Niraparib and Abiraterone Acetate Plus Prednisone to Improve Clinical Outcomes in Patients with Metastatic Castration-Resistant Prostate Cancer and Altered HRR

Abstract

The present disclosure relates to niraparib and abiraterone acetate plus prednisone or prednisolone for use in methods to improve the efficacy of treatment of metastatic castration-resistant prostate cancer (mCRPC) in patients with DNA repair abnormalities, in particular for use to improve median radiographic progression-free survival (rPFS).

Description

[Technical field]

[0001] The present disclosure relates to products and methods for improving clinical outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) and HRR gene alteration(s). [Background technology]

[0002] Worldwide, prostate cancer is the second most common cancer and the fifth leading cause of cancer death in men, accounting for 1.4 million (14.1%) new cancer cases and 375,304 (6.8%) cancer deaths in 2020.

[0003] Although patients with localized prostate cancer may be cured with current therapies, the development of metastases predicts fatal disease. Despite advances in the treatment of men with mCRPC, the median overall survival (OS) in these patients is less than 3 years, and the 5-year survival rate is only approximately 30%.

[0004] Across the spectrum of the disease, prostate cancer depends on androgen-mediated signaling for cancer growth and survival. For decades, the initial (first-line) treatment for metastatic prostate cancer has been surgical castration by bilateral orchiectomy or chemical castration by androgen deprivation therapy (ADT). Although ADT generally provides early benefits, resistance to ADT inevitably develops.

[0005] In addition to androgen dependence, DNA repair abnormalities have been identified in approximately 25-30% of patients with metastatic prostate cancer. These homologous recombination repair (HRR) gene alterations include, but are not limited to, BRCA1, BRCA2, cyclin-dependent kinase 12 [CDK-12], ataxia telangiectasia mutated gene [ATM], Fanconi anemia complementation group A [FANCA], partner and localizer of BRCA2 [PALB2], checkpoint kinase 2 [CHEK2], BRCA1 interacting protein C-terminal helicase 1 [BRIP1], and histone deacetylase 2 [HDAC2].

[0006] Several lines of evidence suggest that HRR gene alterations act as a second oncogenic driver in patients with mCRPC, as evidenced by the worse oncological outcomes of these patients. Patients with mCRPC and HRR gene defects have a shorter life expectancy (median cause-specific survival [CSS] from mCRPC 23.3 months) compared with patients with mCRPC and without HRR gene defects (median cause-specific survival [CSS] from mCRPC 33.2 months).

[0007] mCRPC has historically been treated with ADT if the patient has not previously undergone orchiectomy. Clinical trials have investigated additional therapies for mCRPC, but without differentiation in all participant populations, i.e., without biomarker enrichment. These other therapies that have been studied in clinical trials to date include: Docetaxel: The trial, TAX-327, compared docetaxel (D) with mitoxantrone (M) with an overall survival (OS) benefit of 2.4 months (16.5 months with M to 18.9 months with D); PSA 50 Responses were 32% in M ​​and 45% in D; tumor responses were 7% in M ​​and 12% in D; quality of life (QoL) responses were 13% in M ​​and 22% in D. Abiraterone acetate plus prednisone (AAP): In study COU-301, the comparator was placebo plus prednisone (PP) and the study was conducted in patients with second-line mCRPC or "post-docetaxel" mCRPC, as mentioned later. OS benefit was 3.9 months, from 10.9 months (PP) to 14.8 months (AAP). Radiographic progression-free survival (rPFS) increased from 3.6 months (PP) to 5.6 months (AAP); time to prostate-specific antigen (TTPSA) progression was delayed from 6.6 months (PP) to 10.2 months (AAP); PSA 50Responses were 6% for PP and 29% for AAP; pain response rates were 27% for PP and 44% for AAP. In study COU-302, the active comparator was also placebo plus prednisone (PP), but this time the study was conducted in first-line mCRPC patients or pre-docetaxel mCRPC patients. Key results of COU-302 included: rPFS benefit from 8.3 months (PP) to 16.5 months (AAP); OS benefit of 4.4 months from 30.3 months (PP) to 34.7 months (AAP); delay in median time to opiate use from 23.4 months (PP) to 33.4 months (AAP); reduction in risk of performance status decline by 18%, from 10.9 months (PP) to 12.3 months (AAP); extension of time to cytotoxic chemotherapy from 16.8 months (PP) to 25.2 months (AAP); time to PSA progression essentially doubled from 5.6 months (PP) to 11.1 months (AAP). Enzalutamide (E): In the Affirm study, the comparator was a placebo consisting of labrasol in patients with mCRPC after docetaxel. Key results were: OS benefit of 4.8 months, from 13.6 months (P) to 18.4 months (E); increase in rPFS from 2.9 months (P) to 8.3 months (E); delay in TTPSA progression from 3 months (P) to 8.3 months (E); PSA progression from 2% (P) to 54% (E). 50 response; QoL response rate from 18% (P) to 43% (E). In the Prevail study, the comparator was also a placebo consisting of labrasol, and this time the study was conducted in first-line mCRPC patients, also known as docetaxel-pre-mCRPC patients. Key results were: 12-month rPFS milestone, i.e. 14% (P) vs. 65% (E); median rPFS 3.9 months (P) vs. "not reached" (E); rPFS benefit by BICR hazard ratio was 0.32 (68% reduction); investigator-assessed rPFS was 5.4 months (P) vs. 20 months (E); median OS improvement from 31.3 months (P) to 35.3 months (E); objective response rate (ORR) 5% (P) vs. 59% (E).

[0008] Only one clinical trial included patients with mCRPC and specific HRR gene alterations: the Galahad study, which treated mCRPC HRR-positive patients who had received two or more lines of prior therapy (e.g., AR-targeted therapy, taxane-based chemotherapy, cytotoxic chemotherapy) with niraparib. Despite advanced disease stage and progression on multiple prior therapies, an overall response rate (ORR) of 34.2% was measured in L2+mCRPC BRCA patients, whereas an ORR of 10.6% was found in L2+mCRPC non-BRCA patients; the median OS measured for BRCA patients with L2+mCRPC was 13.01 months, compared to 9.63 months for non-BRCA patients; the median rPFS for BRCA patients with L2+mCRPC was 8.08 months, compared to 3.71 months for non-BRCA patients; a median time to PSA progression of 5.13 months was measured for L2+mCRPC BRCA patients, compared to 3.65 months for non-BRCA patients; a median time to symptomatic skeletal events of 13.80 months was calculated for L2+mCRPC BRCA patients and 10.35 months for non-BRCA patients.

[0009] Currently, there are no approved therapies that specifically target HRR gene alterations in the first-line (L1) mCRPC treatment setting, i.e., in patients who have not yet received any systemic therapy except for ADT and potentially limited exposure to AAP for up to 4 months.

[0010] In the absence of approved targeted therapies, patients with HRR gene alterations are currently managed in the same manner as other patients with L1 mCRPC. In all participants, approved treatment options in the L1 mCRPC setting in the European Union (EU) include docetaxel, abiraterone acetate [AA] (Zytiga®) + prednisone / prednisolone (P), and enzalutamide (Xtandi®). Therapies targeting the AR system (AA and enzalutamide) have been associated with rPFS and survival benefits, as well as improved quality of life (QoL) for patients with L1 mCRPC; however, several studies suggest that patients with mCRPC and HRR gene alterations have a poor prognosis and do not respond as well to these treatments as other patients with mCRPC.

[0011] Thus, there is an unmet need to develop more effective treatment options for patients with mCRPC and HRR gene alterations to improve clinical outcomes in these patients.

[0012] Poly(ADP-ribose) polymerase (PARP) inhibitors represent a novel targeted therapeutic approach for the treatment of prostate cancer and HRR gene alterations. Recently, two PARP inhibitors - olaparib and rucaparib - have been approved for the treatment of L2 mCRPC. Olaparib is approved for patients with deleterious HRR mutations (US) or BRCA mutations (EU) who have progressed after previous treatment with enzalutamide or AAP, and rucaparib is approved for patients with deleterious BRCA mutations (US) who have received previous treatment with AR-targeted therapy and taxane-based chemotherapy.

[0013] Recent clinical data have shown different efficacy results in the combination of AR targeted therapy and PARP inhibitors in metastatic prostate cancer, and the patient population most sensitive to this combination was not yet known at the start of this study. Patients receiving olaparib and AAP had improved rPFS compared to patients receiving AAP alone. However, this benefit was seen in patients with and without DNA repair gene deficiencies (DRDs). Summary of the Invention [Means for solving the problem]

[0014] The aim of the present invention is to improve the efficacy of treatment of mCRPC with HRR gene alterations in patients.

[0015] The objective of the present invention is to improve the efficacy of treatment of mCRPC with HRR gene alterations compared to 1000 mg oral once daily of abiraterone acetate and 10 mg oral once daily of prednisone or prednisolone.

[0016] The aim of the present invention is to improve radiographic progression-free survival (rPFS) in mCRPC patients whose tumors harbor HRR gene alterations.

[0017] The objective of the present invention is to delay time to cytotoxic chemotherapy (TCC) in mCRPC patients whose tumors harbor HRR gene alterations.

[0018] The objective of the present invention is to delay the time to symptomatic progression (TSP) in mCRPC patients whose tumors harbor HRR gene alterations.

[0019] The objective of the present invention is to extend the time to PSA progression (TPP) in mCRPC patients whose tumors harbor HRR gene alterations.

[0020] The objective of the present invention is to increase the objective response rate (ORR) in mCRPC patients whose tumors harbor HRR gene alterations.

[0021] The objective of the present invention is to improve overall survival (OS) of mCRPC patients whose tumors harbor HRR gene alterations and with a manageable safety profile.

[0022] The aim of the present invention is to improve the treatment of mCRPC in patients with HRR gene alterations while minimizing the pain burden and providing an overall positive health-related quality of life (HRQoL). [Brief description of the drawings]

[0023] [Figure 1] Kaplan-Meier plot of rPFS assessed by central review in HRR+ patients (cohort 1) in one arm receiving niraparib and abiraterone acetate plus prednisone and the other arm receiving placebo and abiraterone acetate plus prednisone. [Diagram 2] Kaplan-Meier plot of rPFS assessed by central review in patients with BRCA1 / 2 mutations in one arm receiving niraparib and abiraterone acetate plus prednisone and the other arm receiving placebo and abiraterone acetate plus prednisone. [Diagram 3] Forest plot of centrally reviewed radiographic progression-free survival in subgroups defined by baseline clinical disease characteristics; Cohort 1 overall HRR randomized analysis set (Study 64091742PCR3001) [Figure 4] Kaplan-Meier plot of time to initiation of cytotoxic chemotherapy (TCC) for HRR+ patients (cohort 1) in one arm receiving niraparib and abiraterone acetate + prednisone and in the other arm receiving placebo and abiraterone acetate + prednisone. NE = not estimable. [Diagram 5]Kaplan-Meier plot of time to symptomatic progression (TSP) in HRR+ patients (cohort 1) with one arm receiving niraparib and abiraterone acetate plus prednisone and the other arm receiving placebo and abiraterone acetate plus prednisone. Patients receiving niraparib and abiraterone acetate plus prednisone had a delayed TSP. [Figure 6] Kaplan-Meier plot of overall survival in HRR+ patients (cohort 1), one arm receiving niraparib and abiraterone acetate plus prednisone and the other arm receiving placebo and abiraterone acetate plus prednisone. [Figure 7] Kaplan-Meier plot of time to PSA progression in HRR+ patients (cohort 1), one arm receiving niraparib and abiraterone acetate plus prednisone, and the other arm receiving placebo and abiraterone acetate plus prednisone. Patients receiving niraparib and abiraterone acetate plus prednisone had longer time to PSA progression. [Figure 8] Objective response rate (ORR) in HRR+ patients (cohort 1) and BRCA1 / 2 mutation patients; one arm received niraparib and abiraterone acetate + prednisone, the other arm received placebo and abiraterone acetate + prednisone. Results show a higher ORR in patients receiving niraparib and abiraterone acetate + prednisone. [Figure 9] Study design of gene-by-gene analysis in the MAGNITUDE study. AAP, abiraterone acetate plus prednisone / prednisolone; ARi, androgen receptor inhibitor; BM, biomarker; BPI-SF, Brief Pain Questionnaire-Short form; ECOG PS, Eastern Cooperative Oncology Group performance status; HRR, homologous recombination repair; L1, first-line; mCRPC, metastatic castration-resistant prostate cancer; mCSPC, metastatic castration-sensitive prostate cancer; nmCRPC, non-metastatic castration-resistant prostate cancer; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PSA, prostate-specific antigen; rPFS, radiographic progression-free survival. [Figure 10]Kaplan-Meier plots of time to symptomatic progression for cohort 1 (all-HRR and BRCA, respectively) in interim analysis 2 (IA2). [Figure 11] Kaplan-Meier plots of TCC in cohort 1 (all-HRR and BRCA, respectively) in IA2 are shown. [Figure 12] Kaplan-Meier plot of overall survival for cohort 1 (all HRR) is shown. [Figure 13] Kaplan-Meier plot of overall survival in cohort 1 (BRCA) is shown. [Figure 14] Kaplan-Meier plot of overall survival for cohort 1 (BRCA monogenic). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] The present invention may be understood more readily by reference to the following detailed description taken in conjunction with the accompanying examples, which form a part of this disclosure. It is to be understood that these inventions are not limited to the specific products, methods, conditions, or parameters described and / or illustrated herein, and that the terminology used herein is for the purpose of describing specific embodiments by way of example only, and is not intended to limit the invention as claimed.

[0025] The entire disclosure of each patent, patent application, and publication cited or described in this specification is hereby incorporated by reference.

[0026] definition As used above, and throughout this disclosure, the following terms and abbreviations shall be understood to have the following meanings, unless otherwise indicated:

[0027] In this disclosure, unless expressly stated otherwise, the singular forms "a," "an," and "the" include plural references and a reference to a given numerical value includes at least that given value. Thus, for example, a reference to "an ingredient" is a reference to one or more such ingredients and equivalents thereof known to those skilled in the art, and so forth. Furthermore, when indicating that a particular element "may be" X, Y, or Z, such use is not intended to exclude other options for that element in all instances.

[0028] When values ​​are expressed as approximations by use of the antecedent "about," it is to be understood that the particular value forms another embodiment. As used herein, "about X," where X is a numerical value, preferably refers to ±10% of the stated value, inclusive. For example, the phrase "about 8" refers to values ​​from 7.2 to 8.8, inclusive, and as another example, the phrase "about 8%" refers to values ​​from 7.2% to 8.8%, inclusive. Where present, all ranges are inclusive and combinable. For example, when a range of "1 to 5" is recited, the recited range should be construed to include ranges such as "1 to 4," "1 to 3," "1 to 2," "1 to 2 and 4 to 5," "1 to 3 and 5," etc. It should be noted that when a list of alternatives is expressly provided, such a list may also include embodiments in which any of the alternatives may be excluded. For example, when a range of "1 to 5" is recited, such recitation may support a situation in which any of 1, 2, 3, 4, or 5 is excluded. Thus, a statement "1 through 5" may support "1 and 3 through 5, but not 2" or simply "2 is not included."

[0029] The transitional phrases "comprising," "consisting essentially of," and "consisting" are intended to connote their generally accepted meanings in patent terminology, i.e., (i) "comprising" is synonymous with "comprising," "containing," or "characterized by," is inclusive or open-ended, and does not exclude other unrecited elements or method steps, (ii) "consisting of" excludes any element, step, or ingredient not specified in the claim, and (iii) "consisting essentially of" limits the claim to the materials or steps specified and those that do not materially affect the "basic and novel characteristic(s)" of the claimed invention. An embodiment described with the term "comprising" (or its equivalent) also provides, as an embodiment, those independently described with the terms "consisting of" and "consisting essentially of."

[0030] When lists are presented, unless otherwise stated, it is to be understood that each individual element of that list and every combination of that list is a separate embodiment. For example, a list of embodiments presented as "A, B, or C" should be interpreted to include the embodiments "A," "B," "C," "A or B," "A or C," "B or C," or "A, B, or C."

[0031] As used herein, the term "cancer" refers to an abnormal growth of cells that tends to grow uncontrolled and in some cases to invade (spread).

[0032] As used herein, the term "prostate cancer" refers to histologically or cytologically confirmed adenocarcinoma of the prostate.

[0033] The term "androgen deprivation therapy (ADT)" refers to medical or surgical castration. It is the first-line treatment for advanced prostate cancer and is also used as an adjuvant to local treatment of high-risk disease. Medical castration is achieved using GnRH agonists or GnRH antagonists that act in the anterior pituitary gland to reduce the release of LH through downregulation of the GnRH receptor or by directly inhibiting the GnRH receptor. Surgical castration is achieved by orchiectomy. In both cases, testosterone levels are rapidly reduced to castration levels, which are currently defined as serum testosterone levels of <50 ng / dL (1.7 nmol / L). Examples of common GnRH agonists / antagonists used in ADT include abarelix, leuprolide, goserelin, degarelix, and relugolix.

