WO2025210510A1 - Tmprss2-erg and rb1 as predictive biomarkers for treatment with a parp inhibitor - Google Patents

Abstract

This invention relates to methods for selecting patients having prostate cancer for treatment with a PARP inhibitor, such as talazoparib, or a pharmaceutically acceptable salt thereof, and an androgen receptor inhibitor, such as enzalutamide, or a pharmaceutically acceptable salt thereof, comprising: i) determining an ERG gene alteration status, wherein the ERG gene alteration is a TMPRSS2-ERG gene fusion/rearrangement, and/or determining an RB1 gene alteration status, from a biological sample of the prostate cancer from the subject; and ii) selecting patients with the TMPRSS2-ERG gene fusion/rearrangement and/or the RB1 gene alteration for treatment.

Description

TMPRSS2-ERG AND RB1 AS PREDICTIVE BIOMARKERS FOR TREATMENT WITH A PARP INHIBITOR

Background of the Invention

The present invention relates to methods of selecting patients for prostate cancer treatment with a PARP inhibitor. In particular, this invention relates to methods of selecting a patient for treatment with a PARP inhibitor in combination with an androgen receptor inhibitor, based on a gene alteration status of an ERG gene, specifically TMPRSS2-ERG, or an RB1 gene in the prostate cancer tumor of a patient.

Prostate cancer is the second leading cause of cancer death in men. The androgen receptor (AR) signaling axis, the principal driver of prostate cancer growth, has been targeted by castration and other systemic therapies. Initial treatment for advanced prostate cancer may involve reducing the amount of androgens produced by the body, primarily in the testes. This may be achieved surgically by removal of both testicles (bilateral orchiectomy) or through use of androgen deprivation therapies such as luteinizing hormone-releasing hormone (LHRH) agonist or antagonist drugs, which lower the native production of testosterone (sometimes called “chemical castration”). However, a proportion of tumors progress despite castrate levels of testosterone, at which point the disease is considered castration-resistant. Castration-resistant prostate cancer represents a lethal transition in the progression of prostate cancer, with most patients ultimately succumbing to the disease.

Anti-androgens are thought to suppress androgen activity by a number of different mechanisms. One example of an anti-androgen approved for the treatment of castrationresistant prostate cancer is abiraterone acetate (marketed as Zytiga™), a steroidal CYP17A1 inhibitor. One specific class of anti-androgens are androgen receptor inhibitors, also known as androgen receptor signaling inhibitors or androgen receptor antagonists, which are thought to compete with endogenous ligands, androgens, for the androgen receptor. When an antagonist binds to an androgen receptor it is thought to induce a conformational change in the receptor itself that impedes transcription of key androgen regulated genes and therefore inhibits the biological effects of the androgens themselves, such as testosterone and dihydrotestosterone.

The compound, enzalutamide, which is 4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5- dimethyl-4-oxo-2-thioxo-1-imidazolidinyl]-2-fluoro-N-methyl-benzamide (also known as 4-{3-[4- cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro-/\/- methylbenzamide or also referred to as “RD162” and “MDV3100”) is a non-steroidal androgen receptor inhibitor, having the structure:

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

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

Poly (ADP-ribose) polymerase (PARP) engages in the naturally occurring process of deoxyribonucleic acid (DNA) repair in a cell. PARP inhibition has been shown to be an effective therapeutic strategy against tumors associated with mutations in double-strand DNA repair genes by inducing synthetic lethality (Sonnenblick, A., et al., Nat. Rev. Clin. Oncol, 2015, 12(1), 27-4). PARP inhibition is synthetically lethal in cells with homozygous deletions or deleterious alterations, or both, in DNA damage response (DDR) genes involved either directly or indirectly in homologous recombination repair (HRR) (Lord, CJ, et al., Science, 2017; 355: 1152-1158). PARP inhibitors include olaparib (marketed as Lynparza®), niraparib (marketed as Zejula®), rucaparib (marketed as Rubraca®), and talazoparib (marketed as Talzenna®). An additional PARP inhibitor includes AZD5305.

Talazoparib is a potent, orally available PARP inhibitor, which is cytotoxic to human cancer cell lines harboring gene mutations that compromise DNA repair, an effect referred to as synthetic lethality, and by trapping PARP protein on DNA thereby preventing DNA repair, replication, and transcription.

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

Talazoparib, and pharmaceutically acceptable salts thereof, including the tosylate salt, are disclosed in International Publication Nos. WO 2010/017055 and WO 2012/054698. Additional methods of preparing talazoparib, and pharmaceutically acceptable salts thereof, including the tosylate salt, are described in International Publication Nos. WO 2011/097602, WO 2015/069851 , and WO 2016/019125. Additional methods of treating cancer using talazoparib, and pharmaceutically acceptable salts thereof, including the tosylate salt, are disclosed in International Publication Nos. WO 2011/097334 and WO 2017/075091. Combination treatments using talazoparib, and pharmaceutically acceptable salts thereof, including the tosylate salt, are disclosed in International Publication Nos. WO 2019/075032, WO 2022/200982, WO2024/074959, and WO2024/127140 the contents of which are included herein by reference. Methods of selecting patients for treatment with talazoparib, and pharmaceutically acceptable salts thereof, including the tosylate salt, are disclosed in International Publication Nos. WO 2022/123427 and WO 2023/131894.

