Combination of taprazoparib and enzalutamide for treating metastatic castration-resistant prostate cancer

Abstract

The present invention relates to a method of using taprazoparib or a pharmaceutically acceptable salt thereof in combination with enzalutamide or a pharmaceutically acceptable salt thereof for treating metastatic castration-resistant prostate cancer with homologous recombination repair (HRR) gene mutations and increasing the survival thereof.

Description

Background Art

[0001] Prostate cancer is the second leading cause of cancer death in men. Androgen receptor (AR) signaling axis (the main driver of prostate cancer growth) has become the target of castration and other systemic therapies. The initial treatment of advanced prostate cancer can be related to the amount of androgen produced by the body (mainly in the testicles). This can be achieved by surgically removing two testicles (bilateral orchiectomy) or by using androgen deprivation therapy, such as luteinizing hormone-releasing hormone (LHRH) agonist (agonist) or antagonist drugs, which reduce the natural production of testosterone (sometimes referred to as "chemical castration"). However, although testosterone is castration level, a part of tumor still has progress, and now the disease is considered to be castration-resistant. Castration-resistant prostate cancer represents the fatal transformation in prostate cancer progression, and most patients ultimately die from the disease.

[0002] Antiandrogens are believed to inhibit androgen activity through a variety of different mechanisms. An example of an antiandrogen approved for the treatment of castration-resistant prostate cancer is abiraterone acetate (available as Zytiga TM (sold), a steroidal CYP17A1 inhibitor. A specific type of antiandrogen is an androgen receptor inhibitor, also known as an androgen receptor signaling inhibitor or androgen receptor antagonist, which is believed to compete with endogenous ligands (androgens) for the androgen receptor. When the antagonist binds to the androgen receptor, it is believed to induce a conformational change in the receptor itself, thereby blocking the transcription of key androgen-regulated genes and thus inhibiting the biological effects of the androgens themselves (such as testosterone and dihydrotestosterone).

[0003] The compound enzalutamide is a nonsteroidal androgen receptor inhibitor, which is 4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfo-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 also known as "RD162" and "MDV3100"), and has the following structure:

[0004]

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

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

[0007] Poly (ADP-ribose) polymerase (PARP) is involved in the process of deoxyribonucleic acid (DNA) repair naturally occurring in cells. PARP inhibition has been shown to be an effective therapeutic strategy to combat 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 synthetically lethal to cells with homozygous deletions or deleterious changes, or both, in DNA damage response (DDR) genes that are directly or indirectly involved in homologous recombination repair (HRR) (Lord, CJ et al., Science, 2017; 355: 1152-1158).

[0008] Talazoparib is a potent, orally available PARP inhibitor that is cytotoxic to human cancer cell lines harboring genetic mutations that impair deoxyribonucleic acid (DNA) repair (an effect known as synthetic lethality) by trapping PARP proteins on DNA, thereby preventing DNA repair, replication, and transcription.

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

[0010]

[0011] Talazopanib and its pharmaceutically acceptable salts (including tosylate) are disclosed in International Publication Nos. WO 2010 / 017055 and WO 2012 / 054698. Additional methods for preparing talazopanib and its pharmaceutically acceptable salts (including tosylate) are described in International Publication Nos. WO 2011 / 097602, WO 2015 / 069851, and WO 2016 / 019125. Additional methods for treating cancer using talazopanib and its pharmaceutically acceptable salts (including tosylate) are disclosed in International Publication Nos. WO 2011 / 097334 and WO 2017 / 075091. Combination therapies using talazopanib and its pharmaceutically acceptable salts (including tosylate) are disclosed in International Publication Nos. WO 2019 / 075032 and WO 2022 / 200982, the contents of which are incorporated herein by reference.

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

[0013] There remains a need for improved therapies for treating cancer, particularly metastatic castration-resistant prostate cancer. The combinations of the present invention are believed to have one or more advantages, such as increased survival (including radiographic progression-free survival and overall survival) compared to treatment with either therapeutic agent alone; increased survival (including radiographic progression-free survival and overall survival) compared to patients who have received enzalutamide or a pharmaceutically acceptable salt thereof and placebo; greater efficacy compared to treatment with either therapeutic agent alone; the potential for improved dosing schedules; the potential to overcome resistance mechanisms, etc. Summary of the Invention

[0014] The present invention provides, in part, a method of administering talazoparib or a pharmaceutically acceptable salt thereof with enzalutamide or a pharmaceutically acceptable salt thereof in combination therapy for increasing the survival of a subject with metastatic castration-resistant prostate cancer that carries a genetic mutation associated with DNA damage repair deficiency. This summary is provided to introduce a selection of concepts further described below in a simplified form in the detailed description. This summary is not intended to identify the key features or essential features of the claimed subject matter, nor is it intended to be used independently to help determine the scope of the claimed subject matter.

[0015] According to embodiment 1 of the present invention, a method for increasing the survival of a subject with metastatic castration-resistant prostate cancer carrying a gene mutation associated with DNA damage repair deficiency is provided, 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.

[0016] According to embodiment 2 of the present invention, a method for increasing the survival of a subject with metastatic castration-resistant prostate cancer having a homologous recombination repair (HRR) gene mutation is provided, 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.

[0017] According to embodiment 3 of the present invention, a method for treating metastatic castration-resistant prostate cancer in a subject who has metastatic castration-resistant prostate cancer carrying a gene mutation associated with DNA damage repair deficiency is provided, 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 increase the survival of the subject.

[0018] According to embodiment 4 of the present invention, a method for treating metastatic castration-resistant prostate cancer in a subject with metastatic castration-resistant prostate cancer with HRR gene mutation is provided, 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 increase the survival of the subject.

[0019] According to embodiment 5 of the present invention, a combination of talazoparib or a pharmaceutically acceptable salt thereof and enzalutamide or a pharmaceutically acceptable salt or solvate thereof is provided for increasing the survival of subjects with metastatic castration-resistant prostate cancer with HRR gene mutations, wherein talazoparib or a pharmaceutically acceptable salt thereof is orally administered to the subject once daily, and enzalutamide or a pharmaceutically acceptable salt thereof is orally administered to the subject once daily.

[0020] According to embodiment 6 of the present invention, a combination of talazoparib or a pharmaceutically acceptable salt thereof and enzalutamide or a pharmaceutically acceptable salt or solvate thereof is provided for treating a subject with metastatic castration-resistant prostate cancer with an HRR gene mutation, wherein talazoparib or a pharmaceutically acceptable salt thereof is orally administered to the subject once daily, and enzalutamide or a pharmaceutically acceptable salt thereof is orally administered to the subject once daily, and further wherein the administration of talazoparib or a pharmaceutically acceptable salt thereof and the administration of enzalutamide or a pharmaceutically acceptable salt thereof increase the survival of the subject.

[0021] Described below are embodiments of the present invention, wherein for convenience, embodiments 1, 2, 3, 4, 5 and 6 (E1, E2, E3, E4, E5 and E6) are consistent with the embodiments provided above.

[0022] 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

[0023] The present invention may be understood more readily by reference to the following detailed description of embodiments of the invention and the Examples included therein. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0024] A method of increasing the survival of a subject having metastatic castration-resistant prostate cancer harboring a gene mutation associated with a DNA damage repair defect using E1, as defined above.

[0025] The method of increasing the survival of a subject having metastatic castration-resistant prostate cancer with an HRR gene mutation using E2, as defined above.

[0026] A method of treating metastatic castration-resistant prostate cancer in a subject having metastatic castration-resistant prostate cancer that carries a gene mutation associated with a DNA damage repair defect, wherein the treatment increases the survival of the subject as defined above.

[0027] E4 A method of treating metastatic castration-resistant prostate cancer in a subject having metastatic castration-resistant prostate cancer with an HRR gene mutation, wherein the treatment increases the survival of the subject as defined above.

[0028] A combination of E5 for use in increasing the survival of a subject having metastatic castration-resistant prostate cancer with an HRR gene mutation, as defined above.

[0029] E6 combination for use in treating a subject having metastatic castration-resistant prostate cancer with an HRR gene mutation, wherein administration of the combination increases the survival of the subject, as defined above.

[0030] E7 The method or combination for use according to any one of embodiments 1 to 6, wherein talazoparib or a pharmaceutically acceptable salt thereof and enzalutamide or a pharmaceutically acceptable salt thereof are administered simultaneously.

[0031] E8 The method or combination used in any one of embodiments 1 to 7, wherein the metastatic castration-resistant prostate cancer with an HRR gene mutation has a mutation in at least one gene selected from the group consisting of: ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, and RAD51C.

[0032] E9 The method or combination for use of any one of embodiments 1 to 8, wherein the subject has not received: 1) systemic cancer therapy for non-metastatic castration-resistant prostate cancer or metastatic castration-resistant prostate cancer; 2) treatment with an androgen receptor signaling inhibitor, a PARP inhibitor, cyclophosphamide, or mitoxantrone for prostate cancer; or 3) treatment with platinum-based chemotherapy within 6 months or any history of disease progression on platinum-based therapy within 6 months.

[0033] E10 The method or combination for use according to embodiment 9, wherein the subject has not received systemic cancer treatment for non-metastatic castration-resistant prostate cancer or metastatic castration-resistant prostate cancer.

[0034] E11 The method or combination for use of embodiment 9, wherein the subject has not been treated for prostate cancer with an androgen receptor signaling inhibitor, a PARP inhibitor, cyclophosphamide, or mitoxantrone.

[0035] E12 The method or combination for use according to embodiment 9, wherein the subject has not been treated with an androgen receptor signaling inhibitor.

[0036] E13 The method or combination for use according to any one of embodiments 9, 11 or 12, wherein the androgen receptor signaling inhibitor is a second generation androgen receptor inhibitor.

