Castration-Resistant Prostatic Cancer
Conditions
Brief summary
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.
Interventions
DRUGNiraparib
Participants will receive niraparib 200 mg capsules or tablets once daily.
DRUGAbiraterone Acetate
Participants will receive AA 1000 mg tablets once daily.
DRUGPrednisone
Participants will receive prednisone 10 mg tablets daily.
DRUGPlacebo
Participants will receive matching placebo once daily.
DRUGNew Formulation of Niraparib and Abiraterone Acetate (AA)
Participants will receive a new formulation of niraparib 200 mg and AA 1000 mg tablets once daily.
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* HRR gene alteration (as identified by the sponsor's required assays) as follows: 1. Cohort 1: positive for HRR gene alteration 2. Cohort 2: not positive for DRD (that is, HRR gene alteration) 3. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cohort 1: Radiographic Progression-Free Survival (rPFS) as Assessed by Blinded Independent Central Review (BICR) | Up to 32 months | As per BICR, rPFS is time interval from the date of randomization to radiographic progression or death, whichever occurred 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. |
| Cohort 1 Breast Cancer Gene (BRCA) Subgroup: Radiographic Progression-Free Survival (rPFS) as Assessed by Blinded Independent Central Review (BICR) | Up to 32 months | As per BICR, rPFS is time interval from the date of randomization to radiographic progression or death, whichever occurred first. Radiographic progression was determined by: (1) progression of soft tissue lesions measured by CT or MRI as per RECIST 1.1; (2) Progression of bone lesions observed by bone scan based on PCWG3 criteria. PCWG3 criteria: bone progression was confirmed by subsequent scan \>=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 \<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. |
Secondary
| Measure | 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 |
Countries
Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, China, Czechia, France, Germany, Hungary, Israel, Italy, Malaysia, Mexico, Netherlands, Poland, Portugal, Puerto Rico, Russia, South Africa, South Korea, Spain, Sweden, Taiwan, Turkey (Türkiye), Ukraine, United Kingdom, United States
Contacts
STUDY_DIRECTORJanssen Research & Development, LLC Clinical Trial
Janssen Research & Development, LLC
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: Niraparib 200 mg + Abiraterone Acetate 1000 mg + Prednisone 10 mg Participants with metastatic castration-resistant prostate cancer (mCRPC) and positive homologous recombination repair (HRR) gene alteration, received niraparib 200 milligrams (mg) capsule in combination with abiraterone acetate 1000 mg tablet orally once daily (QD) and prednisone 5 mg tablet orally twice daily (BID) (total dose 10 mg) in each 28 days treatment cycle starting from Cycle 1 Day 1 up to 29 months. Participants were then followed up for safety up to 5 years after last dose or until death, loss to follow-up, withdrawal of consent, or study termination. Participants were continued to receive niraparib 200 mg and abiraterone acetate 1000 mg plus prednisone 10 mg in the open label extension phase. | 212 |
| Cohort 1: Placebo + Abiraterone Acetate 1000 mg + Prednisone 10 mg Participants with mCRPC and positive HRR gene alteration, received placebo in combination with abiraterone acetate 1000 mg tablet orally QD and prednisone 5 mg tablet orally BID (total dose 10 mg) in each 28 days treatment cycle starting from Cycle 1 Day 1 up to 29 months. Participants were then followed up for safety up to 5 years after last dose or until death, loss to follow-up, withdrawal of consent, or study termination. Participants who received placebo and abiraterone acetate plus prednisone were allowed to cross over to receive niraparib 200 mg and abiraterone acetate 1000 mg plus prednisone 10 mg in the open-label extension phase. | 211 |
| Cohort 2: Niraparib 200 mg + Abiraterone Acetate 1000 mg + Prednisone 10 mg Participants with mCRPC and negative HRR gene alteration, received niraparib 200 mg capsule in combination with abiraterone acetate 1000 mg tablet orally QD and prednisone 5 mg tablet orally BID (total dose 10 mg) in each 28 days treatment cycle starting from Cycle 1 Day 1 up to 29 months. Participants were then followed up for safety up to 5 years after last dose or until death, loss to follow-up, withdrawal of consent, or study termination. Participants were continued to receive niraparib 200 mg and abiraterone acetate 1000 mg plus prednisone 10 mg in the open label extension phase. | 123 |