TALZENNA® (talazoparib) has been approved in the United States in combination with enzalutamide for the treatment of adult patients with HRR gene-mutated mCRPC. Talazoparib has also been approved in the European Union in combination with enzalutamide for the treatment of adult patients with mCRPC, with or without gene mutations, in whom chemotherapy is not clinically indicated. Talazoparib is approved or under review with anticipated approvals in additional countries. Development of talazoparib in additional human cancers continues.

Most cancer drugs are effective in some patients, but not in others. This may be due to genetic variation among tumors and may be observed even among tumors within the same patient. Variable patient response is particularly pronounced with respect to targeted therapeutics. Therefore, the full potential of targeted therapies may not be realized without suitable tests for determining which patients will benefit from which drugs. According to the National Institutes of Health (NIH), the term "biomarker" is defined as "a characteristic that is objectively measured and evaluated as an indicator of normal biologic or pathogenic processes or pharmacological response to a therapeutic intervention."

There are three distinct types of cancer biomarkers: (1) prognostic biomarkers, (2) predictive biomarkers, and (3) pharmacodynamic biomarkers. A prognostic biomarker is used to classify a cancer, e.g., a solid tumor, according to aggressiveness, i.e. , rate of growth and/or metastasis, and refractiveness to treatment. This is sometimes called distinguishing "good outcome" tumors from "poor outcome" tumors. A predictive biomarker is used to assess the probability that a particular patient will benefit from treatment with a particular drug. For example, patients with breast cancer in which the ERBB2 (HER2 or NEU) gene is amplified are likely to benefit from treatment with trastuzumab (HERCEPTIN®), whereas patients without ERBB2 gene amplification are unlikely to benefit from treatment with trastuzumab. A pharmacodynamic biomarker is an indication of the effect(s) of a drug on a patient while the patient is taking the drug. Accordingly, pharmacodynamic biomarkers often are used to guide dosage level and dosing frequency, during the early stages of clinical development of a new drug. For a discussion of cancer biomarkers, see, e.g., SAWYERS, C., “The cancer biomarker problem” 2008, Nature, 548-552, vol. 452, no. 7187.

As such, there is a need to select which patients might benefit from treatment with a PARP inhibitor, such as talazoparib, in combination with an androgen receptor inhibitor, such as enzalutamide. Therefore, there is a need for diagnostic methods based on predictive biomarkers that may be used to identify cancer patients that are likely (or unlikely) to respond to treatment with a PARP inhibitor, such as talazoparib, in combination with an androgen receptor inhibitor, such as enzalutamide.

Summary of the Invention

The present invention provides, in part, methods for selecting and treating patients having prostate cancer with a PARP inhibitor, such as talazoparib, or a pharmaceutically acceptable salt thereof, and an androgen receptor inhibitor, such as enzalutamide, or a pharmaceutically acceptable salt thereof, in a combination therapy. This summary is provided to introduce a selection of concepts in a simplified form that are further described below in the detailed description. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used in isolation as an aid in determining the scope of the claimed subject matter.

According to Embodiment 1 of the invention, there is provided a method of selecting a subject having prostate cancer, for treatment with a PARP inhibitor and enzalutamide, or a pharmaceutically acceptable salt thereof, comprising: i) determining one or both of an ERG gene alteration status, wherein the ERG gene alteration is a TMPRSS2-ERG gene fusion/rearrangement, and an RB1 gene alteration status, from a biological sample of the prostate cancer from the subject; and ii) selecting the subject for treatment with the PARP inhibitor and the enzalutamide, or a pharmaceutically acceptable salt thereof, if the subject has one or both of the TMPRSS2-ERG gene fusion/rearrangement and the RB1 gene alteration.

According to Embodiment 2 of the invention, there is provided a method of selecting a subject having prostate cancer, for treatment with a PARP inhibitor and enzalutamide, or a pharmaceutically acceptable salt thereof, comprising: i) determining an ERG gene alteration status, wherein the ERG gene alteration is a TMPRSS2-ERG gene fusion/rearrangement, from a biological sample of the prostate cancer from the subject; ii) determining an RB1 gene alteration status from a biological sample of the prostate cancer from the subject; iii) determining i) or ii); and iv) selecting the subject for treatment with the PARP inhibitor and the enzalutamide, or a pharmaceutically acceptable salt thereof, if the subject has the TMPRSS2- ERG gene fusion/rearrangement or the RB1 gene alteration.

According to Embodiment 3 of the invention, there is provided a method of selecting a subject having prostate cancer, for treatment with a PARP inhibitor and enzalutamide, or a pharmaceutically acceptable salt thereof, comprising: i) determining an ERG gene alteration status, wherein the ERG gene alteration is a TMPRSS2-ERG gene fusion/rearrangement, from a biological sample of the prostate cancer from the subject; and ii) selecting the subject for treatment with the PARP inhibitor and the enzalutamide, or a pharmaceutically acceptable salt thereof, if the subject has the TMPRSS2- ERG gene fusion/rearrangement.