[0037] E14 The method or combination for use according to embodiment 13, wherein the second generation androgen receptor inhibitor is enzalutamide, apalutamide, darolutamide or abiraterone acetate.

[0038] E15 The method or combination for use of embodiment 14, wherein the second generation androgen receptor inhibitor is enzalutamide, apalutamide or darolutamide.

[0039] E16 The method or combination for use of embodiment 9, wherein the subject has not received treatment with platinum-based chemotherapy within 6 months or any history of disease progression on platinum-based therapy within 6 months.

[0040] E17 The method or combination for use according to any one of embodiments 1 to 16, wherein said subject is additionally receiving a gonadotropin-releasing hormone analogue or has undergone bilateral orchiectomy.

[0041] E18 The method or combination for use according to embodiment 17, wherein said subject is additionally receiving a gonadotropin-releasing hormone analogue.

[0042] E19 The method or combination for use according to embodiment 17 or 18, wherein said gonadotropin-releasing hormone analogue is a gonadotropin-releasing hormone agonist.

[0043] E20 The method or combination for use of embodiment 17 or 18, wherein said gonadotropin-releasing hormone analogue is a gonadotropin-releasing hormone antagonist.

[0044] E21 The method or combination for use of embodiment 17, wherein said subject has undergone bilateral orchiectomy.

[0045] E22 The method or combination for use of any one of embodiments 1 to 21, wherein the subject has progressive disease defined by one or more of the following: 1) prostate specific antigen progression, defined by a minimum of 2 rising prostate specific antigen values ​​in 3 consecutive assessments, with an interval of at least 7 days between assessments; 2) soft tissue disease progression, defined by RECIST 1.1; and 3) bone disease progression, defined by Prostate Cancer Working Group 3, with 2 or more new metastatic bone lesions on whole-body radionuclide bone scan.

[0046] E23 The method or combination for use of any one of embodiments 1 to 22, wherein the subject has an Eastern Cooperative Oncology Group (ECOG) performance status ≤1.

[0047] E24 The method or combination for use according to any one of embodiments 1 to 23, wherein the increased survival is a 55% reduction in the risk of disease progression or death compared to a subject who has received enzalutamide or a pharmaceutically acceptable salt thereof and a placebo.

[0048] E25 The method or combination for use according to any one of embodiments 1 to 23, wherein the survival is radiographic progression-free survival.

[0049] E26 The method or combination for use of embodiment 25, wherein the radiographic progression-free survival outcome is a 55% reduction in the risk of disease progression or death compared to subjects who have received enzalutamide or a pharmaceutically acceptable salt thereof and placebo.

[0050] E27 The method or combination for use of embodiment 26, wherein radiographic progression-free survival is increased compared to a subject who has received enzalutamide or a pharmaceutically acceptable salt thereof and placebo.

[0051] E28 The method or combination for use according to embodiment 27, wherein radiographic progression-free survival is a statistically significant improvement compared to subjects who have received enzalutamide or a pharmaceutically acceptable salt thereof and placebo.

[0052] E29 The method or combination used in embodiment 28, wherein the statistically significant improvement is a hazard ratio of 0.45 based on 170 rPFS events (95% CI: [0.33, 0.61]; one-sided P value <0.0001) in favor of talazopanib or a pharmaceutically acceptable salt thereof and enzalutamide or a pharmaceutically acceptable salt thereof.

[0053] E30 The method or combination for use according to any one of embodiments 1 to 23, wherein the survival is overall survival.

[0054] E31 The method or combination for use according to embodiment 30, wherein overall survival is increased compared to a subject who has received enzalutamide or a pharmaceutically acceptable salt thereof and placebo.

[0055] E32 The method or combination for use according to any one of embodiments 1 to 31, wherein talazopanib or a pharmaceutically acceptable salt thereof is administered at a dose equivalent to about 0.1 mg, about 0.25 mg, about 0.35 mg or about 0.5 mg of talazopanib free base once daily.

[0056] E33 The method or combination for use according to embodiment 32, wherein talazopanib or a pharmaceutically acceptable salt thereof is administered in a dose equivalent to about 0.1 mg of talazopanib free base once daily.

[0057] E34 The method or combination for use according to embodiment 32, wherein talazopanib or a pharmaceutically acceptable salt thereof is administered in a dose equivalent to about 0.25 mg of talazopanib free base once daily.

[0058] E35 The method or combination for use of embodiment 34, wherein said subject has severe renal impairment.

[0059] E36 The method or combination for use according to embodiment 32, wherein talazopanib or a pharmaceutically acceptable salt thereof is administered in a dose equivalent to about 0.35 mg of talazopanib free base once daily.

[0060] E37 The method or combination for use of embodiment 36, wherein the subject has moderate renal impairment.

[0061] E38 The method or combination for use according to embodiment 32, wherein talazopanib or a pharmaceutically acceptable salt thereof is administered in a dose equivalent to about 0.5 mg of talazopanib free base once daily.

[0062] E39 The method or combination for use according to any one of embodiments 1 to 38, wherein talazopanib or a pharmaceutically acceptable salt thereof is talazopanib tosylate.

[0063] E40 The method or combination for use according to any one of embodiments 1 to 39, wherein enzalutamide or a pharmaceutically acceptable salt thereof is administered in a dose equivalent to about 160 mg of enzalutamide free base once daily.

[0064] E41 The method or combination for use according to embodiment 40, wherein if enzalutamide or a pharmaceutically acceptable salt thereof is co-administered with a strong CYP2C8 inhibitor, the dose of enzalutamide or a pharmaceutically acceptable salt thereof is reduced.

[0065] E42 The method or combination for use according to embodiment 40, wherein the dose of enzalutamide or a pharmaceutically acceptable salt thereof is reduced to 80 mg once daily.

[0066] E43 The method or combination for use of embodiment 40, wherein if enzalutamide is administered concomitantly with a CYP3A4 inducer, the dose of enzalutamide or a pharmaceutically acceptable salt thereof is increased.

[0067] E44 The method or combination for use according to embodiment 40, wherein the dose of enzalutamide or a pharmaceutically acceptable salt thereof is increased to 240 mg per day.

[0068] E45 The method or combination for use according to any one of embodiments 1 to 44, wherein enzalutamide or a pharmaceutically acceptable salt thereof is a free base.

[0069] E46 The method or combination for use according to any one of embodiments 1 to 45, wherein said method comprises administering an additional anticancer agent.

[0070] E47 The method or combination for use of embodiment 46, wherein the other anticancer 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.

[0071] E48 The method or combination for use in any one of the preceding embodiments, wherein said subject is a human.

[0072] E49 The method or combination for use according to embodiment 48, wherein the human is an adult.

[0073] Each of the embodiments described herein may be combined with any other embodiment(s) described herein that is not inconsistent with the embodiment(s) with which it is combined.

[0074] definition

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

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

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

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

[0079] As used herein, terms including, but not limited to, "agent," "composition," "compound," "drug," "pharmaceutical," and "therapeutic agent" are 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, "DDR mutation(s)," "DDR alterations," "HRR mutation(s)," and "HRR alterations" refer to changes / mutations in genes directly or indirectly involved in homologous recombination repair (HRR). Although less scientifically rigorous than the phrase "DNA damage response," it is generally understood that "DDR" may also be referred to as "DNA damage repair" or "DNA repair." "DDR deficiency" refers to gene mutations associated with defects in deoxyribonucleic acid (DNA) damage repair. A "DDR deficient patient population" or "HRR deficient patient population" is a patient population with gene mutations associated with defects in deoxyribonucleic acid (DNA) damage repair. DDR is a network of pathways that have evolved to repair damaged DNA. These include mismatch repair, base excision repair, and homologous recombination repair (HRR), among others. Given the high fidelity of HRR in repairing double-stranded DNA breaks, HRR is particularly important for maintaining genome integrity. Inhibition of PARP leads to the accumulation of single-stranded DNA breaks and DNA stress due to PARP trapping, which ultimately leads to double-stranded DNA breaks. Thus, PARP inhibitors are selectively lethal to HRR-deficient cancer cells, an example of synthetic lethality, a mechanism in which a functional defect in one gene or gene product alone has minimal effect but is toxic when combined with a functional defect in a second gene or gene product. DDR-HRR genes include, but are not limited to, ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, and RAD51C. Defects in homologous recombination repair can be determined using next-generation sequencing (NGS).

[0081] For the purposes of this invention, the terms "radiological" and "imaging-based" are used interchangeably. For example, "radiological" progression is the same as "imaging-based" progression; radiographic PFS is the same as imaging-based PFS (ibPFS); and rPFS is the same as ibPFS.

[0082] As used herein, "systemic therapy" for mCRPC is a drug or therapeutic agent used to manage mCRPC. A drug or medication is called a systemic therapy because it circulates throughout the body to attack cancer cells anywhere in the body.

[0083] Antiandrogens

[0084] As used herein, the terms "anti-androgen" and "anti-androgens" refer to compounds that prevent androgens (e.g., testosterone and dihydrotestosterone (DHT)) from mediating their biological effects in the body. Anti-androgens can act through one or more of the following hormonal mechanisms: for example, blocking and / or inhibiting and / or regulating the androgen receptor (AR); inhibiting androgen production; suppressing androgen production; degrading AR, inhibiting nuclear translocation, inhibiting AR binding to nuclear DNA; etc. 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, topilutamide, 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 cell ligand binding assays and / or gene expression assays, such as those disclosed in Tran C. et al., Science, 2009, 324, 787-790.

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

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

[0087] Another second generation androgen receptor signaling inhibitor is abiraterone or a pharmaceutically acceptable salt or solvate thereof, such as abiraterone acetate (available as Zytiga TM

[0014] , a steroidal CYP17A1 inhibitor, is disclosed in U.S. Patent No. 5,604,213, issued February 18, 1997, the contents of which are incorporated herein by reference. This second generation AR inhibitor blocks androgen biosynthesis.

