) reducing tumor size, (2) inhibiting (i.e., slowing to some extent, preferably stopping) the appearance of tumor metastases, (3) inhibiting (i.e., slowing to some extent, preferably stopping) tumor growth or tumor invasiveness to some extent, and / or (4) alleviating to some extent (or preferably eliminating) one or more signs or symptoms associated with cancer. The therapeutic or pharmacological effectiveness of doses and administration regimens can also be characterized as their ability to induce, enhance, maintain, or prolong disease control and / or overall survival in patients with these specific tumors, which can be measured as an increase in the time before disease progression.

[0118] As used herein, "ameliorate" refers to any decrease in the degree, severity, frequency, and / or likelihood of a symptom or clinical sign characteristic of a particular disease. "Symptom" refers to any subjective evidence of a disease or condition in a subject.

[0119] In one embodiment, the amount or daily dosage of talazoparib, or a pharmaceutically acceptable salt thereof, preferably the tosylate salt thereof, to be administered to a subject is equivalent to about 0.1 mg to about 1 mg of talazoparib free base once daily. In one embodiment, talazoparib or a pharmaceutically acceptable salt thereof, preferably the tosylate salt thereof, is administered in a daily dosage equivalent to about 0.1 mg of talazoparib free base once daily, about 0.25 mg of talazoparib free base once daily, about 0.35 mg of talazoparib free base once daily, about 0.5 mg of talazoparib free base once daily, about 0.75 mg of talazoparib free base once daily, or about 1 mg of talazoparib free base once daily. In one embodiment, talazoparib or its pharmaceutically acceptable salt, preferably its tosylate, is administered in a daily dosage equivalent to about 0.1 mg of talazoparib free base once a day; about 0.25 mg of talazoparib free base once a day; about 0.35 mg of talazoparib free base once a day; or about 0.5 mg of talazoparib free base once a day. In one embodiment, talazoparib or its pharmaceutically acceptable salt, preferably its tosylate, is administered in a daily dosage equivalent to about 0.1 mg of talazoparib free base once a day. In one embodiment, talazoparib or its pharmaceutically acceptable salt, preferably its tosylate, is administered in a daily dosage equivalent to about 0.25 mg of talazoparib free base once a day. In one embodiment, talazoparib or a pharmaceutically acceptable salt thereof, preferably its tosylate, is administered in a daily dosage equivalent to about 0.35 mg of talazoparib free base once daily. In one embodiment, talazoparib or a pharmaceutically acceptable salt thereof, preferably its tosylate, is administered in a daily dosage equivalent to about 0.5 mg of talazoparib free base once daily. In one embodiment, talazoparib or a pharmaceutically acceptable salt thereof, preferably its tosylate, is administered in a daily dosage equivalent to about 0.75 mg of talazoparib free base once daily. In one embodiment, talazoparib or a pharmaceutically acceptable salt thereof, preferably its tosylate, is administered in a daily dosage equivalent to about 1 mg of talazoparib free base once daily.

[0120] In one embodiment, the amount or daily dosage of talazoparib, or a pharmaceutically acceptable salt thereof, preferably its tosylate salt, to be administered to a subject is about 0.1 mg to about 1 mg, or equivalent, of talazoparib free base once daily. In one embodiment, talazoparib or a pharmaceutically acceptable salt thereof, preferably its tosylate salt, is administered in a daily dosage of about 0.1 mg or equivalent of talazoparib free base once daily; up to about 0.25 mg or equivalent of talazoparib free base once daily; up to about 0.35 mg or equivalent of talazoparib free base once daily; up to about 0.5 mg or equivalent of talazoparib free base once daily; up to about 0.75 mg or equivalent of talazoparib free base once daily; or up to about 1 mg or equivalent of talazoparib free base once daily. In one embodiment, talazoparib or a pharmaceutically acceptable salt thereof, preferably its tosylate, is administered at a daily dosage of about 0.1 mg or equivalent of talazoparib free base once daily; up to about 0.25 mg or equivalent of talazoparib free base once daily; up to about 0.35 mg or equivalent of talazoparib free base once daily; or up to about 0.5 mg or equivalent of talazoparib free base once daily. In one embodiment, talazoparib or a pharmaceutically acceptable salt thereof, preferably its tosylate, is administered at a daily dosage of about 0.1 mg or equivalent of talazoparib free base once daily. In one embodiment, talazoparib or a pharmaceutically acceptable salt thereof, preferably its tosylate, is administered at a daily dosage of about 0.25 mg or equivalent of talazoparib free base once daily. In one embodiment, talazoparib or a pharmaceutically acceptable salt thereof, preferably its tosylate, is administered at a daily dosage of about 0.35 mg or equivalent of talazoparib free base once daily. In one embodiment, talazoparib or a pharmaceutically acceptable salt thereof, preferably its tosylate, is administered at a daily dosage of about 0.5 mg or equivalent of talazoparib free base once daily. In one embodiment, talazoparib or a pharmaceutically acceptable salt thereof, preferably its tosylate, is administered at a daily dosage of about 0.75 mg or equivalent of talazoparib free base once daily. In one embodiment, talazoparib or a pharmaceutically acceptable salt thereof, preferably its tosylate, is administered at a daily dosage of about 1 mg or equivalent of talazoparib free base once daily.

[0121] The dosage amount provided herein refers to the dose of talazoparib free base form or is calculated as the free base equivalent of the talazoparib salt form that is administered.For example, the dosage amount or amount of talazoparib such as 0.25, 0.35 mg or 0.5 mg refers to the free base equivalent amount.

[0122] In one embodiment, enzalutamide is administered at a daily dose of 160 mg once daily according to the XTANDI (Copyright) US approved label. When enzalutamide is administered simultaneously with a strong CYP2C8 inhibitor, for example, those skilled in the art can easily determine the dosage adjustment of enzalutamide according to the complete XTANDI (Copyright) prescribing information, and then the dose of enzalutamide should be reduced to, for example, 80 mg once daily according to the complete prescribing information; or alternatively, when enzalutamide is administered simultaneously with a CYP3A4 inducer, the dose of enzalutamide should be increased to, for example, 240 mg per day according to the complete prescribing information.

[0123] In a preferred embodiment, Enzalutamide or its pharmaceutically acceptable salt is administered at a daily dosage of about 160mg once a day.The dosage amount presented herein refers to the dosage of Enzalutamide free base form, or is calculated as the free base equivalent amount of Enzalutamide salt form that is administered.For example, the dosage amount or amount of Enzalutamide, such as 160mg, refers to free base or equivalent amount.

[0124] The recommended dose of talazoparib is 0.5 mg administered orally once daily in combination with 160 mg of oral enzalutamide once daily until disease progression or unacceptable toxicity occurs. This dosing regimen can be adjusted to obtain the optimal therapeutic response. For example, the dose can be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. To manage adverse reactions, the decision should be made to discontinue treatment with or without dose reduction based on severity and clinical symptoms. 0.35 mg, 0.25 mg, and 0.1 mg capsules are available for dose reduction.