According to Embodiment 4 of the invention, there is provided a method of selecting a subject having prostate cancer, for treatment with a PARP inhibitor and enzalutamide, or a pharmaceutically acceptable salt thereof, comprising: i) determining an RB1 gene alteration status from a biological sample of the prostate cancer from the subject; and ii) selecting the subject for treatment with the PARP inhibitor and the enzalutamide, or a pharmaceutically acceptable salt thereof, if the subject has the RB1 gene alteration. Described below are embodiments of the invention, where for convenience Embodiments 1, 2, 3, and 4 (E1, E2, E3, and E4) are identical to the embodiments provided above.

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.

Brief Description of the Drawings

Figure 1 shows a graphical depiction of non-HRR12 gene alterations of interest. Abbreviations: HR is hazard ratio; ITT is intent-to-treat; non-HRR12m is non-HRR12 gene mutated and refers to mutations in genes that are not ATM, ATR, BRCA1 , BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, and RAD51C; and p value^b is one-sided P value.

Figure 2 is a forest plot showing radiographic progression-free survival as assessed by blinded independent central review by gene alteration status and select non-HRR12 genes. Abbreviations: ^c denotes the intent-to-treat population; Cl is confidence interval; HR is hazard ratio; non-HRR12m is non-HRR12 gene mutated and refers to mutations in genes that are not ATM, ATR, BRCA1 , BRCA2, CHEK2, FANCA, MLH1 , MRE11A, NBN, PALB2, and RAD51C; and NR is not reached.

Figure 3 is a Kaplan-Meier plot showing radiographic progression-free survival as assessed by blinded independent central review by treatment arm and TMPRSS2-ERG gene fusion/rearrangement status in patients with non-HRR12m. Abbreviations: No. is number; non- HRR12m is non-HRR12 gene mutated and refers to mutations in genes that are not ATM, ATR, BRCA1 , BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, and RAD51C; and rPFS is radiographic progression-free survival.

Figure 4 shows the summary of objective response rate (ORR) by select non-HRR12 genes. Abbreviations: ^a measurable disease at baseline; ND is not displayed; and OR is odds ratio.

Detailed Description of the Invention

The present invention may be understood more readily by reference to the following detailed description of the embodiments of the invention and the Examples included herein. It is to be also understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting. E1 A method of selecting a subject having prostate cancer, for treatment with a PARP inhibitor and enzalutamide, or a pharmaceutically acceptable salt thereof, based on the TMPRSS2-ERG gene fusion/rearrangement status and/or the RB1 gene alteration status from a biological sample of the prostate cancer from the subject, as defined above.

E2 A method of selecting a subject having prostate cancer, for treatment with a PARP inhibitor and enzalutamide, or a pharmaceutically acceptable salt thereof, based on the TMPRSS2-ERG gene fusion/rearrangement status and/or the RB1 gene alteration status from a biological sample of the prostate cancer from the subject, as defined above.

E3 A method of selecting a subject having prostate cancer, for treatment with a PARP inhibitor and enzalutamide, or a pharmaceutically acceptable salt thereof, based on the TMPRSS2-ERG gene fusion/rearrangement status from a biological sample of the prostate cancer from the subject, as defined above.

E4 A method of selecting a subject having prostate cancer, for treatment with a PARP inhibitor and enzalutamide, or a pharmaceutically acceptable salt thereof, based on the RB1 gene alteration status from a biological sample of the prostate cancer from the subject, as defined above.

E5 The method of embodiment 1, wherein the PARP inhibitor is talazoparib, olaparib, niraparib, rucaparib, AZD5305, or pharmaceutically acceptable salt thereof.

E6 The method of embodiment 2, wherein the PARP inhibitor is talazoparib, olaparib, niraparib, rucaparib, AZD5305, or pharmaceutically acceptable salt thereof.

E7 The method of embodiment 3, wherein the PARP inhibitor is talazoparib, olaparib, niraparib, rucaparib, AZD5305, or pharmaceutically acceptable salt thereof.

E8 The method of embodiment 4, wherein the PARP inhibitor is talazoparib, olaparib, niraparib, rucaparib, AZD5305, or pharmaceutically acceptable salt thereof.

E9 The method of any one of embodiments 1 to 8, wherein the PARP inhibitor is talazoparib, or a pharmaceutically acceptable salt thereof. E10 The method of any one of embodiments 1 to 9, wherein the biological sample is a ctDNA or a tumor tissue.

E11 The method of embodiment 10, wherein the ctDNA is from a plasma sample.

E12 A method of treating a cancer in a subject, comprising: i) selecting the subject according to any one of embodiments 1 to 11; and ii) administering to the selected subject an amount of the PARP inhibitor and an amount of the enzalutamide, or a pharmaceutically acceptable salt thereof, wherein the amounts are effective in treating the prostate cancer.

E13 The method of embodiment 12, wherein the PARP inhibitor is talazoparib, or a pharmaceutically acceptable salt thereof, and further wherein the amount of the talazoparib, or a pharmaceutically acceptable salt thereof, is administered at a daily dosage equivalent to about 0.1 mg, about 0.25 mg, about 0.35 mg or about 0.5 mg once daily of talazoparib free base.