| Cohort 2: Placebo + Abiraterone Acetate 1000 mg + Prednisone 10 mg Participants with mCRPC and negative HRR gene alteration, received placebo in combination with abiraterone acetate 1000 mg tablet orally QD and prednisone 5 mg tablet orally BID (total dose 10 mg) in each 28 days treatment cycle starting from Cycle 1 Day 1 up to 29 months. Participants were then followed up for safety up to 5 years after last dose or until death, loss to follow-up, withdrawal of consent, or study termination. Participants who received placebo and abiraterone acetate plus prednisone were allowed to cross over to receive niraparib 200 mg and abiraterone acetate 1000 mg plus prednisone 10 mg in the open-label extension phase. | 124 |
| Cohort 3: Niraparib 200 mg and Abiraterone Acetate 1000 mg FDC + Prednisone 10 mg Participants with mCRPC and positive HRR gene alteration, received fixed-dose combination (FDC) of niraparib 200 mg and abiraterone acetate 1000 mg combination tablet orally QD with prednisone 5 mg tablet orally BID (total dose 10 mg) in each 28 days treatment cycle starting from Cycle 1 Day 1 up to 9 months. Participants were then followed up for safety up to 5 years after last dose or until death, loss to follow-up, withdrawal of consent, or study termination. Participants were continued to receive same treatment in long-term extension phase. | 95 |
| Total | 765 |
Baseline characteristics
| Characteristic | Cohort 1: Niraparib 200 mg + Abiraterone Acetate 1000 mg + Prednisone 10 mg | Cohort 1: Placebo + Abiraterone Acetate 1000 mg + Prednisone 10 mg | Cohort 2: Niraparib 200 mg + Abiraterone Acetate 1000 mg + Prednisone 10 mg | Cohort 2: Placebo + Abiraterone Acetate 1000 mg + Prednisone 10 mg | Cohort 3: Niraparib 200 mg and Abiraterone Acetate 1000 mg FDC + Prednisone 10 mg | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 69.2 years STANDARD_DEVIATION 8.79 | 68.6 years STANDARD_DEVIATION 8.17 | 71.2 years STANDARD_DEVIATION 7.11 | 71.1 years STANDARD_DEVIATION 7.52 | 69.2 years STANDARD_DEVIATION 8.99 | 69.7 years STANDARD_DEVIATION 8.25 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 26 Participants | 25 Participants | 8 Participants | 12 Participants | 12 Participants | 83 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 166 Participants | 169 Participants | 110 Participants | 105 Participants | 77 Participants | 627 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 20 Participants | 17 Participants | 5 Participants | 7 Participants | 6 Participants | 55 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 29 Participants | 41 Participants | 45 Participants | 37 Participants | 14 Participants | 166 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 17 Participants | 16 Participants | 5 Participants | 4 Participants | 7 Participants | 49 Participants |
| Race (NIH/OMB) White | 160 Participants | 153 Participants | 72 Participants | 83 Participants | 70 Participants | 538 Participants |
| Region of Enrollment ARGENTINA | 2 Participants | 5 Participants | 2 Participants | 7 Participants | 2 Participants | 18 Participants |
| Region of Enrollment AUSTRALIA | 15 Participants | 12 Participants | 12 Participants | 9 Participants | 3 Participants | 51 Participants |
| Region of Enrollment BELGIUM | 5 Participants | 1 Participants | 2 Participants | 3 Participants | 0 Participants | 11 Participants |
| Region of Enrollment BRAZIL | 20 Participants | 14 Participants | 0 Participants | 0 Participants | 10 Participants | 44 Participants |
| Region of Enrollment BULGARIA | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Region of Enrollment CANADA | 4 Participants | 7 Participants | 1 Participants | 4 Participants | 3 Participants | 19 Participants |
| Region of Enrollment CHINA | 7 Participants | 4 Participants | 0 Participants | 0 Participants | 0 Participants | 11 Participants |
| Region of Enrollment CZECH REPUBLIC | 4 Participants | 3 Participants | 1 Participants | 2 Participants | 1 Participants | 11 Participants |
| Region of Enrollment FRANCE | 13 Participants | 12 Participants | 5 Participants | 4 Participants | 3 Participants | 37 Participants |
| Region of Enrollment GERMANY | 0 Participants | 4 Participants | 0 Participants | 0 Participants | 5 Participants | 9 Participants |
| Region of Enrollment HUNGARY | 7 Participants | 4 Participants | 3 Participants | 2 Participants | 1 Participants | 17 Participants |
| Region of Enrollment ISRAEL | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 3 Participants |
| Region of Enrollment ITALY | 9 Participants | 10 Participants | 3 Participants | 3 Participants | 11 Participants | 36 Participants |
| Region of Enrollment MALAYSIA | 5 Participants | 10 Participants | 17 Participants | 7 Participants | 1 Participants | 40 Participants |
| Region of Enrollment MEXICO | 3 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 5 Participants |
| Region of Enrollment NETHERLANDS | 3 Participants | 4 Participants | 2 Participants | 2 Participants | 0 Participants | 11 Participants |