[0125] In patients with mCRPC and moderate renal impairment (CLcr 30-59 mL / min), the recommended talazoparib dose is 0.35 mg once daily in combination with oral enzalutamide 160 mg once daily.In patients with severe renal impairment (CLcr 15-29 mL / min), the recommended talazoparib dose is 0.25 mg once daily in combination with oral enzalutamide 160 mg once daily.

[0126] In patients with mCRPC, the talazoparib dose should be reduced to 0.35 mg once daily in combination with oral enzalutamide 160 mg once daily when coadministered with certain P-gp inhibitors, such as itraconazole, amiodarone, carvedilol, clarithromycin, itraconazole, and verapamil. If a P-gp inhibitor is discontinued, the talazoparib dose (after 3 to 5 half-lives of the P-gp inhibitor) should be increased to the dose used before the P-gp inhibitor was initiated.

[0127] The compounds of the present invention can be administered orally, either by swallowing, so that the compound enters the gastrointestinal tract, or by using buccal or sublingual administration, by which the compound enters the blood stream directly from the mouth.

[0128] In one preferred embodiment, the daily dose of talazoparib, or a pharmaceutically acceptable salt thereof, is administered orally.

[0129] In one preferred embodiment, the daily dose of enzalutamide, or a pharmaceutically acceptable salt thereof, is administered orally.

[0130] Talazoparib or a pharmaceutically acceptable salt may be present in a pharmaceutical composition containing a pharmaceutically acceptable excipient. A "pharmaceutically acceptable excipient" refers to an ingredient that may be included in the compositions described herein, is physiologically suitable for pharmaceutical use, and does not cause significant adverse or therapeutic effects in the subject. The term "excipient" is used herein to describe any ingredient other than the compound of the present invention. The choice of excipient will largely 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.

[0131] The amount of talazoparib, or a pharmaceutically acceptable salt, in the pharmaceutical composition can be any amount disclosed herein.

[0132] The compound of the method, use or combination of the present invention can be formulated before administration.Preferably, the formulation will be adapted to a specific mode of administration.These compounds can be formulated with pharmaceutically acceptable additives as known in the art, and can be administered in a wide variety of dosage forms as known in the art.The 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 non-aqueous oral solutions and suspensions, which are packaged in containers suitable for dividing into individual doses.

[0133] In another embodiment, the dosage of the compounds or pharmaceutical compositions described herein can vary within a range depending on the dosage form used and the route of administration utilized. In another embodiment, the amount of the compounds or pharmaceutical compositions described herein administered to a subject can depend on factors known to skilled practitioners, including the bioactivity and bioavailability of the compound (e.g., the half-life and stability of the compound in the body), the chemical properties of the compound (e.g., molecular weight, hydrophobicity, and solubility), the route and frequency of administration, and the like. Furthermore, it will be understood that the specific dose of a pharmaceutical composition comprising a compound as disclosed herein can depend on various factors, including the subject's physical condition (e.g., age, sex, weight), and the subject's medical history (e.g., medications being taken, health conditions, other diseases or disorders). The exact dose of the pharmaceutical composition to be administered to a subject can be determined by methods known to skilled practitioners, such as pharmacologists or anesthesiologists.

[0134] Repeated administration or dosing regimen can also be carried out as needed to achieve the desired reduction or decline of cancer cells.As used herein, "continuous dosing schedule" refers to a dosing or dosing regimen that does not have dose interruption, for example, does not have days without treatment.Repeated 28-day treatment cycles without dose interruption between treatment cycles is an example of a continuous dosing schedule.In one embodiment, the compounds of the combination of the present invention can be administered in a continuous dosing schedule.In one embodiment, the compounds of the combination of the present invention can be administered simultaneously in a continuous dosing schedule.

[0135] Treatment Methods and Uses 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.

[0136] In one embodiment, the disclosure provides a method of increasing survival in a subject with 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.

[0137] In one embodiment, the present disclosure provides a method of increasing survival in a subject with metastatic castration-resistant prostate cancer, comprising: 1) orally administering to said subject talazoparib, or a pharmaceutically acceptable salt thereof, once daily; in combination with 2) orally administering to said subject enzalutamide, or a pharmaceutically acceptable salt thereof, once daily.

[0138] In one embodiment, the present disclosure provides a method of treating metastatic castration-resistant prostate cancer in a subject in need thereof, comprising: 1) orally administering talazoparib, or a pharmaceutically acceptable salt thereof, to the subject once daily; and 2) orally administering enzalutamide, or a pharmaceutically acceptable salt thereof, to the subject once daily, wherein the administration of talazoparib, or a pharmaceutically acceptable salt thereof, and the administration of enzalutamide, or a pharmaceutically acceptable salt thereof, increases survival in the subject.

[0139] In one embodiment, the present disclosure provides a method of treating metastatic castration-resistant prostate cancer in a subject in need thereof, comprising: 1) orally administering to said subject talazoparib, or a pharmaceutically acceptable salt thereof, once daily, in combination with 2) orally administering to said subject enzalutamide, or a pharmaceutically acceptable salt thereof, once daily, wherein said combination increases survival in said subject.

[0140] The term "combination," as used herein, unless otherwise indicated, refers to a combination of drugs administered close enough in time to affect the treatment of a subject. The combination of the present invention can be administered simultaneously (i.e., synchronously) or sequentially. Examples of "in combination" include, but are not limited to, "co-administration," "simultaneous administration," "synchronous administration," "sequential administration," and "administered synchronously." The combination of the present invention can be administered simultaneously in the same formulation. The combination of the present invention can be administered simultaneously (i.e., synchronously) in separate formulations. The combination of the present invention can be administered sequentially, i.e., talazoparib is administered first, followed by enzalutamide after a specific period, such as one hour; or enzalutamide is administered first, followed by talazoparib after a specific period, such as one hour. The combination of the present invention is preferably administered simultaneously.

[0141] In one embodiment, the present 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.

[0142] In another aspect, the 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.

[0143] In one embodiment, the combination therapy is administered to subjects who have not received: 1) prior systemic cancer treatment for non-metastatic castration-resistant 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 of the last dose or have any history of disease progression during platinum-based therapy within 6 months of the last dose.

[0144] Further treatments In one embodiment, the methods and combination therapies of the present invention may additionally comprise administering an additional anti-cancer agent, such as an anti-tumor agent, an anti-angiogenic agent, a signal transduction inhibitor, and an anti-proliferative agent. In some such embodiments, the anti-tumor agent is selected from the group consisting of an anti-mitotic agent, an alkylating agent, an antimetabolite, an intercalating antibiotic, a growth factor inhibitor, radiation, a cell cycle inhibitor, an enzyme, a topoisomerase inhibitor, a biological response modifier, an antibody, a cytotoxin, an anti-hormone, an androgen deprivation therapy, and an anti-androgen.

