Prostatic Neoplasms
Conditions
Keywords
Prostate cancer, CRPC, Metastatic castrate-resistant prostate cancer, Prostate neoplasm, Galahad, Niraparib, DNA anomalies, DNA defect, PARP inhibitor, PARPi
Brief summary
The purpose of this study is to assess the efficacy, safety, and pharmacokinetics of niraparib in men with metastatic castration-resistant prostate cancer (mCRPC) and deoxyribonucleic acid (DNA) repair anomalies.
Detailed description
This is a multicenter and open-label (participants and researchers are aware of the treatment that participants are receiving) study that consists of 4 phases: a Prescreening Phase for biomarker evaluation only, a Screening Phase, a Treatment Phase (Cycle 1 Day 1 and will continue until the study drug is discontinued), a Follow-up Phase (every 3 months after end of treatment visit), and a Long-term Extension Phase (until participants no longer derive benefit from treatment or until further notification on different means of study treatment). Participants will be monitored for safety during the study period, and up to 30 days after the last dose of study drug.
Interventions
DRUGNiraparib
Participants will receive 300 mg niraparib (3 capsules\*100 mg) orally once daily.
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed prostate cancer (mixed histology is acceptable, with the exception of the small cell pure phenotype, which is excluded) * Received a taxane-based chemotherapy for the treatment of metastatic prostate cancer with evidence of disease progression on or after treatment, or discontinued from a taxane-based chemotherapy due to an adverse event * Received a second-generation or later androgen receptor (AR)-targeted therapy (for example, abiraterone acetate plus prednisone, enzalutamide, apalutamide) for the treatment of metastatic prostate cancer with evidence of disease progression or non-metastatic castration-resistant prostate cancer with evidence of subsequent metastasis * Biomarker-positive by at least one of the following criteria: (a) Biallelic deoxyribonucleic acid (DNA)-repair anomaly based on a sponsor validated blood or tissue assay; (b) Germline pathogenic Breast Cancer gene (BRCA) 1 or BRCA2 by any test (somatic local results must be confirmed as positive by the sponsor-validated assay before dosing) * Progression of metastatic prostate cancer in the setting of castrate levels of testosterone or history of bilateral orchiectomy at study entry
Exclusion criteria
* Prior treatment with a poly (adenosine diphosphate \[ADP\] ribose) polymerase (PARP) inhibitor * Prior platinum-based chemotherapy for the treatment of prostate cancer * Known history or current diagnosis of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) * Symptomatic or impending cord compression * Symptomatic brain metastases
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) for Participants With Measurable Metastatic Castration-resistant Prostate Cancer (mCRPC) and Breast Cancer Gene (BRCA) Mutation | Up to 52 months | ORR defined as percentage of participants with BRCA DNA-repair anomalies and measurable disease whose best response is either complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and with no evidence of bone progression per Prostate Cancer Working Group 3 (PCWG3) criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Circulating Tumor Cells (CTC) Response Rate | At 8 weeks post-baseline | CTC response rate was defined as the percentage of participants with CTC equals to (=) 0 per 7.5 milliliter (mL) blood at 8 weeks post-baseline in participants with baseline CTC greater than (\>) 0. |
| Overall Survival (OS) | Up to 52 months | OS is defined as time from enrollment to death from any cause. |
| Radiographic Progression-Free Survival (rPFS) | Up to 52 months | rPFS was defined as time from enrollment to radiographic progression or death from any cause, whichever occurred first. Radiographic progression was evaluated per RECIST 1.1 criteria for soft tissue disease and per PCWG3 criteria for bone disease. |
| Time to Symptomatic Skeletal Event (SSE) | Up to 52 months | Time to SSE was defined as the time from enrollment to first occurrence of one of the following symptomatic skeletal events: tumor-related spinal cord compression, radiation to bone to relieve skeletal symptoms, surgery to bone or need for tumor-related orthopedic surgical intervention, symptomatic or pathologic fracture. |