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

[0089]

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

[0091] An example of an androgen receptor inhibitor is apalutamide ( sell):

[0092]

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

[0094] An example of an androgen receptor inhibitor is darolutamide ( sell):

[0095]

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

[0097] An example of an androgen receptor inhibitor is bicalutamide:

[0098]

[0099] or a pharmaceutically acceptable salt or solvate thereof, is sold and is disclosed in U.S. Patent No. 4,636,505, issued January 13, 1987, the contents of which are incorporated herein by reference.

[0100] An example of an androgen receptor inhibitor is nilutamide ( sold) or a pharmaceutically acceptable salt or solvate thereof.

[0101] An example of an androgen receptor inhibitor is flutamide ( sold) or a pharmaceutically acceptable salt or solvate thereof.

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

[0103] Androgen deprivation therapy

[0104] Androgen deprivation therapy (also called ADT) uses surgery or medication to lower the levels of androgens produced by the testicles.

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

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

[0107] Other examples of pharmaceutical androgen deprivation therapies include leuprolide (also known as leuprorelin, such as Lupron or Eligardor Viadur, etc.); buserelin (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; ozarelix; elagolix (e.g., Orilissa); relugolix; and linzagolix.

[0108] Salt

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

[0110] Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include, but are not limited to, acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hyphenate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, Malonate, methanesulfonate, methylsulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, 1,5-naphthalenedisulfonate, and xinofoate salts.

[0111] 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, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts.

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

[0113] 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.

[0114] Application and dosing

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

[0116] "Subjects" or "patients" according to the combination of the present invention can be imaged while receiving therapy to assess their response to treatment. Response criteria, particularly Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), are standardized and can be used at different time points to classify responses into multiple categories, such as complete remission (CR), partial remission (PR), stable disease (SD), or progressive disease. At the trial level, the categorized responses of all patients are summarized as imaging-based trial endpoints.

[0117] A "subject" or "patient" according to the combination of the present invention may have: 1) a histologically or cytologically confirmed case of a leukemia with no small cells or signet ring cells; 1) adenocarcinoma of the prostate characterized by chromatin (C) cell-derived prostate cancer; 2) asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer; 3) DNA damage repair (DDR) deficiencies, as assessed centrally by a next-generation sequencing (NGS) biomarker mutation panel containing DDR genes potentially sensitive to PARP inhibition; 4) surgical or medical castration with serum testosterone ≤50 ng / dL (≤1.73 nmol / L) at screening; 5) ongoing androgen deprivation therapy with a gonadotropin-releasing hormone (GnRH) agonist or antagonist for patients who have not undergone bilateral orchiectomy; 6) metastatic disease in bone as documented on bone scan or metastatic disease in soft tissue as documented on CT / MRI scan; 7) in the setting of medical or surgical castration, progressive disease at study entry, as defined by one or more of the following three criteria: i) prostate-specific antigen (PSA) progression, as defined by at least two rising PSA values ​​in three assessments with an interval of at least 7 days between assessments; ii) soft tissue disease progression, as defined by RECIST 1.1 definition; and iii) bone disease progression, as defined by the Prostate Cancer Working Group 3 (PCWG3), with two or more new metastatic bone lesions on whole-body radionuclide bone scan; 8) current use of bisphosphonates or denosumab; 9) Eastern Cooperative Oncology Group (ECOG) performance status ≤1; and 10) life expectancy ≥12 months as assessed by the investigator.

[0118] As used herein, the term "cancer" refers to or describes a physiological condition in a subject patient that is typically characterized by unregulated cell growth. Cancer refers to any malignant and / or invasive growth or tumor caused by abnormal cell growth. The term "metastatic," when used in connection with cancer, includes but is not limited to cancer that spreads from its initial location to other parts of the body, recurrence of an initial primary cancer after remission, and a second primary cancer, which is a new primary cancer of a different type than the previous cancer in a subject with a history of prior cancer. One skilled in the art will be able to identify and diagnose metastatic cancer in a patient.

[0119] As used herein, "treat" or "treating" metastatic cancer (such as mCRPC) 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 reducing the number of cancer cells; reducing tumor size; reducing the rate of cancer cell infiltration into peripheral organs; or reducing the rate of tumor metastasis or tumor growth; reversing, alleviating, inhibiting the progression of the disorder or condition to which the term applies, or preventing the disease or disorder to which the term applies or one or more symptoms of the disease or condition. Unless otherwise indicated, as used herein, the term "treatment" or "therapy" refers to the act of treating as "treating" is defined immediately above. For the purposes of the present invention, beneficial or desired clinical outcomes include, but are not limited to, one or more of the following: reducing the proliferation of neoplastic or cancerous cells or destroying neoplastic or cancerous cells; inhibiting metastasis or inhibiting neoplastic cells; shrinking or reducing tumor size; alleviating cancer; reducing symptoms caused by cancer; improving the quality of life of patients suffering from cancer; reducing the dose of other drugs required to treat cancer; delaying the progression of cancer; curing cancer; overcoming one or more resistance mechanisms of cancer; and / or prolonging the survival of cancer patients. Positive therapeutic effects in cancer can be measured in a variety of ways (see WA Weber, J. Nucl. Med. 50: 1S-10S (2009)).

[0120] In one embodiment, the treatment achieved by the combination of the invention is increased survival of the subject.

[0121] In one embodiment, the increase in survival is measured by any one of the following: progression-free survival (PFS), radiographic PFS (rPFS) and overall survival (OS). PFS, rPFS and OS are clinically significant endpoints for measuring the increase in survival of patients treated with the combination of the present invention. PFS is the duration that a patient coexists with the disease but the disease does not worsen during and after treatment of a disease (such as cancer). OS is the duration that a patient survives after diagnosis or the start of treatment for a disease (such as cancer). In clinical trials, measuring PFS and OS is a way to observe how a new treatment works. For the purposes of the clinical trials described herein, rPFS is defined as the time from the date of randomization to the first objective evidence of radiographic progression, as determined by blinded independent central review (BICR), in soft tissue according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1), or in bone according to the Prostate Cancer Working Group 3 (PCWG3) guidelines (after subsequent confirmation), or death, whichever occurs first; for the purposes of the clinical trials described herein, OS is defined as the time from the date of randomization to death from any cause.

[0122] In one embodiment, progression-free survival is increased compared to subjects who have received enzalutamide or a pharmaceutically acceptable salt thereof. In one embodiment, progression-free survival is increased compared to subjects who have received enzalutamide or a pharmaceutically acceptable salt thereof and a placebo. For the purposes of the present invention, treatment with a placebo means that patients with metastatic castration-resistant prostate cancer that has a homologous recombination repair (HRR) gene mutation or with metastatic castration-resistant prostate cancer that carries a gene mutation associated with DNA damage repair deficiency are not treated with talazoparib.

[0123] In one embodiment, radiographic progression-free survival is increased compared to subjects who have received enzalutamide or a pharmaceutically acceptable salt thereof. In one embodiment, radiographic progression-free survival is increased compared to subjects who have received enzalutamide or a pharmaceutically acceptable salt thereof and a placebo. For the purposes of the present invention, treatment with a placebo means that patients with metastatic castration-resistant prostate cancer that has a homologous recombination repair (HRR) gene mutation or with metastatic castration-resistant prostate cancer that carries a gene mutation associated with DNA damage repair deficiency are not treated with talazoparib.

[0124] An "amount" for use and for treating a subject refers to an amount that provides a detectable response of any duration (short-term, intermediate or long-term), any measurable or detectable degree, or a desired outcome or objective or subjective benefit of any duration (e.g., hours, days, months, years, remission or cure) in a subject, in a single or multiple doses, alone or in combination with one or more other agents. Such an amount is typically effective to ameliorate the disease or one, multiple or all side effects / symptoms, consequences or complications of the disease to a measurable extent, but reducing or inhibiting the progression or worsening of the disease, or providing a stable (i.e., non-worsening) state of the disease is considered a satisfactory result. The term "therapeutically effective amount" also means an amount of an agent, alone or in combination with one or more other agents, that is effective, upon administration to a subject, to produce the desired therapeutic effect, e.g., to prevent the growth of a cancerous tumor or to cause the shrinkage of a cancerous tumor. With respect to the treatment of cancer, a therapeutically effective amount is an amount that has the following effects: (1) reduces tumor size, (2) inhibits (i.e., slows to some extent, preferably stops) the appearance of tumor metastases, (3) inhibits (i.e., slows to some extent, preferably stops) tumor growth or tumor invasiveness, and / or (4) alleviates (or preferably eliminates) to some extent one or more signs or symptoms associated with cancer. The therapeutic or pharmacological effectiveness of the dosing and administration regimen can also be characterized by the ability to induce, enhance, maintain or prolong disease control and / or overall survival in patients with these specific tumors, which can be measured as a prolongation of the time before disease progression.

[0125] As used herein, "improvement" refers to any decrease in the extent, severity, frequency, and / or likelihood of symptoms or clinical signs characteristic of a particular disease. "Symptoms" refers to any subjective evidence of a disease or condition in a subject.