[0145] In one embodiment, the methods and combination therapies of the present invention may additionally comprise administering an additional active agent, wherein the additional active agent is androgen deprivation therapy.

[0146] In one embodiment, the androgen deprivation therapy is a luteinizing hormone-releasing hormone (LHRH) agonist, an LHRH antagonist, a gonadotropin-releasing hormone (GnRH) agonist, or a GnRH antagonist.

[0147] In one embodiment, the androgen deprivation therapy is a GnRH agonist or a GnRH antagonist.

[0148] In one embodiment, the androgen deprivation therapy is a GnRH agonist.

[0149] In one embodiment, the androgen deprivation therapy is a GnRH antagonist.

[0150] In one embodiment, the androgen deprivation therapy is an LHRH agonist or an LHRH antagonist.

[0151] In one embodiment, the androgen deprivation therapy is an LHRH agonist.

[0152] In one embodiment, the androgen deprivation therapy is an LHRH antagonist.

[0153] In one embodiment, androgen deprivation therapy is leuprolide (also known as leuprorelin, e.g., Lupron or Eligardone) Viadur and the like); buserelin (e.g., Suprefact); gonadorelin; goserelin (e.g., Zoladex); histrelin (e.g., Vantas); nafarelin; triptorelin (e.g., Trelstar); deslorelin; fertirelin; abarelix (e.g., Plenaxis); cetrorelix; degarelix (e.g., Firmagon); ganirelix; ozalelix; elagolix (e.g., Orilissa); relugolix; and linzagolix.

[0154] 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; ozalelix; elagolix; relugolix; and linzagolix.

[0155] In one embodiment, the androgen deprivation therapy is selected from the group consisting of leuprolide, goserelin, and degarelix.

[0156] In one embodiment, the androgen deprivation therapy is leuprolide. In some embodiments, 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.

[0157] In one embodiment, the androgen deprivation therapy is leuprolide. In some embodiments, 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 twelve months.

[0158] In one embodiment, the androgen deprivation therapy is goserelin. In some embodiments, goserelin is administered subcutaneously at a dose of about 3.6 mg every month or about 10.8 mg every three months.

[0159] In one embodiment, the androgen deprivation therapy is degarelix. In some embodiments, degarelix is ​​administered intramuscularly at an initial dose of about 240 mg, which may be divided into multiple smaller doses, for example, two doses of about 120 mg, followed by monthly maintenance doses of about 80 mg.

[0160] In one embodiment of the methods and combination therapies of the invention, the regimen includes an additional active agent, and the additional active agent is etoposide. In some embodiments, etoposide is administered according to its approved labeling, e.g., at 50-100 mg / m once daily on days 1-5. 2 or 5 to 100 mg / m once daily on days 1, 3, and 5 2 In one example, etoposide is administered intravenously at a dose of 80 to 120 mg / m on days 1, 2, and 3 of each 21-day cycle. 2 may be administered for 1, 2, 3, 4, 5 or 6 cycles at a dose of [Example]

[0161] Clinical trial design: This was TALAPRO-2 (NCT03395197), a randomized, double-blind, two-part, international phase 3 trial for patients with mCRPC.

[0162] Part 1 was open-label and non-randomized and evaluated the safety, tolerability, and pharmacokinetics (PK) of talazoparib (Tala) in combination with enzalutamide (Enza). In Part 2, 19 patients with mCRPC were enrolled to establish an appropriate starting dose of talazoparib in combination with enzalutamide. 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 received a reduced starting dose of talazoparib / placebo of 0.35 mg / day.

[0163] 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 in combination with open-label enzalutamide or a matching placebo. Randomization was stratified by prior novel hormonal therapy or taxane-based chemotherapy for castration-sensitive prostate cancer, e.g., abiraterone, orteronel, or docetaxel (yes / no), and DDR mutation status, also known as homologous recombination repair (DR) gene alteration status (deficient vs. nondeficient / unknown). Stratification factors were assigned by the investigator and recorded in the interactive web response system (IWRS) before randomization and were used for stratified analyses of the primary efficacy endpoint. However, a secondary stratification analysis based on homologous recombination repair gene alteration status obtained from the clinical database was also performed and used to identify the non-deficient subpopulation as IWRS grouped non-deficient and unknown status.

[0164] Genomic screening to identify alterations in DDR genes was optional for patients in Part 1 but required for randomization in Part 2. Mutation status was determined by testing for the presence of mutations in defined DDR genes likely to confer sensitivity to PARP inhibition using a next-generation sequencing (NGS)-based gene panel test. Prior to randomization, patients consented to provide solid tumor tissue (de novo or archival) and / or blood-based samples to be prospectively evaluated for alteration status in DNA damage response genes directly or indirectly involved in homologous recombination repair (BRCA1, BRCA2, PALB2, ATM, ATR, CHEK2, FANCA, RAD51C, NBN, MLH1, MRE11A, CDK12) using FoundationOne® and / or FoundationOneLiquid® CDx. Of the 805 patients enrolled, tumor tissue to inform stratification was available for 804 (99.9%) patients, and 114 (14.2%) patients also had blood-based testing available for circulating tumor DNA (ctDNA). One patient enrolled solely based on ctDNA results. In an exploratory analysis, available blood-based samples (not collected in China) were retrospectively tested using FoundationOneLiquid® CDx to determine the status of patients with unknown prospective evaluation status.

[0165] Unless, in the investigator's opinion, the patient was not benefiting at this time, study treatment (including enzalutamide) was continued until radiological / imaging-based progression as determined by (BICR) (Part 2) or local review (Part 1), an adverse event (AE) leading to permanent discontinuation, the patient's decision to discontinue treatment, or death.

[0166] There were two patient cohorts in Part 2: the first, an all-comers cohort, and then a DDR-deficient cohort. Results from the all-comers cohort unselected for HRR gene alterations in Part 2 of the study, e.g., patients with and without tumor HRR gene alterations, are obtained in this example. The DDR-deficient cohort is still ongoing.