[0034] As used herein, the term "CRPC" refers to castration-resistant prostate cancer. CRPC is prostate cancer that continues to grow despite the suppression of male hormones that stimulate the growth of prostate cancer cells.

[0035] The term "metastatic castration-resistant prostate cancer" or "mCRPC" refers to castration-resistant prostate cancer that has spread to other parts of the body.

[0036] The term "non-metastatic castration-resistant prostate cancer" or "nmCRPC" is characterized by the following elements: (a) histologically or cytologically confirmed adenocarcinoma, urothelial carcinoma, squamous cell carcinoma, basal cell carcinoma, or neuroendocrine tumor(s) of the prostate; (b) elevated serum PSA levels despite ADT or orchiectomy (serum testosterone ≦1.7 nmol / L or ≦50 ng / mL) as evidenced by three consecutive PSA increases at 1-week intervals, two with a 50% increase relative to nadir, and a final PSA >2 ng / mL (based on the Prostate Cancer Working Group 2 Criteria, 2007); and (c) no distant metastases detectable by bone scan, CT, or MRI scan.

[0037] The term "chemotherapy-naive metastatic castration-resistant prostate cancer" refers to metastatic castration-resistant prostate cancer that has not been previously treated with a chemotherapeutic agent.

[0038] The terms "treat", "treating" and "treatment" refer to the eradication, removal, alteration, management or control of tumors or primary, localized or metastatic cancer cells or tissues, particularly prostate cancer cells or tissues, and the minimization or slowing of the spread of cancer, particularly prostate cancer. Minimizing or slowing the spread of cancer includes inhibiting the progression of cancer, slowing the rate of cancer progression, or stopping the rate of cancer progression.

[0039] The term "randomization," when applied to a clinical trial, refers to the point in time at which patients are identified as eligible for the clinical trial and assigned to treatment groups.

[0040] The terms "kit" and "article of manufacture" are used synonymously.

[0041] The terms "subject" and "patient" and "human" are used interchangeably. Typically, a subject, patient, or human is a male subject, patient, or human.

[0042] The term "formulation" refers to a pharmaceutical formulation containing niraparib and abiraterone acetate.

[0043] The terms "sale" or "selling" refer to the transfer of title to a formulation, eg, a pharmaceutical composition or oral dosage form, in an arm's length transaction from a seller to a purchaser.

[0044] The term "offering for sale" refers to a proposal by a seller to sell formulations, such as pharmaceutical compositions and oral dosage forms, to a purchaser.

[0045] As used herein, unless otherwise defined, the term "clinically effective amount" means an amount of one or more active pharmaceutical ingredients that provides for the achievement of prevention, delay in onset, or amelioration of symptoms or growth of prostate cancer in a patient, as confirmed by efficacy data secured through clinical trials.

[0046] The term "pharmaceutical acceptable" means generally safe, non-toxic, and not biologically or otherwise undesirable, and includes acceptable for pharmaceutical use in humans.

[0047] The terms "formulation" and "composition" may be used interchangeably in this disclosure. Both "formulation" and "composition" refer to combining two active pharmaceutical ingredients (APIs) as either a fixed dose combination or a free dose combination. In other words, "formulation" or "composition" refers to a dual drug combination. Thus, the term "pharmaceutical formulation" refers to fixed dose combinations and free dose combinations. The two or more components herein include at least 1) abiraterone acetate; 2) niraparib, and any pharmaceutically acceptable salts, solvates, and hydrate forms thereof, such as niraparib tosylate monohydrate; and 3) additional pharmaceutically acceptable components. Additional components include pharmaceutically acceptable carriers and excipients.

[0048] As used herein, a "fixed dose combination" (FDC) is a formulation or composition comprising abiraterone acetate and niraparib and any pharma- ceutically acceptable salts, solvates, and hydrate forms thereof, e.g., niraparibut tosylate monohydrate, in a single oral dosage form.

[0049] In contrast, a "free dose combination" (FrDC) is a formulation or composition that contains two or more active ingredients combined in separate dosage forms, such as 1) a dosage form containing abiraterone acetate; and 2) a separate dosage form containing niraparib and any pharma- ceutically acceptable salts, solvates, and hydrate forms thereof, such as niraparib tosylate monohydrate.

[0050] The terms "excipient" and "carrier" are used interchangeably in this disclosure. The European Pharmacopoeia (Ph.Eur.) defines an excipient as "any ingredient, other than the active substance(s), present in a pharmaceutical product or used in the manufacture of the product." The intended function of an excipient is to act as a carrier (vehicle or main ingredient) or component of the carrier of the active substance(s), thereby contributing to product attributes such as stability, biopharmaceutical profile, appearance and patient acceptability, as well as the ease with which the product can be manufactured. Usually, two or more excipients are used in the formulation of a pharmaceutical product. The terms vehicle and main ingredient are further defined by the same Pharmacopoeia: "A vehicle is a carrier for active substance(s) in liquid preparations, composed of one or more excipients" and "A standard is a carrier for active substance(s) in semi-solid and solid preparations, composed of one or more excipients."

[0051] "Granules", "granulate", or "granulated particles" are defined herein as particles formed by granulation that contain one or more active pharmaceutical ingredients (APIs) and at least one pharma- ceutically acceptable carrier. A granule composition according to the present disclosure comprises two APIs and at least one pharma- ceutically acceptable carrier. A portion of the granule composition, i.e., a first portion of the granules, may consist essentially of one API and at least one pharma- ceutically acceptable carrier, and another portion of the granule composition, i.e., a second portion of the granules, may consist essentially of another API and at least one pharma- ceutically acceptable carrier. In another embodiment, each and every portion of the granule composition, i.e., each and every granule, comprises two APIs and at least one pharma- ceutically acceptable carrier.

[0052] Radiographic progression-free survival (rPFS) is defined as the time interval from the date of randomization to the first date of radiographic progression or death from any cause, whichever occurs first. Radiographic progression is determined by the first occurrence of soft tissue disease progression by bone scan (per PCWG3 criteria) or CT or MRI (per RECIST 1.1 criteria).

[0053] Radiographic progression should be assessed as follows: Progression of soft tissue disease as measured by CT or MRI as defined by RECIST 1.1. Progression due to bone disease as observed by bone scan and based on PCWG3. Under these criteria, bone progression must be confirmed by a subsequent scan after 6 weeks or more. The week 8 scan (first post-treatment scan) should be used as the baseline against which all subsequent scans are compared to determine progression. Bone progression is defined as one of the following: 1.1) Subjects observed to have two or more new bone lesions at the week 8 scan will be classified into one of the following two categories: a. Subjects whose confirmatory scan (performed 6 weeks or later) shows 2 or more new lesions compared to the week 8 scan (i.e., a total of 4 or more new lesions compared to the baseline scan) are considered to have bone scan progression at week 8. b) Subjects whose confirmatory scan did not show 2 or more new lesions compared to the week 8 scan are not considered to have bone scan progression. The week 8 scan is considered the baseline to which subsequent scans are compared. The first scan time point showing 2 or more new lesions compared to the week 8 scan is considered a bone scan progression time point if these new lesions are confirmed by a subsequent scan 6 weeks or more later. 2. For subjects whose week 8 scan does not have two or more new bone lesions compared to the baseline scan, the first scan timepoint showing two or more new lesions compared to week 8 will be considered a bone scan progression timepoint if these new lesions are confirmed by a subsequent scan 6 weeks or more later.

[0054] Subjects without radiographic progression or death are censored at the date of last disease assessment if they do not initiate subsequent anticancer therapy, or at the date of last disease assessment before the initiation of subsequent anticancer therapy if they initiate subsequent anticancer therapy. Important censoring rules are summarized below.

[0055] [Table 1] The term "overall survival" is defined as the time from randomization to the date of death from any cause. Survival data for subjects alive at the time of analysis was censored at the most recent date for which they were known to be alive. In addition, for subjects not alive after baseline information, data was censored at the date of randomization, and for subjects lost to follow-up due to unknown whereabouts or who withdraw consent, data was censored at the most recent date for which they were known to be alive. Administration of safe and effective amounts of the dual combination of the present invention provides improved antitumor activity as measured by overall survival.

[0056] The term "time to symptomatic progression" is defined as the time from randomization to documentation of a Case Report Form (CRF) for any of the following (whichever occurs first): (1) the occurrence of a skeletal related event (SRE): pathologic fracture, spinal cord compression, or need for surgical intervention or radiation therapy to bone; (2) progression or worsening of disease-related symptomatic pain requiring initiation of new systemic anti-cancer therapy; or (3) the onset of clinically significant symptoms due to locoregional tumor progression requiring surgical intervention or radiation therapy. In some embodiments, administration of a safe and effective amount of a dual combination of the invention improves anti-tumor activity as measured by time to symptomatic progression.

[0057] Time to symptomatic progression (TSP) is also defined as the need to start: external beam radiation therapy (EBRT) for skeletal symptoms, tumor-related orthopedic interventions, other cancer-related procedures (e.g.: nephrostomy insertion, bladder catheter insertion, EBRT, or surgery for non-skeletal tumor symptoms), new systemic anti-cancer therapy for cancer pain or for having a cancer-related morbid event (e.g.: fracture, symptomatic and / or morbid, spinal cord compression, urinary obstructive event).

[0058] The term "time to initiation of cytotoxic chemotherapy" or "time to cytotoxic chemotherapy" (TCC) is defined as the time from randomization to documentation (e.g., survival follow-up CRF) of new cytotoxic chemotherapy administered to a subject. For subjects who have not begun cytotoxic chemotherapy, the time to initiation of cytotoxic chemotherapy is censored at the most recent interrogation date. In some embodiments, administration of a safe and effective amount of a dual combination of the invention provides improved anti-tumor activity as measured by time to cytotoxic chemotherapy.

[0059] Time to PSA progression means the time from randomization to the first date of documented PSA progression by PCWG3 criteria. PSA progression occurs after a decline from baseline: PSA increase ≧25% and ≧2 ng / mL above nadir confirmed by a second value ≧3 weeks later (i.e., a confirmed upward trend); and no decline from baseline: PSA increases ≧25% from baseline and ≧2 ng / mL for more than 12 weeks.

[0060] Subjects without PSA progression at the time of analysis will be censored at the last date they were known to be progression-free.Subjects without a baseline PSA or without a post-baseline value will be censored at the date of randomization.

[0061] PSA response rate is the percentage of subjects who achieved a PSA decline of 50% or more, confirmed by week 12 and after 3-4 weeks per PCWG3 criteria during the treatment period.

[0062] Time to pain progression is defined as the time from the date of randomization to the date of the first observation of pain progression. Pain progression is defined as a 2-point increase from baseline in the worst pain intensity (item 3) of the BPI-SF questionnaire observed at two consecutive assessments ≥3 weeks apart. Subjects without pain progression at the time of analysis will be censored at the last date of BPI-SF pain score collection.

[0063] The time to start of subsequent treatment is defined as the time from the date of randomization to the date of start of subsequent anti-cancer treatment for prostate cancer.Subjects who have not started subsequent anti-cancer therapy at the time of analysis are censored at the last visit date before the last known survival date or at the last known survival date.Subsequent anti-cancer therapy for prostate cancer includes the categories of chemotherapy, hormonal therapy, PARPi, and any other type of therapy for prostate cancer.

[0064] Objective response rate (ORR) is defined as the proportion of subjects with measurable disease whose best response is either complete response (CR) or partial response (PR) by BICR defined by RECIST 1.1 with no evidence of bone progression by PCWG3 criteria.

[0065] Duration of response (based on modified RECIST 1.1) in subjects with measurable disease is defined as the time of documented response to the first date of documented disease progression. This endpoint considers only subjects who (1) had measurable lesions at baseline by RECIST 1.1 (i.e., have a record in the target dataset) and (2) had a tumor response of CR or PR after baseline and before pharmacodynamic (PD) identified by RECIST. For RECIST lesions, the scan date associated with a given visit may span more than one day, so the PD date is the earliest scan date of the visit, and all other responses are linked to the last scan date of the visit. The definition of PD and censoring rules are the same as those for rPFS by BICR.

[0066] Progression-free survival (PFS2) on first subsequent therapy is defined as the time from randomization to the date of progression (radiological, clinical, or PSA progression) on first subsequent therapy or death from any cause, whichever occurs first. General rules for PFS2 events and censoring: 1. For subjects who have started subsequent anticancer therapy: If there is disease progression at the time of the first subsequent anticancer therapy or death, this is a PFS2 event, where the PFS2 date = the minimum of the date of disease progression and the date of death. b. If there is no disease progression on the first subsequent anti-cancer therapy and no death before the start of the second subsequent anti-cancer therapy, this is not a PFS2 event and the subject is censored at the start date of the second subsequent anti-cancer therapy -1 day. c. If there is no disease progression on the first subsequent anti-cancer therapy, no death, and no initiation of a second subsequent anti-cancer therapy, this is not a PFS2 event and the subject is censored at the last known survival date. 2. For subjects who have not received any subsequent anti-cancer therapy: If a subject dies, this is a PFS2 event where the date of death is the PFS2 day. b. If the subject does not die, this is not a PFS2 event and the subject will be censored at their last known alive date.

[0067] As used herein, "PSA 50 The term "response" means a 50% decrease in serum prostate specific antigen from baseline.

[0068] As used herein, the term "survival benefit" refers to an increase in a patient's survival time from the time of randomization in a clinical trial of the administered drug until death. In some embodiments, the survival benefit is about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 15 months, about 20 months, about 25 months, about 30 months, about 35 months, about 40 months, about 45 months, about 50 months, about 55 months, about 60 months, about 80 months, about 100 months, or more than 100 months.

[0069] As used herein, the term "delaying symptoms associated with disease progression" refers to an increase in the time from the time of randomization in a clinical trial of the administered drug to the onset of symptoms such as pain, urinary obstruction, and quality of life considerations.

[0070] EMBODIMENTS OF THE PRESENT DISCLOSURE The invention comprises a dual combination of 100 mg niraparib and 500 mg abiraterone acetate, optionally formulated in a film coated tablet with a pharma- ceutically acceptable carrier; 1. A formulation for use in combination with prednisone or prednisolone in a method of improving median radiographic progression-free survival (rPFS) in patients with metastatic castration-resistant prostate cancer (mCRPC) who are positive for germline and / or somatic homologous recombination repair (HRR) gene alteration(s), comprising: HRR gene alteration(s) a) BRCA2 (breast cancer gene 2) or BRCA1 (breast cancer gene 1), b) BRCA2; c) BRCA2, BRCA1, PALB2 (partner and localizer of the BRCA2 gene), or CHEK2 (checkpoint kinase 2 gene), or d) BRCA2, BRCA1, CHEK2, HDAC2 (histone deacetylase 2), BRIP1 (BRCA1-interacting protein C-terminal helicase 1 gene), FANCA (Fanconi anemia complementation group A gene) or PALB2; and wherein the alteration is selected from one or more alterations in any one of the groups selected from: The method of improving median rPFS relates to a formulation in which the daily dosage is a single dose of 200 mg niraparib and 1000 mg abiraterone acetate, optionally equivalent to two film-coated tablets; and a dose of 10 mg prednisone or prednisolone.

[0071] The invention comprises a dual combination of 50 mg niraparib and 500 mg abiraterone acetate, optionally formulated in a film coated tablet with a pharma- ceutically acceptable carrier; 1. A formulation for use in combination with prednisone or prednisolone in a method of improving median rPFS in patients with mCRPC who are positive for germline and / or somatic HRR gene alteration(s), comprising: HRR gene alteration(s) a) BRCA2 or BRCA1 b) BRCA2; c) BRCA2, BRCA1, PALB2, or CHEK2, or d) one or more alterations in any one of the group selected from BRCA2, BRCA1, CHEK2, HDAC2, BRIP1, FANCA, or PALB2; The method of improving median rPFS relates to a formulation in which the daily dosage is a single dose of 100 mg niraparib and 1000 mg abiraterone acetate, optionally equivalent to two film-coated tablets; and a dose of 10 mg prednisone or prednisolone.

[0072] The present invention relates to a method of improving median rPFS in patients with mCRPC who are positive for germline and / or somatic HRR gene alteration(s), the method comprising administering to the patient a formulation comprising the dual combination of 100 mg niraparib and 500 mg abiraterone acetate, optionally wherein the dual combination is formulated in a film coated tablet with a pharma- ceutically acceptable carrier; HRR gene alteration(s) a) BRCA2 or BRCA1 b) BRCA2; c) BRCA2, BRCA1, PALB2, or CHEK2, or d) one or more alterations in any one of the group selected from BRCA2, BRCA1, CHEK2, HDAC2, BRIP1, FANCA, or PALB2; The present invention relates to a method of improving median rPFS, wherein the daily dosage of the method of improving median rPFS is a single dose of 200 mg niraparib and 1000 mg abiraterone acetate, optionally equivalent to two film-coated tablets; and a dose of 10 mg prednisone or prednisolone.