[0126] In one embodiment, the amount or daily dose of talazopanib or a pharmaceutically acceptable salt thereof, and preferably a tosylate salt thereof, administered to the subject is equivalent to about 0.1 mg to about 1 mg of talazopanib free base once daily. In one embodiment, talazopanib or a pharmaceutically acceptable salt thereof, and preferably a tosylate salt thereof, is administered at a daily dose equivalent to about 0.1 mg of talazopanib free base once daily, to about 0.25 mg of talazopanib free base once daily, to about 0.35 mg of talazopanib free base once daily, to about 0.5 mg of talazopanib free base once daily, to about 0.75 mg of talazopanib free base once daily, or to about 1 mg of talazopanib free base once daily. In one embodiment, talazopanib or a pharmaceutically acceptable salt thereof, and preferably a tosylate salt thereof, is administered at a daily dose equivalent to about 0.1 mg of talazopanib free base once daily, to about 0.25 mg of talazopanib free base once daily, to about 0.35 mg of talazopanib free base once daily, or to about 0.5 mg of talazopanib free base once daily. In one embodiment, talazopanib or a pharmaceutically acceptable salt thereof, and preferably a tosylate salt thereof, is administered at a daily dose equivalent to about 0.1 mg of talazopanib free base once daily. In one embodiment, talazopanib or a pharmaceutically acceptable salt thereof, and preferably a tosylate salt thereof, is administered at a daily dose equivalent to about 0.25 mg of talazopanib free base once daily. In one embodiment, talazopanib or a pharmaceutically acceptable salt thereof, and preferably a tosylate salt thereof, is administered at a daily dose equivalent to about 0.35 mg of talazopanib free base once daily. In one embodiment, talazopanib or a pharmaceutically acceptable salt thereof, and preferably a tosylate salt thereof, is administered at a daily dose equivalent to about 0.5 mg of talazopanib free base once daily. In one embodiment, talazopanib or a pharmaceutically acceptable salt thereof, and preferably a tosylate salt thereof, is administered at a daily dose equivalent to about 0.75 mg of talazopanib free base once daily. In one embodiment, talazopanib or a pharmaceutically acceptable salt thereof, and preferably a tosylate salt thereof, is administered at a daily dose equivalent to about 1 mg of talazopanib free base once daily.

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

[0128] The dosages provided herein refer to the dosage of the free base form of talazopanib, or are calculated as the free base equivalent of the administered talazopanib salt form. For example, a dosage or amount of talazopanib (such as 0.25, 0.35 mg or 0.5 mg) refers to the free base equivalent.

[0129] In one embodiment, enzalutamide is administered according to The US approved label is for a daily dose of 160 mg once daily. The prescribing information readily identifies dose adjustments for enzalutamide, such as if enzalutamide is co-administered with a strong CYP2C8 inhibitor, then the dose of enzalutamide should be reduced according to the full prescribing information, such as to 80 mg once daily; or alternatively, if enzalutamide is co-administered with a CYP3A4 inducer, then the dose of enzalutamide should be increased according to the full prescribing information, such as to 240 mg daily.

[0130] In a preferred embodiment, enzalutamide or a pharmaceutically acceptable salt thereof is administered once daily at a daily dose of about 160 mg. The dosages provided herein refer to the dosage of the free base form of enzalutamide or are calculated as the free base equivalent of the enzalutamide salt form administered. For example, a dosage or amount of enzalutamide, such as 160 mg, refers to the free base or an equivalent.

[0131] The recommended dose of talazoparib is 0.5 mg orally administered once daily in combination with 160 mg of enzalutamide orally once daily until disease progression or unacceptable toxicity occurs. This dosing regimen can be adjusted to provide 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, consider interrupting treatment with or without dose reduction based on severity and clinical manifestations. 0.35 mg, 0.25 mg, and 0.1 mg capsules can be used for dose reduction.

[0132] For patients with mCRPC and moderate renal impairment (CLcr 30-59 mL / min), the recommended dose of talazopanib is 0.35 mg once daily in combination with 160 mg of enzalutamide taken orally once daily. For patients with severe renal impairment (CLcr 15-29 mL / min), the recommended dose of talazopanib is 0.25 mg once daily in combination with 160 mg of enzalutamide taken orally once daily.

[0133] For patients with mCRPC, when co-administered with certain P-glycoprotein (P-gp) inhibitors (such as itraconazole, amiodarone, carvedilol, clarithromycin, itraconazole, and verapamil), the talazopanib dose is reduced to 0.35 mg once daily in combination with 160 mg of enzalutamide orally once daily. When the P-gp inhibitor is discontinued, the talazopanib dose is increased (after 3-5 half-lives of the P-gp inhibitor) to the dose used before starting the P-gp inhibitor.

[0134] The compounds of the present invention may be administered orally. Oral administration may involve swallowing, allowing the compound to enter the gastrointestinal tract, or buccal or sublingual administration may be employed, where the compound enters the bloodstream directly from the mouth.

[0135] In a preferred embodiment, the daily dose of talazoparib or a pharmaceutically acceptable salt thereof is administered orally.

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

[0137] Talazoparib or a pharmaceutically acceptable salt may be present in a pharmaceutical composition comprising a pharmaceutically acceptable excipient. A "pharmaceutically acceptable excipient" refers to a component that can be included in the compositions described herein, is physiologically suitable for pharmaceutical use, and does not cause significant adverse effects and therapeutic effects on the subject. The term "excipient" is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will depend to a large extent on factors such as the mode of administration, the effect of the excipient on solubility and stability, and the properties of the dosage form.

[0138] The amount of talazoparib or a pharmaceutically acceptable salt in the pharmaceutical composition may be any amount disclosed herein.

[0139] The compounds of the methods, uses, or combinations of the present invention may be formulated prior to administration. The formulation will preferably be suitable for the particular mode of administration. The compounds may be formulated with pharmaceutically acceptable excipients known in the art and administered in a wide variety of dosage forms known in the art. Unit dosage forms or pharmaceutical compositions suitable for oral administration include, but are not limited to, tablets; capsules, such as gelatin capsules; pills; powders; granules; aqueous and non-aqueous oral solutions and suspensions, packaged in containers suitable for subdivision into individual doses.

[0140] In another embodiment, the dosage of the compounds or pharmaceutical compositions described herein may vary within a range depending on the dosage form used and the route of administration used. In another embodiment, the amount of the compounds or pharmaceutical compositions described herein administered to a subject may depend on factors known to those skilled in the art, including the biological activity and bioavailability of the compound (e.g., the half-life and stability of the compound in vivo), 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 disclosed herein may depend on a variety of factors, including the subject's physical condition (e.g., age, sex, weight) and the subject's medical history (e.g., medications taken, health conditions, other diseases or conditions). The precise dose of the pharmaceutical composition administered to a subject can be determined by methods known to those skilled in the art, such as pharmacologists or anesthesiologists.

[0141] The repetition of administration or dosing regimen can be carried out as needed to achieve the reduction or weakening of the desired cancer cells. As used herein, a "continuous dosing schedule" is an administration or dosing schedule without dose interruptions (e.g., without treatment stop days). The repetition of a 28-day treatment cycle without dose interruptions 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.

[0142] Treatment methods and uses

[0143] The methods and combination therapies of the present invention can be used to treat mCRPC.

[0144] In one embodiment, the present disclosure provides a method of increasing survival of a subject with metastatic castration-resistant prostate cancer 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.

[0145] 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 talazoparib, or a pharmaceutically acceptable salt thereof, to the subject once daily in combination with 2) orally administering enzalutamide, or a pharmaceutically acceptable salt thereof, to the subject once daily.

[0146] 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 increase the survival of the subject.

[0147] 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 in combination with 2) orally administering enzalutamide, or a pharmaceutically acceptable salt thereof, to the subject once daily, wherein the combination increases the survival of the subject.

[0148] Unless otherwise indicated, as used herein, the term "combination" means a combination of agents administered in close enough time to affect the treatment of a subject. The combination of the present invention may be administered simultaneously (i.e., synchronously) or sequentially. Examples of "combination" include, but are not limited to, "simultaneous administration," "co-administration," "simultaneous administration," "sequential administration," and "administered simultaneously." The combination of the present invention may be co-administered in the same formulation. The combination of the present invention may be administered simultaneously (i.e., synchronously) in separate formulations. The combination of the present invention may be administered sequentially, i.e., talazopanib is administered first, followed by enzalutamide after a specific period of time (such as one hour); or enzalutamide is administered first, followed by talazopanib after a specific period of time (such as one hour). The combination of the present invention is preferably administered simultaneously.

[0149] In one embodiment, the present invention provides a combination of talazoparib, or a pharmaceutically acceptable salt thereof, and enzalutamide, or a pharmaceutically acceptable salt or solvate thereof, for use in increasing overall survival in treating metastatic castration-resistant prostate cancer in a subject.

[0150] In another aspect, the present invention relates to the use of talazoparib or a pharmaceutically acceptable salt thereof and enzalutamide or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for increasing overall survival in treating metastatic castration-resistant prostate cancer in a subject.

[0151] In one embodiment, the combination therapy is administered to a subject who has not received: 1) prior systemic cancer therapy for non-metastatic castration-resistant prostate cancer or metastatic castration-resistant prostate cancer; 2) prior treatment for prostate cancer with an androgen receptor signaling inhibitor, a PARP inhibitor, cyclophosphamide, or mitoxantrone; or 3) prior treatment with platinum-based chemotherapy within 6 months of the last dose or any history of disease progression on a platinum-based therapy within 6 months of the last dose.

[0152] In one embodiment, the combination therapy is administered to a subject who has not received: 1) systemic cancer therapy 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 of the last dose or any history of disease progression on a platinum-based therapy within 6 months of the last dose.

[0153] Additional therapeutic agents

[0154] In one embodiment, the methods and combination therapies of the present invention may further comprise the administration of another anticancer 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 mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxic agents, anti-hormones, androgen deprivation therapy, and anti-androgens.

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

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

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

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

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

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

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

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

[0163] In one embodiment, the androgen deprivation therapy is selected from leuprolide (also known as leuprolide, such as Lupron or Eligardor Viadur, etc.); 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; ozarelix; elagolix (e.g., Orilissa); relugolix; and linzagolix.

[0164] In one embodiment, the androgen deprivation therapy is selected from leuprolide; buserelin; gonadorelin; goserelin; histrelin; nafarelin; triptorelin; deserelin; futirelin; abarelix; cetrorelix; degarelix; ganirelix; ozarelix; elagolix; rellugolix; and linzagolix.