[0167] Selection criteria: 1. Histologically or cytologically confirmed adenocarcinoma of the prostate not having small cell or signet ring cell type. 2. Asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer (mCRPC) (must score <4 on BPI-SF Question #3). 3. Part 2 participation only (optional for Part 1): Assessment of DDR mutation status. 4. Consent to collection of saliva samples for germline control (optional for patients in Part 1), unless prohibited by national regulations or an ethics committee decision. 5. Serum testosterone ≤50 ng / dL (≤1.73 nmol / L) at screening and surgically or medically castrated. 6. Metastatic disease in bone as documented on bone scan or soft tissue as documented on CT / MRI scan. 7. Progressive disease at the time of study entry in the setting of medical or surgical castration, as defined by one or more of the following three criteria (prostate-specific antigen only or imaging-based): a. Prostate-specific antigen (PSA) transition defined as a rise in PSA levels on at least two of three consecutive assessments with at least seven days between assessments. b. Soft tissue disease progression as defined by RECIST 1.1. c. Progressive bone disease as defined by the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) with two or more new metastatic bone lesions on a whole-body radionuclide bone scan. 8. Ongoing use of bisphosphonates or denosumab on Day 1 (Part 1) or prior to randomization (Part 2) is permitted but not required. 9. Eastern Cooperative Oncology Group (ECOG) performance status of ≤1. 10. Life expectancy ≥ 12 months as assessed by the investigator. 11. Able to swallow the investigational drug and have no known intolerance to the investigational drug or excipients. 12. Agree to use condoms when engaging in sexual intercourse with your partner from the time of your first dose of study drug until 4 months after your last dose of study treatment, and your non-pregnant female partner of childbearing potential must agree to use an additional highly effective method of contraception when engaging in sexual intercourse with your partner from the time of your first dose of study treatment until 4 months after your last dose of study treatment. 13. Agree not to donate sperm from the time of first administration of study drug until 4 months after the last administration of study drug. 14. Evidence of a signed and dated informed consent document (and consent for molecular prescreening, if appropriate) by the patient [or legal representative / guardian] indicating that the patient has been informed of all relevant aspects of the study. 15. Willingness and ability to comply with all scheduled clinic visits, treatment plans, laboratory tests, and other study procedures.

[0168] Exclusion criteria: 1. Any prior systemic cancer treatment initiated in non-metastatic CRPC and mCRPC disease. 2. Patients in whom the only evidence of metastasis is adenopathy below the aortic bifurcation. 3. Prior treatment with second-generation androgen receptor inhibitors (enzalutamide, apalutamide, and darolutamide), PARP inhibitors, cyclophosphamide, or mitoxantrone for prostate cancer. 4. History of either prior treatment with platinum-based chemotherapy within 6 months (from last dose) prior to Day 1 (Part 1) or randomization (Part 2), or disease progression on platinum-based therapy within 6 months (from last dose). 5. Treatment with cytotoxic chemotherapy, biotherapy including sipuleucel-T, or radionuclide therapy received for castration-sensitive prostate cancer is not excluded if discontinued 28 days prior to Day 1 (Part 1) or randomization (Part 2). 6. Upfront docetaxel and abiraterone or orteronel in castration-sensitive settings were not excluded. 7. Treatment with any investigational agent within 4 weeks prior to Day 1 (Part 1) or randomization (Part 2). 8. Prior treatment with opioids for pain associated with either primary prostate cancer or metastases within 28 days prior to Day 1 (Part 1) or randomization (Part 2). 9. Current use of an active P-gp inhibitor within 7 days prior to Day 1 (Part 1) or randomization (Part 2). 10. Major surgery (as defined by the investigator) within 2 weeks prior to Day 1 (Part 1) or randomization (Part 2), or palliative localized radiotherapy within 3 weeks prior to randomization (Part 2). 11. Clinically significant cardiovascular disease 12. Significant renal impairment as defined by any of the following laboratory abnormalities: a. Renal: eGFR<30 mL / min / 1.73 m2 by MDRD formula (available at www.mdrd.com). 13. For patients participating in Part 1 only: Moderate renal impairment (eGFR 30-59 mL / min / 1.73 m2) at screening. 14. Significant liver dysfunction as defined by any of the following laboratory abnormalities on screening laboratory tests: Total serum bilirubin >1.5 times the upper limit of normal (ULN) (>3 × ULN in patients with documented Gilbert syndrome or indirect bilirubin concentrations suggesting an extrahepatic source of elevation). b. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 times the ULN (>5 × ULN if liver function abnormalities are due to liver metastases). c. Albumin < 2.8g / dL 15. Absolute neutrophil count <1500 / μL, platelets <100,000 / μL, or hemoglobin <9 g / dL (cannot have received growth factors or blood transfusions within 14 days prior to obtaining blood laboratory values ​​at screening). 16. Known or suspected brain metastases or active leptomeningeal disease. 17. Symptomatic or impending spinal cord compression or cauda equina syndrome. 18. History of myelodysplastic syndrome, acute myeloid leukemia, or any preceding malignancy, except all of the following: Carcinoma in situ or non-melanoma skin cancer. b. Any prior malignancy ≥3 years prior to randomization without subsequent evidence of recurrence or progression, regardless of stage. c. Stage 0 or stage 1 cancer less than 3 years prior to randomization with no significant risk of recurrence or progression in the opinion of the investigator. 19. Gastrointestinal disorders affecting absorption. 20. Fertile male subjects who are unwilling or unable to use highly effective contraception for the duration of the study and for 4 months after the last dose of investigational product. 21. Patients who are staff of the clinical trial site directly involved in the conduct of this study and their families, staff of the clinical trial site otherwise under the direction and supervision of the investigator, or Pfizer employees, including their families, who are directly involved in the conduct of this study. 22. Any other acute or chronic medical (concomitant illness, infection, or comorbidity) or psychiatric condition, including recent (within the past year), or active suicidal thoughts or behavior or abnormal clinical laboratory values ​​that interfere with the ability to participate in this study, may increase the risks associated with study participation or administration of the investigational product, or may interfere with the interpretation of the study results and, in the investigator's judgment, may make the patient unsuitable for participation in this trial. 23. History of seizures or any condition predisposing to seizures (e.g., prior cortical stroke, significant brain trauma), as well as a history of loss of consciousness or transient ischemic attack within 12 months of randomization (Part 2).

[0169] Statistical analysis: Approximately 750 patients were enrolled in the all-comers cohort. For the primary comparison in the all-comers population, 333 ibPFS events (based on BICR) provided 85% power to detect a hazard ratio of 0.696 using a one-sided stratified log-rank test at a significance level of 0.0125 (to maintain an overall type I error rate of 0.025 or less one-sided, the alpha for ibPFS by BICR was split equally between the all-comers [cohort 1] and the upcoming molecularly selected cohort 2; one-sided alpha of 0.0125 for each).

[0170] Overall survival was tested only if ibPFS showed a statistically significant improvement in the hierarchical stepwise procedure, maintaining overall type I error rates. Other endpoints were not adjusted for multiplicity.

[0171] Sample size and power calculations for ibPFS included the following assumptions: median ibPFS would be 16 months in the placebo + enzalutamide arm and 23 months in the talazoparib + enzalutamide arm in the all-comers population; approximately 15% of the all-comers population would have homologous recombination repair gene alterations.

