A Study of Comparative Formulations of Niraparib and Abiraterone Acetate (AA) in Men With Prostate Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine the relative bioavailability (rBA; Period 1) and bioequivalence (BE; Period 2 and 3) of various strengths and formulations of niraparib and abiraterone acetate (AA) at steady state under modified fasted conditions in participants with metastatic castration-resistant prostate cancer (mCRPC).

Detailed Description
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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 which selectively inhibits the enzyme 17 alpha-hydroxylase/C17,20-lyase (CYP17), that is found in the testes and adrenals (leading to systemic inhibition of testosterone production), as well as in prostate tissues and tumors. The rationale of the study is to investigate the various strengths and formulations of niraparib and AA plus prednisone or prednisolone (P) in metastatic castration resistant prostate cancer (mCRPC) participants with and without homologous recombination repair (HRR) gene alterations. In participants with metastatic prostate cancer, DNA-repair anomalies are found in approximately 15 percent (%) to 20% of tumors. This study consists 4 periods: screening phase (up to 21 days); treatment phase (up to 22 days); extension and long-term extension phases (from day 23 until discontinuation); and post-treatment follow up phase (end of treatment [EoT] visit within 30 days after the last dose of study treatment). Total duration of study is up to 1.4 years. Efficacy, safety, pharmacokinetics (PK), and biomarkers will be assessed at specified time points during this study. Participants safety will be monitored throughout the study.

Official Title
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An Open-label, Randomized Study to Assess the Relative Bioavailability (BA) and Bioequivalence (BE) of Comparative Formulations of Niraparib and Abiraterone Acetate (AA) in Men With Prostate Cancer

Conditions
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Prostatic Neoplasms

Intervention / Treatment
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* Drug: Niraparib
* Drug: Abiraterone Acetate (AA)
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed adenocarcinoma of the prostate Diagnosed with metastatic castration-resistant prostate cancer (mCRPC), who in the opinion of the investigator may benefit from treatment in this study Able to continue gonadotropin-releasing hormone analogues (GnRHa) therapy during the study if not surgically castrate (that is, participants who have not undergone bilateral orchiectomy) Eastern Cooperative Oncology Group Performance Status (ECOG PS) of less than or equal to (<=) 1 Willing to provide a tumor sample (archival) for determination of homologous recombination repair (HRR) gene alteration status Exclusion Criteria: Symptomatic brain metastases Prior disease progression during treatment with abiraterone acetate (AA) alone or when combined with a poly adenosine diphosphate (ADP)-ribose polymerase inhibitor (PARPi). Prior discontinuation of treatment with AA or PARPi due to AA- or PARPi related toxicity. History or current diagnosis of myelodysplastic syndrome (MDS)/ acute myeloid leukemia (AML) Known allergies, hypersensitivity, or intolerance to niraparib or AA or the corresponding excipients of niraparib/AA Any medical condition that would make prednisone/prednisolone use contraindicated