[0165] In one embodiment, the androgen deprivation therapy is selected from leuprolide, goserelin, and degarelix.

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

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

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

[0169] In one embodiment, the androgen deprivation therapy is degarelix. In some embodiments, degarelix is ​​administered intramuscularly in an initial dose of about 240 mg (which initial dose can optionally be divided into several smaller doses, e.g., two doses of about 120 mg), followed by a monthly maintenance dose of about 80 mg.

[0170] In one embodiment of the methods and combination therapies of the present invention, the regimen includes another active agent, wherein the other active agent is etoposide. In some embodiments, etoposide is administered intravenously according to the approved label, for example, at a dose of 50 to 100 mg / m2 once a day on days 1 to 5. 2 or 5 to 100 mg / m once a day on days 1, 3, and 5 2 In one example, etoposide may be administered at a dose of 80 to 120 mg / m2 on days 1, 2, and 3 of each 21-day cycle. 2 The dose is administered for 1, 2, 3, 4, 5 or 6 cycles.

[0171] Example

[0172] Study Design

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

[0174] Part 1 was open-label and non-randomized and evaluated the safety, tolerability, and pharmacokinetics (PK) of the combination of talazopanib and enzalutamide. Nineteen patients with mCRPC were enrolled to determine the appropriate starting dose for the combination of talazopanib and enzalutamide in Part 2. The starting dose in Part 2 was a combination of 0.5 mg / day of talazopanib / placebo and 160 mg / day of enzalutamide. At screening, patients with moderate renal impairment had a reduced starting dose of 0.35 mg / day of talazopanib / placebo.

[0175] Part 2 is randomized, double-blind, and placebo-controlled, and evaluates the efficacy and safety of the combination of talazopanib and enzalutamide compared to the combination of placebo and enzalutamide. From February 2019 to January 2022, 399 patients (169 from Cohort 1) were randomized in a 1:1 ratio to receive talazopanib or matching placebo once daily in combination with open-label enzalutamide. Randomization was stratified by prior novel hormonal therapy or taxane-based chemotherapy, such as abiraterone, orteronel, or docetaxel for castration-sensitive prostate cancer (yes / no) and DDR mutation status (also known as homologous recombination repair gene change status (deficient vs. non-deficient / unknown)). Stratification factors were specified by the investigator and recorded in the interactive web response system (IWRS) before randomization and used for stratified analysis of the primary efficacy endpoint. However, because the IWRS groups non-deficient and unknown status, a secondary stratified analysis based on alteration status of homologous recombination repair genes derived from a clinical database was also performed and used to identify the non-deficient subgroup.

[0176] Genetic screening to identify alterations in DDR genes was optional for patients in Part 1 but required for randomization in Part 2. Mutational status was determined using next-generation sequencing (NGS)-based genomic testing by testing for the presence of mutations in pre-defined DDR genes that may be sensitive to PARP inhibition. Prior to randomization, patients consented to provide solid tumor tissue (new or archived) and / or blood-based samples, which were used CDx and / or CDx was prospectively evaluated for alterations in homologous recombination repair (HRR) genes (BRCA1, BRCA2, PALB2, ATM, ATR, CHEK2, FANCA, RAD51C, NBN, MLH1, MRE11A, CDK12). Of the 805 enrolled patients, tumor tissue for informing stratification was available from 804 (99.9%) patients, of whom 114 (14.2%) also had blood-based testing available for circulating tumor DNA (ctDNA). Only one patient was enrolled based on ctDNA results. For exploratory analyses, 1 patient was enrolled using CDx retrospectively tests available blood-based samples (not collected in China) to determine the status of patients with unknown prospectively assessed status.

[0177] Study treatment, which includes enzalutamide, will continue until radiographic progression as determined by the (BICR) (Part 2) or local review (Part 1) (unless, in the investigator's opinion, the patient is still benefiting at this time), or until an adverse event leading to permanent discontinuation, or until the patient decides to discontinue treatment, or until death.

[0178] In Part 2, there were two patient cohorts. Cohort 1 (the all-participants cohort) enrolled patients with mCRPC regardless of DDR status. After enrollment of patients in Cohort 1 was completed on September 17, 2020, patients with gene mutations associated with DNA damage repair defects (DDR-deficient patient population, Cohort 2) were further enrolled based on an interactive web response system (IWRS).

[0179] The full participant cohort achieved its primary endpoint in an early readout on September 26, 2022. The DDR-deficient patient population (Cohort 2) included patients with DDR deficiency according to the IWRS from both cohorts.

[0180] The results for the DDR defect group (Group 2) in Part 2 of the study are provided in this Example.

[0181] Research objectives

[0182] Main objectives:

[0183] ● Demonstrate superiority of talazoparib plus enzalutamide compared with placebo plus enzalutamide in prolonging radiographic progression-free survival (rPFS) as assessed by BICR

[0184] Key secondary objectives :

[0185] ● Demonstrate the superiority of talazoparib plus enzalutamide over placebo plus enzalutamide in prolonging OS (with alpha protection)

[0186] To evaluate the safety / toxicity profile of talazoparib and enzalutamide when administered in combination Inclusion criteria:

[0187] 1. Histologically or cytologically confirmed adenocarcinoma of the prostate without small cell or signet ring cell features.

[0188] 2. Asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer (mCRPC) (the score on the Brief Pain Inventory (Brief Pain Inventory) (Short Form) Question 3 must be <4).

[0189] 3. For Part 2 only (optional in Part 1): Assess DDR mutation status.

[0190] 4. Consent for saliva sample collection for germline comparator (optional for patients in Part 1), unless prohibited by local regulations or ethics committee decision.

[0191] 5. Surgical or medical castration, with serum testosterone ≤50 ng / dL (≤1.73 nmol / L) at screening.

[0192] 6. Bone metastases documented on bone scan or soft tissue metastases documented on CT / MRI scan.

[0193] 7. In the case of medical or surgical castration, progressive disease at study entry as defined by one or more of the following 3 criteria:

[0194] a. Prostate-specific antigen (PSA) progression, defined by a minimum of 2 rising PSA values ​​in 3 consecutive assessments with an interval of at least 7 days between assessments.

[0195] b. Soft tissue disease progression as defined by RECIST 1.1.

[0196] c. Bone disease progression, as defined by the Prostate Cancer Working Group 3 (PCWG3) as 2 or more new metastatic bone lesions on whole-body radionuclide bone scan.

[0197] 8. Current use of bisphosphonates or denosumab before Day 1 (Part 1) or randomization (Part 2) is allowed but not mandatory.

[0198] 9. Eastern Cooperative Oncology Group (ECOG) performance status ≤1.

[0199] 10. Life expectancy ≥ 12 months as assessed by the investigator.

[0200] 11. Able to swallow study drug and have no known intolerance to study drug or excipients.

[0201] 12. Patients must agree to use condoms when having sexual intercourse with their spouse from the time of the first dose of study drug to 4 months after the last dose of study treatment. They must also agree that their female spouse with reproductive potential use an additional highly effective form of contraception when having sexual intercourse with a non-pregnant female spouse with reproductive potential from the time of the first dose of study treatment to 4 months after the last dose of study treatment.

[0202] 13. Must agree not to donate sperm from the first dose of study drug to 4 months after the last dose of study drug.

[0203] 14. Evidence of personally signed and dated informed consent documentation (and, if appropriate, molecular pre-screening consent) indicating that the patient [or legally acceptable representative / legal guardian] has been informed of all relevant aspects of the study.

[0204] 15. Willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.

[0205] Exclusion criteria:

[0206] 1. Any previous systemic cancer therapy initiated in non-metastatic CRPC and mCRPC disease states.

[0207] 2. Patients with evidence of metastasis only in patients with adenopathy below the aortic bifurcation.

[0208] 3. Previous treatment for prostate cancer with second-generation androgen receptor inhibitors (enzalutamide, apalutamide, and darolutamide), PARP inhibitors, cyclophosphamide, or mitoxantrone.

[0209] 4. Prior treatment with platinum-based chemotherapy within 6 months (from last dose) before Day 1 (Part 1) or randomization (Part 2), or history of any disease progression on platinum-based therapy within 6 months (from last dose).

[0210] 5. Treatment with cytotoxic chemotherapy, biological therapy (including sipuleucel T), or radionuclide therapy received in castration-sensitive prostate cancer is not excluded if interrupted on Day 1 (Part 1) or 28 days before randomization (Part 2).

[0211] 6. Treatment with any investigational agent within 4 weeks before Day 1 (Part 1) or randomization (Part 2).

[0212] 7. Prior treatment with opioids for pain related to primary prostate cancer or metastases on Day 1 (Part 1) or within 28 days before randomization (Part 2).

[0213] 8. Current use of a strong P-gp inhibitor on Day 1 (Part 1) or within 7 days before randomization (Part 2).

[0214] 9. Major surgery (defined by the investigator) within 2 weeks before Day 1 (Part 1) or randomization (Part 2), or use of palliative local radiation therapy within 3 weeks before randomization (Part 2).

[0215] 10. Clinically significant cardiovascular disease.

[0216] 11. Significant renal dysfunction as defined by any of the following laboratory abnormalities:

[0217] a. Kidney: Estimated glomerular filtration rate (eGFR) by the MDRD equation, which estimates glomerular filtration rate based on creatinine and patient characteristics (available at www.mdrd.com), <30 mL / min / 1.73 m2.

[0218] 12. Patients enrolled in Part 1 only: moderate renal impairment at screening (eGFR 30-59 mL / min / 1.73 m2).