[0172] Time-to-event endpoints were compared between treatment arms using the stratified log-rank test. Hazard ratios and associated 95% two-sided confidence intervals (CIs) were estimated by Cox proportional hazards models. Median time-to-event endpoints were estimated by the Kaplan-Meier method, and 95% CIs were based on the Brookmeyer-Crowley method. Missing or incomplete dates were entered as specified per protocol. No other missing data were entered.

[0173] Patient population: The primary population for assessing efficacy endpoints, as well as patient characteristics, was the intention-to-treat (ITT) population, which included all patients who were randomized with their randomization-specified treatment assignment, regardless of whether they received the study treatment.

[0174] The safety analysis population consisted of all patients who received at least one dose of study treatment (talazoparib / placebo or enzalutamide) based on treatment actually received. This population was the primary population for evaluating safety.

[0175] Between January 7, 2019, and September 17, 2020, a total of 805 patients were enrolled and randomized in the all-comers cohort (402 to talazoparib plus enzalutamide and 403 to placebo plus enzalutamide; intention-to-treat population). 398 patients in the talazoparib plus enzalutamide group and 401 patients in the placebo plus enzalutamide group received study treatment (all-comers safety population). The data cutoff was August 16, 2022.

[0176] The treatment phase of patients is summarized in Table 1 below.

[0177] [Table 1]

[0178] Baseline demographic / disease characteristics were well balanced. Patient representativeness is shown in Table 2.

[0179] [Table 2-1]

[0180] [Table 2-2]

[0181] Table 3 shows baseline patient demographic and disease characteristics (all-comers intention-to-treat population), which were well balanced between treatment arms.

[0182] [Table 3-1]

[0183] [Table 3-2]

[0184] Biomarker status was prospectively available from tissue in 99.9% of patients. Of 805 patients, 804 had tissue available for prospective testing of homologous recombination repair gene status (one patient had ctDNA results only). Table 4 shows the source of tumor DNA for evaluation and baseline HRR gene status.

[0185] [Table 4]

[0186] Prospective testing revealed that 426 patients (52.9%) had no detectable homologous recombination repair gene alterations (non-defective), 167 patients (20.7%) had detectable alterations (defective), and 212 patients (26.3%) had unknown alteration status (Table 3). BRCA alterations were detected in 6.7% (n = 27) of the talazoparib + enzalutamide arm and 7.9% (n = 32) of the placebo + enzalutamide arm. Table 5 includes a summary of homologous recombination repair gene alterations, demonstrating that HRR gene alterations were well balanced between treatment arms. An exploratory analysis, including retrospective ctDNA results to analyze the status of prospectively unknown patients, found that 547 patients (68.0%) had non-defective alteration status, 214 patients (26.6%) had deletion status, and 44 patients (5.5%) had unknown alteration status. Unless otherwise stated, all results were based on IWRS.

[0187] [Table 5]

[0188] Key efficacy results and supportive findings: The primary endpoint was BICR-assessed rPFS, also referred to as ibPFS by BICR, per RECIST 1.1 and PCWG3. Based on the data cutoff of August 16, 2022, the number of events in the talazoparib plus enzalutamide group was 151 / 402, and the number of events in the placebo plus enzalutamide group was 191 / 403. The median follow-up for rPFS was 24.9 months and 24.6 months for the talazoparib plus enzalutamide and placebo plus enzalutamide groups, respectively. The stratified hazard ratio (HR) for the primary endpoint (talazoparib plus enzalutamide vs. placebo plus enzalutamide) was 0.627 (95% CI: [0.506, 0.777]; one-sided P<0.0001; two-sided P<0.0001) in favor of talazoparib plus enzalutamide. Median rPFS was not estimable (NE) / not reached (NR) (95% CI: [27.5, NE / not reached]) months in the talazoparib plus enzalutamide group vs. 21.9 months (95% CI: [16.6, 25.1]) in the placebo plus enzalutamide group. Treatment with talazoparib plus enzalutamide resulted in a 37% lower or reduced risk of imaging-based progression (blinded independent central review) or death compared with placebo plus enzalutamide.

[0189] Investigator-assessed rPFS was a secondary efficacy endpoint. The stratified hazard ratio (talazoparib plus enzalutamide vs. placebo plus enzalutamide) observed for the secondary endpoint favored talazoparib plus enzalutamide: 0.637 (95% CI: [0.501, 0.811]; one-sided P value: 0.0001). Median rPFS was NE (95% CI: [30.4, NE]) months in the talazoparib plus enzalutamide group vs. 30.3 months (95% CI: [24.3, NE]) in the placebo plus enzalutamide group.

[0190] OS was an alpha-protected key secondary endpoint; however, OS data were immature (31% maturity). Based on the data cutoff of August 16, 2022, the number of events in the talazoparib plus enzalutamide arm was 123 / 402, and the number of events in the placebo plus enzalutamide arm was 129 / 402. A total of 252 deaths were observed (123 [30.6%] deaths in the talazoparib plus enzalutamide arm vs. 129 [32.0%] deaths in the placebo plus enzalutamide arm). Based on the data cutoff of August 16, 2022, the median follow-up period was 28.0 months in the talazoparib plus enzalutamide arm and 27.1 months in the placebo plus enzalutamide arm. An interim analysis of OS was performed based on a prespecified O'Brien-Fleming alpha-spending function. The stratified hazard ratio (talazoparib plus enzalutamide vs. placebo plus enzalutamide) observed for OS based on 252 deaths was 0.888 (95% CI: [0.693, 1.138]; p=0.35) in favor of talazoparib plus enzalutamide. Median OS was 36.4 months (95% CI: [33.5, NE / not reached]) in the talazoparib plus enzalutamide group and NE / not reached (95% CI: [33.7, NE / not reached]) in the placebo plus enzalutamide group. Interim OS results did not cross the prespecified O'Brien-Fleming efficacy boundary.

[0191] Based on the data cutoff date of March 28, 2023, a total of 330 deaths were observed (156 [38.8%] deaths in the talazoparib-enzalutamide group vs. 175 [43.25] deaths in the placebo-enzalutamide group). The median follow-up period was 35.8 months in the talazoparib-enzalutamide group and 34.6 months in the placebo-enzalutamide group. The stratified hazard ratio for OS was 0.837 (95% CI: 0.674, 1.040; one-sided P: 0.00537) in favor of talazoparib-enzalutamide. Median OS was NE (95% CI: [37.3, NE]) in the talazoparib plus enzalutamide group and 38.2 months (95% CI: [34.1, 43.1]) in the placebo plus enzalutamide group. OS results did not cross the prespecified O'Brien-Fleming efficacy boundary.