[0073] The present invention relates to a method of improving median rPFS in patients with mCRPC who are positive for germline and / or somatic HRR gene alteration(s), the method comprising administering to the patient a formulation comprising the dual combination of 50 mg niraparib and 500 mg abiraterone acetate, optionally wherein the dual combination is formulated in a film coated tablet with a pharma- ceutically acceptable carrier; HRR gene alteration(s) a) BRCA2 or BRCA1 b) BRCA2; c) BRCA2, BRCA1, PALB2, or CHEK2, or d) one or more alterations in any one of the group selected from BRCA2, BRCA1, CHEK2, HDAC2, BRIP1, FANCA, or PALB2; The method of improving median rPFS relates to a formulation in which the daily dosage is a single dose of 100 mg niraparib and 1000 mg abiraterone acetate, optionally equivalent to two film-coated tablets; and a dose of 10 mg prednisone or prednisolone.

[0074] The mCRPC is preferably first-line (L1) mCRPC; L1 mCRPC is defined for patients who have not been treated with any therapy in the metastatic castration-resistant setting, except for i) androgen deprivation therapy (ADT), and / or ii) up to 2 or 4 months of prior exposure to abiraterone acetate plus prednisone or prednisolone.

[0075] The mCRPC patient is preferably asymptomatic or has mild symptoms.

[0076] An mCRPC patient may also be defined as a patient with prostate cancer that has progressed to mCRPC.

[0077] In one embodiment, the patient with mCRPC is a patient for whom chemotherapy is not clinically indicated.

[0078] In one embodiment, the improved median rPFS in HRR+ patients treated with the formulation in combination with prednisone or prednisolone is about 16.5 months, with a hazard ratio for rPFS equal to 0.729, with a 95% confidence interval (95%CI) of (0.556, 0.956), and a two-sided p-value of 0.0217. This is a 27.1% reduction in the risk of radiographic progression or death. The median rPFS of 212 patients treated with 200 mg niraparib, 1000 mg abiraterone acetate once daily orally, and a daily oral dose of 10 mg prednisone or prednisolone (investigational drug) was 16.5 months, compared with 13.7 months for 211 patients treated daily with 1000 mg abiraterone acetate + 10 mg prednisone / prednisolone (placebo).

[0079] The term "investigational drug" as used herein refers to 200 mg of niraparib, 1000 mg of abiraterone acetate administered orally once daily, and 10 mg of prednisone or prednisolone administered orally daily.

[0080] The term "placebo" as used in the "Detailed Description", "Figures", and "Examples" sections refers to 1000 mg abiraterone acetate + 10 mg prednisone / prednisolone. In the context of treatment of mCRPC, men receiving placebo may need to continue to maintain castrate levels of testosterone by either co-administration of a GnRH agonist / antagonist or orchiectomy.

[0081] In one embodiment, the subgroup of patients with HRR gene alteration(s) selected from BRCA2 and / or BRCA1 has an improved median rPFS of about 16.6 months, with an HR for rPFS equal to 0.533, 95% CI (0.361, 0.789), and a two-sided p-value of 0.0014. This is a 47% reduction in the risk of radiographic progression or death. 113 BRCA2 and / or BRCA1 positive patients treated daily with the investigational drug had a median rPFS of 16.6 months, compared to a median rPFS of 10.9 months in 112 BRCA2 and / or BRCA1 positive patients treated daily with placebo.

[0082] In one embodiment, in the subgroup of patients with HRR gene alteration(s) selected from BRCA2, BRCA1, CHEK2, HDAC2, BRIP1, FANCA, or PALB2, the improved median rPFS is about 16.7 months, with a HR for rPFS equal to 0.760, 95% CI (0.595, 0.972), and a nominal p-value of 0.0280.

[0083] In one embodiment, in the subgroup of patients with HRR gene alteration(s) selected from BRCA2 and / or BRCA1, the improved median rPFS is about 19.5 months, with a HR for rPFS equal to 0.553, 95% CI (0.3921, 0.782), and a nominal p-value of 0.0007.

[0084] In one embodiment, in the subgroup of patients with HRR gene alteration(s) selected from one or more alterations in BRCA2, BRCA1, BRIP1, CHEK2, FANCA, HDAC2, PALB2, or CDK12, the improved median rPFS is about 16.5 months, with an HR for rPFS equal to 0.663, a 95% CI of (0.489, 0.900), and a nominal p-value of 0.0079. 169 patients positive for one or more alterations in BRCA2, BRCA1, BRIP1, CHEK2, FANCA, HDAC2, PALB2, or CDK12 treated daily with the investigational drug had a median rPFS of 16.5 months, compared to a median rPFS of 11.2 months in 169 patients positive for the same one or more alterations treated daily with placebo.

[0085] In one embodiment, in the subgroup of patients with HRR gene alteration(s) selected from one or more alterations in BRCA2, BRCA1, BRIP1, CHEK2, FANCA, HDAC2, or PALB2, the improved median rPFS is about 16.5 months, with an HR for rPFS equal to 0.640, a 95% CI of (0.469, 0.872), and a nominal p-value of 0.0044. 162 patients positive for one or more alterations in BRCA2, BRCA1, BRIP1, CHEK2, FANCA, HDAC2, or PALB2 treated daily with the investigational drug had a median rPFS of 16.5 months, compared to a median rPFS of 11.2 months in 160 patients positive for the same one or more alterations treated daily with placebo.

[0086] In one embodiment, in the subgroup of patients with HRR gene alteration(s) selected from one or more alterations in ATM, BRIP1, CHEK2, FANCA, HDAC2, PALB2, or CDK12, which is a non-BRCA population, the median rPFS is about 14.8 months, with an HR for rPFS equal to 0.986, a 95% CI of (0.675, 1.442), and a nominal p-value of 0.9437. 99 patients positive for one or more alterations in ATM, BRIP1, CHEK2, FANCA, HDAC2, PALB2, or CDK12 (non-BRCA population) treated daily with the investigational drug had a median rPFS of 14.8 months, compared to a median rPFS of 16.4 months in 99 patients positive for the same one or more alterations treated daily with placebo.

[0087] In one embodiment, the dual combination comprises 100 mg of niraparib and 500 mg of abiraterone acetate, optionally formulated in a film-coated tablet with a pharma- ceutically acceptable carrier; the formulation is further used in combination with prednisone or prednisolone in a method of extending time to cytotoxic chemotherapy (TCC) in patients with mCRPC who are positive for germline and / or somatic homologous recombination repair (HRR) gene alteration(s); The HRR gene alteration(s) is selected from one or more alterations in BRCA2, BRCA1, ATM, BRIP1, CHEK2, FANCA, HDAC2, PALB2, or CDK12; preferably the HRR gene alteration(s) is selected from one or more alterations in BRCA2, BRCA1, ATM, BRIP1, CHEK2, FANCA, HDAC2, or PALB2; The daily dosage of the method for extending the TCC is a single dose of 200 mg niraparib and 1000 mg abiraterone acetate, optionally equivalent to two film-coated tablets; and a dose of 10 mg prednisone or prednisolone, The HR for TCC was equal to 0.588 with a 95% CI of (0.389, 0.889) and a two-sided p-value of 0.0108.

[0088] In 212 patients treated daily with the study drug, the median TCC had not yet been reached, compared with a median of 26 months in 211 patients treated daily with placebo.

[0089] In one embodiment, the dual combination comprises 50 mg of niraparib and 500 mg of abiraterone acetate, optionally formulated in a film-coated tablet with a pharma- ceutically acceptable carrier; the formulation is further used in combination with prednisone or prednisolone in a method of extending time to cytotoxic chemotherapy (TCC) in patients with mCRPC who are positive for germline and / or somatic homologous recombination repair (HRR) gene alteration(s); The HRR gene alteration(s) is selected from one or more alterations in BRCA2, BRCA1, ATM, BRIP1, CHEK2, FANCA, HDAC2, PALB2, or CDK12; preferably the HRR gene alteration(s) is selected from one or more alterations in BRCA2, BRCA1, ATM, BRIP1, CHEK2, FANCA, HDAC2, or PALB2; The daily dosage of the TCC extension method is a single dose of 100 mg niraparib and 1000 mg abiraterone acetate, optionally equivalent to two film-coated tablets; and a dose of 10 mg prednisone or prednisolone.

[0090] In one embodiment, the formulation is further used in combination with prednisone or prednisolone in a method to prolong TCC in a subgroup of patients with mCRPC who have an HRR gene alteration(s) selected from BRCA2 and / or BRCA1, with a HR for TCC equal to 0.578, 95% CI (0.332, 1.006), and a nominal p-value of 0.0495. Median TCC had not yet been reached in 113 BRCA2 and / or BRCA1 positive patients treated daily with the investigational drug, compared to a median TCC at 26 months in 112 BRCA2 and / or BRCA1 positive patients treated daily with placebo.

[0091] In one embodiment, the formulation is further used in combination with prednisone or prednisolone in a method of prolonging TCC in a subgroup of patients with mCRPC who have an HRR gene alteration(s) selected from one or more alterations in BRCA2, BRCA1, BRIP1, CHEK2, FANCA, HDAC2, PALB2, or CDK12, with an HR for TCC equal to 0.728, 95% CI (0.468, 1.133), and a nominal p-value of 0.1582. Median TCC had not yet been reached in 169 patients positive for one or more alterations in BRCA2, BRCA1, BRIP1, CHEK2, FANCA, HDAC2, PALB2, or CDK12 treated daily with the investigational drug, compared to the median TCC at 26 months in 169 patients positive for the same one or more alterations treated daily with placebo.

[0092] In one embodiment, the formulation is further used in combination with prednisone or prednisolone in a method of prolonging TCC in a subgroup of patients with mCRPC who have an HRR gene alteration(s) selected from one or more alterations in BRCA2, BRCA1, BRIP1, CHEK2, FANCA, HDAC2, or PALB2, with a HR for TCC equal to 0.678, 95% CI (0.433, 1.064), and a nominal p-value of 0.0888. Median TCC had not yet been reached in 162 patients positive for one or more alterations in BRCA2, BRCA1, BRIP1, CHEK2, FANCA, HDAC2, or PALB2 treated daily with the investigational drug, compared to the median TCC at 26 months in 160 patients positive for the same one or more alterations treated daily with placebo.

[0093] In one embodiment, the formulation is further used in combination with prednisone or prednisolone in a method of prolonging TCC in a subgroup of patients with mCRPC having HRR gene alteration(s) selected from one or more alterations in ATM, BRIP1, CHEK2, FANCA, HDAC2, PALB2, or CDK12, which is a non-BRCA population, with a HR for TCC equal to 0.601, a 95% CI of (0.324, 1.116), and a nominal p-value of 0.1033. In 99 patients positive for one or more alterations in ATM, BRIP1, CHEK2, FANCA, HDAC2, PALB2, or CDK12 treated daily with the investigational drug, i.e., the non-BRCA patient population, the median TCC was not yet reached, compared to the median TCC not reached in 99 patients positive for the same one or more alterations treated daily with placebo.

[0094] In one embodiment, the dual combination comprises 100 mg of niraparib and 500 mg of abiraterone acetate, optionally formulated in a film-coated tablet with a pharma- ceutically acceptable carrier; the formulation is further used in combination with prednisone or prednisolone in a method of delaying the time to symptomatic progression (TSP) in patients with mCRPC who are positive for germline and / or somatic homologous recombination repair (HRR) gene alteration(s); The HRR gene alteration(s) is selected from one or more alterations in BRCA2, BRCA1, ATM, BRIP1, CHEK2, FANCA, HDAC2, PALB2, or CDK12; preferably the HRR gene alteration(s) is selected from one or more alterations in BRCA2, BRCA1, ATM, BRIP1, CHEK2, FANCA, HDAC2, or PALB2; the daily dosage of the method for delaying TSP is a single dose of 200 mg niraparib and 1000 mg abiraterone acetate, optionally equivalent to two film-coated tablets; and a dose of 10 mg prednisone or prednisolone; The HR for TSP was equal to 0.686 with a 95% CI of (0.474, 0.993) and a two-sided p value of 0.0444.

[0095] The median TSP had not yet been reached in the 212 patients treated daily with the study drug, nor in the 211 patients treated daily with placebo.

[0096] In one embodiment, the dual combination comprises 50 mg of niraparib and 500 mg of abiraterone acetate, optionally formulated in a film-coated tablet with a pharma- ceutically acceptable carrier; the formulation is further used in combination with prednisone or prednisolone in a method of delaying the time to symptomatic progression (TSP) in patients with mCRPC who are positive for germline and / or somatic homologous recombination repair (HRR) gene alteration(s); The HRR gene alteration(s) is selected from one or more alterations in BRCA2, BRCA1, ATM, BRIP1, CHEK2, FANCA, HDAC2, PALB2, or CDK12; preferably the HRR gene alteration(s) is selected from one or more alterations in BRCA2, BRCA1, ATM, BRIP1, CHEK2, FANCA, HDAC2, or PALB2; The daily dosage of the method for delaying TSP is a single dose of 100 mg niraparib and 1000 mg abiraterone acetate, optionally equivalent to two film-coated tablets; and a dose of 10 mg prednisone or prednisolone.

[0097] In one embodiment, the formulation is further used in combination with prednisone or prednisolone in a method to delay TSP in a subgroup of patients with mCRPC who have an HRR gene alteration selected from BRCA2 and / or BRCA1, with a HR for TSP equal to 0.683, 95% CI (0.420, 1.111), and a nominal p-value of 0.1224. In 113 BRCA2 and / or BRCA1 positive patients treated daily with the investigational drug, the median TSP had not yet been reached, compared to a median TSP of 19.8 months in 112 BRCA2 and / or BRCA1 positive patients treated daily with placebo.

[0098] In one embodiment, the formulation is further used in combination with prednisone or prednisolone in a method to delay TSP in a subgroup of patients with mCRPC having HRR gene alteration(s) selected from one or more alterations in BRCA2, BRCA1, BRIP1, CHEK2, FANCA, HDAC2, PALB2, or CDK12, with a HR for TSP equal to 0.687, 95% CI (0.462, 1.021), and a nominal p-value of 0.0615. In 169 patients positive for one or more alterations in BRCA2, BRCA1, BRIP1, CHEK2, FANCA, HDAC2, PALB2, or CDK12 treated daily with the investigational drug, the median TSP had not yet been reached, compared to a median TSP of 24.2 months in 169 patients positive for the same one or more alterations treated daily with placebo.

[0099] In one embodiment, the formulation is further used in combination with prednisone or prednisolone in a method to delay TSP in a subgroup of patients with mCRPC having HRR gene alteration(s) selected from one or more alterations in BRCA2, BRCA1, BRIP1, CHEK2, FANCA, HDAC2, or PALB2, with a HR for TSP equal to 0.720, a 95% CI of (0.480, 1.080), and a nominal p-value of 0.1107. The median TSP had not yet been reached in 162 patients positive for one or more alterations in BRCA2, BRCA1, BRIP1, CHEK2, FANCA, HDAC2, or PALB2 treated daily with the investigational drug, and the median TSP had not yet been reached in 160 patients positive for the same one or more alterations treated daily with placebo.

[0100] In one embodiment, the formulation is further used in combination with prednisone or prednisolone in a method to delay TSP in a subgroup of patients with mCRPC having HRR gene alteration(s) selected from one or more alterations in ATM, BRIP1, CHEK2, FANCA, HDAC2, PALB2, or CDK12, which is a non-BRCA population, with an HR for TSP equal to 0.690, a 95% CI of (0.391, 1.218), and a nominal p-value of 0.1982. In 99 patients positive for one or more alterations in ATM, BRIP1, CHEK2, FANCA, HDAC2, PALB2, or CDK12, i.e., the non-BRCA patient population, treated daily with the investigational drug, the median TSP had not yet been reached, nor had the median TSP been reached in 99 patients positive for the same one or more alterations treated daily with placebo.

[0101] In one embodiment, the dual combination comprises 100 mg of niraparib and 500 mg of abiraterone acetate, optionally formulated in a film-coated tablet with a pharma- ceutically acceptable carrier; the formulation is further used in combination with prednisone or prednisolone in a method of delaying time to PSA progression (TPP) to about 18.5 months in patients with mCRPC who are positive for germline and / or somatic homologous recombination repair (HRR) gene alteration(s); The HRR gene alteration(s) is selected from one or more alterations in BRCA2, BRCA1, ATM, BRIP1, CHEK2, FANCA, HDAC2, PALB2, or CDK12; preferably the HRR gene alteration(s) is selected from one or more alterations in BRCA2, BRCA1, ATM, BRIP1, CHEK2, FANCA, HDAC2, or PALB2; the daily dosage of the method for delaying TPP is a single dose of 200 mg niraparib and 1000 mg abiraterone acetate, optionally equivalent to two film-coated tablets; and a dose of 10 mg prednisone or prednisolone; The HR for TPP was equal to 0.569 with a 95% CI of (0.425, 0.760) and a nominal p value of 0.0001.