[0219] 13. Significant liver function abnormalities as defined by any of the following laboratory abnormalities during laboratory screening:

[0220] a. Total serum bilirubin >1.5 times the upper limit of normal (ULN) (>3 times ULN for patients with documented Gilbert syndrome or indirect bilirubin concentrations indicating an extrahepatic source of elevation)

[0221] b. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 times ULN (> 5 times ULN if liver function abnormality is caused by liver metastasis)

[0222] c. Albumin <2.8 g / dL.

[0223] 14. Absolute neutrophil count <1500 / μL, platelets <100,000 / μL, or hemoglobin <9 g / dL (no growth factor or blood transfusion within 14 days before hematology values ​​were obtained at screening).

[0224] 15. Known or suspected brain metastasis or active leptomeningeal disease.

[0225] 16. Symptomatic or impending spinal cord compression or cauda equina syndrome.

[0226] 17. Any history of myelodysplastic syndrome, acute myeloid leukemia, or previous malignancy, except any of the following:

[0227] a. Carcinoma in situ or non-melanoma skin cancer

[0228] b. Any prior malignancy, regardless of stage, ≥3 years before randomization, with no evidence of subsequent recurrence or progression.

[0229] c. Stage 0 or 1 cancer less than 3 years before randomization, with a very low probability of recurrence or progression in the opinion of the investigator.

[0230] 18. Gastrointestinal disorders that affect absorption.

[0231] 19. Male subjects of reproductive potential who are unwilling or unable to use highly effective contraceptive methods during the study and 4 months after the last dose of the study product.

[0232] 20. Patients who are investigator site staff and their family members who are directly involved in the conduct of the study, site staff who are otherwise supervised by the investigator, or Pfizer employees (including their family members) who are directly involved in the conduct of the study.

[0233] 21. Other acute or chronic medical conditions (concurrent illnesses, infections, or comorbidities) or psychiatric disorders (including recent (within the past year) or active suicidal thoughts or behaviors or laboratory abnormalities) that interfere with the ability to participate in the 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 judgment of the investigator, would make the patient unsuitable for participation in this study.

[0234] 22. History of epilepsy or any condition that may predispose to epilepsy (e.g., previous cortical stroke, significant brain trauma). In addition, history of loss of consciousness or transient ischemic attack within 12 months of randomization (Part 2).

[0235] Patient population :

[0236] The primary population used to assess efficacy endpoints and patient characteristics was the intention-to-treat (ITT) population. This population included all randomized patients who were assigned treatment according to the randomization group, regardless of whether they received study treatment.

[0237] The safety analysis population consisted of all patients who received at least one dose of study treatment (talazopanib / placebo or enzalutamide) and was based on the actual treatment received. This population was the primary population for evaluating safety.

[0238] Between February 12, 2019, and January 20, 2022, a total of 399 patients with DDR deficiency were randomly assigned (200 to the talazopanib plus enzalutamide group and 199 to the placebo plus enzalutamide group). A total of 198 patients in the talazopanib plus enzalutamide group and 199 patients in the placebo plus enzalutamide group received study treatment.

[0239] Table 1 shows baseline patient demographics and disease characteristics (HRR-deficient patient population), which were well balanced between treatment groups.

[0240] Table 1. Baseline Patient Demographics and Disease Characteristics (HRR-Deficient Patient Population)

[0241]

[0242]

[0243] * One patient in each treatment group received ortrona.

[0244] Table 2 shows the baseline HRR gene changes in the HRR-deficient patient population, which is consistent with previously published studies (Chung JH et al., JCO Precis Oncol. 2019; 3: PO. 18.00283; Abida W et al., JCO Precis Oncol 2017; 1: PO. 17.00029).

[0245] Table 2. Baseline HRR gene changes in the HRR-deficient patient population.

[0246]

[0247] The patient treatment period disposition is summarized in Table 3 below.

[0248] Table 3. Distribution of patients during the treatment period of the study (safety population)

[0249] Treatment period Tarazopanib + Enzalutamide (N=198) Placebo + enzalutamide (N=199) <![CDATA[ Tarazopanib / placebo: ]]> 197(99.5％) 199(100.0％) in progress 95(48.0％) 60(30.2％) Interrupt 102(51.5％) 139(69.8％) Adverse events 19(9.6％) 11(5.5％) die 1(0.5％) 4(2.0％) Lost to follow-up 0 0 Disease progression 39(19.7％) 60(30.2％) Deviation from the plan 0 0 Patient withdrawal 11(5.6％) 13(6.5％) No longer meets the eligibility criteria 0 0 Overall deterioration of health status 24(12.1％) 40(20.1％) No longer clinically beneficial 5(2.5％) 8(4.0％) other 3(1.5％) 3(1.5％) <![CDATA[ Enzalutamide :]]> 197(99.5％) 199(100.0％) in progress 99(50.0％) 60(30.2％) Interrupt 98(49.5％) 139(69.8％) Adverse events 14(7.1％) 11(5.5％) die 1(0.5％) 4(2.0％) Lost to follow-up 0 0 Disease progression 40(20.2％) 60(30.2％) Patient withdrawal 12(6.1％) 13(6.5％) No longer meets the eligibility criteria 0 0 Overall deterioration of health status 23(11.6％) 40(20.1％) No longer clinically beneficial 6(3.0％) 8(4.0％) other 2(1.0％) 3(1.5％)

[0250] Key efficacy results and supporting findings:

[0251] The primary endpoint was rPFS as assessed by BICR. A pre-planned interim efficacy analysis was conducted based on data cutoff date of October 3, 2022. The DDR-deficient patient population met its primary endpoint of radiographic progression-free survival (rPFS), as assessed by blinded independent central review (BICR) in a pre-planned interim analysis. Based on 170 rPFS events (66 in the talazopanib + enzalutamide group and 104 in the placebo + enzalutamide group), the observed stratified hazard ratio for the primary endpoint (talazopanib + enzalutamide vs. placebo + enzalutamide) was 0.447 / 0.45 (95% CI: [0.328 / 0.33, 0.610 / 0.61]; one-sided P value <0.0001; two-sided P value <0.0001) favoring talazopanib + enzalutamide. For the talazopanib + enzalutamide group, the median rPFS was not estimable / evaluable (NE) or not reached (NR) (95% CI: [21.9, NE / NR]) and was 13.8 months for the placebo + enzalutamide group (95% CI: [11.0, 16.7]). The rPFS results exceeded the pre-specified O'Brien-Fleming efficacy boundary, which was a one-sided P value of ≤0.0038. This interim analysis became the final analysis of rPFS. Treatment with talazopanib plus enzalutamide resulted in a 55% reduction in the risk of progression or death relative to treatment with placebo plus enzalutamide. The median follow-up for rPFS was 17.5 months for talazopanib plus enzalutamide and 16.8 months for the placebo plus enzalutamide group.

[0252] Investigator-assessed rPFS was a secondary efficacy endpoint. The stratified hazard ratio (talazopanib plus enzalutamide vs. placebo plus enzalutamide) based on 134 observed rPFS events was 0.475 / 0.48 (95% CI: [0.334 / 0.33, 0.673 / 0.67]; one-sided P value < 0.0001), favoring talazopanib plus enzalutamide. Median rPFS was not estimable / evaluable (NE) or not reached (NR) in the talazopanib plus enzalutamide group (95% CI: [30.3, NE / NR]) and 16.9 months in the placebo plus enzalutamide group (95% CI: [13.9, 21.3]).

[0253] Overall survival (OS) was the key secondary efficacy endpoint for alpha protection. A preplanned interim analysis of OS was performed, with 96 deaths (43 events in the talazopanib plus enzalutamide group and 53 events in the placebo plus enzalutamide group) (24% mortality and 55% information fraction), and it was not mature at the cutoff date (24% overall maturity, 21.5% (talazopanib plus enzalutamide) and 26.6% (placebo plus enzalutamide) patients died). The observed stratified hazard ratio (talazopanib plus enzalutamide vs. placebo plus enzalutamide) was 0.687 / 0.69 (95% CI: [0.458 / 0.46, 1.031 / 1.03]; one-sided P value: 0.0338; two-sided P value: 0.068), favoring talazopanib plus enzalutamide. Median OS was not estimable / evaluable (NE) or not reached (NR) for the talazoparib plus enzalutamide group (95% CI: [36.4, NE / NR]) and 33.7 months for the placebo plus enzalutamide group (95% CI: [27.6, NE / NR]). The OS results did not exceed the prespecified O'Brien-Fleming efficacy limit, with a one-sided P value of ≤0.0009. The stratified hazard ratio for the BRCA alteration subgroup was 0.61 (95% CI, 0.31-1.23; P = 0.16), and the stratified hazard ratio for the non-BRCA alteration subgroup was 0.66 (95% CI, 0.40-1.10; P = 0.11). Eighteen patients in the placebo plus enzalutamide group and three patients in the talazoparib plus enzalutamide group subsequently received olaparib. Survival will continue to be followed.

[0254] The objective response rate (ORR) was a secondary endpoint and was defined as the proportion of patients with measurable soft tissue disease at baseline who achieved a best overall confirmed soft tissue response (CR) or PR according to RECIST 1.1. The ORR, as assessed by BICR, was 67.1% (49 / 73) (95% CI: [55.1, 77.7]) in the talazopanib + enzalutamide group and 40.0% (26 / 65) (95% CI: [28.0, 52.9]) in the placebo + enzalutamide group. The difference in ORR between the two groups was 27.1% (95% CI: [11.1, 43.2]; one-sided nominal p-value: 0.0007; two-sided p-value: 0.0015). The CR rates were 38.4% and 18.5% in the talazopanib + enzalutamide and placebo + enzalutamide groups, respectively. The PR rates were 28.8% and 21.5% in the talazopanib + enzalutamide group and the placebo + enzalutamide group, respectively. The SD rates were 26.0% (19 / 73) and 32.3% (21 / 65) in the talazopanib + enzalutamide group and the placebo + enzalutamide group, respectively. The PD rates were 5.5% (4 / 73) and 20.0% (13 / 65) in the talazopanib + enzalutamide group and the placebo + enzalutamide group, respectively. The higher complete remission (CR) rates suggest a synergistic effect of talazopanib plus enzalutamide treatment.