[0192] The secondary endpoint was objective response rate (ORR), defined as the proportion of patients with measurable soft-tissue disease at baseline by BICR who had a best overall confirmed soft-tissue response of CR or PR by RECIST 1.1. The objective response rates, as assessed by BICR, were 61.7% (74 / 120 events; 95% CI: [52.4, 70.4]) in the talazoparib plus enzalutamide group and 43.9% (58 / 132; 95% CI: [35.3, 52.8]) in the placebo plus enzalutamide group, respectively. The difference in objective response rate between the two groups was 17.7% (95% CI: [5.6, 29.9]; one-sided p-value: 0.0025). The CR rates were 37.5% (45 / 120) and 18.2% (24 / 132) in the talazoparib plus enzalutamide and placebo plus enzalutamide groups, respectively. The higher CR rates suggested a synergistic effect of talazoparib plus enzalutamide treatment.

[0193] PSA response was a secondary endpoint, defined as a decline of at least 50% from baseline PSA and confirmed by a second consecutive value at least 3 weeks later. The PSA response rates were 83.6% (95% CI: [79.6, 87.1]) in the talazoparib-enzalutamide group and 72.1% (95% CI: [67.4, 76.5]) in the placebo-enzalutamide group, respectively. The difference in PSA response was 11.5% (95% CI: [5.8, 17.2]; one-sided P value < 0.0001).

[0194] Time to PSA progression was a secondary endpoint, defined as the time from randomization to first PSA progression, defined as a ≥25% increase from nadir and an absolute increase of ≥2 μg / L. The stratified hazard ratio (talazoparib plus enzalutamide vs. placebo plus enzalutamide) observed for time to PSA progression was 0.715 (95% CI: [0.577, 0.886]; one-sided P value: 0.0010) in favor of talazoparib plus enzalutamide. The median time to PSA progression was 26.7 months (95% CI: [21.2, 30.4]) in the talazoparib plus enzalutamide group and 17.5 months (95% CI: [14.1, 20.8]) in the placebo plus enzalutamide group. Treatment with talazoparib plus enzalutamide extended the time to PSA progression.

[0195] The benefit of talazoparib plus enzalutamide was consistently observed across other secondary endpoints. Time to PSA progression, use of subsequent cytotoxic chemotherapy, and use of subsequent antineoplastic therapy was significantly prolonged in the talazoparib plus enzalutamide arm, as shown in Table 6.

[0196] [Table 6-1]

[0197] [Table 6-2]

[0198] Talazoparib plus enzalutamide reduced the risk of progression or death in subgroups with deficient homologous recombination repair, non-defective or unknown status, and non-defective status based on prospective tumor tissue studies.

[0199] In subgroup analyses by homologous recombination repair gene alteration status, the HR for ibPFS favored talazoparib plus enzalutamide versus placebo plus enzalutamide: 0.46 (95% CI, 0.30 to 0.70; P < 0.001) for patients with deficient status and 0.70 (95% CI, 0.54 to 0.89; P = 0.004) for patients with non-deficient or unknown status. In patients with a missing status, median ibPFS was 27.9 months (95% CI: [16.6-NE / NR]) in the talazoparib plus enzalutamide group based on 37 events in the talazoparib plus enzalutamide group in 85 patients versus 16.4 months (95% CI: [10.9-24.6]) in the placebo plus enzalutamide group based on 49 events in the placebo plus enzalutamide group in 84 patients. In patients with non-missing or unknown status, median iBPFS was NR (95% CI: [27.5-NE / NR]) months in the talazoparib plus enzalutamide arm based on 114 events in 317 patients vs. 22.5 months (95% CI: [19.1-30.5]) in the placebo plus enzalutamide arm based on 142 events in 319 patients. A clinically significant reduction in the risk of progression or death was observed regardless of HRR status.

[0200] In an exploratory subgroup analysis of patients with HRR-deficient status determined solely by prospective tumor tissue examination, talazoparib plus enzalutamide conferred a 34% lower risk of imaging-based progression or death than placebo plus enzalutamide (HR 0.66; 95% CI, 0.49-0.91; P = 0.009). In patients without HRR gene alterations detected by prospective tumor tissue examination, median iBFFS by BICR was NR (95% CI: [25.8-NE / NR]) months in the talazoparib plus enzalutamide group based on 70 events in the talazoparib plus enzalutamide group (198 patients) versus 22.1 months in the placebo plus enzalutamide group (95% CI: [16.6-NE / NR]) based on 96 events in the placebo plus enzalutamide group (214 patients).

[0201] In exploratory subgroup analyses, patients whose tumors harbored BRCA alterations had a 77% lower risk of imaging-based progression or death (HR, 0.23; 95% CI, 0.10 to 0.53; P < 0.001), those with non-BRCA homologous recombination repair gene alterations had a 34% lower risk (HR, 0.66; 95% CI, 0.39 to 1.12; P = 0.12), and patients with no BRCA alterations or unknown status had a 31% lower risk (HR, 0.69; 95% CI, 0.55 to 0.86; P = 0.001).

[0202] Additionally, in patients with DDR deficiency by IWRS in the all-comers cohort, the stratified hazard ratio (HR) for BICR-assessed rPFS (talazoparib plus enzalutamide vs. placebo plus enzalutamide) was 0.457 (95% CI: [0.297, 0.702]; one-sided P value: 0.0001) favoring talazoparib plus enzalutamide. Median rPFS was 27.9 months (95% CI: [16.6, NE]) in the talazoparib plus enzalutamide group vs. 16.4 months (95% CI: [10.9, 24.6]) in the placebo plus enzalutamide group. Based on a data cutoff of March 28, 2023, in patients with DDR deficiency by IWRS in the all-comers cohort, the observed stratified hazard ratio for OS was 0.569 (95% CI: [0.355, 0.912]; one-sided P value: 0.0088) in favor of talazoparib plus enzalutamide. Median OS was 41.9 months (95% CI: [36.4, NE]) in the talazoparib plus enzalutamide group versus 31.1 months (95% CI: [26.1, NE]) in the placebo plus enzalutamide group.

[0203] In patients with a non-deficient / unknown DDR by IWRS, the stratified hazard ratio (HR) for BICR-assessed rPFS (talazoparib plus enzalutamide vs. placebo plus enzalutamide) was 0.697 (95% CI: [0.544, 0.892]; P = 0.004) in favor of talazoparib plus enzalutamide. The median rPFS was NE (95% CI: [27.5, NE]) in the talazoparib plus enzalutamide group vs. 22.5 months (95% CI: [19.1, 30.5]) in the placebo plus enzalutamide group. Based on the data cutoff date of March 28, 2023, the observed stratified hazard ratio for OS in patients with non-deficient / unknown DDR by IWRS was 0.930 (95% CI: [0.729, 1.188]; one-sided P value: 0.2808) in favor of talazoparib plus enzalutamide. Median OS was NE (95% CI: [37.0, NE]) in the talazoparib plus enzalutamide group versus 38.7 months (95% CI: [35.0, NE]) in the placebo plus enzalutamide group.