| Objective Response Rate for Participants With Measurable Metastatic Castration-resistant Prostate Cancer (mCRPC) and Non-Breast Cancer Gene (BRCA) Mutation | Up to 52 months | ORR defined as percentage of participants with BRCA deoxyribonucleic acid (DNA)-repair anomalies and measurable disease whose best response is either CR or PR per RECIST 1.1 and with no evidence of bone progression per PCWG3 criteria. |
| Time to Prostate-Specific Antigen (PSA) Progression | Up to 52 months | Time to PSA progression was defined as time from enrollment to the first date of documented PSA progression based on PCWG3 criteria. A participant was considered to have a PSA progression if the PSA level had a 25 percent (%) or greater increase from nadir and an absolute increase of 2 nanograms per milliliter (ng/mL) or more, which is confirmed by a second value obtained in 3 or more weeks. |
| Duration of Objective Response | Up to 52 months | Duration of objective response is defined as time from CR or PR to radiographic progression of disease, unequivocal clinical progression or death, whichever occurs first. Unequivocal clinical progression defined as one or more of following: 1) deterioration in Eastern Cooperative Oncology Group Performance Status (ECOG PS) to Grade 3 or higher; 2) need to initiate any of following because of tumor progression (even in absence of radiographic evidence of disease): alternative anticancer therapy for prostate cancer, radiation therapy, surgical interventions for complications due to tumor progression. |
| Number of Participants With Adverse Events (AEs) | Up to 52 months | 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. |
| Number of Participants With Worst Toxicity Grades for Clinical Laboratory Tests Based on National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) | Up to 52 months | Number of participants with worst toxicity grades for clinical laboratory tests (chemistry and hematology) based on NCI-CTCAE were reported. The chemistry laboratory parameters were: alanine aminotransferase (ALT) increased, alkaline phosphatase increased, aspartate aminotransferase (AST) increased, blood bilirubin increased, creatinine increased, gamma glutamyl transferase (GGT) increased and the hematology parameters were: hemoglobin increased, lymphocyte count increased. Grading was done as: Grade 1 (=mild), Grade 2 (=moderate), Grade 3 (=severe) and Grade 4 (=potentially life-threatening). |
| Time to Radiographic Progression | Up to 52 months | Time to radiographic progression is defined as time from enrollment to radiographic progression or death due to disease progression, whichever occurs first. Disease progression is defined as at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. |
Countries
Australia, Belgium, Brazil, Canada, Denmark, France, Israel, Netherlands, Russia, South Korea, Spain, Sweden, Taiwan, United Kingdom, United States
Participant flow
Pre-assignment details
For long-term extension (LTE) phase, as pre planned in the protocol no efficacy analysis was performed. Due to change in the conduct of the study, no adverse events data were collected and thus no adverse event data were reported for the LTE phase.
Participants by arm
| Arm | Count |
|---|---|
| Niraparib Male Subjects who were over the age of 18 years with metastatic castration-resistant prostate cancer (based (mCRPC) and deoxyribonucleic acid (DNA) repair anomalies and who had received prior taxane-based chemotherapy milligrams chemotherapy and androgen receptor (AR)-targeted therapy received once daily oral dose of 300 milligrams (or(mg) niraparib capsules starting Day 1 until disease progression, unacceptable toxicity, death, or termination subjects termination of the study by the sponsor (up to 52 months). After completion of treatment phase, subjects were offered entry into the long-term extension (LTE) phase (which was planned as per protocol amendment 8, dated 17-Jul-2020) with a separate informed consent and to continue treatment per the investigator's discretion until no benefits from treatment or Sponsor's decision. | 289 |
| Total | 289 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Death | 208 |
| Overall Study | Lost to Follow-up | 5 |
| Overall Study | Other | 45 |
| Overall Study | Physician Decision | 6 |
| Overall Study | Withdrawal by Subject | 24 |
Baseline characteristics
| Characteristic | Niraparib |
|---|---|
| Age, Continuous | 68.8 years STANDARD_DEVIATION 7.8 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Asian | 16 Participants |