[0255] PSA remission was also a secondary endpoint and was defined as a decrease of at least 50% from baseline PSA and confirmed by a second consecutive value at least 3 weeks later. The PSA remission rate was 86.4% (95% CI: [80.8, 90.8]) in the talazoparib + enzalutamide group and 63.1% (95% CI: [56.0, 69.9]) in the placebo + enzalutamide group. The difference in PSA remission was 23.2% (95% CI: [15.0, 31.5]; one-sided P value <0.0001; two-sided P value <0.0001).

[0256] Time to PSA progression was a secondary endpoint and was measured from randomization to the first occurrence of PSA progression, defined as an increase of ≥25% and an absolute increase of ≥2 μg / L above nadir. The observed stratified hazard ratio for time to PSA progression (talazopanib plus enzalutamide vs. placebo plus enzalutamide) was 0.410 / 0.41 (95% CI: [0.296 / 0.30, 0.568 / 0.57]; one-sided P value <0.0001), favoring talazopanib plus enzalutamide. The median time to PSA progression was 28.6 months (95% CI: [26.7, NE / NR]) in the talazopanib plus enzalutamide group and 11.1 months (95% CI: [9.3, 13.9]) in the placebo plus enzalutamide group. Treatment with talazopanib plus enzalutamide prolonged the time to PSA progression.

[0257] The benefits of talazopanib plus enzalutamide were consistently observed in other secondary endpoints, such as time to subsequent cytotoxic chemotherapy and progression-free survival 2 (PFS2), which was based on investigator assessment (time from randomization to the date of first documented progression on subsequent anti-tumor therapy or death from any cause, whichever occurred first).

[0258] Duration of cytotoxic chemotherapy was a secondary endpoint. For the duration of cytotoxic chemotherapy, the stratified hazard ratio (talazopanib plus enzalutamide vs. placebo plus enzalutamide) for 103 observed events (38 events in the talazopanib plus enzalutamide group and 65 events in the placebo plus enzalutamide group) was 0.46 (95% CI: [0.31, 0.70]; two-sided P value = 0.0001), favoring talazopanib plus enzalutamide. The median duration of cytotoxic chemotherapy was NE / NR (95% CI: [NE / NR, NE / NR]) for the talazopanib plus enzalutamide group and NE / NR (95% CI: [22.7, NE / NR]) for the placebo plus enzalutamide group.

[0259] Time to initiation of antineoplastic therapy was a secondary endpoint. The observed stratified hazard ratio for time to initiation of antineoplastic therapy (talazopanib plus enzalutamide vs. placebo plus enzalutamide) was 0.40 (95% CI: [0.28, 0.58]; two-sided P value < 0.0001), favoring talazopanib plus enzalutamide. PFS2 was a secondary endpoint. For time to cytotoxic chemotherapy, the stratified hazard ratio for 105 observed events (44 events in the talazopanib plus enzalutamide group and 61 events in the placebo plus enzalutamide group) was 0.57 (95% CI: [0.39, 0.85]; two-sided P value = 0.0045), favoring talazopanib plus enzalutamide. The median PFS2 was 36.4 months (95% CI: [36.4, NE / NR]) for the talazoparib + enzalutamide group; and 28.1 months (95% CI: [24.5, NE / NR]) for the placebo + enzalutamide group.

[0260] In addition, BICR-assessed rPFS and OS were determined for patients with or without BRCA1 / 2 mutations. Treatment benefit was observed in patients with or without BRCA1 / 2 mutations.

[0261] Within the DDR-deficient patient population (N=155), patients with BRCA1 / 2 mutations (BRCA alterations) had an observed stratified hazard ratio (talazopanib + enzalutamide group vs. placebo + enzalutamide group) of 0.203 / 0.20 (95% CI: [0.114 / 0.11, 0.361 / 0.36]; one-sided P value = <0.0001; two-sided P value = <0.001) for BICR rPFS based on 69 rPFS events (15 events in the talazopanib + enzalutamide group and 54 events in the placebo + enzalutamide group) in favor of talazopanib + enzalutamide. The median rPFS was NE (95% CI: [NE, NE]) for the talazoparib + enzalutamide group and 11 months (95% CI: [8.3, 11.1]) for the placebo + enzalutamide group.

[0262] Within the DDR-deficient patient population (N=240), patients with non-BRCA1 / 2 mutations (non-BRCA alterations) had a stratified hazard ratio (talazopanib+enzalutamide vs. placebo+enzalutamide) of 0.685 / 0.68 (95% CI: [0.462 / 0.46, 1.017 / 1.02]; one-sided P value = 0.0298; two-sided P value = 0.06) for BICR rPFS based on 100 rPFS events (50 events in the talazopanib+enzalutamide group and 50 events in the placebo+enzalutamide group) in favor of talazopanib+enzalutamide. The median rPFS was 24.7 months (95% CI: [16.4, NE]) for the talazoparib + enzalutamide group and 16.7 months (95% CI: [13.8, 27.7]) for the placebo + enzalutamide group.

[0263] In the DDR-deficient patient population, patients with BRCA1 / 2 mutations had an observed stratified hazard ratio (HR) of 0.613 (95% CI: [0.306, 1.230]; one-sided P value = 0.0821) for OS based on 34 rPFS events (talazopanib + enzalutamide vs. placebo + enzalutamide), favoring talazopanib + enzalutamide. Median rPFS was NE (95% CI: [29.8, NE]) for the talazopanib + enzalutamide group and NE (95% CI: [24.5, NE]) for the placebo + enzalutamide group.

[0264] In the DDR-deficient patient population, OS in patients with non-BRCA1 / 2 mutations had an observed stratified hazard ratio (talazopanib + enzalutamide vs. placebo + enzalutamide) of 0.664 (95% CI: [0.399, 1.105]; one-sided P value = 0.0560) based on 61 rPFS events, favoring talazopanib + enzalutamide. Median rPFS was 36.4 months (95% CI: [36.4, NE]) for the talazopanib + enzalutamide group and 33.7 months (95% CI: [27.6, NE]) for the placebo + enzalutamide group.

[0265] In Table 4, consistent treatment effects were found with talazopanib plus enzalutamide across prespecified subgroups. HRs for all patients and by BRCA alteration status were based on Cox models stratified by the randomization stratification factor. For all subgroups, HRs were based on unstratified Cox models with treatment as the only covariate.

[0266] As detailed in Table 4, with talazopanib plus enzalutamide, patients with BRCA1 / 2 alterations had an 80% risk reduction for imaging-based progression or death (HR, 0.20; 95% CI, 0.11 to 0.36; P < 0.001); those with non-BRCA1 / 2 alterations had a 32% risk reduction (HR, 0.68; 95% CI, 0.46 to 1.02; P = 0.06).

[0267] Table 4: Subgroup Analysis of rPFS Assessed by BICR in the HRR-Deficient Patient Population

[0268]

[0269]

[0270] *Each treatment group included one patient who had previously received ortrona. Among patients who had received abiraterone or ortrona (n=34), the HR was 0.53 (95% CI, 0.20-1.42; P=0.20), and among those who had received docetaxel (n=117), the HR was 0.39 (95% CI, 0.22 to 0.69; P<0.001).

[0271] Broad treatment effects with talazoparib plus enzalutamide were found across gene subsets in Table 5. The gene clustering alteration dominance hierarchy was defined as any BRCA1 / 2 alteration (BRCA cluster), followed by any PALB2 (PALB2 cluster), followed by any CDK12 (CDK12 cluster), followed by any ATM (ATM cluster), followed by any of all other HRR12 genes (with each patient counted only once).

[0272] Table 5: rPFS assessed by BICR in the HRR-deficient patient population by selected gene subsets

[0273]

[0274]

[0275] Exploratory subgroup analyses of rPFS for patients with BRCA mutations (BRCAm) and non-BRCAm HRRm are presented in Table 6.

[0276] Table 6. Exploratory rPFS Subgroup Analysis by BRCAm Status for TALAPRO-2 (HRR Gene Mutation mCRPC)

[0277]

[0278] Abbreviations: BRCAm = breast cancer susceptibility gene mutation; CI = confidence interval; HRRm = homologous recombination repair gene mutation; NE = not evaluable; rPFS = radiographic progression-free survival.

[0279] * This included 4 patients who were mistakenly randomized in the HRRm stratum and did not have HRR gene mutations.

[0280] Security:

[0281] The safety population consisted of 397 patients treated with at least one dose of study treatment; 198 patients were treated with talazoparib + enzalutamide and 199 patients were treated with placebo + enzalutamide.

[0282] The median duration of treatment with talazopanib was 63 weeks and the median duration of treatment with placebo was 52 weeks. The median duration of treatment with enzalutamide was 64 weeks for the talazopanib + enzalutamide group and 53 weeks for the placebo + enzalutamide group. See Table 7 below.

[0283] Table 7. Dosing Exposure (Safety Population)

[0284]

[0285] The number of patients with treatment-emergent AEs and SAEs is summarized in Table 8. Treatment-emergent was defined as the time between the first dose of study treatment and 28 days after the last dose of study treatment or before any new antineoplastic therapy, whichever occurred first. There were no cases of myelodysplastic syndrome or acute myeloid leukemia. Pulmonary embolism was reported in 4 patients (2.0%) in the talazopanib plus enzalutamide group (3 patients were grade 3; the rest were grade 2) and in 2 patients (1.0%) in the placebo plus enzalutamide group (both were grade 3). There were more dose interruptions and dose reductions due to adverse events in the talazopanib group than in the placebo group, but the permanent discontinuation rates were similar (10% of patients discontinued talazopanib vs. 7% of patients discontinued placebo; 8% discontinued enzalutamide vs. 7%).

