Metastatic Castration Resistant Prostate Cancer
Conditions
Keywords
CRPC, PARP inhibitor, PARPi, BRCA, ATM, HRD, TRITON, homologous recombination, DNA repair, DNA defect, DNA anomaly, germline, somatic, mCRPC
Brief summary
The purpose of this study is to determine how participants with metastatic castration-resistant prostate cancer, and evidence of a homologous recombination gene deficiency, respond to treatment with rucaparib versus treatment with physician's choice of abiraterone acetate, enzalutamide, or docetaxel.
Interventions
DRUGRucaparib
Rucaparib will be administered daily.
DRUGAbiraterone acetate or Enzalutamide or Docetaxel
Abiraterone acetate and enzalutamide will be administered daily. Docetaxel will be administered every 3 weeks.
Sponsors
Foundation Medicine
pharmaand GmbH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Be 18 years old at the time the informed consent is signed * Have a histologically or cytologically confirmed adenocarcinoma or poorly differentiated carcinoma of the prostate that is metastatic * Be surgically or medically castrated, with serum testosterone levels of ≤ 50 ng/dL (1.73 nM) * Be eligible for treatment with physician's choice of comparator treatment (abiraterone acetate, enzalutamide or docetaxel) * Experienced disease progression after having received 1 prior next generation androgen receptor-targeted therapy * Have a deleterious mutation in a BRCA1/2 or ATM gene
Exclusion criteria
* Active second malignancy, with the exception of curatively treated non melanoma skin cancer, carcinoma in situ, or superficial bladder cancer * Prior treatment with any PARP inhibitor * Prior treatment with chemotherapy for metastatic castration-resistant prostate cancer * Symptomatic and/or untreated central nervous system metastases * Pre-existing duodenal stent and/or any gastrointestinal disorder or defect that would, in the opinion of the investigator, interfere with absorption of study drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Radiographic Progression-free Survival (rPFS) by IRR in Participants With a BRCA Alteration | From enrollment to primary completion of study (Total follow-up was up to approximately 4 years) | The primary efficacy endpoint for the study is rPFSirr, defined as the time from randomization to the first objective evidence of radiographic progression, or death due to any cause (whichever occurs first). Radiographic disease progression includes confirmed soft tissue disease progression and confirmed bone disease progression as per modified RECIST Version 1.1 (at least a 20% increase in the sum of the LD of target lesions or appearance of one or more new extra-skeletal lesions and/or unequivocal progression of existing nontarget lesions) or PCWG3 criteria Progression by bone is determined by PCWG3 criteria in which at least two new lesions appearing during the first 12-week flare window followed by 2 additional new lesions in the confirmatory scan appearing after the 12-week flare window, or after the 12-week flare window, at least 2 new lesions relative to the first post-treatment scan confirmed on a subsequent scan). |
| Radiographic Progression-free Survival (rPFS) by IRR in Participants With a BRCA or ATM Alteration Combined | From enrollment to primary completion of study (Total follow-up was up to approximately 4 years) | The primary efficacy endpoint for the study is rPFSirr, defined as the time from randomization to the first objective evidence of radiographic progression, or death due to any cause (whichever occurs first). Radiographic disease progression includes confirmed soft tissue disease progression and confirmed bone disease progression as per modified RECIST Version 1.1 (at least a 20% increase in the sum of the LD of target lesions or appearance of one or more new extra-skeletal lesions and/or unequivocal progression of existing nontarget lesions) or PCWG3 criteria (Progression by bone is determined by PCWG3 criteria in which at least two new lesions appearing during the first 12-week flare window followed by 2 additional new lesions in the confirmatory scan appearing after the 12-week flare window, or after the 12-week flare window, at least 2 new lesions relative to the first post-treatment scan confirmed on a subsequent scan). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) by IRR in Participants With a BRCA Alteration | From enrollment to primary completion of study (Total follow-up was up to approximately 4 years) | ORR is defined as the percentage of participants with a confirmed best response of Complete response (CR) or Partial Response (PR) in participants with measurable disease at study entry. Modified RECIST Version 1.1 criteria is used to determine ORR (ie, CR or PR by IRR assessment and no progression in bone per PCWG3 by IRR assessment). CR is disappearance of all target and non-target lesions; any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. |
| Objective Response Rate (ORR) by IRR in Participants With a BRCA or ATM Alteration Combined | From enrollment to primary completion of study (Total follow-up was up to approximately 4 years) | ORR is defined as the percentage of participants with a confirmed best response of Complete response (CR) or Partial Response (PR) in participants with measurable disease at study entry. Modified RECIST Version 1.1 criteria is used to determine ORR (ie, CR or PR by IRR assessment and no progression in bone per PCWG3 by IRR assessment). CR is disappearance of all target and non-target lesions; any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. |
| Duration of Response (DOR) by IRR in Participants With a BRCA Alteration | From enrollment to primary completion of study (Total follow-up was up to approximately 4 years) | DOR is defined as the time from the first confirmed response (CR or PR by modified RECIST Version 1.1 in participants with nodal or visceral ± nodal disease) until the first date that Progressive Disease (PD) (using the same criteria) is documented. |