[0102] The 212 patients treated daily with the study drug had a delay in TPP of 18.5 months compared with a delay of 9.3 months in the 211 patients treated daily with placebo.

[0103] In one embodiment, the dual combination comprises 50 mg of niraparib and 500 mg of abiraterone acetate, optionally formulated in a film-coated tablet with a pharma- ceutically acceptable carrier; the formulation is further used in combination with prednisone or prednisolone in a method of delaying time to PSA progression (TPP) to about 18.5 months in patients with mCRPC who are positive for germline and / or somatic homologous recombination repair (HRR) gene alteration(s); The HRR gene alteration(s) is selected from one or more alterations in BRCA2, BRCA1, ATM, BRIP1, CHEK2, FANCA, HDAC2, PALB2, or CDK12; preferably the HRR gene alteration(s) is selected from one or more alterations in BRCA2, BRCA1, ATM, BRIP1, CHEK2, FANCA, HDAC2, or PALB2; The daily dosage of the method for delaying TPP is a single dose of 100 mg niraparib and 1000 mg abiraterone acetate, optionally equivalent to two film-coated tablets; and a dose of 10 mg prednisone or prednisolone.

[0104] In one embodiment, the formulation is further used in combination with prednisone or prednisolone in a method to delay TPP in a subgroup of patients with mCRPC who have an HRR gene alteration selected from BRCA2 and / or BRCA1, with an HR for TPP equal to 0.455, 95% CI (0.299, 0.692), and a nominal p-value of 0.0002. In 113 BRCA2 and / or BRCA1 positive patients treated daily with the investigational drug, a delay in TPP had not yet been reached, compared to a delay of TPP of 9.2 months in 112 BRCA2 and / or BRCA1 positive patients treated daily with placebo.

[0105] In one embodiment, the formulation is further used in combination with prednisone or prednisolone in a method to delay TPP to about 18.4 months in a subgroup of patients with mCRPC having HRR gene alteration(s) selected from one or more alterations in BRCA2, BRCA1, BRIP1, CHEK2, FANCA, HDAC2, PALB2, or CDK12, with an HR for TPP equal to 0.566, 95% CI (0.411, 0.780), and a nominal p-value of 0.0004. 169 patients positive for one or more alterations in BRCA2, BRCA1, BRIP1, CHEK2, FANCA, HDAC2, PALB2, or CDK12 treated daily with the investigational drug had a median delay in TPP of 18.4 months compared to a median delay in TPP of 9.23 months in 169 patients positive for the same one or more alterations treated daily with placebo.

[0106] In one embodiment, the formulation is further used in combination with prednisone or prednisolone in a method to delay TPP to about 18.4 months in a subgroup of patients with mCRPC who have an HRR gene alteration(s) selected from one or more alterations in BRCA2, BRCA1, BRIP1, CHEK2, FANCA, HDAC2, or PALB2, with an HR for TPP equal to 0.554, a 95% CI of (0.399, 0.769), and a nominal p-value of 0.0003. 162 patients positive for one or more alterations in BRCA2, BRCA1, BRIP1, CHEK2, FANCA, HDAC2, or PALB2 treated daily with the investigational drug had a median delay in TPP of 18.4 months, compared to a median delay in TPP of 9.23 months in 160 patients positive for the same one or more alterations treated daily with placebo.

[0107] In one embodiment, the dual combination comprises 100 mg of niraparib and 500 mg of abiraterone acetate, optionally formulated in a film-coated tablet with a pharma- ceutically acceptable carrier; the formulation is further used in combination with prednisone or prednisolone in a method to improve the objective response rate (ORR) to about 59.8% in patients with mCRPC who are positive for germline and / or somatic homologous recombination repair (HRR) gene alteration(s); The HRR gene alteration(s) is selected from one or more alterations in BRCA2, BRCA1, ATM, BRIP1, CHEK2, FANCA, HDAC2, PALB2, or CDK12; preferably the HRR gene alteration(s) is selected from one or more alterations in BRCA2, BRCA1, ATM, BRIP1, CHEK2, FANCA, HDAC2, or PALB2; the daily dose of the method for improving the ORR is a single dose of 200 mg niraparib and 1000 mg abiraterone acetate, optionally equivalent to two film-coated tablets; and a dose of 10 mg prednisone or prednisolone; The relative risk (RR) for ORR was equal to 2.131 with a 95% CI of (1.450, 3.132) and a chi-square test nominal p-value of less than 0.001.

[0108] The 92 patients treated daily with the study drug had an ORR of 59.8%, compared with an ORR of 28% in the 82 patients treated daily with placebo.

[0109] In one embodiment, the dual combination comprises 50 mg of niraparib and 500 mg of abiraterone acetate, optionally formulated in a film-coated tablet with a pharma- ceutically acceptable carrier; the formulation is further used in combination with prednisone or prednisolone in a method to improve the objective response rate (ORR) to about 59.8% in patients with mCRPC who are positive for germline and / or somatic homologous recombination repair (HRR) gene alteration(s); The HRR gene alteration(s) is selected from one or more alterations in BRCA2, BRCA1, ATM, BRIP1, CHEK2, FANCA, HDAC2, PALB2, or CDK12; preferably the HRR gene alteration(s) is selected from one or more alterations in BRCA2, BRCA1, ATM, BRIP1, CHEK2, FANCA, HDAC2, or PALB2; The daily dose of the method to improve ORR is a single dose of 100 mg niraparib and 1000 mg abiraterone acetate, optionally equivalent to two film-coated tablets; and a dose of 10 mg prednisone or prednisolone.

[0110] In one embodiment, the formulation is further used in combination with prednisone or prednisolone in a method to improve the ORR to about 51.8% in a subgroup of patients with mCRPC who have an HRR gene alteration selected from BRCA2 and / or BRCA1, with a RR of ORR equal to 1.657, a 95% CI of (1.015, 2.705), and a chi-squared p-value of 0.035.

[0111] The 56 BRCA2- and / or BRCA1-positive patients treated daily with the study drug had an ORR of 51.8%, compared with an ORR of 31.3% in the 48 BRCA2- and / or BRCA1-positive patients treated with placebo.

[0112] In any of the embodiments presented herein relating to the medical use of the formulations or methods of treatment with the formulations, the patient has previously undergone gonadotropin releasing hormone (GnRH) analog therapy or has undergone a bilateral orchiectomy.

[0113] If the patient has not been surgically castrated, they preferably continue to receive GnRH analog therapy.

[0114] In any of the embodiments presented herein relating to the medical use of the formulations or methods of treatment with the formulations, the patient has previously received an antiandrogen selected from enzalutamide, apalutamide, nilutamide, flutamide, bicalutamide, darolutamide, or abiraterone acetate.

[0115] Previous antiandrogen therapy is preferably discontinued.

[0116] In any of the embodiments presented herein relating to the medical use of the formulation or the method of treatment with the formulation, the patient has previously received a taxane chemotherapy, optionally selected from docetaxel or cabazitaxel.

[0117] In any of the embodiments presented herein relating to the medical use of the formulations or methods of treatment with the formulations, niraparib is in a salt form selected from tosylate monohydrate, sulfate, benzenesulfate, fumarate, succinate, camphorate, mandelate, camsylate, lauryl sulfate, or a mixture of tosylate monohydrate and lauryl sulfate.

[0118] In any of the embodiments presented herein relating to the medical use of the formulation or the method of treatment with the formulation, the formulation comprising the dual combination of 100 mg niraparib and 500 mg abiraterone acetate is in the form of a film-coated tablet consisting of i) a tablet core comprising the following excipients: colloidal anhydrous silica, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, silicified microcrystalline cellulose, sodium lauryl sulfate, and ii) a film coating comprising the following excipients: red ferric oxide (E172), yellow ferric oxide (E172), sodium lauryl sulfate, glycerol monocaprylocaprate, polyvinyl alcohol, talc, and titanium dioxide (E171).

[0119] In a preferred embodiment, the tablet has the following composition:

[0120] [Table 2] a Purified water is removed during processing; b The salt coefficient is 1.594; 159.40 mg of niraparib tosylate is equivalent to a 100.00 mg dose of niraparib; The tablets are film coated with approximately 64 mg of coating powder Opadry® AMB II 88A170010 Beige and 256 mg of purified water, the latter of which is removed during processing.

[0121] In any of the embodiments presented herein relating to the medical use of the formulation or the method of treatment with the formulation, the formulation comprising the dual combination of 100 mg niraparib and 500 mg abiraterone acetate is in the form of a capsule.

[0122] The capsule contains i) the dual combination of 100 mg of niraparib and 500 mg of abiraterone acetate, and ii) a pharma- ceutically acceptable carrier comprising crospovidone, hypromellose, sodium lauryl sulfate, lactose monohydrate, and magnesium stearate.

[0123] Preferably, two film-coated tablets or two capsules are administered daily at least two hours after a meal, and food should not be eaten for at least one hour after administration.

[0124] In any of the embodiments presented herein relating to the medical use of the formulation or the method of treatment with the formulation, the germline and / or somatic HRR gene alteration(s) is / are determined by using a validated testing method.

[0125] Examples of commercially available germline genetic and somatic tests for prostate cancer are provided herein below:

[0126] [Table 3]

[0127] The invention further relates to any of the methods presented herein, the methods further comprising marketing such a formulation, wherein the reference listed drug formulation label of such formulation comprises instructions for treating mCRPC.

[0128] In one embodiment, the formulation label includes rPFS, TCC, TSP, TPP, or ORR data.

[0129] The invention further relates to marketing such formulations, wherein the formulation label of the reference listed drug of such approved formulation includes rPFS, TCC, TSP, TPP, or ORR data.

[0130] Niraparib Niraparib is an orally available, highly selective inhibitor of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) with activity against PARP-1 and PARP-2 deoxyribonucleic acid (DNA) repair polymerases. The preparation of niraparib is described in U.S. Patent Nos. 8,071,623 and 8,436,185, both of which are incorporated herein by reference.

[0131] Niraparib is currently marketed under the ZEJULA® brand as a capsule formulation containing 159.4 mg of niraparib tosylate monohydrate (equivalent to 100 mg of niraparib free base) as the active ingredient.

[0132] [ka]

[0133] As used herein, the term “niraparib” refers to either the free base compound (2-[4-[(3S)-piperidin-3-yl]phenyl]-2H-indazole-7-carboxamide), salt forms, including pharma- ceutically acceptable salts of 2-[4-[(3S)-piperidin-3-yl]phenyl]-2H-indazole-7-carboxamide (e.g., 4-methylbenzenesulfonic acid, 2-[4-[(3S)-piperidin-3-yl]phenyl]-2H-indazole-7-carboxamide), and / or solvated forms, including hydrated forms thereof (e.g., 2-[4-[(3S)-piperidin-3-yl]phenyl]-2H-indazole-7-carboxamide tosylate monohydrate). Such forms may be individually referred to as "niraparib free base," "niraparib tosylate," and "niraparib tosylate monohydrate," respectively.

[0134] The term "niraparib eq." or "niraparib equivalent" refers to the free base dose of niraparib.

[0135] Abiraterone acetate Abiraterone acetate has the formula:

[0136] [ka] and is a prodrug of abiraterone, a potent, selective, orally active inhibitor of 17α-hydroxylase-C17, 20-lyase, also known as steroid 17α-monooxygenase inhibitors or human cytochrome P45017α, a key enzyme in testosterone synthesis. Inhibition of testosterone synthesis has been demonstrated with abiraterone acetate in patients with prostate cancer. This compound is disclosed in WO 93 / 20097 A1.

[0137] Abiraterone acetate plus prednisone is approved for use in patients with metastatic castration-resistant prostate cancer (mCRPC) or metastatic hormone-sensitive prostate cancer (mHSPC). Abiraterone acetate tablets are currently available as 250 or 500 mg oral tablets.

[0138] Methods of Treatment and Medical Use The method of treating prostate cancer, or medical use of the pharmaceutical formulation, comprises, consists of and / or consists essentially of administering to a patient in need thereof a clinically effective amount of niraparib, a clinically effective amount of abiraterone acetate, and optionally a clinically effective amount of another formulation, such as a glucocorticoid, such as prednisone or prednisolone.

[0139] The method of treating prostate cancer, or the medical use of the pharmaceutical formulation, comprises, consists of, and / or consists essentially of administering to a patient in need thereof niraparib and abiraterone acetate, formulated in a single oral dosage form and administered in a clinically effective amount. The method of treating prostate cancer, or the medical use of the pharmaceutical formulation, comprises, consists of, and / or consists essentially of administering to a patient in need thereof, in addition to the above combination, a glucocorticoid, e.g., prednisone or prednisolone, in a clinically effective amount.

[0140] Also disclosed are dosing regimens for the oral dosage forms disclosed herein, the dosing regimens comprising, consisting of, and / or consisting essentially of a two-drug combination, dual combination, or FDC of niraparib and abiraterone acetate, and optionally a glucocorticoid, such as prednisone or prednisolone, administered in a total amount clinically effective for the treatment of prostate cancer in humans.

[0141] The disclosure also discloses a kit comprising, consisting of, and / or consisting essentially of a two-drug combination, dual combination, or FDC comprising niraparib and abiraterone acetate and instructions for administering the combination to a human patient with prostate cancer.

[0142] The kit may comprise, consist of, and / or consist essentially of a two-drug combination comprising niraparib and abiraterone acetate, a dual combination, or a separate composition comprising an FDC, a glucocorticoid, such as prednisone or prednisolone; and instructions for administering the combination to a human patient with prostate cancer.

[0143] Where specific reference is made to "prednisone" in this disclosure, one of skill in the art will recognize that prednisone may be substituted with different glucocorticoids, such as prednisolone, hydrocortisone, methylprednisolone, or dexamethasone. One of skill in the art will know how to substitute prednisone for these other drugs and adjust their dosages as necessary.

[0144] Specific suitable glucocorticoids include, but are not limited to, (1) dexamethasone (e.g., Decadron, oral; Decadron-LA injection, etc.), (2) prednisolone (e.g., Delta-CORTEF®, prednisolone acetate (ECONOPRED®), prednisolone sodium phosphate (HYDELTRASOL®), prednisolone tebutate (HYDELTRA-TBA®, etc.)), (3) prednisone (DELTASONE®, etc.), or (4) methylprednisolone (e.g., MEDROL®), and combinations thereof. See, e.g., GOODMAN & GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, 10th EDITION 2001.

[0145] The formulations described herein are used in a method for treating prostate cancer patients with a positive biomarker status of homologous recombination deficiency (HRD). HRD can also be called homologous recombination repair (HRR) gene deficiency or alteration, and can result from DNA repair gene deficiency (DRD). HRD or HRR gene alteration encompasses DRD and also encompasses gene mutations or alterations outside of DNA repair pathways. HRD or HRR gene deficiency or alteration positive status may be detected by assessing somatic or germline alterations, or by assessing genome-wide loss of heterozygosity (LOH), or homozygous deleterious alterations of DNA repair genes. HRD or HRR gene deficiency or alteration positive status is also synonymous with PARP biomarker positive status.

[0146] The positive biomarker status may be HRR positive status. HRR positive status may be defined as having monoallelic or biallelic, germline and / or somatic alterations in one or more DNA repair genes, including but not limited to alterations in BRCA2 (breast cancer gene 2), BRCA1 (breast cancer gene 1), ATM (ataxia telangiectasia mutated), BRIP1 (BRCA1 interacting protein C-terminal helicase 1 gene), CHEK2 (checkpoint kinase 2 gene), FANCA (Fanconi anemia complementation group A gene), HDAC2 (histone deacetylase 2), PALB2 (partner and localizer of BRCA2 gene), or CDK12 (cyclin-dependent kinase 12).

[0147] Germline and / or somatic HRR gene alterations are determined by using validated testing methods. HRR status may be assessed, preferably by either plasma (Resolution Bioscience) or tissue-based tests (Foundation Medicine), in particular by detecting circulating plasma DNA or circulating tumor cells. A list of tests for determining germline and / or somatic HRR gene alterations is provided herein above.

[0148] Gene expression profile analysis and protein biomarkers may also be used to risk stratify patients with prostate cancer to guide treatment decisions. Commercially available tests include Prolaris® (Myriad Genetics, Salt Lake City, UT); OncotypeDx® Prostate Cancer Assay (Genomic Health, Redwood City, CA); ProMark™ Protein Biomarker Test / ProMark™ Risk Score (Metamark Genetics, Cambridge, MA); FoundationOne® CdX (Foundation Medicine, Cambridge, MA); FoundationOne® Liquid CdX (Foundation Medicine, Cambridge, MA); Caris Molecular Intelligence (Caris Life Sciences, Irving, TX); Guardant360 (Guardant Health Inc., Redwood City, CA); ProstateNext® (Ambry Genetics, Aliso Viejo, CA); Color Hereditary Cancer Test (Color Genomics, Burlingame, CA); Invitae Prostate Cancer Panel (Invitae Corp., San Francisco, CA); Prostate Gene (GeneHealth, Cambridge, UK); Myriad myRisk® Hereditary Cancer Test (Myriad Genetics Inc., Salt Lake City, UT) and Decipher® Prostate Cancer Test (GenomeDx Biosciences, San Diego, CA), the latter based on the expression patterns of 22 RNA markers in biopsy or radical prostatectomy specimens. Prolaris®, OncotypeDx®, and Decipher® are tissue-based gene expression tests.