E14 The method of embodiment 13, wherein the talazoparib, or a pharmaceutically acceptable salt thereof, is talazoparib tosylate.

E15 The method of any one of embodiments 12 to 14, wherein the amount of the enzalutamide, or a pharmaceutically acceptable salt thereof, is administered at a dosage equivalent to about 160 mg once daily of enzalutamide free base.

E16 The method of embodiment 15, wherein the enzalutamide, or a pharmaceutically acceptable salt thereof, is a free base.

E17 The method of any one of embodiments 12 to 16, wherein the subject is additionally receiving a gonadotropin-releasing hormone analog or has had a bilateral orchiectomy.

E18 The method of embodiment 17, wherein the gonadotropin-releasing hormone analog is a gonadotropin releasing hormone agonist.

E19 The method of embodiment 17, wherein the gonadotropin-releasing hormone analog is a gonadotropin-releasing hormone antagonist. E20 The methods of any one of embodiments 1 to 19, wherein the prostate cancer is castration-resistant prostate cancer.

E21 The methods of embodiment 20, wherein the castration- resista nt prostate cancer is metastatic castration-resistant prostate cancer.

E22 The methods of any one of embodiments 1 to 21 , wherein the treatment is a first-line treatment.

E23 The methods of any of the proceeding embodiments, wherein the subject is a human.

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

Definitions

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

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

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

As used herein, the term “about” when used to modify a numerically defined parameter (e.g., the dose of a talazoparib, or a pharmaceutically acceptable salt thereof) means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter. For example, a dose of about 1 mg means 1 mg ± 10%, i.e., it may vary between 0.9 mg and 1.1 mg.

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

For purposes of the present invention, “DDR mutation(s)”, “DDR alteration(s)”, ”HRR mutation(s)” and “HRR alteration(s)” refer to alterations/mutations in genes involved directly or indirectly in homologous recombination repair (HRR). Though not as scientifically robust as the phrase “DNA damage response”, it is commonly understood that “DDR” may also be referred to as “DNA damage repair” or “DNA repair”. “DDR-deficient” refers to gene mutations associated with deficiencies in deoxyriboneclueic acid (DNA) damage repair. A “DDR-deficient patient population” or an “HRR-deficient patient population” is a patient population with gene mutations associated with deficiencies in deoxyriboneclueic acid (DNA) damage repair. DDR is a network of pathways which have evolved to repair damaged DNA. These include mismatch repair, base excision repair, and homologous recombination repair (HRR) among others. HRR is particularly important in maintaining genomic integrity given its high fidelity in repairing double-strand DNA breaks. Inhibition of PARP results in accumulation of single-strand DNA breaks and in DNA stress due to PARP trapping, which ultimately culminates in double-strand DNA breaks. Hence, PARP inhibitors are selectively lethal to cancer cells deficient in HRR - this is an example of synthetic lethality, a mechanism whereby deficiency in function of one gene or gene product has little effect alone but is toxic in combination with deficiency in function of a second gene or gene product. DDR-HRR genes include, but are not limited to, ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1 , MRE11A, NBN, PALB2, and RAD51C. HRR12 genes include ATM, ATR, BRCA1 , BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, and RAD51C. A deficiency in homologous recombination repair may be determined using next generation sequencing (NGS).

For purposes of the present invention, a “biological sample of the prostate cancer” includes circulating tumor deoxyribonucleic acid (ctDNA), which is DNA fragments released from tumor cells into the bloodstream, and tumor tissue, as provided in the Example below. ctDNA, a portion of cell-free DNA (cfDNA) in the blood, is released from cancer cells and may be found in plasma, which is the liquid part of blood. ctDNA analysis in plasma is used to monitor cancer progression, treatment response, and detect recurrence.

For purposes of the present invention, non-HRR12 genes refer to genes, which are not HRR12 genes. non-HRR12 genes are genes that are not ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, and RAD51C. non-HRR12 genes include, but are not limited to, ERG, TMPRSS2-ERG, KRAS, RB1 , and MLL2.

For purposes of the present invention, an “alteration” is defined as a known/likely pathogenic variant.

For purposes of the present invention, “radiographic” and “imaging-based” may be used interchangeably. For example, “radiographic” 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.

As used herein, “systemic therapy” for mCRPC are drugs or therapeutic agents used to manage mCRPC. The medicines or drugs are referred to as systemic therapies because they circulate throughout the body to attack cancer cells wherever they may be located in the body. Anti-androgens

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

First generation androgen receptor signaling inhibitors include bicalutamide (marketed as Casodex®), nilutamide (marketed as Nilandron®), or flutamide (marketed as Eulexin®).

Second-generation androgen receptor signaling inhibitors include enzalutamide, apalutamide (marketed as ERLEADA®) and darolutamide (marketed as NLIBEQA®).

A further second-generation androgen receptor signaling inhibitor is abiraterone, or a pharmaceutically acceptable salt or solvate thereof (abiraterone acetate, marketed as Zytiga®). This second-generation AR inhibitor prevents androgen biosynthesis.