[0204] Additionally, in patients with BRCA mutations within the all-comers cohort, the observed stratified hazard ratio for OS was 0.558 (95% CI [0.263, 1.187]; one-sided P value: 0.0622) in favor of talazoparib plus enzalutamide. Median OS was 41.9 months (95% CI: [24.9, NE]) in the talazoparib plus enzalutamide group and 26.1 months (95% CI: [15.2, NE]) in the placebo plus enzalutamide group.

[0205] In non-BRCA-mutated DDR-deficient patients within the all-comers cohort, the stratified hazard ratio observed for OS was 0.594 (95% CI: [0.322, 1.094]; one-sided P value: 0.0454) in favor of the talazoparib plus enzalutamide arm and 38.2 months (95% CI: [29.0, NE]) in the placebo plus enzalutamide arm.

[0206] In non-BRCA-mutated patients in the all-comers cohort, the observed stratified hazard ratio for OS was 0.874 (95% CI: [0.696, 1.097]; one-sided P value: 0.1225) in favor of talazoparib plus enzalutamide. Median OS was NE (95% CI: [37.3, NE]) in the talazoparib plus enzalutamide group and 38.7 months (95% CI: [35.0, 45.3]) in the placebo plus enzalutamide group.

[0207] Results for secondary endpoints by deficient or non-defective / unknown homologous recombination repair gene alteration status are in Table 7. A summary of selected subsequent systemic therapies for prostate cancer is shown in Table 8.

[0208] [Table 7-1]

[0209] [Table 7-2]

[0210] [Table 8]

[0211] In Table 9, a consistent treatment effect with talazoparib plus enzalutamide was seen in prespecified subgroups. HRs for all patients were based on Cox models stratified by randomization stratification factors. For all subgroups, HRs were based on unstratified Cox models with treatment as the only covariate.

[0212] [Table 9-1]

[0213] [Table 9-2]

[0214] As shown in Table 9, all participating patients (N=805) had prospective tumor tissue HRR study results. Overall, baseline characteristics were relatively well balanced between treatment groups and by HRR status; however, in the younger group (<65 years), there were more HRR+ (29.6%) than HRR- / unknown (19.3%) pts, and HRR+ patients had evidence of more aggressive disease. Treatment with talazoparib plus enzalutamide improved ORR and prolonged time to PSA progression; time to initiation of cytotoxic chemotherapy; and PFS2 versus placebo plus enzalutamide, with benefit seen in both the HRR+ and HRR- / unknown subgroups.

[0215] Tables 10 and 11 below show forest plot data of OS by baseline characteristics and DDR subgroups based on the following definitions: prospective tumor tissue and prospective ctDNA samples; prospective samples + prospective ctDNA samples; tumor tissue samples only; and retrospective ctDNA samples only.

[0216] [Table 10-1]

[0217] [Table 10-2]

[0218] [Table 11-1]

[0219] [Table 11-2]

[0220] Safety: A comprehensive safety analysis is ongoing. To date, the safety profile of talazoparib in combination with enzalutamide for mCRPC is generally consistent with the known safety profiles of each drug.

[0221] The safety population consisted of 799 patients treated with at least one dose of study treatment; 398 patients were treated with talazoparib plus enzalutamide and 401 patients were treated with placebo plus enzalutamide.

[0222] The median duration of treatment was 19.8 months for talazoparib and 22.2 months for enzalutamide in the talazoparib plus enzalutamide group, and 16.1 months for placebo and 16.6 months for enzalutamide in the placebo plus enzalutamide group. The median relative dose intensity in the talazoparib plus enzalutamide group was 83.5% for talazoparib and 100% for enzalutamide.

[0223] 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 in the talazoparib + enzalutamide group and 72 weeks in the placebo + enzalutamide group. See Table 12 below.

[0224] [Table 12]

[0225] The number of patients with treatment-emergent AEs (TEAEs) and serious adverse events (SAEs) are summarized in Table 13. Treatment-emergent events are defined as the period from the first dose of study treatment to 28 days after the last dose of the last study treatment or before any new anti-neoplastic therapy, whichever occurred first.

[0226] [Table 13]

[0227] The most common treatment-emergent AEs of any grade (G) experienced in ≥10% of patients in either arm and causality are summarized in Table 14 below and are organized in descending order based on the frequency of events in the talazoparib + enzalutamide group.

[0228] [Table 14]

[0229] The most common SAEs observed in the study were anemia, which occurred in 55 (13.8%) patients in the talazoparib plus enzalutamide group and 1 (0.2%) patient in the placebo plus enzalutamide group; hematuria, which occurred in 10 (2.5%) patients in the talazoparib plus enzalutamide group and 4 (1.0%) patients in the placebo plus enzalutamide group; and urinary tract infection, which occurred in 9 (2.3%) patients in the talazoparib plus enzalutamide group and 3 (0.7%) patients in the placebo plus enzalutamide group. See Table 15 below.

[0230] [Table 15]

[0231] Fourteen patients (3.5%) died within 28 days of the last dose of study treatment in the talazoparib plus enzalutamide group, and 20 patients (5.0%) died within 28 days of the last dose in the placebo plus enzalutamide group, respectively.

[0232] The most common overall treatment-emergent adverse events are shown in Table 16.

[0233] [Table 16]

[0234] The most common overall treatment-emergent adverse events (≥30% of patients) in the talazoparib plus enzalutamide group were anemia, neutropenia, and fatigue.

[0235] The three most common non-hematologic TEAEs were fatigue (33.7%; 4.0% G3), back pain (22.1%; 2.5% G3), and decreased appetite (21.6%; 1.3% G3).

[0236] The three most common hematologic total TEAEs and associated dose modifications were anemia, neutropenia, and thrombocytopenia, details of which are provided in Table 17 below.

[0237] [Table 17]

[0238] In the talazoparib plus enzalutamide group, the most common grade 3–4 adverse events (≥10% of patients) were anemia (46.5%) and neutropenia (18.3%).

[0239] To ensure optimal dosing of talazoparib at the individual patient level, the protocol did not require dose changes until anemia reached grade (G) ≥ 3. The median time to the first occurrence of G ≥ 3 anemia was 3.3 months. After grade 3–4 anemia, the protocol required maintenance and then reduction of the talazoparib dose. At baseline, 49.0% had grade 1–2 anemia. According to the protocol, 43.2% had anemia leading to dose reduction (with or without transfusions); 20.6% had recurrent grade 3–4 anemia; and 8.3% discontinued talazoparib due to anemia.