[0149] The formulations described herein may be used in methods of treating prostate cancer in patients with detectable circulating tumor cells (CTCs), circulating DNA, or reduced plasma DNA.The formulations described herein may be used in methods of treating metastatic prostate cancer in patients with detectable CTCs and / or measurable and non-measurable bone disease or lesions.CTC clearance in patients with metastatic prostate cancer may be established when detecting 5 or more cells per 7.5 mL of blood at baseline and less than 5 cells per 7.5 mL of blood at nadir, and is further confirmed by a second consecutive value obtained 4 weeks or more later.

[0150] The subject may be surgically or chemically castrated.

[0151] The patient may have received one or more other types of treatment for prostate cancer prior to the first dose of the two-drug combination, dual combination, or FDC of niraparib and abiraterone acetate. For example, the patient may have received taxane-based chemotherapy prior to administering the combination of niraparib and abiraterone acetate. Additionally or alternatively, the patient may have received at least one line of androgen receptor targeted therapy, such as apalutamide and / or enzalutamide, prior to administering the combination of niraparib and abiraterone acetate. In one aspect, the patient is initially unresponsive or resistant to previous treatment prior to administering the combination of niraparib and abiraterone acetate. Optionally, a glucocorticoid, such as prednisone or prednisolone, may also be administered in addition to the combination of niraparib and abiraterone acetate.

[0152] Two tablets or capsules containing niraparib and abiraterone acetate are administered once daily at least 1 hour before or at least 2 hours after a meal. In one embodiment, two tablets or capsules containing niraparib and abiraterone acetate are administered once daily with water on an empty stomach at least 1 hour before or at least 2 hours after a meal.

[0153] In one embodiment, the glucocorticoid is administered once or twice daily.In one embodiment, the prednisone or prednisolone tablet or capsule is administered once or twice daily.

[0154] In one embodiment, one or two tablets or capsules containing the two-drug combination, dual combination, or FDC of niraparib and abiraterone acetate are administered once daily, and one tablet or capsule of a glucocorticoid, e.g., prednisone, is administered once or twice daily.

[0155] When administering a two-drug combination, dual combination, or FDC of niraparib and abiraterone acetate to a patient, the dosage level selected for each drug will depend on a variety of factors, including, but not limited to, the activity of the particular compound, the severity of the individual's symptoms, the route of administration, the time of administration, the rate of excretion of the compound, the duration of treatment, the other drugs, compounds, and / or materials used in combination, and the age, sex, weight, condition, general health, and medical history of the patient. The amount of niraparib, the amount of abiraterone acetate, and optionally the amount of prednisone or prednisolone are ultimately at the discretion of the physician, but the dosage will generally be such as to achieve a local concentration that achieves the desired effect at the site of action without causing significant adverse or toxic side effects.

[0156] The two-drug combination, dual combination, or FDC may, for example, comprise about 33 to about 350 mg of niraparib and about 100 to about 1500 mg of abiraterone acetate. Preferably, the FDC comprises 100 mg of niraparib and 500 mg of abiraterone acetate. Alternatively, the FDC comprises 50 mg of niraparib and 500 mg of abiraterone acetate.

[0157] Clinically effective amounts of niraparib, abiraterone acetate, and optionally separately administered glucocorticoids, such as prednisone, prednisolone, hydrocortisone, methylprednisolone, and dexamethasone, are administered to a patient, such as a patient in need thereof, in combination with anticancer agents (e.g., docetaxel, mitoxantrone, cabazitaxel, cisplatin, carboplatin, oxaliplatin, and etoposide), immunotherapeutics (e.g., pembrolizumab, sipuleucel-T), bone targeted therapies (e.g., denosumab, zoledronic acid, alendronate, radium-223, strontium-89, samarium-153), gonadol, sirolimus ... Described herein is a method of treating cancer in which a clinically effective amount of at least one additional therapeutic agent is administered in combination with a gonadotropin releasing hormone agonist (GnRHa, including but not limited to, triptorelin, nafarelin, goserelin, leuprorelin or leuprolide, histrelin, gonadorelin and buserelin) and a hormone therapy (e.g., nilutamide, flutamide, bicalutamide, goserelin, histrelin, leuprolide, triptorelin, degarelix, enzalutamide, apalutamide, darolutamide, diethylstilbestrol, estrogen). Thus, the method may be directed to treating chemotherapy-resistant prostate cancer in a patient, and a clinically effective amount of niraparib and abiraterone acetate is administered to a patient currently receiving an anticancer drug.

[0158] Furthermore, the method of treating cancer described herein may be combined with ADT. The method of treating cancer described herein may be combined with radiation therapy, preferably in HRR+ patients. In one embodiment, the method of treating cancer described herein may be combined with ADT and external beam radiation therapy (EBRT). The method of treating cancer described herein may be combined with alternative energy sources, such as high intensity focused ultrasound (HIFU), cryosurgery, and laser therapy.

[0159] The two-drug combination, dual combination, or FDC of the present invention and a separately administered glucocorticoid (e.g., prednisone, prednisolone, hydrocortisone, methylprednisolone, or dexamethasone; preferably, prednisone or prednisolone) may be administered to patients with metastatic prostate cancer. In particular, the two-drug combination, dual combination, or FDC of the present invention and a separately administered glucocorticoid (e.g., prednisone, prednisolone, hydrocortisone, methylprednisolone, or dexamethasone; preferably, prednisone or prednisolone) may be administered to patients with mCRPC, such as first-line (L1) mCRPC (e.g., subjects who have not been treated with any therapy in the metastatic castration-resistant setting, except for limited exposure to ADT and abiraterone acetate + prednisone). The patient is positive for HRR changes. Metastatic prostate cancer may be confirmed by a positive bone scan or metastatic lesions on computed tomography (CT) or magnetic resonance imaging (MRI). The patient may have castrate levels of testosterone below 50 ng / dL and may be on ADT. The patient may continue ADT. The patient may have an Eastern Cooperative Oncology Group Performance Score (ECOG PS) grade of 0 or 1.

[0160] The two-drug combination, dual combination, or FDC of the present invention and a glucocorticoid administered separately (e.g., prednisone, prednisolone, hydrocortisone, methylprednisolone, or dexamethasone; preferably prednisone or prednisolone) may be administered to patients with metastatic castration-resistant prostate cancer (mCRPC) with HRR alterations and optionally with cyclin-dependent kinase 12 (CDK12) pathogenic alterations. The FDC may be low strength: 100 mg niraparib equivalent / 1000 mg abiraterone acetate given as 2xFDC tablets (50 mg niraparib equivalent / 500 mg abiraterone acetate) administered orally as a single dose under modified fasting conditions. The FDC may be of regular strength: 200mg niraparib eq. / 1000mg abiraterone acetate given as 2xFDC tablets (100mg eq. niraparib / 500mg abiraterone acetate) administered orally as a single daily dose under modified fasting conditions. Patients may be allowed to continue GnRHa therapy during FDC+prednisone (or prednisolone) treatment if they are not surgically castrated (i.e., subjects who have not undergone bilateral orchiectomy). Patients may have an Eastern Cooperative Oncology Group performance status (ECOG PS) of 1 or less. Prior to FDC+prednisone (or prednisolone) treatment, patients may have been exposed to antiandrogens including nilutamide, flutamide, bicalutamide, enzalutamide, apalutamide, darolutamide, or abiraterone acetate, preferably with prior antiandrogen therapy appropriately withdrawn before administering the first dose of FDC+prednisone or prednisolone. For bicalutamide, flutamide, and nilutamide, the drug-free period is about 2 weeks. For enzalutamide, the drug-free period is about 8 weeks. For apalutamide, the drug-free period is about 6 weeks.

[0161] Also disclosed is a kit comprising a composition comprising niraparib and abiraterone acetate, and a separate composition optionally comprising prednisone or prednisolone, and instructions for administering the compositions to a human patient with prostate cancer. The instructions may provide instructions for administering each composition once a day. For example, the instructions may provide instructions for administering a composition comprising niraparib and abiraterone acetate once a day to a human patient with prostate cancer, and instructions for administering a composition comprising prednisone or prednisolone once or twice a day to a human patient.

[0162] The present disclosure further relates to a method for determining the bioequivalence of a test fixed dose combination (FDC) formulation of niraparib and abiraterone acetate to an oral dosage form of the disclosure, the method comprising: i) measuring bioequivalence parameters of the test FDC formulation and, optionally, measuring bioequivalence parameters of the oral dosage form of the disclosure; and ii) comparing the bioequivalence parameters of the test FDC formulation to the corresponding bioequivalence parameters of the oral dosage form of the disclosure.

[0163] In one embodiment, the bioequivalence parameter is AUC (0~t) , AUC (0~∞) , residual area, C max and t max , AUC (0~72h) , the disappearance rate constant (λ z ), t 1 / 2 , AUC (0~τ) , C max,ss , t max,ss , Ae (0~t) , and R max and these bioequivalence parameters are well known to those skilled in the art of bioequivalence and pharmacokinetics.

[0164] Sales method In another aspect, described herein is a method of selling a dual combination of the present invention, comprising, consisting of, or consisting essentially of introducing the dual combination into the stream of commerce, wherein the dual combination is accompanied by a package insert containing instructions for safely and effectively treating prostate cancer using the dual combination.

[0165] In a further aspect, described herein is a method of selling a pharmaceutical composition containing the dual combination as an FDC, comprising, consisting of, or consisting essentially of introducing such a pharmaceutical composition into the stream of commerce, such pharmaceutical composition being accompanied by a package insert containing instructions for safely and effectively treating prostate cancer using the dual combination.

[0166] In a further aspect, described herein is a method of selling the dual combination as a free dose combination (FrDC), comprising, consisting of, or consisting essentially of separately entering into the stream of commerce such niraparib and abiraterone acetate, each independently accompanied by a package insert containing instructions for safely and effectively treating prostate cancer using the dual combination.

[0167] In still a further aspect, described herein is a method of offering for sale a dual combination, comprising, consisting of, or consisting essentially of offering the dual combination into the stream of commerce, wherein the dual combination is accompanied by a package insert containing instructions for safely and effectively treating prostate cancer using the dual combination.

[0168] The present invention is further defined in the following examples, which include unexpected and advantageous results. It should be understood that these examples, while showing preferred embodiments of the present invention, are provided as examples only and should not be interpreted as limiting the scope of the appended claims. From the above discussion and these examples, those skilled in the art can confirm that the essential features of the present invention can be variously changed and modified to suit various uses and conditions without departing from the spirit and scope of the present invention. EXAMPLES

[0169] Example 1 - Formulation composition

[0170] [Table 4] a Removed during processing b Salt coefficient = 1.594; 79.70 mg of niraparib tosylate is equivalent to a 50.00 mg dose of niraparib (base)

[0171] [Table 5] a Removed during processing

[0172] [Table 6] a Removed during processing b Salt coefficient = 1.594; 159.40 mg of niraparibut tosylate is equivalent to a 100.00 mg dose of niraparib (base).

[0173] [Table 7] a Removed during processing

[0174] [Table 8] a Salt coefficient = 1.594; 53.13 mg of niraparibut tosylate is equivalent to a 33.00 mg dose of niraparib (base)

[0175] [Table 9] a Removed during processing

[0176] [Table 10] a Salt factor = 1.594

[0177] [Table 11] a Removed during processing

[0178] [Table 12] a Salt factor = 1.594

[0179] [Table 13] a Removed during processing

[0180] [Table 14] a Salt factor = 1.594

[0181] [Table 15] a Removed during processing

[0182] Example 2 - Preparation of coated tablets containing co-granules of abiraterone acetate and niraparibut tosylate monohydrate prepared by wet granulation 2.1 Wet granulation of abiraterone acetate and niraparibut tosylate monohydrate The binder solution was made by dissolving HPMC 2910 15 mPa.s and sodium lauryl sulfate in purified water until a clear solution was obtained. The ingredients Abiraterone acetate, Niraparibut tosylate monohydrate, Lactose monohydrate, and Crospovidone were screened, pre-mixed, and transferred to a suitable wet granulation equipment, Fluid Bed Granulator GPCG30. The ingredients were warmed while fluidizing. The complete binder solution was sprayed onto the ingredients using wet granulation techniques. After spraying, the granules were dried while fluidizing. The dried powder was collected and filled into aluminum bags.

[0183] 2.2 Granular outer phase and compression Silicified microcrystalline cellulose, crospovidone, sodium lauryl sulfate, and colloidal anhydrous silica were screened and added to the fluid bed granulation. All materials were screened and mixed in a suitable blender. Magnesium stearate was screened and added to a container and all materials were mixed again in a suitable blender. This blend was then compressed into core tablets using a tableting module S (KC11).

[0184] The tablets were collected and packaged in a suitable container.

[0185] 2.3 Film Coating The coating suspension was prepared by dispersing the coating powder in purified water until a suspension was obtained. The core tablets were transferred to a suitable coating pan. The coating solution was then sprayed onto the core tablets using film coating techniques. The film-coated tablets were dried in the same coating pan after spraying. The coated tablets were collected and packaged in a suitable container.

[0186] The resulting film-coated tablets of Table 2 showed no scuffing and no other defects were observed.

[0187] The obtained film-coated tablets of Table 4 showed no scuffing defects and no white spots on their surface.

[0188] In summary, the film-coated tablets of Tables 2 and 4 were successfully manufactured without any defects.

[0189] Example 3 - Preparation of coated tablets containing granules of abiraterone acetate prepared by fluid bed granulation and niraparibut tosylate monohydrate prepared by dry granulation 3.1 Dry granulation of niraparibut tosylate monohydrate Niraparibut tosylate monohydrate, lactose monohydrate, microcrystalline cellulose, povidone K30, crospovidone, colloidal anhydrous silica, and magnesium stearate were screened and mixed using a suitable blender. The blend was then milled and the milled material was further mixed in a suitable blender. A suitable compaction technique, such as a roller compactor, was used to produce dry granules, and a suitable dry mill was used to further mill the dry granules.

[0190] 3.2 Wet granulation of abiraterone acetate Abiraterone acetate, lactose monohydrate, and croscarmellose sodium were mixed and optionally sieved. A binder solution containing hypromellose, sodium lauryl sulfate (SLS), and purified water was prepared and added to the mixture of abiraterone acetate, lactose monohydrate, and croscarmellose sodium. Granules were then formed by fluid bed granulation, followed by drying.

[0191] 3.3 Granular outer phase and compression The resulting abiraterone acetate granules and niraparibut tosylate monohydrate granules were screened and mixed with silicified microcrystalline cellulose, crospovidone, sodium lauryl sulfate, and colloidal anhydrous silica in a suitable blender. Magnesium stearate was screened and added to a container and all materials were mixed again in a suitable blender.

[0192] The mixture containing niraparibut tosylate monohydrate granules and abiraterone acetate granules was then compressed into core tablets using a suitable tablet press. The tablets were collected and packaged in suitable containers.

[0193] 3.4 Film coating The coating suspension was prepared by dispersing the coating powder in purified water until a suspension was obtained. The core tablets were transferred to a suitable coating pan. The coating solution was then sprayed onto the core tablets using film coating techniques. The film-coated tablets were dried in the same coating pan after spraying. The coated tablets were collected and packaged in a suitable container.

[0194] Example 4 - Preparation of coated tablets containing co-granules of abiraterone acetate and niraparibut tosylate monohydrate prepared by dry granulation 4.1 Dry granulation of niraparibut tosylate monohydrate and abiraterone acetate Abiraterone acetate, niraparibut tosylate monohydrate, lactose monohydrate, crospovidone, sodium lauryl sulfate, colloidal anhydrous silica, microcrystalline cellulose, and magnesium stearate are selected and mixed using a suitable blender.The blend is then milled and the milled material is further mixed in a suitable blender.A suitable compaction technique, such as a roller compactor, is used to make dry granules, and a suitable dry mill is used to further mill the dry granules.

[0195] 4.2 Granular outer phase and compression The resulting abiraterone acetate and nirapaributyric acid monohydrate co-granules were screened and mixed with silicified microcrystalline cellulose, crospovidone, sodium lauryl sulfate, and colloidal anhydrous silica in a suitable blender. Magnesium stearate was screened and added to a container and all materials were mixed again in a suitable blender.

[0196] The mixture was then compressed into tablets using a suitable tablet press. The tablets were collected and packaged in suitable containers.

[0197] 4.3 Film Coating The coating suspension was prepared by dispersing the coating powder in purified water until a suspension was obtained. The core tablets were transferred to a suitable coating pan. The coating solution was then sprayed onto the core tablets using film coating techniques. The film-coated tablets were dried in the same coating pan after spraying. The coated tablets were collected and packaged in a suitable container.