An example of an androgen receptor inhibitor is N-desmethyl enzalutamide or a pharmaceutically acceptable salt or solvate thereof, also known as 4-[3-[4-cyano-3- (trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]-2-fluorobenzamide; or Mil; which is disclosed in PCT/US2010/025283, which published on 2^nd September 2010 as WO 2010/099238, the contents of which are included herein by reference.

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

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

An example of surgical ADT is bilateral orchiectomy.

Examples of medicinal ADT include a luteinizing hormone-releasing hormone (LHRH) agonist, a LHRH antagonist, a gonadotropin-releasing hormone (GnRH) agonist and a GnRH antagonist.

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

Salts

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

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

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

Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts. For a review on suitable salts, see Paulekun, G. S. et al., Trends in Active Pharmaceutical Ingredient Salt Selection Based on Analysis of the Orange Book Database, J. Med. Chem. 2007; 50(26), 6665-6672.

Administration and Dosing

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

A “subject” or “patient” according to this invention may have imaging performed while receiving therapy to evaluate their response to treatment. Response criteria, specifically Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), are standardized and may be used at different time points to classify response into the categories, which include, but are not limited to, complete response (CR), partial response (PR), stable disease (SD), or disease progression. At the trial level, categorical responses for all patients are summated into image-based trial endpoints.

A “subject” or “patient” according to this invention may have: 1) histologically or cytologically confirmed adenocarcinoma of the prostate without small cell or signet cell features; 2) asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer; 3) DNA damage repair (DDR) deficiency as assessed centrally by a next-generation sequencing (NGS) biomarker mutation panel that contains DDR genes likely to sensitize to PARP inhibition; 4) surgically or medically castrated, with serum testosterone < 50 ng/dL (< 1.73 nmol/L) at screening; 5) ongoing androgen deprivation therapy with a gonadotropin-releasing hormone (GnRH) agonist or antagonist for patients who have not undergone bilateral orchiectomy; 6) metastatic disease in bone documented on bone scan or in soft tissue documented on CT/MRI scan; 7) progressive disease at study entry in the setting of medical or surgical castration as defined by one or more of the following three criteria: i) prostate specific antigen (PSA) progression defined by a minimum of two rising PSA values from 3 assessments with an interval of at least 7 days between assessments; ii) soft tissue disease progression as defined by RECIST v1.1 ; and iii) bone disease progression defined by Prostate Cancer Working Group 3 (PCWG3) with 2 or more new metastatic bone lesions on a whole body radionuclide bone scan; 8) ongoing bisphosphonate or denosumab use; 9) Eastern Cooperative Oncology Group (ECOG) performance status < 1; and 10) life expectancy > 12 months as assessed by the investigator. As used herein, the term “cancer” refers to or describes the physiological condition in a patient or subject that is typically characterized by unregulated cell growth. Cancer refers to any malignant and/or invasive growth or tumor caused by abnormal cell growth. The term “metastatic” as it relates to cancer, includes but is not limited to, a cancer that has spread from the place in which it started to other parts of the body, a recurrence from the original primary cancer after remission, and a second primary cancer that is a new primary cancer in a subject with a history of previous cancer of different type from latter one. Those skilled in the art will be able to recognize and diagnose metastatic cancer in a patient.

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

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

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

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

Dosage amounts provided herein refer to the dose of the free base form of talazoparib, or are calculated as the free base equivalent of an administered talazoparib salt form. For example, a dosage or amount of talazoparib, such as 0.1 mg, 0.25 mg, 0.35 mg or 0.5 mg refers to the free base equivalent.

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

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

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

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

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

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

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

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

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

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

The compounds used in the present invention may be formulated prior to administration. The formulation will preferably be adapted to the particular mode of administration. These compounds may be formulated with pharmaceutically acceptable excipients as known in the art and administered in a wide variety of dosage forms as known in the art. Dosage unit forms or pharmaceutical compositions suitable for oral administration include, but are not limited to tablets, capsules, such as gelatin capsules, pills, powders, granules, aqueous and nonaqueous oral solutions and suspensions, packaged in containers adapted for subdivision into individual doses.

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

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

Therapeutic Methods and Uses

The methods and combination therapies of the present invention are useful for treating prostate cancer, castraction resistant prostate cancer, and in particular, mCRPC.

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

In one embodiment, the disclosure provides a combination of talazoparib, or a pharmaceutically acceptable salt thereof, and enzalutamide, or a pharmaceutically acceptable salt thereof, for use in the treatment of prostate cancer in a subject, comprising: i) determining an ERG gene alteration status, wherein the ERG gene alteration is a TMPRSS2-ERG gene fusion/rearrangement, from a biological sample of the prostate cancer from the subject; ii) determining an RB1 gene alteration status from a biological sample of the prostate cancer from the subject; iii) determining i) or ii); and iv) selecting the subject for treatment with the PARP inhibitor and the enzalutamide, or a pharmaceutically acceptable salt thereof, if the subject has the TMPRSS2- ERG gene fusion/rearrangement or the RB1 gene alteration.

