A Study of Niraparib in Combination With Abiraterone Acetate and Prednisone Versus Abiraterone Acetate and Prednisone for the Treatment of Participants With Deleterious Germline or Somatic Homologous Recombination Repair (HRR) Gene-Mutated Metastatic Castration-Sensitive Prostate Cancer (mCSPC)

Study Overview
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Brief Summary
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The purpose of the study is to determine if the combination of niraparib with Abiraterone Acetate (AA) plus prednisone compared with AA plus prednisone in participants with deleterious germline or somatic Homologous Recombination Repair (HRR) gene-mutated Metastatic Castration-Sensitive Prostate Cancer (mCSPC) provides superior efficacy in improving radiographic progression-free survival (rPFS).

Detailed Description
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Prostate cancer is a heterogenous disease and recent genomic analyses have highlighted specific germline and somatic mutations and alternative driver growth signaling pathways in patients with metastatic disease. Abiraterone acetate plus prednisone (AAP) is an established standard of care for the treatment of participants with mCSPC and is included in widely accepted clinical treatment guidelines. Niraparib is an investigational agent in the castration-sensitive cancer population and has been approved for the treatment of ovarian cancer. The addition of niraparib to the AAP backbone regimen may improve initial disease control and long-term outcomes compared with AAP alone in a biomarker selected population. The study will consist of 4 phases; a Prescreening Phase for biomarker evaluation for eligibility only, a Screening Phase, a Treatment Phase, and a Follow-up Phase. Efficacy evaluations include the following: tumor measurements by computed tomography (CT), magnetic resonance imaging (MRI; abdomen, chest, and pelvis), Technetium-99m (99mTc) bone scans, serum prostate sensitive antigen (PSA) evaluations, and patient reported outcomes (PROs). Safety evaluations include incidence of adverse events and clinical laboratory parameters.

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 for the Treatment of Participants With Deleterious Germline or Somatic Homologous Recombination Repair (HRR) Gene-Mutated Metastatic Castration-Sensitive Prostate Cancer (mCSPC)

Conditions
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Metastatic Castration-sensitive Prostate Cancer

Intervention / Treatment
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* Drug: Niraparib
* Drug: Abiraterone acetate (AA)
* Drug: Prednisone
* Drug: Placebo for Niraparib


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Pathological diagnosis of prostate adenocarcinoma Must have appropriate deleterious homologous recombination repair (HRR) gene alteration Metastatic disease as documented by conventional imaging with computed tomography (CT) or magnetic resonance imaging (MRI) (for soft tissue lesions) or 99mTc bone scan (for bone lesions). Participants with a single bone lesion on Technetium-99m (99mTc) bone scan with no other non-nodal metastatic disease must have confirmation of bone metastasis by CT or MRI. Participants with lymph node-only disease are not eligible Androgen deprivation therapy (either medical or surgical castration) must have been started >=14 days prior to randomization and participants be willing to continue androgen deprivation therapy (ADT) through the treatment phase Other allowed prior therapy for metastatic castration-sensitive prostate cancer (mCSPC): (a) maximum of 1 course of radiation and 1 surgical intervention for symptomatic control of prostate cancer (example, uncontrolled pain, impending spinal cord compression or obstructive symptoms). Participants with radiation or surgical interventions to all known sites of metastatic disease will be excluded from trial participation. Radiation must be completed prior to randomization (b) Up to a maximum of 6 months of ADT prior to randomization; (c) Up to a maximum of 45 days of abiraterone acetate + prednisone (AA-P) prior to randomization (d) Up to a maximum of 2 weeks of ketoconazole for prostate cancer prior to randomization Exclusion criteria: Prior treatment with a poly (adenosine diphosphate-ribose) polymerase inhibitor (PARP inhibitor) History of adrenal dysfunction Long-term use of systemically administered corticosteroids (greater than [>] 5 milligrams [mg] of prednisone or the equivalent) during the study is not allowed. Short-term use (<=4 weeks, including taper) and locally administered steroids (for example, inhaled, topical, ophthalmic, and intra-articular) are allowed, if clinically indicated History or current diagnosis of myelodysplastic syndrome (MDS)/ acute myeloid leukemia (AML)

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Niraparib with Abiraterone Acetate plus Prednisone (AAP)<br>Participants will receive the following in each 28-day treatment cycle: niraparib 200 milligrams (mg), abiraterone acetate (AA) 1000 mg plus prednisone 5 mg once daily. | Drug: Niraparib<br>* Participants will receive Niraparib 200 mg once daily.<br>Drug: Abiraterone acetate (AA)<br>* Participants will receive AA 1000 mg once daily.<br>Drug: Prednisone<br>* Participants will receive prednisone 5 mg once daily.<br>|
| Active Comparator: AA plus Prednisone (AAP)<br>Participants will receive the following in each 28-day treatment cycle: matching placebo for Niraparib along with AA 1000 mg plus prednisone 5 mg once daily. | Drug: Prednisone<br>* Participants will receive prednisone 5 mg once daily.<br>Drug: Placebo for Niraparib<br>* Participants will receive matching placebo for Niraparib once daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiographic Progression-free Survival (rPFS) | rPFS is defined as time from randomization date to date of radiographic progression or death, whichever occurs first. Radiographic progression will be evaluated by Prostate Cancer Working Group 3 (PCWG3) criteria and Response Evaluation Criteria in Solid Tumors (RECIST 1.1). | Up to 47 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined as the time from date of randomization to date of death from any cause. | Up to 78 months | 
| Time to Symptomatic Progression | Time to symptomatic progression is defined as time from the date of randomization to the date of any of the following (whichever occurs first): a) the use of external beam radiation therapy for skeletal or pelvic symptoms; b) the need for tumor-related orthopedic surgical intervention; c) other cancer-related procedures; d) cancer-related morbid events; e) initiation of a new systemic anti-cancer therapy because of cancer symptoms. | Up to 47 months | 
| Time to Subsequent Therapy | Time to Subsequent Therapy is defined as the time from date of randomization to the date of initiation of subsequent therapy for prostate cancer. | Up to 47 months | 
| Number of Participants with Adverse Events as a Measure of Safety and Tolerability | An adverse event (AE) is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non investigational) product. AE does not necessarily have a causal relationship with intervention. | Up to 78 months |