[0198] Example 5 - A Phase 3 Randomized, Placebo-Controlled, Double-Blind Study of Niraparib in Combination with Abiraterone Acetate and Prednisone Versus Abiraterone Acetate and Prednisone for the Treatment of Subjects with Severe, Metastatic Prostate Cancer The objective of this study was to evaluate the efficacy and safety of niraparib 200 mg daily in combination with abiraterone acetate (AA) 1000 mg once daily + 10 mg prednisone compared with placebo + abiraterone acetate + prednisone (AAP) in subjects with metastatic castration-resistant prostate cancer (mCRPC). Subjects were prospectively enrolled into cohort 1 or cohort 2 based on the presence or absence of homologous recombination repair (HRR) gene alterations. In addition, after completion of enrollment in cohorts 1 and 2, another open-label cohort, cohort 3, was enrolled to gain clinical experience with a fixed-dose combination (FDC) tablet formulation of niraparib and AA.

[0199] Study population Male subjects aged 18 years or older with mCRPC with or without HRR gene alterations who had not been treated in the metastatic castration-resistant setting, except for limited exposure to AAP and ongoing ADT, were eligible for the study. 1. Cohort 1: Subjects with HRR gene alterations in BRCA1, BRCA2, CDK12, FANCA, PALB2, CHEK2, BRIP1, HDAC2, or ATM genes 2. Cohort 2: subjects without HRR gene alterations, i.e. negative for alterations in the genes listed for Cohort 1. 3. Cohort 3: Subjects with HRR gene alterations: Same gene alterations as listed for Cohort 1

[0200] At the time the study was designed, there was inconclusive data supporting the use of PARP inhibitors in combination with AR-targeted therapy in subjects with mCRPC and without HRR gene alterations. Therefore, to ensure that subjects in cohort 2 without HRR gene alterations were not unnecessarily exposed to the niraparib + AAP combination if there was no clear benefit, a futility analysis was planned after approximately 200 subjects had been enrolled in cohort 2 and approximately 125 progression events (composite of radiographic progression survival and PSA progression) had occurred in this cohort.

[0201] After off-study data suggested limited benefit for subjects with ATM alterations, enrollment of subjects with ATM alterations was halted with implementation of protocol amendment 3. Of note, CDK12 gene alterations were reclassified as HRR gene alterations with protocol amendment 4 based on off-study data (deBono, 2020). Subsequent subjects with CDK12 alterations were prospectively randomized into cohort 1. Prior to amendment 4, subjects with CDK12 alterations were enrolled into cohort 2.

[0202] All subjects were enrolled after testing for HRR changes using the FoundationOne CDX tissue assay Resolution HRD plasma assay, AmoyDx tissue assay, Invitae blood or saliva assay.

[0203] Randomization For cohorts 1 and 2, subjects were randomized in a 1:1 ratio using a permuted block scheme to receive niraparib + AAP or placebo + AAP. Subjects were stratified by prior taxane chemotherapy (yes vs. no), prior AR-targeted therapy (prior novel antiandrogen therapy, e.g., enzalutamide, apalutamide, darolutamide vs. no prior novel antiandrogen therapy), and prior AAP use (yes vs. no). Additionally, for cohort 1, stratification was performed by gene mutation group (BRCA1 or BRCA2 vs. all other HRR gene alterations). Randomization was performed at all study centers using a centralized interactive web-based automated response system (IWRS).

[0204] Cohort 3 was non-randomized, open-label, and all subjects received the FDC formulation of niraparib + AA + prednisone.

[0205] Treatment duration / trial duration The study consists of four phases: a pre-screening phase for biomarker assessment only, a screening phase, a treatment phase, and a follow-up phase for collection of secondary endpoints.

[0206] Subjects received continuous daily treatment. A treatment cycle is defined as 28 days. Imaging (technetium bone scan and CT / MRI, including chest, abdominal, and pelvic imaging) was performed at screening, cycle 3 day 1, cycle 5 day 1, cycle 7 day 1, and every 12 weeks thereafter. All subjects were monitored for safety during the prescreening, screening, and treatment phases, and for up to 30 days after the last dose of any study treatment. Treatment continued until unequivocal clinical progression, unacceptable toxicity, death, or sponsor termination of the study. The study was considered completed at the last study evaluation for the last subject enrolled in the study.

[0207] Investigational Drug Information All study treatments were provided directly by the sponsor.

[0208] For cohorts 1 and 2, niraparib was provided as a 100 mg capsule for oral administration. Niraparib placebo was provided as a tablet formulation, matched for size, color, and shape to maintain the blinded nature of the study. AA was provided as a 250 mg tablet for oral administration, and prednisone was provided as a 5 mg tablet for oral administration.

[0209] For cohort 3, niraparib / AA FDC was provided as regular strength tablets containing 100 mg niraparib / 500 mg AA per tablet. Prednisone was provided as 5 mg tablets for oral administration. Low strength (LS) FDC tablets containing 50 mg / 500 mg niraparib / AA per tablet were also available in case of need for niraparib dose modification. For subjects needing to discontinue one of the drugs due to toxicity, single dose niraparib was available as 100 mg capsules and AA was available as 250 mg tablets, both for oral administration.

[0210] Dosage and Administration Subjects in cohorts 1 and 2 were randomized in a 1:1 ratio to receive either 200 mg niraparib, 1,000 mg AA, and 10 mg prednisone daily (nira+AAP) and / or matching placebo, 1,000 mg AA, and 10 mg prednisone (PBO+AAP). Subjects in cohort 3 received 200 mg niraparib / 1,000 mg AAP (hereafter referred to as FDC) and 10 mg prednisone daily (FDC+P).

[0211] Study treatments were to be taken in the morning on an empty stomach, without food for at least 2 hours before and at least 1 hour after dosing. Study treatments were swallowed completely with water. Study treatments were administered together, except for prednisone, which was taken twice daily. If subjects forgot to take the study treatment(s) at their usual time, the missed dose(s) was to be replaced only if remembered within the same day.

[0212] Background treatment with GnRHa for patients not previously surgically castrated was mandatory to maintain castrate levels of testosterone (≤50 ng / dL). The choice of GnRHa was at the investigator's discretion. The dose and administration schedule (without interruption) were consistent with the prescribing information for the GnRHa agent used and were adjusted only if clinically indicated to maintain castrate levels of testosterone.

[0213] Prohibited Concomitant Medications The following medications / therapy were prohibited during the study: Investigational drugs other than test treatments Other anti-cancer therapies Other drugs that target the androgen system (e.g., antiandrogens such as enzalutamide and apalutamide, or CYP17 inhibitors such as ketoconazole) ·testosterone Radiation therapy for tumor progression. Subjects may receive palliative radiation therapy in selected cases after discussion with the sponsor. ·Chemotherapy ·Immunotherapy Diethylstilbestrol or similar estrogen receptor agonists Pomegranate and pomegranate juice Spironolactone Radiopharmaceuticals such as radium-223, strontium, or samarium Strong inducers of CYP3A4 (e.g., rifampin)

[0214] Prohibited Concomitant Medications Based on potential niraparib / AAP drug interactions, use of the following medications was restricted: Substrates of CYP2D6: Caution is advised when administering AA with medicinal products that are activated or metabolized by CYP2D6, especially those with narrow therapeutic indices. Consider dose reduction of medicinal products with narrow therapeutic indices metabolized by CYP2D6. Substrates of CYP2C8: In a CYP2C8 drug-drug interaction study in healthy subjects, the AUC of pioglitazone was increased by 46% when pioglitazone was administered with a single dose of 1,000 mg of AA. No clinically significant increases in exposure were demonstrated when AA was combined with drugs that are primarily eliminated by CYP2C8; however, subjects should be monitored for signs of toxicity associated with CYP2C8 substrates with narrow therapeutic indexes when used concomitantly with AA.

[0215] Inclusion criteria Subjects were required to meet the following key inclusion criteria: 1. Had HRR gene alteration status (as identified by sponsor required assay or local testing for HRR gene alterations) as follows: Cohort 1: Positive for HRR gene alterations b. Cohort 2: Not positive for HRR gene alterations (i.e., no HRR gene alterations) c. Cohort 3: positive for HRR gene alterations 2. Had metastatic disease documented by a positive bone scan or metastatic lesions on CT or MRI. 3. Had metastatic prostate cancer in the setting of castration levels of testosterone ≦50 ng / dL on GnRHa or bilateral orchiectomy as evidenced by PSA progression or radiographic progression. 4. If not surgically castrated, GnRHa may be continued for the duration of the study. They had an ECOG performance score grade of 5.0 or 1. 6. Had a score of 3 or less on BPI-SF question #3 (worst pain in last 24 hours). 7. Screening laboratory values: ANC≧1.5x10 9 / L. b. Hemoglobin ≥ 9.0 g / dL, independent of transfusions for at least 30 days. c. Platelet count ≧100x10 9 / L.

[0216] Exclusion criteria Subjects were not enrolled in the study if they met any of the following important exclusion criteria during pretesting: 1. Prior treatment with a PARP inhibitor. 2. Received systemic therapy in the mCRPC setting (i.e., novel second-generation AR-targeted therapy such as enzalutamide, apalutamide, or darolutamide; taxane-based chemotherapy, or AAP >4 months prior to randomization) or AAP outside the mCRPC setting. 3. Subjects who received 2-4 months of AAP prior to randomization for treatment of mCRPC should have had no evidence of progression by PSA (per PCWG3) during screening. These potential subjects were required to have two PSA values ​​during the prescreening and screening phases. The second PSA value should be within 2 weeks of randomization, and the PSA rise should be considered due to a flare, and the investigator should confirm the absence of radiographic progression. 4. Uncontrolled hypertension (sustained systolic blood pressure (BP) ≥ 160 mmHg or diastolic BP ≥ 100 mmHg) was present. Subjects with a history of hypertension were allowed if BP was controlled within these limits with antihypertensive treatment. 5. Subject has had the following within 28 days prior to randomization: A blood transfusion (platelets or red blood cells). b. Hematopoietic growth factors. c.An investigational drug for prostate cancer. d. Major surgery (the sponsor should be consulted as to what constitutes major surgery). e. Radiation therapy

[0217] Sample size determination Cohort 1: Approximately 400 subjects with mCRPC and HRR gene alterations were randomized 1:1 to receive nira+AAP or PBO+AAP to observe approximately 220 rPFS events, providing 87% power to detect a difference at a two-sided significance level of 0.05, assuming a HR of 0.65. Approximately 50% of subjects had a BRCA1 or BRCA2 (BRCA) alteration, resulting in approximately 102 rPFS events in the BRCA subgroup, providing 93% power to detect a difference, assuming a HR of 0.50 at a two-sided significance level of 0.05.

[0218] Cohort 2: Approximately 600 subjects with mCRPC and no HRR gene alterations were randomized 1:1 to receive nira+AAP or PBO+AAP if futility was not met. A preplanned futility analysis for this cohort was performed on 247 subjects enrolled (14 subjects with CDK12 alterations were excluded from the futility analysis). Enrollment into cohort 2 was stopped if futility was met. Subjects were unblinded (except for the 14 subjects with CDK12 alterations) and were given the opportunity to continue nira+AAP, niraparib (if AAP was discontinued due to toxicity), or discontinue nira+AAP and receive AAP alone, at the investigator's discretion based on benefit-risk assessment.

[0219] Cohort 3: Approximately 100 subjects with HRR gene alterations (approximately half with BRCA alterations) were to be enrolled in Cohort 3.

[0220] Futility analysis of cohort 2 A preplanned futility analysis for cohort 2 was performed on August 13, 2020, when 247 subjects had been enrolled and 113 composite progression events (PSA progression or radiographic progression or death, whichever was first) had been observed (40 rPFS events and 73 PSA events). The prespecified criterion for futility of HR>1 was met and futility was declared for this cohort, with HR=1.087, 95%CI (0.751, 1.571) for the composite progression endpoint. At the time of the futility analysis, a time-to-PSA progression analysis (83 PSA events, HR=1.032, 95%CI (0.671, 1.588)) and rPFS analysis were also performed (65 rPFS events, HR=1.027, 95%CI (0.631, 1.671)). The Independent Data Monitoring Committee (IDMC) recommended that "treatment / enrollment may be interrupted for this subject cohort." The sponsors committee accepted the IDMC recommendation, stopped enrollment, and unblinded the cohort. Subjects in cohort 2 with CDK12 mutations were excluded from the futility analysis and remained blinded. These subjects, along with subjects prospectively randomized to cohort 1 as part of amendment 3, were to be included in a sensitivity analysis. Subjects who were not blinded were given the option to continue niraparib or AAP alone. Subjects continued to be followed for safety.

[0221] Statistical testing strategy for primary endpoints The primary endpoint of the study, rPFS, is defined as the time interval from the date of randomization to the first date of radiographic progression or death from any cause as assessed by blinded independent central review (BICR), whichever occurs first. BICR is based on CT or MRI scans of the chest, abdomen, and pelvis, and total body bone scan ( 99mTc) was used to assess the efficacy and safety of rPFS. Given that cohort 2 met futility, the overall statistical approach was to test the primary endpoint of rPFS with an overall alpha of 0.05 in cohort 1. Within cohort 1, rPFS was first tested in the BRCA subgroup of cohort 1 with alpha = 0.05 (two-sided). If the results were statistically significant, rPFS in the full cohort 1 was to be tested with alpha = 0.05 (two-sided) based on a predefined testing strata. Analysis of rPFS for non-BRCA subgroups in cohort 1 was preplanned in the SAP, but no formal statistical testing procedures with alpha allocation for this analysis were performed.

[0222] Interim analysis of secondary endpoints Two interim analyses (IA) and one final analysis were planned for the main secondary endpoints by group sequential design: overall survival (OS) in cohort 1, time to symptomatic progression (TSP), also defined as the need to initiate: EBRT for skeletal symptoms, tumor-related orthopedic interventions, other cancer-related procedures (e.g.: nephrostomy insertion, bladder catheter insertion, EBRT, or surgery for non-skeletal tumor symptoms), time to new systemic anticancer therapy and cytotoxic chemotherapy for cancer pain or for having cancer-related morbid events (e.g.: fractures, symptomatic and / or morbid, spinal cord compression, urinary obstructive events). If the rPFS result in cohort 1 was statistically significant, the three secondary endpoints were to be tested simultaneously to allow alpha reuse by group sequential design.

[0223] Main purpose: To evaluate the efficacy of niraparib and AAP compared with AAP and placebo

[0224] Secondary Objectives: To evaluate the clinical benefit of niraparib and AAP compared with AAP and placebo To characterize the safety profile of niraparib when administered with an AAP compared with an AAP with placebo

[0225] Analysis method Estimates of time-to-event endpoints were obtained using Kaplan-Meier estimates of survival distributions, and stratified Cox models were used to obtain HRs with associated 95% confidence intervals. Testing of these other efficacy endpoints was based on the stratified log-rank test.

[0226] ORR and PSA response rates were summarized by descriptive statistics (counts and percentages) by treatment group. Relative risks are reported with corresponding two-sided 95% CIs. The chi-square test was used to compare the two treatment groups. Fisher's exact test was sometimes used when the expected count in a fraction of cells was less than 5.

[0227] Most important results summary demographics In cohort 1, 423 subjects with HRR gene alterations were randomized (212 subjects to the niraparib + AAP group and 211 subjects to the placebo + AAP group), of which 225 subjects (113 subjects in the niraparib + AAP group and 112 subjects in the placebo + AAP group) constituted the BRCA subgroup.

[0228] Subject demographics and baseline disease characteristics were generally balanced between the two groups, except that 38.7% of patients in the niraparib + AAP arm had an ECOG score of 1 compared with 30.8% in the placebo + AAP group. The randomized HRR cohort population had a median age of 69 years, with 29.7% of niraparib + AAP and 23.2% of placebo + AAP being 75 years or older. At study entry, 86.3% of niraparib + AAP and 80.6% of placebo + AAP had bone metastases, and 24.1% of niraparib + AAP and 18.5% of placebo + AAP had visceral disease. Most subjects (95.7%) had received prior hormonal therapy, with 23.6% in the niraparib + AAP arm and 22.7% in the placebo + AAP arm receiving prior AAP, which was tolerated for up to 4 months without progression prior to randomization.

[0229] At clinical cutoff (CCO) of October 8, 2021, the median follow-up for all subjects in cohort 1 was 18.6 months. Subjects in the niraparib + AAP group received a median of 13.8 months of treatment compared with a median of 12.1 months in the placebo + AAP group. 45.8% of subjects in the niraparib group and 58.3% of subjects in the placebo group discontinued treatment, with progressive disease being the most common reason for treatment discontinuation (34.0% of subjects in the niraparib + AAP group and 51.2% of subjects in the placebo + AAP group).

[0230] Effectiveness Primary endpoint: rPFS by central review The primary endpoint was rPFS assessed by blinded independent central review (BICR), analyzed first in the BRCA subgroup and then all HRRs together in cohort 1 based on the predefined study procedures in SAP.