In another aspect, this invention relates to the use of talazoparib, or a pharmaceutically acceptable salt thereof, and enzalutamide, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of prostate cancer in a subject, comprising: i) determining an ERG gene alteration status, wherein the ERG gene alteration is a TMPRSS2-ERG gene fusion/rearrangement, from a biological sample of the prostate cancer from the subject; ii) determining an RB1 gene alteration status from a biological sample of the prostate cancer from the subject; iii) determining i) or ii); and v) selecting the subject for treatment with the PARP inhibitor and the enzalutamide, or a pharmaceutically acceptable salt thereof, if the subject has the TMPRSS2- ERG gene fusion/rearrangement or the RB1 gene alteration.

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

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

Further Therapeutic Aqents

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

In one embodiment, the methods of the present invention may additionally comprise administering a further active agent, wherein the further active agent is androgen deprivation therapy.

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

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

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

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

In one embodiment, the androgen deprivation therapy is a LHRH agonist or LHRH antagonist.

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

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

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

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

In one embodiment, the androgen deprivation therapy is selected from the group consisting of leuprolide, goserelin and degaralix.

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

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

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

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

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

EXAMPLE

In order that this invention may be better understood, the following example is set forth. This example is for purposes of illustration only and is not to be construed as limiting the scope of the invention in any manner.

Abbreviations

AR: androgen receptor; BICR: blinded independent central review; ctDNA: circulating tumor deoxyribonucleic acid;

Cl: confidence interval;

HRRm: HRR gene mutated;

HRR12: genes included in a 12 HRR gene panel, which includes ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1 , MRE11A, NBN, PALB2, and RAD51C;

HR: hazard ratio; ibPFS: imaging based progression-free survival;

N and n: number;

ITT: intent- to- treat;

ORR: objective response rate; non-HRR12m: non-HRR12 gene mutated, which refers to mutations in genes that are not ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1 , MRE11A, NBN, PALB2, and RAD51C;

PCWG3: Prostate Cancer Clinical Trials Working Group 3; and rPFS: radiographic progression-free survival

Post Hoc Exploratory Analysis in the All-Comers (Cohort 1) Population of the TALAPRO- 2 Clinical Study

Overview: TALAPRO-2 Clinical Study

TALAPRO-2 was an international, Phase 3, randomized, double-blind, two-part study of talazoparib + enzalutamide versus placebo + enzalutamide as first-line treatment in patients with metastatic castration-resistant prostate cancer (NCT03395197).

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

Part 2 was randomized, double-blind, and placebo-controlled and evaluated the efficacy and safety of talazoparib in combination with enzalutamide compared with placebo in combination with enzalutamide. Patients were randomized 1 :1 to receive either talazoparib or matching placebo in combination with open-label enzalutamide. Randomization was stratified by prior novel hormonal therapy or taxane-based chemotherapy, e.g., abiraterone, orteronel, or docetaxel for castration-sensitive prostate cancer (yes/no) and HRR mutational status, also referred to as, homologous recombination repair gene alteration status (deficient vs. non deficient/unknown). Stratification factors were specified by the investigator, recorded in the interactive web response system (IWRS) before randomization and used for the stratified analysis of the primary efficacy endpoint. However, as the IWRS grouped non-deficient and unknown status, a secondary stratified analysis based on homologous recombination repair gene alteration status derived from the clinical database was also performed and used to identify the non-deficient subpopulation.

Genomic screening to identify alterations in HRR genes was optional for patients in Part 1, but it was required for randomization in Part 2. Mutational status was determined by testing for the presence of mutations in defined HRR genes likely to sensitize to PARP inhibition using next generation sequencing (NGS) based gene panel test. Prior to randomization, patients consented to provide solid tumor tissue (de novo or archival) and/or blood-based samples, which were prospectively assessed for the alteration status of DNA damage response genes directly or indirectly involved in homologous recombination repair (BRCA1, BRCA2, PALB2, ATM, ATR, CHEK2, FANCA, RAD51C, NBN, MLH1, MRE11A, CDK12) using the US FDA- approved companion diagnostic FoundationOne® and/or FoundationOneLiquid® CDx.

Study treatment (including enzalutamide) continued until radiographic/imaging-based progression was determined by BICR (Part 2) or local review (Part 1) unless in the opinion of the investigator the patient was still deriving benefit at this time, or an adverse event leading to permanent discontinuation, or patient decision to discontinue treatment, or death.

There were two patient cohorts in Part 2: first the all-comers cohort, then the HRR- deficient cohort.

The primary endpoint was BICR-assessed rPFS, also referred to as ibPFS by BICR, per RECIST v1.1 and PCWG3. Based on the data cutoff on 16 August 2022, the number of events in the talazoparib+enzalutamide group was 151/402 and the number of events in the placebo+enzalutamide group was 191/403. The median follow-up for rPFS was 24.9 months and 24.6 months for the talazoparib+enzalutamide and placebo+enzalutamide groups, respectively. The observed stratified hazard ratio (talazoparib+enzalutamide vs. placebo+enzalutamide) for the primary endpoint was 0.627 (95% Cl: [0.506, 0.777]; one-sided P-value <0.0001 ; two-sided P-value <0.0001) in favor of tai azo pa rib + enzalutamide. Median rPFS was not estimable (NE)/not reached (NR) (95% Cl: [27.5, NE/not reached]) months for the talazoparib + enzalutamide group vs. 21.9 months (95% Cl: [16.6, 25.1]) months for the placebo + enzalutamide group. Treatment with talazoparib plus enzalutamide resulted in a 37% lower or reduced risk of imaging-based progression (blinded independent central review) or death than placebo plus enzalutamide.