| Region of Enrollment POLAND | 12 Participants | 12 Participants | 11 Participants | 15 Participants | 4 Participants | 54 Participants |
| Region of Enrollment PORTUGAL | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 3 Participants | 5 Participants |
| Region of Enrollment RUSSIAN FEDERATION | 19 Participants | 21 Participants | 6 Participants | 1 Participants | 3 Participants | 50 Participants |
| Region of Enrollment SOUTH KOREA | 8 Participants | 22 Participants | 21 Participants | 17 Participants | 10 Participants | 78 Participants |
| Region of Enrollment SPAIN | 12 Participants | 9 Participants | 9 Participants | 12 Participants | 3 Participants | 45 Participants |
| Region of Enrollment SWEDEN | 4 Participants | 2 Participants | 1 Participants | 1 Participants | 1 Participants | 9 Participants |
| Region of Enrollment TAIWAN | 8 Participants | 4 Participants | 7 Participants | 12 Participants | 3 Participants | 34 Participants |
| Region of Enrollment TURKEY | 18 Participants | 16 Participants | 6 Participants | 6 Participants | 5 Participants | 51 Participants |
| Region of Enrollment UKRAINE | 18 Participants | 20 Participants | 12 Participants | 11 Participants | 9 Participants | 70 Participants |
| Region of Enrollment UNITED KINGDOM | 2 Participants | 1 Participants | 0 Participants | 3 Participants | 3 Participants | 9 Participants |
| Region of Enrollment UNITED STATES | 12 Participants | 11 Participants | 2 Participants | 3 Participants | 8 Participants | 36 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 212 Participants | 211 Participants | 123 Participants | 124 Participants | 95 Participants | 765 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 55 / 212 | 59 / 211 | 53 / 123 | 44 / 123 | 9 / 95 |
| other Total, other adverse events | 198 / 212 | 178 / 211 | 117 / 123 | 108 / 123 | 83 / 95 |
| serious Total, serious adverse events | 76 / 212 | 52 / 211 | 66 / 123 | 45 / 123 | 21 / 95 |
Outcome results
Primary
Cohort 1 Breast Cancer Gene (BRCA) Subgroup: 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 occurred first. Radiographic progression was determined by: (1) progression of soft tissue lesions measured by CT or MRI as per RECIST 1.1; (2) Progression of bone lesions observed by bone scan based on PCWG3 criteria. PCWG3 criteria: bone progression was confirmed by subsequent scan \>=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 \<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.
Time frame: Up to 32 months
Population: The randomized analysis set for cohort 1 BRCA subgroup included all randomized participants in Cohort 1 BRCA subgroup. Data for this outcome measure was planned to be collected and analyzed for BRCA subgroup of Cohort 1 only.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Niraparib 200 mg + Abiraterone Acetate 1000 mg + Prednisone 10 mg | Cohort 1 Breast Cancer Gene (BRCA) Subgroup: Radiographic Progression-Free Survival (rPFS) as Assessed by Blinded Independent Central Review (BICR) | 16.56 Months |
| Cohort 1: Placebo + Abiraterone Acetate 1000 mg + Prednisone 10 mg | Cohort 1 Breast Cancer Gene (BRCA) Subgroup: Radiographic Progression-Free Survival (rPFS) as Assessed by Blinded Independent Central Review (BICR) | 10.87 Months |
p-value: 0.001495% CI: [0.361, 0.789]Log Rank
Primary
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 occurred 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.
Time frame: Up to 32 months
Population: The randomized analysis set for cohort 1 included all randomized participants in Cohort 1. Data for this outcome measure was planned to be collected and analyzed for Cohort 1 only.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Niraparib 200 mg + Abiraterone Acetate 1000 mg + Prednisone 10 mg | Cohort 1: Radiographic Progression-Free Survival (rPFS) as Assessed by Blinded Independent Central Review (BICR) | 16.46 Months |
| Cohort 1: Placebo + Abiraterone Acetate 1000 mg + Prednisone 10 mg | Cohort 1: Radiographic Progression-Free Survival (rPFS) as Assessed by Blinded Independent Central Review (BICR) | 13.70 Months |
p-value: 0.021795% CI: [0.556, 0.956]Log Rank
Secondary
Cohort 1: Overall Survival (OS)
Time frame: Up to 97 months
Secondary
Cohort 1: Time to Initiation of Cytotoxic Chemotherapy
Time frame: Up to 97 months
Secondary
Cohort 1: Time to Symptomatic Progression
Time frame: Up to 97 months
Secondary
Number of Participants With Abnormalities in Laboratory Values
Time frame: Up to 96 months
Secondary
Number of Participants With Treatment-Emergent Adverse Events by Severity
Time frame: Up to 96 months
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
Time frame: Up to 96 months
Secondary
Observed Plasma Concentrations of Abiraterone
Time frame: Up to 97 months
Secondary
Observed Plasma Concentrations of Niraparib
Time frame: Up to 97 months