| Race/Ethnicity, Customized Black or African American | 9 Participants |
| Race/Ethnicity, Customized More than one race | 3 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Other | 5 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 51 Participants |
| Race/Ethnicity, Customized White | 205 Participants |
| Region of Enrollment AUSTRALIA | 31 Participants |
| Region of Enrollment BELGIUM | 18 Participants |
| Region of Enrollment BRAZIL | 12 Participants |
| Region of Enrollment CANADA | 21 Participants |
| Region of Enrollment DENMARK | 1 Participants |
| Region of Enrollment FRANCE | 48 Participants |
| Region of Enrollment ISRAEL | 6 Participants |
| Region of Enrollment NETHERLANDS | 6 Participants |
| Region of Enrollment RUSSIAN FEDERATION | 7 Participants |
| Region of Enrollment SOUTH KOREA | 5 Participants |
| Region of Enrollment SPAIN | 39 Participants |
| Region of Enrollment SWEDEN | 24 Participants |
| Region of Enrollment TAIWAN | 9 Participants |
| Region of Enrollment UNITED KINGDOM | 17 Participants |
| Region of Enrollment UNITED STATES | 45 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 289 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 208 / 289 |
| other Total, other adverse events | 280 / 289 |
| serious Total, serious adverse events | 134 / 289 |
Outcome results
Primary
Objective Response Rate (ORR) for Participants With Measurable Metastatic Castration-resistant Prostate Cancer (mCRPC) and Breast Cancer Gene (BRCA) Mutation
ORR defined as percentage of participants with BRCA DNA-repair anomalies and measurable disease whose best response is either complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and with no evidence of bone progression per Prostate Cancer Working Group 3 (PCWG3) criteria.
Time frame: Up to 52 months
Population: Measurable intent to treat (ITT) population also referred to as efficacy analysis set included all participants who received at least 1 dose of study drug and have BRCA (biallelic or germline DNA-repair anomalies) and measurable disease at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Niraparib | Objective Response Rate (ORR) for Participants With Measurable Metastatic Castration-resistant Prostate Cancer (mCRPC) and Breast Cancer Gene (BRCA) Mutation | 34.2 percentage of participants |
Secondary
Circulating Tumor Cells (CTC) Response Rate
CTC response rate was defined as the percentage of participants with CTC equals to (=) 0 per 7.5 milliliter (mL) blood at 8 weeks post-baseline in participants with baseline CTC greater than (\>) 0.
Time frame: At 8 weeks post-baseline
Population: ITT analysis set included all participants who received at least 1 dose of study drug. Here 'N' (number of participants analysed) specifies the participants with baseline CTC (per 7.5 mL blood) \> 0. Here, 'n' (number analyzed) specifies the number of participants evaluated for specific categories.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Niraparib | Circulating Tumor Cells (CTC) Response Rate | BRCA | 23.7 percentage of participants |
| Niraparib | Circulating Tumor Cells (CTC) Response Rate | Non-BRCA | 8.5 percentage of participants |
Secondary
Duration of Objective Response
Duration of objective response is defined as time from CR or PR to radiographic progression of disease, unequivocal clinical progression or death, whichever occurs first. Unequivocal clinical progression defined as one or more of following: 1) deterioration in Eastern Cooperative Oncology Group Performance Status (ECOG PS) to Grade 3 or higher; 2) need to initiate any of following because of tumor progression (even in absence of radiographic evidence of disease): alternative anticancer therapy for prostate cancer, radiation therapy, surgical interventions for complications due to tumor progression.
Time frame: Up to 52 months
Population: Measurable ITT responder analysis set included all participants who received at least 1 dose of study drug, responded to it and have BRCA or non-BRCA and measurable disease at baseline. Here, 'n' (number analyzed) specifies the number of participants evaluated for specific categories.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Niraparib | Duration of Objective Response | BRCA | 5.55 months |
| Niraparib | Duration of Objective Response | non-BRCA | 5.16 months |
Secondary
Number of Participants With Adverse Events (AEs)
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.