The all-comers cohort met its primary endpoint. Talazoparib demonstrated clinical benefit in combination with enzalutamide in metastatic mCRPC. Talazoparib in combination with enzalutamide statistically significantly prolonged rPFS when compared with placebo in combination with enzalutamide in mCRPC patients unselected for HRR status. The robust, highly consistent efficacy was demonstrated in men both with and without homologous recombination repair gene mutations. Across the all-comers population and pre-specified subgroups, talazoparib plus enzalutamide resulted in clinically meaningful and statistically significant benefits over enzalutamide plus placebo. Benefits were consistently observed across the secondary endpoints. In patients with measurable disease who received talazoparib plus enzalutamide, the complete response rate was double that with placebo plus enzalutamide. Results from the primary analysis of the all-comers population of the TALAPRO- 2 trial support the use of talazoparib plus enzalutamide as a first-line treatment in patients with metastatic castration-resistant prostate cancer unselected for homologous recombination repair gene alterations.

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

Rationale for the Post Hoc Exploratory Analysis

Previous molecular subgroup analyses of TALAPRO-2 focused on the association of tumor HRR12 gene alterations with outcome (Zschabitz S, et al. J Clin Oncol 2024;42:Suppl 4 abstract #178). The current post hoc exploratory analysis identified non-HRR12 genes where alterations might be associated with clinical benefit from the combination of talazoparib + enzalutamide versus placebo + enzalutamide. The post hoc exploratory analysis used the allcomers population of the TALAPRO-2 study (N=805) to investigate the efficacy of talazoparib + enzalutamide in patients with: a) >1 non-HRR12 gene alteration; b) >1 non-HRR12 gene alteration with HRR12 gene alteration(s); or c) >1 non-HRR12 gene alteration without HRR12 gene alteration(s).

Methods

A retrospective, agnostic signal-finding sweep of alterations in >300 non-HRR12 genes was performed using screening ctDNA with FoundationOne®Liquid CDx. A total of 687 informative records (N=687) were identified, which represented the largest all-comers genomic dataset from TALAPRO-2 to date.

The results of this dataset were anticipated to better reflect the current alteration status of non-HRR genes compared with older tumor tissue samples and prospectively tested ctDNA, which included a smaller number of samples (Zurita AJ, et al. JCO Precis Oncol. 2022;6:2200195; Azad A, et al. JCO 2023;41 :Suppl 16 abstract #5056). The efficacy endpoints included rPFS by BICR and ORR per RECIST v1.1. Analyses focus on single genes. No additional candidate predictive genes emerged from similar analyses of gene pairs/triplet alterations, and alteration-positiveAnegative gene pairs.

Table 1 and Figure 1 show the non-HRR12 gene alteration results in the 687 informative records from the all-comers genomic dataset from TALAPRO-2. Gene alterations of interest featured a HR <0.45, an upper 95% Cl <1 , and one-sided P value <0.05. KRASm was not pursued further because of an upper 95% Cl >1.

Table 1. Selection of Non-HRR12 Gene Alterations of Interest^{3 a}With calculable HR and P value, prevalence threshold for display of >5 across treatment arms ^bBased on rPFS; ^c1-sided; includes fusion/rearrangement with active partner ERG or other partners; ^eAII ERG alterations were TMPRSS2-ERG fusion/rearrangements.

Figure 2 shows radiographic progression-free survival as assessed by blinded independent central review by gene alteration status and select non-HRR12 genes.

In patients with a TMPRSS2-ERG negative background and non-HRR12m, patients with MLL2m had a HR=0.62; 95% Cl, 0.27-1.45 and patients with RB1m had a HR=0.24; 95% Cl, 0.07-0.81 . MLL2m was therefore deselected as a gene whose alteration status was of independent interest for this analysis.

Figure 3 and Table 2 show radiographic progression-free survival as assessed by blinded independent central review by treatment arm and TMPRSS2-ERG gene fusion/rearrangement status in patients with non-HRR12m. Patients bearing TMPRSS2-ERG may represent a subgroup with potential for high rPFS benefit from talazoparib plus enzalutamide.

Table 2. rPFS by treatment arm and TMPRSS2-ERG gene fusion/rearrangement status in patients with non-HRR12m ^a2-sided P value from Logrank test.

Figure 4 shows the summary of ORR by select non-HRR12 genes. In patients with an RB1 gene alteration, ORR was 62% in those receiving talazoparib + enzalutamide vs 0% in those receiving placebo + enzalutamide; however, the sample size was low in this comparison.