[0231] In the BRCA subgroup, a statistically significant and clinically meaningful improvement in rPFS was observed in the niraparib + AAP arm, with a 47% reduction in the risk of radiographic progression or death compared with the placebo + AAP arm (HR=0.533; 95% CI: [0.361, 0.789], two-sided p=0.0014). Median rPFS was 16.6 months in the niraparib + AAP arm and 10.9 months in the placebo + AAP arm.

[0232] rPFS was then examined in cohort 1 (all HRR) and demonstrated a statistically significant improvement in the risk of radiographic progression or death of 27.1% in the niraparib + AAP group compared with the placebo + AAP group (HR=0.729; 95%CI:[0.556, 0.956], two-sided p=0.0217). Median rPFS was 16.5 months in the niraparib + AAP group and 13.7 months in the placebo + AAP group. Prespecified subgroup analysis results for rPFS were generally consistent with the overall results.

[0233] Figure 1 shows a Kaplan-Meier plot of centrally reviewed rPFS for cohort 1 (all HRR).

[0234] [Table 16]

[0235] Figure 2 shows the Kaplan-Meier plot of rPFS by central review (BRCA subgroups).

[0236] [Table 17]

[0237] Figure 3 shows a forest plot of radiographic progression-free survival by central review for subgroups defined by baseline clinical disease characteristics, cohort 1 overall HRR randomized analysis set (study 64091742PCR3001)

[0238] Key: AAP = abiraterone acetate + prednisone.

[0239] Note: Gene mutation categories relate to IWRS stratification by genetic alteration. Hazard ratios were obtained using unstratified Cox proportional hazards models.

[0240] Investigator-performed sensitivity analysis for rPFS Sensitivity analyses using investigator-determined rPFS were performed for rPFS in both BRCA subgroups and Cohort 1. These analyses showed results consistent with the primary analysis of rPFS by BICR.

[0241] For the BRCA subgroup, investigator-assessed rPFS showed an HR of 0.499, 95% CI (0.334, 0.748) and p-value=0.0006, with medians of 19.3 months in the niraparib + AAP group and 12.4 months in the placebo + AAP group. In cohort 1 (all HRR), investigator-assessed rPFS had an HR of 0.644, 95% CI (0.486, 0.855) and corresponding p-value of 0.0022, with medians of 19.0 months in the niraparib + AAP group and 13.9 months in the placebo + AAP group.

[0242] Sensitivity analysis of rPFS by central review assessing selected genetic alterations: To assess the consistency of response to niraparib + AAP across genetic alterations, the impact of ATM alterations on rPFS in cohort 1 (all HRR) subjects was evaluated in a prespecified analysis of subjects with all HRR excluding ATM alterations, showing an HR of 0.663, 95% CI (0.489, 0.900), nominal p=0.0079 for rPFS, with a median of 16.5 months in the niraparib + AAP arm compared with 11.2 months in the placebo + AAP arm.

[0243] Excluding both ATM and CDK12 changes from cohort 1 (total HRR) in a separate prespecified analysis showed a HR of 0.640, 95% CI (0.469, 0.872).

[0244] The non-BRCA HRR subgroup was also evaluated based on prespecified subgroup analysis and was found to have a HR of 0.986 for rPFS, 95% CI (0.675, 1.442), nominal p=0.9437, with median rPFS of 14.8 months in the niraparib + AAP group and 16.4 months in the placebo + AAP group.

[0245] Overall, a clinical benefit was observed in rPFS for all HRRs, however upon removal of ATM and CDK12 alterations, genes without established PARPi activity, an advantage was observed for the remaining non-BCRA genes, leading to improved HR for the remainder of cohort 1. Further analyses are warranted to fully understand the impact of single and co-occurring mutations, as well as other genetic alterations (e.g., p53).

[0246] [Table 18] ** Nominal p-values ​​from unstratified log-rank tests

[0247] Update of the primary efficacy endpoint rPFS by BICR in interim analysis 2 (IA2) (clinical cutoff CCO date: June 17, 2022)

[0248] Because statistical significance was declared for rPFS for both the BRCA subgroups and the total HRR (cohort 1) population in the primary analysis, the updated rPFS data presented herein from the time of secondary endpoint IA2 were not formally statistically tested.

[0249] With an additional 8.2 months of follow-up after the primary analysis, rPFS in both the overall HRR population and the BRCA subgroup showed consistent and clinically meaningful improvements in the niraparib + AAP arm compared to the PBO + AAP arm. Notably, in the BRCA subgroup, median rPFS estimates became more stable with additional follow-up, with median rPFS improving by 8.6 months for niraparib + AAP-treated subjects in the BRCA subgroup, further highlighting the benefit of niraparib + AAP in this subgroup of subjects for whom standard of care (SOC) AAP therapy is inadequate (see Table 16).

[0250] [Table 19] * Nominal p-value #Statistically significant

[0251] Noting the heterogeneity even within the BRCA subgroup, especially in patients with co-occurring alterations, further analysis was performed excluding subjects with co-occurring alterations. In subjects with genetic alterations in BRCA1 or BRCA2 only, but not co-occurring alterations, a more robust and clinically meaningful improvement in rPFS was demonstrated, with HR=0.465 (95%CI: 0.320, 0.674), nominal p-value=<0.0001 (see Table 24). A pre-planned sensitivity analysis evaluating investigator-assessed rPFS also continued to show benefit of treatment with niraparib + AAP for all HRRs, with a particular benefit again observed in the BRCA subgroup, where the median survival of niraparib + AAP-treated subjects was more than twice that of PBO + AAP-treated subjects.

[0252] Secondary Efficacy Endpoints All secondary endpoints were formally tested for the entire cohort 1 (total HRR). No formal statistical testing was planned for secondary endpoints in the BRCA subgroups given the expected small number of events in this analysis, but sensitivity analyses were eventually performed for all subgroups.

[0253] This first interim analysis of secondary endpoints was performed using very conservative boundaries for significance (0.0001 for TSP and TCC, and 0.0005 for OS) with less than half the expected number of events required for the final analysis.

[0254] As none of the secondary endpoints reached statistical significance at interim analysis 1 (IA1), all secondary endpoints were formally tested for Cohort 1 overall (total HRR) at IA2 at the CCO on June 17, 2022.

[0255] Time to cytotoxic chemotherapy (TCC) In cohort 1 (all HRR), treatment with niraparib + AAP extended the time to cytotoxic chemotherapy, HR=0.588, 95%CI (0.389, 0.889), p-value 0.0108. Although the significance boundary for TCC in this first interim analysis was 0.0001, the improvement in TCC was seen early, maintaining separation of the KM curves, and the median TCC for treatment with niraparib + AAP was not reached, whereas the median for placebo + AAP-treated subjects was 26.0 months.

[0256] TCC improvement was consistent across genetic alterations, with the BRCA subgroup showing an HR of 0.578, 95% CI: (0.332, 1.006).

[0257] A prespecified analysis of subjects with total HRR excluding ATM changes showed a HR of 0.728, 95% CI (0.468, 1.133) for TCC in favor of niraparib plus AAP.

[0258] A separate prespecified analysis of subjects with overall HRR but excluding both ATM and CDK12 alterations showed a HR of 0.678, 95% CI (0.433, 1.064) for TCC in favor of niraparib + AAP.

[0259] In the non-BRCA subgroup, TCC similarly showed an HR of 0.601, 95% CI: (0.324, 1.116), demonstrating the consistency of improvement in TCC across all HRR alterations, even including ATM and CDK12 alterations.

[0260] See Figure 4, which shows a Kaplan-Meier plot of time to initiation of cytotoxic chemotherapy for cohort 1 (overall HRR).

[0261] [Table 20] * Nominal p-value ** Nominal p-values ​​from unstratified log-rank tests

[0262] In interim analysis 2 (IA2), in cohort 1 (all HRR), treatment with niraparib + AAP extended the time to cytotoxic chemotherapy, with HR = 0.666, 95% CI (0.471, 0.942), and p-value 0.0206. The p-value approached statistical significance, with the IA2 efficacy boundary at p ≤ 0.0183, and α repurposed from the TSP. Figure 11 shows the Kaplan-Meier plot of TCC (all HRR and BRCA, respectively) for cohort 1 of this IA2. A clinically meaningful improvement in TCC was seen in the BRCA subgroup, showing a HR of 0.558, 95% CI: (0.346, 0.900), nominal p = 0.0152, with a clear and wide separation in the KM curves (see Table 18).

[0263] [Table 21] * Nominal p-value

[0264] Time to symptomatic progression (TSP) Improvements were also seen in cohort 1 (overall HRR) for TSP, prolonging the time to symptomatic progression, HR=0.686, 95%CI: (0.474, 0.993), p-value 0.0444. The significance boundary for TSP in this first interim analysis was also 0.0001. As with TCC, separation of the KM curves was seen early and maintained. Median values ​​were not reached in either treatment arm.

[0265] Improvement in TSP was also consistent across genetic alterations, with the BRCA subgroup showing HR 0.683 95% CI: (0.420, 1.111).

[0266] A prespecified analysis of subjects with all HRRs excluding ATM changes showed an HR of 0.687, 95% CI (0.462, 1.021) for TSP.

[0267] A separate prespecified analysis of subjects with all HRR alterations but excluding both ATM and CDK12 alterations showed a HR of 0.720, 95% CI (0.480, 1.080) for TSP in favor of niraparib + AAP.

[0268] The non-BRCA subgroup similarly showed a HR of 0.690 (95%CI: (0.391, 1.218) suggesting that TSP improved consistently across all HRR changes.

[0269] Figure 5 shows a Kaplan-Meier plot of time to symptomatic progression for cohort 1 (all HRR).

[0270] [Table 22] * Nominal p-value ** Nominal p-values ​​from unstratified log-rank tests

[0271] In IA2, a statistically significant extension of TSP was observed in cohort 1 (all HRR), HR=0.596 95%CI: (0.422, 0.841), two-sided p-value=0.0029, which exceeded the prespecified significance boundary of 0.012 for TSP in this IA2. Separation of the KM curves was seen early and widened over time, with median TSP not yet reached in the niraparib+AAP group and a median of 30.6 months in PBO+AAP-treated subjects (see Figure 10).

[0272] A strong improvement in TSP consistent with that observed in the overall HRR group was observed in the BRCA subgroup, with a HR of 0.544, 95% CI: (0.347, 0.853), nominal p=0.0071. Again, the KM curves separated early and widened over time (see Table 20).

[0273] [Table 23] * Nominal p-value #Statistically significant

[0274] Overall survival (OS) No adverse effect on OS was observed in cohort 1 with treatment with niraparib + AAP in this first interim analysis, with approximately 46.3% deaths (55 events in niraparib + AAP and 59 events in placebo + AAP) required for the final OS analysis, HR = 0.938, 95% CI (0.648, 1.358), p = 0.7333. The significance boundary for OS in this first interim analysis was 0.0005. The median was not reached for either treatment group. Of note, 2% of niraparib + AAP subjects who received subsequent therapy received a PARPi, compared with 16% of the placebo + AAP group.

[0275] A prespecified analysis of subjects with all HRRs excluding ATM changes showed a HR of 0.910, 95% CI (0.608, 1.362) for OS.

[0276] A separate prespecified analysis of subjects with all HRR alterations but excluding both ATM and CDK12 alterations showed a HR of 0.883, 95% CI (0.586, 1.330) for OS in favor of niraparib + AAP.

[0277] OS analysis for the non-BRCA subgroup showed a HR of 0.917, 95% CI (0.547, 1.536) and nominal p=0.7407.

[0278] Further follow-up and further analysis of OS are justified to fully understand the impact of subsequent treatment with respect to individual genes and co-occurring mutations.

[0279] Figure 6: Kaplan-Meier plot of overall survival for cohort 1 (all HRR).

[0280] [Table 24] * Nominal p-value ** Nominal p-values ​​from unstratified log-rank tests

[0281] Overall survival (OS) for all HRRs In IA2, the median follow-up for OS was 26.8 months compared to 18.6 months in IA1. In IA2, cohort 1 had HR=1.010, 95%CI (0.751, 1.357), p=0.9480 (IA1: HR=0.938, 95%CI (0.648, 1.358), p=0.7333) (see Figure 12 with Kaplan-Meier plot of overall survival for cohort 1 (overall HRR)). Median OS for niraparib + AAP treatment was 29.3 months with 95% CI (24.87, NE) and for PBO + AAP treated subjects was 32.2 months with 95% CI (27.7, NE), however these medians remain unstable and the data are immature given the high degree of censoring, suggesting that further maturation of OS data is needed in the total HRR population.

[0282] BRCA Overall Survival In IA2, the median follow-up for OS was 24.8 months in the BRCA subgroup. Improved OS was observed in subjects with BRCA alterations, HR=0.881, 95%CI (0.582,1.335) (IA1: HR=0.961; 95%CI:0.565,1.633) (see Figure 13 with Kaplan-Meier plot of overall survival for cohort 1 (BRCA)). Median OS for treatment with niraparib+AAP was 29.27 months, 95%CI (27.7, NE), and for PBO+AAP treated subjects it was 28.6 months, 95%CI (23.8, 32.95). Furthermore, there was still a large number of censored subjects in IA2, so the data remain immature.

[0283] Subjects with BRCA monogenic alterations showed a trend towards improved OS [HR=0.786 (95%CI: 0.505, 1.225)], nominal p=0.2868 (see Figure 14 with Kaplan-Meier plot of overall survival for cohort 1 (BRCA monogenic)).

[0284] safety As hypothesized, a higher rate of adverse events was seen in the niraparib + AAP than in the placebo + AAP, and these differences were primarily driven by hematologic adverse events known to be associated with niraparib. Compared with placebo + AAP, the most common TEAEs in the niraparib + AAP arm were anemia, hypertension, constipation, fatigue, nausea, and thrombocytopenia.

[0285] Cohort 3 results Cohort 3 was enrolled after completing enrollment of cohorts 1 and 2 and consisted of 95 subjects with HRR gene alterations (approximately 50% with BRCA gene alterations), all of whom received open-label FDC tablets (niraparib + abiraterone acetate) + prednisone. No subjects with ATM gene alterations were enrolled in cohort 3 per protocol amendment 4. Cohort 3 provided clinical experience with the FDC tablet formulation and no formal hypotheses were tested for cohort 3.

[0286] Baseline demographics were consistent with Cohort 1. The median age of the FDC cohort population was 70.0 years, with 23.2% of subjects aged 75 years or older. Most subjects (86.2%) had bone metastases, and 13.8% had visceral disease at study entry. A similar profile of treatment-emergent adverse events was observed in Cohort 3 compared with niraparib + AAP in Cohort 1, although in general, incidence was lower with shorter exposure to FDC in Cohort 3.

[0287] IA2 Conclusion In the primary analysis for both the total HRR and BRCA groups, the primary endpoint of rPFS reached statistical significance. Updated rPFS data for IA2 indicate that benefit is maintained with additional exposure and follow-up. In subjects with BRCA gene alterations, a 45% reduction in the risk of radiographic progression or death (HR=0.553; 95%CI:0.3921, 0.782, nominal p=0.0007) was observed, which was associated with an extension of the median rPFS of approximately 8.5 months for IA2, nearly 3 months longer than for IA1. Of note, the median rPFS in the control arm of the BRCA subgroup remained stable at 10.9 months, reinforcing that these subjects have a particularly poor prognosis with SOC treatment. However, with the combination of niraparib+AAP, the median rPFS improved to 19.5 months, which exceeds the predicted median of AAP alone (approximately 16.5 months) in an unselected mCRPC patient population.

[0288] In IA2, a statistically significant and clinically meaningful improvement was observed in TSP in the total HRR population (HR=0.596; 95%CI: 0.422, 0.841, p=0.0029), with a consistent effect in subjects with BRCA alterations (HR=0.544; 95%(0,347.0 / 853)(nominal p=0.0071). Clinically meaningful improvements were also observed in TCC for both the total HRR and BRCA populations, respectively (HR=0.666; 95%CI: 0.471, 0.942, p=0.0206 in total HRR; HR=0.024 in BRCA). 558; 95%CI: 0.346, 0.900, nominal p=0.0152). A clear separation in the KM curves for both TSP and TCC endpoints was observed early and strengthened by longer follow-up for both the total HRR and BRCA populations. Both of these endpoints are well established in mCRPC and are highly patient-relevant endpoints that describe the impact of treatment on the occurrence of significant symptoms known to impact patient experience, such as the need for palliative radiation or surgical intervention, or chemotherapy-related morbidity.

[0289] An overall survival benefit in the total HRR population was not demonstrated in interim analysis 2 (HR=1.010; 95%CI: 0.751, 1.357, p=0.9480). However, prespecified multivariate analysis (HR=0.815; 95%CI: 0.603, 1.101) and analysis assessing the impact of subsequent treatment (IPCW analysis HR=0.696; 95%CI: 0.492, 0.986) suggest a potential OS benefit in the total HRR population.