[0240] There were more dose interruptions and reductions due to adverse events in the talazoparib plus enzalutamide group than in the placebo plus enzalutamide group (Table 13). Talazoparib was discontinued due to adverse events in 300 patients (75.4%) compared with 94 patients (23.4%) who had placebo dose interruptions. The talazoparib dose was reduced due to adverse events in 223 patients (56.0%), and the placebo dose was reduced in 29 patients (7.2%). The most common adverse events leading to talazoparib dose reductions were anemia (179 patients [45.0%]), neutropenia (62 patients [15.6%]), thrombocytopenia (23 patients [5.8%]), and leukopenia (9 patients [2.3%]). The three most common adverse events leading to dose reductions of talazoparib were anemia (43.2%), neutropenia (15.1%), and thrombocytopenia (5.5%). Discontinuation of talazoparib occurred in 76 patients (19.1%), and 49 patients (12.2%) discontinued placebo due to adverse events. The most common adverse events leading to discontinuation of talazoparib were anemia (33 patients [8.3%]) and neutropenia (13 patients [3.3%]). The rate of enzalutamide discontinuation due to adverse events was 10.8% (talazoparib + enzalutamide arm) vs. 11.0% (placebo + enzalutamide arm).

[0241] [Table 18]

[0242] [Table 19]

[0243] In the talazoparib plus enzalutamide arm, there was one case of myelodysplastic syndrome during the safety reporting period and one case of acute myeloid leukemia during the follow-up period (none in the placebo plus enzalutamide arm).Venous embolic and thrombotic events were reported in 16 (4.0%) patients in the talazoparib plus enzalutamide arm, including 10 (2.5%) patients with pulmonary embolism (grade ≥3 in 9 patients), and in 3 (0.7%) patients in the placebo plus enzalutamide arm, all with grade ≥3 pulmonary embolism.

[0244] The safety profile of talazoparib plus enzalutamide was consistent with the individual profiles, and TEAEs were generally managed with dose modifications and supportive measures. Talazoparib 0.5 mg QD plus enzalutamide 160 mg QD was generally manageable with talazoparib dose modifications and / or standard supportive care. Anemia was the most common TEAE, leading to discontinuation of talazoparib in 8.3% of patients. Table 20 provides an overview of supportive care for treating anemia. G≥3 hematologic AEs typically occurred within 6 months of initiation of treatment and were transient, with decreases in hemoglobin levels most pronounced early in treatment followed by rebound hemoglobin levels.

[0245] [Table 20]

[0246] Patient-reported results The median time to definitive clinically meaningful deterioration in Global Health Status / Quality of Life (GHS / QoL) was significantly longer in the talazoparib plus enzalutamide arm (30.8 months [95% CI, 27-39.6] based on 138 events) than in the placebo plus enzalutamide arm (25 months [95% CI, 22.9-30.4] based on 146 events; HR 0.78 [95% CI, 0.62-0.99]; P = 0.04). Final clinically meaningful deterioration was defined as a ≥ 10-point decline from baseline and no subsequent observations with a < 10-point decline from baseline, as assessed by the European Organisation for Research and Treatment of Cancer cancer-specific global health questionnaire (EORTC QLQ-C30). Talazoparib plus enzalutamide significantly prolonged the time to final clinically important deterioration in GHS / QoL.

[0247] The combined estimated mean change in global health status / quality of life was significantly in favor of placebo plus enzalutamide (-2.5; 95% CI, -4.6 to -0.5; P = 0.014).

[0248] conclusion The all-comers cohort met its primary endpoint. Talazoparib demonstrated clinical benefit in combination with enzalutamide in metastatic mCRPC. Talazoparib in combination with enzalutamide statistically significantly extended rPFS compared with enzalutamide in combination with placebo in mCRPC patients unselected for DDR status. Robust and highly consistent efficacy was demonstrated in men with and without homologous recombination repair gene mutations. Across the all-comers population and prespecified subgroups, talazoparib plus enzalutamide provided a clinically meaningful and statistically significant benefit over enzalutamide plus placebo. Consistent benefit was observed across secondary endpoints. In patients with measurable disease receiving talazoparib plus enzalutamide, the complete response rate was twice that of placebo plus enzalutamide. Results from the primary analysis of the all-comers population of the TALAPRO-2 trial support the use of talazoparib plus enzalutamide as first-line treatment in patients with metastatic castration-resistant prostate cancer who are not selected for homologous recombination repair gene alterations.

[0249] First-line talazoparib plus enzalutamide significantly reduced the risk of disease progression or death by 37% versus placebo plus enzalutamide for molecularly unselected patients with metastatic castration-resistant prostate cancer.

[0250] All publications and patent applications cited herein are incorporated by reference in their entirety. While the foregoing invention has been described in some detail and by way of illustration and example, it will be readily apparent to those skilled in the art, in view of the teachings of the invention, that certain changes and modifications can be made thereto without departing from the spirit and scope of the appended claims.

Claims

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

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

3. The method of claim 1 or claim 2, wherein the subject has not received 1) systemic cancer treatment for non-metastatic castration-resistant prostate cancer or metastatic castration-resistant prostate cancer; 2) treatment 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 has no history of disease progression during platinum-based therapy within 6 months.

4. 4. The method of any one of claims 1 to 3, wherein the subject is additionally receiving a gonadotropin-releasing hormone analog or has undergone bilateral orchiectomy.

5. 5. The method of claim 4, wherein the gonadotropin-releasing hormone analog is a gonadotropin-releasing hormone agonist or a gonadotropin-releasing hormone antagonist.

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

7. 7. The method of any one of claims 1 to 6, wherein survival is imaging-based progression-free survival.

8. The method of claim 7, wherein the imaging-based progression-free survival is increased when compared to subjects receiving enzalutamide, or a pharmaceutically acceptable salt thereof, and a placebo.

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

10. 10. The method of claim 9, wherein overall survival is increased when compared to a subject receiving enzalutamide, or a pharmaceutically acceptable salt thereof, and a placebo.

11. The method of any one of claims 1 to 6, wherein survival is a significantly reduced risk of disease progression or death when compared to subjects receiving enzalutamide, or a pharmaceutically acceptable salt thereof, and a placebo.

12. The method of claim 11, wherein the significantly reduced risk of disease progression or death is at least a 37% reduction when compared to subjects receiving enzalutamide, or a pharmaceutically acceptable salt thereof, and a placebo.

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

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

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

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

17. The method of claim 16, wherein the dosage of enzalutamide, or a pharmaceutically acceptable salt thereof, is reduced when enzalutamide, or a pharmaceutically acceptable salt thereof, is administered simultaneously with a strong CYP2C8 inhibitor.

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

19. The method of claim 16, wherein the dose of enzalutamide, or a pharmaceutically acceptable salt thereof, is increased when enzalutamide is administered simultaneously with a CYP3A4 inducer.

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

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

22. 10. The method of any preceding claim, wherein the subject is a human.

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

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