Time frame: Up to 52 months
Population: Safety analysis set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Niraparib | Number of Participants With Adverse Events (AEs) | 288 Participants |
Secondary
Number of Participants With Worst Toxicity Grades for Clinical Laboratory Tests Based on National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE)
Number of participants with worst toxicity grades for clinical laboratory tests (chemistry and hematology) based on NCI-CTCAE were reported. The chemistry laboratory parameters were: alanine aminotransferase (ALT) increased, alkaline phosphatase increased, aspartate aminotransferase (AST) increased, blood bilirubin increased, creatinine increased, gamma glutamyl transferase (GGT) increased and the hematology parameters were: hemoglobin increased, lymphocyte count increased. Grading was done as: Grade 1 (=mild), Grade 2 (=moderate), Grade 3 (=severe) and Grade 4 (=potentially life-threatening).
Time frame: Up to 52 months
Population: Safety analysis set included all participants who received at least 1 dose of study drug and with at least one postbaseline assessment for the specific lab test within the time period. Here, 'n' (number analyzed) specifies the number of participants evaluated for specific categories.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Niraparib | Number of Participants With Worst Toxicity Grades for Clinical Laboratory Tests Based on National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) | Lymphocyte count increased (Grade 1 or 2) | 6 Participants |
| Niraparib | Number of Participants With Worst Toxicity Grades for Clinical Laboratory Tests Based on National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) | Lymphocyte count increased (Grade 3 or 4) | 0 Participants |
| Niraparib | Number of Participants With Worst Toxicity Grades for Clinical Laboratory Tests Based on National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) | ALT increased (Grade 1 or 2) | 67 Participants |
| Niraparib | Number of Participants With Worst Toxicity Grades for Clinical Laboratory Tests Based on National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) | ALT increased (Grade 3 or 4) | 4 Participants |
| Niraparib | Number of Participants With Worst Toxicity Grades for Clinical Laboratory Tests Based on National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) | Alkaline phosphatase increased (Grade 1 or 2) | 102 Participants |
| Niraparib | Number of Participants With Worst Toxicity Grades for Clinical Laboratory Tests Based on National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) | Alkaline phosphatase increased (Grade 3 or 4) | 7 Participants |
| Niraparib | Number of Participants With Worst Toxicity Grades for Clinical Laboratory Tests Based on National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) | AST increased (Grade 1 or 2) | 70 Participants |
| Niraparib | Number of Participants With Worst Toxicity Grades for Clinical Laboratory Tests Based on National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) | AST increased (Grade 3 or 4) | 4 Participants |
| Niraparib | Number of Participants With Worst Toxicity Grades for Clinical Laboratory Tests Based on National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) | Blood bilirubin increased (Grade 1 or 2) | 9 Participants |
| Niraparib | Number of Participants With Worst Toxicity Grades for Clinical Laboratory Tests Based on National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) | Blood bilirubin increased (Grade 3 or 4) | 2 Participants |
| Niraparib | Number of Participants With Worst Toxicity Grades for Clinical Laboratory Tests Based on National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) | Creatinine increased (Grade 1 or 2) | 45 Participants |
| Niraparib | Number of Participants With Worst Toxicity Grades for Clinical Laboratory Tests Based on National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) | Creatinine increased (Grade 3 or 4) | 2 Participants |
| Niraparib | Number of Participants With Worst Toxicity Grades for Clinical Laboratory Tests Based on National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) | GGT increased (Grade 1 or 2) | 105 Participants |
| Niraparib | Number of Participants With Worst Toxicity Grades for Clinical Laboratory Tests Based on National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) | GGT increased (Grade 3 or 4) | 14 Participants |
| Niraparib | Number of Participants With Worst Toxicity Grades for Clinical Laboratory Tests Based on National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) | Hemoglobin increased (Grade 1 or 2) | 0 Participants |
| Niraparib | Number of Participants With Worst Toxicity Grades for Clinical Laboratory Tests Based on National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) | Hemoglobin increased (Grade 3 or 4) | 0 Participants |
Secondary
Objective Response Rate for Participants With Measurable Metastatic Castration-resistant Prostate Cancer (mCRPC) and Non-Breast Cancer Gene (BRCA) Mutation
ORR defined as percentage of participants with BRCA deoxyribonucleic acid (DNA)-repair anomalies and measurable disease whose best response is either CR or PR per RECIST 1.1 and with no evidence of bone progression per PCWG3 criteria.