[0290] A trend towards improved OS was observed in the BRCA subgroup, HR = 0.881, 95% CI: 0.582, 1.335. Adjusting for imbalances in baseline characteristics, prespecified multivariate analysis showed a treatment benefit in OS in the BRCA subgroup, HR = 0.682 (95% CI: 0.445, 1.046).

[0291] Within the BRCA group, subjects with BRCA monogenic alterations experienced robust clinically meaningful benefits in all primary and secondary endpoints, with HRs for rPFS, TCC, and TSP all less than 0.5, 95% confidence intervals all well outside 1, and a clear trend toward improved overall survival when treated with niraparib + AAP (HR = 0.786; 95% CI: 0.505, 1.225). The imbalance in enrollment of subjects with BRCA1 genetic alterations between treatment arms limits the interpretation of efficacy results in subjects with single BRCA1 mutations. Although a heterogeneous group, no benefit was evident in subjects with BRCA co-occurring alterations.

[0292] Among subjects with non-BRCA genetic alterations, those prespecified by genetic analysis reinforced clear benefit across all primary and secondary endpoints in PALB2 and CHEK2 and functional categories: HRR-Fanconi pathway (BRIP1, FANCA, and PALB2) and HRR-related (CHEK2 and HDAC2). In these subjects, the combination of Niraparib + AAP may fulfill an unmet need. Of note, subjects with concomitant alterations in CDK12, ATM, and non-BRCA did not benefit from treatment with Niraparib + AAP.

[0293] Furthermore, no adverse HRQoL outcomes were observed with niraparib plus AAP treatment in the overall HRR cohort.Among subjects with BRCA gene alterations, niraparib plus AAP treatment was associated with improved time to BPI-SF worst pain intensity progression and pain interference progression.

[0294] Based on the overall data, subjects with BRCA alterations, particularly BRCA2 alterations, derive strong benefit from treatment with niraparib plus AAP, as do subjects with select subgroups of other HRR gene alterations.

[0295] With the longer exposure period, the safety profile of niraparib + AAP in IA2 was consistent with IA1, with no new safety signals associated with the longer exposure period and the additional follow-up of 8.2 months. The combination was tolerable despite the high baseline disease burden in an elderly population, with 26.5% over 75 years of age. Treatment with niraparib + AAP was manageable with dose interruptions, reductions, and supportive care. The majority of subjects were able to continue treatment until disease progression, with 15.1% discontinuing treatment due to AEs compared with 7.1% in the PBO + AAP arm, with COVID-19 being the most common AE leading to discontinuation. The adverse event profile in subjects receiving FDC (cohort 3) appears to be consistent with that observed in cohort 1.

[0296] For mCRPC patients whose tumors harbor BRCA alterations, especially BRCA monogenic alterations, the combination of niraparib + AAP represents a new treatment option with favorable benefits: a risk profile that results in a statistically significant and clinically meaningful improvement in rPFS, prolongs the time to symptomatic progression with delayed need for cytotoxic chemotherapy, and does not compromise OS with manageable toxicity. Furthermore, patients with selected HRR monogenic alterations in genes other than BRCA (e.g., HRR-Fanconi and HRR-related functional groups, especially those with PALB2 and CHEK2 gene alterations) also benefit from treatment with niraparib + AAP, as reflected by improvements in the primary and all secondary endpoints.

[0297] Major patient-reported outcome (PRO) findings from the Magnitude study Strong PRO compliance and completion rates with assessments aligned with study visits Patients had minimal pain burden and generally positive HRQoL at baseline (no difference between arms) On-treatment analysis showed: Most patients maintained low levels of pain intensity and interference over time. Long-term follow-up is needed. No clinically meaningful differences in overall HRQoL between arms or over time. No clinically meaningful differences in prostate cancer symptoms between arms or over time. There is a moderate decrease in physical health with niraparib caused by known symptomatic side effects. Niraparib is associated with worse side effects, lack of energy, nausea, and a greater risk of feeling sick / ill. However, most patients reported minimal symptomatic side effects / side effect burden. No change in patients' physical and role functioning over time or between treatment arms.

[0298] Example 6 - Gene-by-Gene Analysis of the MAGNITUDE Study of Niraparib (NIRA) with Abiraterone Acetate and Prednisone (AAP) in Patients (pts) with Metastatic Castration-Resistant Prostate Cancer (mCRPC) and Homologous Recombination Repair (HRR) Gene Alterations Important matters · Although the prognostic impact of BRCA and response to PARPi are well characterized, PARP inhibitor (PARPi) activity in other HRR genetic alterations is less well understood. Gene-by-gene analysis in subjects with non-BRCA1 / 2 genetic alterations demonstrated benefit to treatment with NIRA+AAP for primary and secondary endpoints.

[0299] conclusion Benefits from treatment with NIRA+AAP were observed for both primary and secondary endpoints. In addition to improving radiographic progression-free survival (rPFS), improvements in secondary endpoints such as delay in time to cytotoxic chemotherapy and delay in time to symptomatic progression are particularly relevant for improving patient experience. · These data support the overall conclusions of the MAGNITUDE primary analysis and support the benefit of NIRA+AAP in pts with HRR mutations beyond BRCA1 / 2

[0300] introduction · NIRA+AAP significantly improved primary, secondary and other endpoints in pts with mCRPC and HRR gene alterations in the Phase 3 MAGNTUDE study. · There is a lack of data supporting the use of PARP inhibitors in pts with HRR gene alterations other than BRCA1 / 2. · We report on the efficacy of NIRA+AAP in pts with mCRPC and eligible single-gene HRR alterations other than BRCA1 / 2. · Mutations occurring simultaneously with BRCA genes have been previously reported as part of the BRCA subgroup (Chi KN, et al. J Clin Oncol. 2022;40:suppl 6;12), but other simultaneous mutations are not reported here due to the small sample size per each combination that does not allow meaningful conclusions to be drawn.

[0301] the purpose · Efficacy of NIRA+AAP in pts with mCRPC and eligible single-gene HRR alterations other than BRCA1 / 2.

[0302] method Pre-specified analyses were performed across 186 pts (91 randomized to NIRA+AAP, 95 randomized to PBO+AAP) with ATM, BRIP1, CDK12, CHEK2, FANCA, HDAC2, or PALB2 gene alterations (excluding concomitant alterations) for the primary endpoint (rPFS by BICR), secondary endpoints (time to cytotoxic chemotherapy [TCC], time to symptomatic progression [TSP], overall survival [OS]), as well as time to PSA progression (TPSA) and overall response rate (ORR) (Figure 9). This analysis of individual changes was not powered for formal statistical inference. Taking into account the rarity of some variations, groups based on functional similarity are also presented.

[0303] result Patients with PALB2 or CHEK2 alterations had consistent improvements across all endpoints (Tables 21-23). In patients with ATM alterations, benefits were observed in TCC, TSP, TPSA, and ORR (Tables 21 and 23). For patients with CDK12 alterations, there was benefit only in TPSA and ORR (Tables 22-23). When combined into functional groups, patients with alterations in the HRR-Fanconi pathway (BRIP1, FANCA, and PALB2) and those with HRR-related alterations (CHEK2 or HDAC2) showed improvement in all endpoints (Tables 21-23). With the exception of CDK12, all individual genes showed improvement across primary and secondary endpoints (Tables 21-23).

[0304] [Table 25] HRR, homologous recombination repair; PBO, placebo; AAP, abiraterone acetate plus prednisone / prednisolone; rPFS, radiographic progression-free survival; TCC, time to cytotoxic therapy; TSP, time to symptomatic progression; OS, overall survival

[0305] [Table 26] HRR, homologous recombination repair; PBO, placebo; AAP, abiraterone acetate plus prednisone / prednisolone; TPSA, prostate-specific antigen time to progression

[0306] [Table 27] HRR, homologous recombination repair; PBO, placebo; AAP, abiraterone acetate plus prednisone / prednisolone; ORR, overall response rate

[0307] IA2: Gene-specific analysis of rPFS, TCC, TSP and OS endpoints In Table 24, none of the genes or gene groups (other than the BRCA subgroup for the rPFS analysis) were powered for formal statistical testing because certain genetic alterations are particularly rare. Therefore, results are provided for genes grouped based on functionally and biologically similar roles, as well as for each genetic alteration separately (see Table 24).

[0308] [Table 28-1]

[0309] [Table 28-2] Key: AAP = abiraterone acetate plus prednisone; ATM = ataxia telangiectasia mutated gene; BRCA = breast cancer gene; BRIP1 = BRCA1-interacting protein C-terminal helicase 1; CDK12 = cyclin-dependent kinase 12; CHEK2 = checkpoint kinase 2; CI = confidence interval; FANCA = Fanconi anemia complementation group A gene; HDAC2 = histone deacetylase 2; HR = hazard ratio; HRR = homologous recombination repair. ;N=number, NE=not estimable;nira=niraparib;ORR=objective response rate;OS=overall survival;PALB2=partner and localizer of BRCA2;PBO=placebo;PSA=prostate-specific antigen;rPFS=radiographic progression-free survival;RR=risk ratio;TCC=time to start of cytotoxic chemotherapy;TPSA=time to PSA progressionTSP=time to symptomatic progressionNote: Non-estimable HRs are due to few or no events.

[0310] Subjects with BRCA alterations In the MAGNITUDE study, subjects were stratified by BRCA versus other HRR gene alterations, as subjects with BRCA gene alterations are known to have a particularly poor prognosis from prostate cancer. As noted above, rPFS was significant in the BRCA subgroup in the primary analysis, TCC and TSP showed clear improvements, and a trend toward benefit was observed in OS with the niraparib + AAP combination.

[0311] The BRCA monogenic alteration group shows robust improvement across all primary and secondary endpoints.

[0312] Subjects with BRCA single gene alterations 191 subjects with BRCA monogenic alterations were enrolled in cohort 1. In these subjects, there was a clear clinically relevant benefit across the primary and all secondary endpoints. The HR point estimates for rPFS, TCC, and TSP were all <0.5. A trend towards improved OS (HR=0.786; 95%CI:0.505, 1.225) was observed in subjects with BRCA monogenic alterations treated with niraparib + AAP. Of these, 175 subjects with monogenic BRCA2 alterations constituted the majority of subjects enrolled in the BRCA cohort. In subjects with BRCA2 alterations, there was a clear clinically relevant benefit across the primary and all secondary endpoints. The HRs for rPFS, TCC, and TSP were all <0.5, and all three of these 95% confidence intervals excluded 1. A clear trend towards improved OS (HR=0.772; 95%CI:0.488,1.220) was also observed in subjects with BRCA2 monogenic alterations. The 16 enrolled subjects with BRCA1 alterations were unevenly distributed among the treatment groups, with 4 subjects treated with PBO+AAP and 12 subjects treated with niraparib+AAP. This imbalance, with few subjects receiving PBO+AAP, limits the interpretation of the effect of the niraparib+AAP combination in this population. HRs for the primary and all secondary endpoints were >1.0.

[0313] Subjects with HRR-Fanconi anemia pathway gene alterations (BRIP1, FANCA, or PALB2) HRR / Fanconi anemia pathway genes, including FANCA, BRIP1, and PALB2, are involved in the cell cycle via the HRR pathway. Prostate cancer tumors with these mutations exhibit a BRCAness signature (Chung 2019). Overall, 31 subjects with these types of genetic alterations were enrolled (8 subjects with BRIP1, 11 subjects with FANCA, and 12 subjects with PALB2 alterations). When analyzed together as a functional group, clinical benefit was demonstrated across all of the study endpoints: rPFS, TCC, TSP, and OS. These data suggest that subjects with HRR / Fanconi anemia pathway genetic alterations will benefit from niraparib + AAP treatment.

[0314] Among individual genes, subjects with PALB2 gene alterations showed particularly strong benefit with niraparib + AAP treatment, as point estimates for all endpoints favored niraparib + AAP.

[0315] Subjects with HRR-related gene alterations (CHEK2 and HDAC2) HRR-related genes, CHEK2 and HDAC2, indirectly regulate HRR repair. Subjects with HRR-related gene alterations as a group also showed clinical benefit in all endpoints, including rPFS, TCC, TSP, and OS. These data suggest that subjects with CHEK2 and HDAC2 gene alterations will benefit from Niraparib + AAP treatment. Among individual genes, subjects with CHEK2 alterations showed particularly strong benefit, as point estimates for all endpoints favored treatment with niraparib plus AAP.

Claims

1. a dual combination of 100 mg naraparib and 500 mg abiraterone acetate, optionally formulated in a film-coated tablet with a pharmaceutically acceptable carrier; 1. A formulation for use in combination with prednisone or prednisolone in a method of improving median radiographic progression-free survival (rPFS) in patients with metastatic castration-resistant prostate cancer (mCRPC) who are positive for germline and / or somatic homologous recombination repair (HRR) gene alteration(s), comprising: the HRR gene alteration(s) a) BRCA2 (breast cancer gene 2) or BRCA1 (breast cancer gene 1), b) BRCA2, c) BRCA2, BRCA1, PALB2 (partner and localizer of the BRCA2 gene), or CHEK2 (checkpoint kinase 2 gene), or d) BRCA2, BRCA1, CHEK2, HDAC2 (histone deacetylase 2), BRIP1 (BRCA1-interacting protein C-terminal helicase 1 gene), FANCA (Fanconi anemia complementation group A gene) or PALB2; and wherein the amino acid sequence is selected from one or more changes in any one of the groups selected from: A formulation wherein the daily dosage of the method for improving rPFS is a single dose of 200 mg niraparib and 1000 mg abiraterone acetate, optionally equivalent to two film-coated tablets; and a dose of 10 mg prednisone or prednisolone.

2. 2. The formulation for use according to claim 1, wherein the mCRPC is first-line (L1) mCRPC, L1 mCRPC being defined for patients who have not been treated with any therapy in the metastatic castration-resistant setting except for i) androgen deprivation therapy (ADT), and / or ii) up to 2 or 4 months of prior exposure to abiraterone acetate plus prednisone or prednisolone.

3. 3. The formulation for use according to claim 1 or 2, wherein the mCRPC patient is asymptomatic or has mild symptoms, or the mCRPC patient is a prostate cancer patient who has progressed to mCRPC, or chemotherapy is not clinically indicated for the patient.

4. 3. The formulation for use of claim 1 or 2, wherein the HRR gene alteration(s) is / are selected from BRCA2, BRCA1, CHEK2, HDAC2, BRIP1, FANCA, or PALB2, and the improved median rPFS is about 16.7 months, with a hazard ratio (HR) for rPFS equal to 0.760, a 95% confidence interval (95% CI) of (0.595, 0.972), and a nominal p-value of 0.0280.

5. 3. The formulation for use according to claim 1 or 2, wherein the HRR gene alteration(s) is / are selected from BRCA2 and / or BRCA1, and the improved median rPFS is about 19.5 months, with an HR for rPFS equal to 0.553, 95% CI (0.3921, 0.782), and a nominal p-value of 0.0007.

6. 3. The formulation for use according to claim 1 or 2, wherein the patient has previously undergone gonadotropin-releasing hormone (GnRH) analogue therapy or has undergone bilateral orchiectomy.

7. 7. The formulation for use according to claim 6, wherein the patient continues to receive GnRH analogue therapy if not surgically castrated.

8. 3. The formulation for use according to claim 1 or 2, wherein the patient may have previously been administered an antiandrogen selected from enzalutamide, apalutamide, nilutamide, flutamide, bicalutamide, darolutamide, or abiraterone acetate.

9. 3. The formulation for use according to claim 1 or 2, wherein the patient has previously received a taxane chemotherapy, optionally selected from docetaxel or cabazitaxel.

10. 3. The formulation for use according to claim 1 or 2, wherein niraparib is in a salt form selected from tosylate monohydrate, sulfate, benzenesulfate, fumarate, succinate, camphorate, mandelate, camsylate, lauryl sulfate, or a mixture of tosylate monohydrate and lauryl sulfate.

11. 3. A formulation for use according to claim 1 or 2, wherein the film-coated tablet consists of i) a tablet core comprising the following excipients: colloidal anhydrous silica, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, silicified microcrystalline cellulose, sodium lauryl sulfate, and ii) a film coating comprising the following excipients: red iron oxide (E172), yellow iron oxide (E172), sodium lauryl sulfate, glycerol monocaprylocaprate, polyvinyl alcohol, talc, and titanium dioxide (E171).

12. The tablet has the following composition: Table 1 ａ the purified water is removed during processing; ｂ The salt coefficient is 1.594; 159.40 mg of niraparibut tosylate is equivalent to a 100.00 mg dose of niraparib; 3. A formulation for use according to claim 1 or 2, wherein the tablet is film-coated with approximately 64 mg of coating powder Opadry® AMB II 88A170010 Beige and 256 mg of purified water, the latter of which is removed during processing.

13. 3. The formulation for use according to claim 1 or 2, wherein the dual combination is formulated with a pharmaceutically acceptable carrier in a capsule.

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