[0286] Table 8. Treatment-emergent AEs (Safety Population)

[0287]

[0288]

[0289] *Includes permanent discontinuation / dose reduction / dose interruption of talazopanib / placebo only plus permanent discontinuation / dose reduction / dose interruption of both talazopanib / placebo and enzalutamide.

[0290] ** Includes permanent discontinuation / dose reduction / dose interruption of enzalutamide alone plus talazopanib / placebo and permanent discontinuation / dose reduction / dose interruption of both enzalutamide and talazopanib.

[0291] § The median relative dose intensity of talazoparib remained >80%.

[0292] The numbers of patients with treatment-related AEs and SAEs are summarized in Table 9.

[0293] Table 9. Treatment-related AEs (TRAEs) (Safety Population)

[0294]

[0295] The most common treatment-emergent AEs (TEAEs) of any cause experienced in either group are summarized in Table 10 below and are arranged in descending order based on the frequency of events in the talazopanib + enzalutamide group. Grade 3-4 treatment-emergent adverse events (TEAEs) were reported by 66.2% of patients in the talazopanib plus enzalutamide group and 37.2% of patients in the placebo plus enzalutamide group.

[0296] Table 10. Most Common (>20%) All-Cause TEAEs (Safety Population)

[0297]

[0298] In the talazopanib plus enzalutamide group, the most common TEAEs leading to talazopanib dose reductions were anemia (42.9%), neutropenia (15.2%), and thrombocytopenia (5.6%). Talazopanib plus enzalutamide was associated with a significantly higher incidence of TEAEs compared to placebo plus enzalutamide (9.0%). > Grade 3 hematologic TEAEs (anemia, neutropenia, thrombocytopenia, leukopenia, and lymphopenia) occurred at a higher rate (49.5%). 55.6% of patients had Grade 1-2 anemia at baseline. The median duration of Grade 3-4 anemia onset was 3.3 months and was reported in 40.9% of patients. 42.9% of patients had dose reductions due to anemia. 4.0% of patients discontinued talazoparib due to anemia. Hematologic TEAEs were managed with dose adjustments, hematologic supportive care, and packed red blood cell transfusions. The median relative dose intensity of talazoparib remained >80%.

[0299] The most frequent treatment-emergent AEs of any grade and origin experienced by ≥10% of patients in either group are summarized in Table 11 below and are arranged in descending order based on the frequency of events in the talazoparib + enzalutamide group.

[0300] Table 11. TEAEs in ≥10% of Patients - All Causes (Safety Population)

[0301]

[0302]

[0303] The most frequent SAEs were anemia, which occurred in 17 (8.6%) patients in the talazopanib + enzalutamide group and 2 (1.0%) patients in the placebo + enzalutamide group; urinary tract infection, which occurred in 4 (2.0%) patients in the talazopanib + enzalutamide group and 3 (1.5%) patients in the placebo + enzalutamide group; and syncope, which occurred in 4 (2.0%) patients in the talazopanib + enzalutamide group and 1 (0.5%) patient in the placebo + enzalutamide group. See Table 12 below.

[0304] Table 12. SAEs in ≥2% of Patients - All Causes (Safety Population)

[0305]

[0306] In the talazoparib plus enzalutamide group, there were 3 deaths (1.5%) within 28 days of the last dose of study treatment, and in the placebo plus enzalutamide group, there were 6 deaths (3.0%) within 28 days of the last dose. There were no treatment-related deaths.

[0307] Comprehensive safety analyses are ongoing. To date, the safety profile of the talazoparib and enzalutamide combination in mCRPC is generally consistent with the known safety profiles of the individual medicines.

[0308] in conclusion

[0309] In this large, randomized trial involving patients with mCRPC and HRR gene alterations, talazopanib plus enzalutamide resulted in a statistically significant and clinically meaningful improvement in the primary endpoint (rPFS, assessed by BICR) compared with placebo plus enzalutamide. The rPFS benefit was greater for patients with BRCAm (HR 0.20; 95% CI, 0.11-0.36; P < 0.0001) relative to patients with non-BRCAm (HR 0.68; 95% CI, 0.46-1.02; P = 0.060, and HR 0.72; 95% CI, 0.49-1.07 if 4 patients without HRR gene mutations who were mistakenly randomized to the HRRm stratum were included). Although OS data were immature at the time of the rPFS analysis (24% of patients died, with 21.5% of patients in the talazoparib plus enzalutamide group and 26.6% of patients in the placebo plus enzalutamide group dying), there was a favorable trend toward improved survival for patients with HRR gene alterations (HR 0.69; 95% CI, 0.46-1.03; P = 0.068). Consistent rPFS results were observed in patients who received or did not receive prior CYP17 inhibitors (abiraterone or abiraterone) or taxane-based chemotherapy. No new safety signals were identified. On-target anemia was the most common grade 3 / 4 AE.

[0310] In summary, the DDR-deficient patient population (cohort 2) met its primary endpoint (rPFS) at the pre-planned interim efficacy analysis, which now becomes the final analysis of rPFS. When compared with placebo plus enzalutamide, the combination of talazopanib and enzalutamide in first-line mCRPC patients with DDR defects resulted in a statistically significant and clinically meaningful improvement in rPFS assessed by BICR. Based on the results of this clinical trial in the HRR-deficient patient population (cohort 2), the combination of talazopanib and enzalutamide is a first-line treatment option for patients with mCRPC and HRR gene changes.

[0311] All publications and patent applications cited in this specification are incorporated herein by reference in their entirety. Although the foregoing invention has been described in considerable detail by way of illustration and example, it will be apparent to those skilled in the art, based on the teachings of this invention, that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Claims

1. A method for increasing the survival of a subject with metastatic castration-resistant prostate cancer having a homologous recombination repair (HRR) gene mutation, 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.

2. A method of treating metastatic castration-resistant prostate cancer in a subject having metastatic castration-resistant prostate cancer with an HRR gene mutation, 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 increase the survival of the subject.

3. The method according to claim 1 or 2, wherein the talazoparib or a pharmaceutically acceptable salt thereof and the enzalutamide or a pharmaceutically acceptable salt thereof are administered simultaneously.

4. The method of any one of claims 1 to 3, wherein the metastatic castration-resistant prostate cancer with an HRR gene mutation has a mutation in at least one gene selected from the group consisting of: ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, and RAD51C.

5. The method of any one of claims 1 to 4, wherein the subject has not received: 1) systemic cancer therapy for non-metastatic castration-resistant prostate cancer or metastatic castration-resistant prostate cancer; 2) treatment with an androgen receptor signaling inhibitor, a PARP inhibitor, cyclophosphamide, or mitoxantrone for prostate cancer; or 3) treatment with platinum-based chemotherapy within 6 months or any history of disease progression on a platinum-based therapy within 6 months.

6. The method of claim 5, wherein the subject has not been treated for prostate cancer with an androgen receptor signaling inhibitor, a PARP inhibitor, cyclophosphamide, or mitoxantrone; and further wherein the androgen receptor signaling inhibitor is a second generation androgen receptor inhibitor.

7. The method of claim 6, wherein the second-generation androgen receptor inhibitor is enzalutamide, apalutamide, darolutamide, or abiraterone acetate.

8. The method according to any one of claims 1 to 6, wherein the subject is additionally receiving a gonadotropin-releasing hormone analogue or has undergone bilateral orchiectomy.

9. The method of claim 8, wherein the gonadotropin-releasing hormone analog is a gonadotropin-releasing hormone agonist.

10. The method of claim 8, wherein the gonadotropin-releasing hormone analog is a gonadotropin-releasing hormone antagonist.

11. The method of any one of claims 1 to 10, wherein the increased survival is a 55% reduction in the risk of disease progression or death compared to a subject who has received enzalutamide or a pharmaceutically acceptable salt thereof and a placebo.

12. The method according to any one of claims 1 to 10, wherein the survival is radiographic progression-free survival.

13. The method of claim 12, wherein the radiographic progression-free survival outcome is a 55% reduction in the risk of disease progression or death compared to subjects who have received enzalutamide or a pharmaceutically acceptable salt thereof and placebo.

14. The method of claim 13, wherein radiographic progression-free survival is increased compared to a subject who has received enzalutamide or a pharmaceutically acceptable salt thereof and a placebo.

15. The method of claim 14, wherein radiographic progression-free survival is statistically significantly improved compared to subjects who have received enzalutamide or a pharmaceutically acceptable salt thereof and placebo.

16. The method of claim 15, wherein the statistically significant improvement is a hazard ratio of 0.45 (95% CI: [0.33, 0.61]; one-way P value <0.0001) based on 170 rPFS events in favor of talazoparib or a pharmaceutically acceptable salt thereof and enzalutamide or a pharmaceutically acceptable salt thereof.

17. The method according to any one of claims 1 to 10, wherein the survival is overall survival.

18. The method of claim 17, wherein overall survival is increased compared to a subject who has received enzalutamide or a pharmaceutically acceptable salt thereof and a placebo.

19. The method of any one of claims 1 to 18, wherein the talazoparib or a pharmaceutically acceptable salt thereof is administered at a dose equivalent to about 0.1 mg, about 0.25 mg, about 0.35 mg, or about 0.5 mg of talazoparib free base once daily.

20. The method according to any one of claims 1 to 19, wherein the talazoparib or a pharmaceutically acceptable salt thereof is talazoparib tosylate.

21. The method of any one of claims 1 to 20, wherein the enzalutamide or a pharmaceutically acceptable salt thereof is administered at a dose equivalent to about 160 mg of enzalutamide free base once daily.

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

23. The method of any one of the preceding claims, wherein the subject is a human.

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