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: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Sequence ABD<br>Participants will receive single doses of niraparib and abiraterone acetate (AA) using niraparib Formulation 1 as Treatment A in Treatment Period 1, followed by multiple doses of niraparib and AA using niraparib Formulation 2 as Treatment B in Treatment Period 2, followed by multiple doses of niraparib and AA using niraparib Formulation 4 as Treatment D in Treatment Period 3. From Period 2 onwards and during Extension and Long-term Extension Phases, all participants will continue to receive treatment with niraparib and AA-prednisone (AAP) or AAP alone. | Drug: Niraparib<br>* Niraparib will be administered orally.<br>Drug: Abiraterone Acetate (AA)<br>* Abiraterone Acetate will be administered orally.<br>Drug: Prednisone<br>* Prednisone will be administered orally.<br>|
| Experimental: Treatment Sequence ADB<br>Participants will receive Treatment A in Treatment Period 1 followed by Treatment D in Treatment Period 2, followed by Treatment B in Treatment Period 3. From Period 2 onwards and during Extension and Long-term Extension Phases, all participants will continue to receive treatment with niraparib and AAP or AAP alone. | Drug: Niraparib<br>* Niraparib will be administered orally.<br>Drug: Abiraterone Acetate (AA)<br>* Abiraterone Acetate will be administered orally.<br>Drug: Prednisone<br>* Prednisone will be administered orally.<br>|
| Experimental: Treatment Sequence CBD<br>Participants will receive single doses of niraparib and AA using niraparib Formulation 3 as Treatment C in Treatment Period 1, followed by Treatment B in Treatment Period 2, followed by Treatment D in Treatment Period 3. From Period 2 onwards and during Extension and Long-term Extension Phases, all participants will continue to receive treatment with niraparib and AAP or AAP alone. | Drug: Niraparib<br>* Niraparib will be administered orally.<br>Drug: Abiraterone Acetate (AA)<br>* Abiraterone Acetate will be administered orally.<br>Drug: Prednisone<br>* Prednisone will be administered orally.<br>|
| Experimental: Treatment Sequence CDB<br>Participants will receive Treatment C in Treatment Period 1, followed by Treatment D in Treatment Period 2, followed by Treatment B in Treatment Period 3. From Period 2 onwards and during Extension and Long-term Extension Phases, all participants will continue to receive treatment with niraparib and AAP or AAP alone. | Drug: Niraparib<br>* Niraparib will be administered orally.<br>Drug: Abiraterone Acetate (AA)<br>* Abiraterone Acetate will be administered orally.<br>Drug: Prednisone<br>* Prednisone will be administered orally.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Analyte Concentration at Steady State (Cmax,ss) of Niraparib and Abiraterone Acetate (AA) [Period 2 and Period 3] | Cmax,ss is defined as maximum observed analyte concentration at steady state. | Predose, up to 10 hour post dose | 
| Area Under the Plasma Concentration-time Curve from Time Zero to 24 Hours at Steady State (AUC [0-24h],ss) of Niraparib and AA (Period 2 and Period 3) | AUC (0-24h),ss is defined as area under the plasma concentration-time curve from time zero to 24 hours at steady state. | Predose, up to 24 hours post dose | 
| Ratio of Individual Cmax,ss Values Between Test and Reference Treatment (Period 2 and Period 3) | Ratio of individual Cmax,ss values between test and reference treatment will be assessed. | Predose, up to 10 hours post dose | 
| Ratio of individual AUC (0-24h),ss Values Between Test and Reference Treatment (Period 2 and Period 3) | Ratio of individual AUC (0-24h),ss values between test and reference treatment will be assessed. | Predose, up to 24 hours post dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Analyte Concentration at (Cmax) of Niraparib and AA (Period 1) | Cmax is defined as maximum observed analyte concentration. | Predose, up to 72 hours post dose | 
| Area Under the Plasma Concentration-time Curve from Time Zero to 72 Hours (AUC [0-72h]) of Niraparib and AA (Period 1) | AUC (0-72h) is defined as area under the plasma concentration-time curve from time zero to 72 hours post dosing. | Predose, up to 72 hours post dose | 
| Ratio of individual AUC (0-72h) Values Between Test and Reference Treatment (Period 1) | Ratio of individual AUC (0-72h) values between test and reference treatment will be assessed. | Predose, up to 72 hours post dose | 
| Serum Testosterone Level | Serum testosterone level will be assessed. | Predose on Day -7, Day 11, Day 12 and Day 23 | 
| Number of Participants with Adverse Events (AEs) as a Measure of Safety and Tolerability | An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. | From study start until study completion (up to 3.1 years) | 
| Number of Participants with AEs by Severity | Severity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Severity scale ranges from Grade 1 (Mild) to Grade 5 (Death). Grade 1= Mild, Grade 2= Moderate, Grade 3= Severe, Grade 4= Life-threatening and Grade 5= Death. | From study start until study completion (up to 3.1 years) | 
| Number of Participants with Clinical Laboratory Abnormalities | Number of participants with clinical laboratory abnormalities including hematology, serum chemistry and urinalysis will be reported. | From study start until study completion (up to 3.1 years) |