Discussion of TMPRSS2-ERG results

■ TMPRSS2-ERG has been detected in around 30% of advanced prostate cancer tumors (Zurita AJ, et al. JCO Precis Oncol. 2022;6:e2200195) ■ Implicated in androgen biosynthesis and a target of the AR (Scaravilli M, et al. Front Cell Dev Biol. 2021 ;9:623809; Knuuttila M, et al. Endocr Relat Cancer. 2018;25:807-819; and Powell K, et al. Clin Cancer Res. 2015;21 :2569-2579)

■ Facilitates AR signaling by maintaining coregulator complexes at AR-bound sites (Shah N, et al. Cancer Res. 2020;80:4612-4619)

■ AR-dependent gene expression signatures are associated with differential benefit from talazoparib + enzalutamide in TALAPRO-2 (AACR 2024 abstract presentation CT231)

■ In addition, TMPRSS2-ERG may sensitize prostate cancer cells to talazoparib + enzalutamide by inhibiting non-homologous end joining (Chatterjee P, et al. Mol Cancer The 2015;14:1896-1906)

Discussion of RB1 results

■ Loss of RB1 is associated with resistance to enzalutamide (Abida W, et al. Proc Natl Acad Sci U S A. 2019; 116(23): 11428-11436)

■ An RB1 alteration via a BRCA2 codeletion may sensitize prostate tumors to talazoparib + enzalutamide (Chakraborty G, et al. Clin Cancer Res. 2020;26:2047-2064)

• However, BRCA2 codeletion is not always detectable by panel-based sequencing of ctDNA

■ Alternatively, a RB1/BRCA2/RNASEH2B codeletion may sensitize prostate tumors to PARPi (Miao C, et al. Sci Adv. 2022;18:eabl9794)

Conclusion

Talazoparib + enzalutamide improved efficacy outcomes compared with placebo + enzalutamide in patients with alterations in specific non-HRR genes (regardless of HRR12 gene alteration status).

TMPRSS2-ERG and RB1 are candidate predictive biomarkers for efficacy favoring talazoparib + enzalutamide versus placebo + enzalutamide as first-line treatment in patients with mCRPC.

The combination of talazoparib + enzalutamide may partially overcome RB7-mediated resistance to enzalutamide.

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

Claims

What is claimed is:

1. A method of selecting a subject having prostate cancer, for treatment with a PARP inhibitor and enzalutamide, or a pharmaceutically acceptable salt thereof, comprising: i) determining one or both of an ERG gene alteration status, wherein the ERG gene alteration is a TMPRSS2-ERG gene fusion/rearrangement, and an RB1 gene alteration status, from a biological sample of the prostate cancer from the subject; and ii) selecting the subject for treatment with the PARP inhibitor and the enzalutamide, or a pharmaceutically acceptable salt thereof, if the subject has one or both of the TMPRSS2-ERG gene fusion/rearrangement and the RB1 gene alteration.

2. The method of claim 1, wherein the PARP inhibitor is talazoparib, olaparib, niraparib, rucaparib, AZD5305, or pharmaceutically acceptable salt thereof.

3. The method of claim 2, wherein the PARP inhibitor is talazoparib, or a pharmaceutically acceptable salt thereof.

4. The method of any one of claims 1 to 3, wherein the biological sample is a ctDNA or a tumor tissue.

5. The method of claim 4, wherein the ctDNA is from a plasma sample.

6. A method of treating a prostate cancer in a subject, comprising: i) selecting the subject according to the method of any one of claims 1 to 5; and ii) administering to the selected subject an amount of the PARP inhibitor and an amount of the enzalutamide, or a pharmaceutically acceptable salt thereof, wherein the amounts are effective in treating the prostate cancer.

7. The method of claim 6, wherein the PARP inhibitor is talazoparib, or a pharmaceutically acceptable salt thereof, and further wherein the amount of the talazoparib, or a pharmaceutically acceptable salt thereof, is administered at a daily dosage equivalent to about 0.1 mg, about 0.25 mg, about 0.35 mg or about 0.5 mg once daily of talazoparib free base.

8. The method of claim 7, wherein the talazoparib, or a pharmaceutically acceptable salt thereof, is administered as talazoparib tosylate.

9. The method of any one of claims 6 to 8, wherein the amount of the enzalutamide, or a pharmaceutically acceptable salt thereof, is administered at a dosage equivalent to about 160 mg once daily of enzalutamide free base.

10. The method of claim 9, wherein the enzalutamide, or a pharmaceutically acceptable salt thereof, is administered as a free base.

11. The method of any one of claims 6 to 10, wherein the subject is additionally receiving a gonadotropin-releasing hormone analog or has had a bilateral orchiectomy.

12. The method of claim 11 , wherein the gonadotropin-releasing hormone analog is a gonadotropin releasing hormone agonist.

13. The method of claim 11 , wherein the gonadotropin-releasing hormone analog is a gonadotropin-releasing hormone antagonist.

14. The methods of any one of the preceding claims, wherein the prostate cancer is castration-resistant prostate cancer.

15. The methods of claim 14, wherein the castration-resistant prostate cancer is metastatic castration-resistant prostate cancer.

16. The methods of any one of the preceding claims, wherein the treatment is a first-line treatment.

17. The methods of any one of the proceeding claims, wherein the subject is a human.