Time frame: Up to 52 months
Population: Measurable ITT analysis set included all participants who received at least 1 dose of study drug and have non-BRCA (biallelic DNA-repair anomaly) and measurable disease at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Niraparib | Objective Response Rate for Participants With Measurable Metastatic Castration-resistant Prostate Cancer (mCRPC) and Non-Breast Cancer Gene (BRCA) Mutation | 10.6 percentage of participants |
Secondary
Overall Survival (OS)
OS is defined as time from enrollment to death from any cause.
Time frame: Up to 52 months
Population: ITT analysis set included participants who had received at least 1 dose of study drug. Here, 'n' (number analyzed) specifies the number of participants evaluated for specific categories.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Niraparib | Overall Survival (OS) | BRCA | 13.01 months |
| Niraparib | Overall Survival (OS) | Non-BRCA | 9.63 months |
Secondary
Radiographic Progression-Free Survival (rPFS)
rPFS was defined as time from enrollment to radiographic progression or death from any cause, whichever occurred first. Radiographic progression was evaluated per RECIST 1.1 criteria for soft tissue disease and per PCWG3 criteria for bone disease.
Time frame: Up to 52 months
Population: ITT analysis set included participants who had received at least 1 dose of study drug. Here, 'n' (number analyzed) specifies the number of participants evaluated for specific categories.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Niraparib | Radiographic Progression-Free Survival (rPFS) | BRCA | 8.08 months |
| Niraparib | Radiographic Progression-Free Survival (rPFS) | Non-BRCA | 3.71 months |
Secondary
Time to Prostate-Specific Antigen (PSA) Progression
Time to PSA progression was defined as time from enrollment to the first date of documented PSA progression based on PCWG3 criteria. A participant was considered to have a PSA progression if the PSA level had a 25 percent (%) or greater increase from nadir and an absolute increase of 2 nanograms per milliliter (ng/mL) or more, which is confirmed by a second value obtained in 3 or more weeks.
Time frame: Up to 52 months
Population: ITT analysis set included participants who had received at least 1 dose of study drug. Here, 'n' (number analyzed) specifies the number of participants evaluated for specific categories.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Niraparib | Time to Prostate-Specific Antigen (PSA) Progression | BRCA | 5.13 months |
| Niraparib | Time to Prostate-Specific Antigen (PSA) Progression | Non-BRCA | 3.65 months |
Secondary
Time to Radiographic Progression
Time to radiographic progression is defined as time from enrollment to radiographic progression or death due to disease progression, whichever occurs first. Disease progression is defined as at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression.
Time frame: Up to 52 months
Population: ITT analysis set included participants who had received at least 1 dose of study drug. Here, 'n' (number analyzed) specifies the number of participants evaluated for specific categories.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Niraparib | Time to Radiographic Progression | BRCA | 8.08 months |
| Niraparib | Time to Radiographic Progression | Non-BRCA | 3.78 months |
Secondary
Time to Symptomatic Skeletal Event (SSE)
Time to SSE was defined as the time from enrollment to first occurrence of one of the following symptomatic skeletal events: tumor-related spinal cord compression, radiation to bone to relieve skeletal symptoms, surgery to bone or need for tumor-related orthopedic surgical intervention, symptomatic or pathologic fracture.
Time frame: Up to 52 months
Population: ITT analysis set included participants who had received at least 1 dose of study drug. Here, 'n' (number analyzed) specifies the number of participants evaluated for specific categories.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Niraparib | Time to Symptomatic Skeletal Event (SSE) | BRCA | 13.80 months |
| Niraparib | Time to Symptomatic Skeletal Event (SSE) | Non-BRCA | 10.35 months |