A Study of Niraparib in Combination With Abiraterone Acetate and Prednisone Versus Abiraterone Acetate and Prednisone for Treatment of Participants With Metastatic Prostate Cancer

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effectiveness of niraparib in combination with abiraterone acetate plus prednisone (AAP) compared to AAP and placebo.

Detailed Description
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This study will assess efficacy and safety of niraparib in combination with AAP for the treatment of participants with metastatic castration resistant prostate cancer. Niraparib is an orally available, highly selective poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor, with potent activity against PARP-1 and PARP-2 deoxyribonucleic acid (DNA)-repair polymerases. AA is a pro-drug of abiraterone and selectively inhibits the enzyme 17 alpha-hydroxylase/C17,20-lyase (CYP17), which is found in the testes and adrenals, as well as in prostate tissues and tumors. In participants with metastatic prostate cancer, DNA-repair anomalies are identified in approximately 15 percent (%) to 20% of tumors. The study will consist of 5 phases: a prescreening phase for biomarker evaluation only, a screening phase, a treatment phase, a follow up phase, and an extension phase (either open-label extension [OLE] or long-term extension [LTE]). During the prescreening phase participants will be evaluated for homologous recombination repair (HRR) gene alteration status and then will be assigned to one of the 2 cohorts based on their biomarker status. Treatment will be administered daily and is planned to be continuous until disease progression, unacceptable toxicity, death, or the sponsor terminates the study. Efficacy, pharmacokinetics, biomarkers, participants reported outcomes and safety will be assessed. The total duration of study will be approximately 66 months.

Official Title
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A Phase 3 Randomized, Placebo-controlled, Double-blind Study of Niraparib in Combination With Abiraterone Acetate and Prednisone Versus Abiraterone Acetate and Prednisone in Subjects With Metastatic Prostate Cancer

Conditions
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Castration-Resistant Prostatic Cancer

Intervention / Treatment
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* Drug: Niraparib
* Drug: Abiraterone Acetate
* Drug: Prednisone
* Drug: Placebo
* Drug: New Formulation of Niraparib and Abiraterone Acetate (AA)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HRR gene alteration (as identified by the sponsor's required assays) as follows: Cohort 1: positive for HRR gene alteration Cohort 2: not positive for DRD (that is, HRR gene alteration) Cohort 3: eligible by HRR status Metastatic disease documented by positive bone scan or metastatic lesions on computed tomography (CT) or magnetic resonance imaging (MRI) Metastatic prostate cancer in the setting of castrate levels of testosterone less than or equal to (<=) 50 nanogram per deciliter (ng/dL) on a gonadotropin releasing hormone analog (GnRHa) or bilateral orchiectomy Able to continue GnRHa during the study if not surgically castrate Score of <= 3 on the brief pain inventory-short form (BPI-SF) question number 3 (worst pain in last 24 hours) Exclusion Criteria: Prior treatment with a poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor Systemic therapy (that is, novel second-generation AR-targeted therapy such as enzalutamide, apalutamide, or darolutamide; taxane-based chemotherapy, or more than 4 months of abiraterone acetate plus prednisone [AAP] prior to randomization) in the metastatic castration-resistant prostate cancer (mCRPC) setting; or AAP outside of the mCRPC setting Symptomatic brain metastases History or current diagnosis of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) Other prior malignancy (exceptions: adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, or any other cancer in situ currently in complete remission) <= 2 years prior to randomization, or malignancy that currently requires active systemic therapy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Participants with mCRPC and HRR Gene Alteration<br>Participants with L1 metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alteration will receive combination of niraparib 200 milligrams (mg) or matching placebo and abiraterone acetate (AA) 1000 mg plus prednisone 10 mg. In the open label extension (OLE) phase participants earlier receiving the combination of niraparib and AAP may continue to receive open-label combination of niraparib 200 mg and AA 1000 mg plus prednisone 10 mg and those receiving placebo and AAP may cross over depending on the outcome of study to receive open-label combination of niraparib 200 mg and AA 1000 mg plus prednisone 10 mg. | Drug: Niraparib<br>* Participants will receive niraparib 200 mg capsules once daily.<br>* Other names: JNJ-64091742;Drug: Abiraterone Acetate<br>* Participants will receive AA 1000 mg tablets once daily.<br>Drug: Prednisone<br>* Participants will receive prednisone 10 mg tablets daily.<br>Drug: Placebo<br>* Participants will receive matching placebo once daily.<br>|
| Experimental: Cohort 2: Participants with mCRPC and No HRR Gene Alteration<br>Participants with L1 mCRPC and no HRR Gene alteration will receive combination of niraparib 200 mg or matching placebo and AA 1000 mg plus prednisone 10 mg. In the OLE phase participants earlier receiving the combination of niraparib and AAP may continue to receive open-label combination of niraparib 200 mg and AA 1000 mg plus prednisone 10 mg and those receiving placebo and AAP may cross over depending on the outcome of study to receive open-label combination of niraparib 200 mg and AA 1000 mg plus prednisone 10 mg. | Drug: Niraparib<br>* Participants will receive niraparib 200 mg capsules once daily.<br>* Other names: JNJ-64091742;Drug: Abiraterone Acetate<br>* Participants will receive AA 1000 mg tablets once daily.<br>Drug: Prednisone<br>* Participants will receive prednisone 10 mg tablets daily.<br>Drug: Placebo<br>* Participants will receive matching placebo once daily.<br>|
| Experimental: Cohort 3 (Open-label): Participants with mCRPC<br>Participants with mCRPC will receive a new formulation of niraparib 200 mg and AA 1000 mg tablets plus prednisone 10 mg. | Drug: Prednisone<br>* Participants will receive prednisone 10 mg tablets daily.<br>Drug: New Formulation of Niraparib and Abiraterone Acetate (AA)<br>* Participants will receive a new formulation of niraparib 200 mg and AA 1000 mg tablets once daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohort 1: Radiographic Progression-Free Survival (rPFS) as Assessed by Blinded Independent Central Review (BICR) | As per BICR, rPFS is time interval from the date of randomization to radiographic progression or death, whichever occurs first. Radiographic progression was determined by: 1) progression of soft tissue lesions measured by computerized tomography (CT) or magnetic resonance imaging (MRI) as per response evaluation criteria in solid tumors (RECIST) 1.1; 2) Progression of bone lesions observed by bone scan based on prostate cancer working group 3 (PCWG3) criteria. PCWG3 criteria: bone progression was confirmed by subsequent scan greater than or equal to (>=) 6 weeks later. Week 8 scan was baseline to which all subsequent scans were compared to determine progression. Confirmatory scan >=2 new lesions indicate progression; scan does not show >= 2 new lesions means no progression. If Week 8 scan less than (<) 2 new bone lesions compared to baseline, the initial scan >=2 new lesions compared to Week 8 scan indicates progression if confirmed by subsequent scan >=6 weeks later. | Up to 32 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohort 1: Overall Survival (OS) |  | Up to 97 months | 
| Cohort 1: Time to Symptomatic Progression |  | Up to 97 months | 
| Cohort 1: Time to Initiation of Cytotoxic Chemotherapy |  | Up to 97 months | 
| Observed Plasma Concentrations of Niraparib |  | Up to 97 months | 
| Observed Plasma Concentrations of Abiraterone |  | Up to 97 months | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) |  | Up to 96 months | 
| Number of Participants With Treatment-Emergent Adverse Events by Severity |  | Up to 96 months | 
| Number of Participants With Abnormalities in Laboratory Values |  | Up to 96 months |