| Duration of Response (DOR) by IRR in Participants With a BRCA or ATM Alteration Combined | From enrollment to primary completion of study (Total follow-up was up to approximately 4 years) | DOR is defined as the time from the first confirmed response (CR or PR by modified RECIST Version 1.1 in participants with nodal or visceral ± nodal disease) until the first date that Progressive Disease (PD) (using the same criteria) is documented. |
| PSA Response in Participants With a BRCA Alteration | From enrollment to primary completion of study (up to approximately 5 years) | Confirmed PSA response is defined as ≥ 50% reduction in PSA from baseline on at least two assessments conducted at least 3 weeks apart. PSA response is calculated for all participants with PSA values at baseline and at least one post-baseline assessment. PSA is assessed by a local laboratory. |
| PSA Response in Participants With a BRCA or ATM Alteration Combined | From enrollment to primary completion of study (up to approximately 5 years) | Confirmed PSA response is defined as ≥ 50% reduction in PSA from baseline on at least two assessments conducted at least 3 weeks apart. PSA response is calculated for all participants with PSA values at baseline and at least one post-baseline assessment. PSA is assessed by a local laboratory. |
| Clinical Benefit Rate (CBR) by IRR at 6 Months in Participants With a BRCA Alteration | From enrollment to 6 months | Defined as the percentage of participants with a complete response (CR), partial response (PR), and stable disease (SD) according to modified RECIST Version 1.1 with no progression in bone per PCWG3 criteria. |
| Overall Survival in Participants With a BRCA Alteration | From enrollment to completion of study (up to approximately 7 years) | Overall survival time is calculated as the time from randomization to death (by any cause) +1 day. Participants who have not died will be censored on the date the participant was last known to be alive. |
| Time to Prostate Specific Antigen (PSA) Progression in Participants With a BRCA Alteration | From enrollment to primary completion of study (up to approximately 5 years) | Time to PSA progression is defined as the time from randomization to the date that a ≥ 25% increase and absolute increase of ≥ 2 ng/mL above the nadir (or baseline value for participants who did not have a decline in PSA) in PSA was measured. The increase must be confirmed by a second consecutive assessment conducted at least 3 weeks later. |
| Time to Prostate Specific Antigen (PSA) Progression in Participants With a BRCA or ATM Alteration Combined | From enrollment to primary completion of study (up to approximately 5 years) | Time to PSA progression is defined as the time from randomization to the date that a ≥ 25% increase and absolute increase of ≥ 2 ng/mL above the nadir (or baseline value for participants who did not have a decline in PSA) in PSA was measured. The increase must be confirmed by a second consecutive assessment conducted at least 3 weeks later. |
| Change in Patient-reported Outcome (PRO) in Participants With a BRCA Alteration: FACT-P | From enrollment to up to approximately 25 weeks | Changes in health and pain status from baseline to week 25 using: Functional Assessment of Cancer Therapy-Prostate questionnaire (FACT-P total score, on a scale of 0 to 156 where a higher score is better quality of life). The greater the decrease in score (ie more negative) from baseline to week 25 the greater the decrease in health status. Assessments completed during screening, at study treatment visits (Day 1, Day 15, Day 29, Day 43, Day 57, and every 29 days thereafter) (during the Treatment Phase, the Treatment Discontinuation Visit, and during the Follow-up Phase. |
| Change in Patient-reported Outcome (PRO) in Participants With a BRCA Alteration: BPI-SF | From enrollment to up to approximately 25 weeks | Changes in health and pain status from baseline to week 25 using: Brief Pain Inventory-Short Form (BPI-SF) questionnaire (on a scale of 1 to 10, from mild to severe, for pain and pain-interference scores). A decrease indicates less severe pain/interference. Assessments completed during screening, at study treatment visits (Day 1, Day 15, Day 29, Day 43, Day 57, and every 29 days thereafter) (during the Treatment Phase, the Treatment Discontinuation Visit, and during the Follow-up Phase. |
| Change in Patient-reported Outcome (PRO) in Participants With a BRCA Alteration: EQ-5D-5L | From enrollment to up to approximately 25 weeks | Changes in health and pain status from baseline to week 25 using: EuroQol-5D-5L Visual Analogue Scale (EQ-5D-5L VAS; on a scale from 100 to 0, from best to worst health status). The greater the increase in score (including more negative) from baseline to week 25 the greater the increase in health status. Assessments completed during screening, at study treatment visits (Day 1, Day 15, Day 29, Day 43, Day 57, and every 29 days thereafter) during the Treatment Phase, the Treatment Discontinuation Visit, and during the Follow-up Phase. |
| Trough Plasma PK (Cmin) of Rucaparib Based on Sparse Sampling | From enrollment to week 5 of dosing | Mean trough PK plasma concentration over time in the safety population with at least one PK sample collected at timepoints week 5, 9, 13 and 17; only Week 5 data presented. |
| Clinical Benefit Rate (CBR) by IRR at 6 Months in Participants With a BRCA or ATM Alteration Combined | From enrollment to 6 months | Defined as the percentage of participants with a Complete Response (CR), Partial Response (PR), and Stable Disease (SD), according to Modified RECIST Version 1.1 with no progression in bone per PCWG3 Criteria. |
| Overall Survival in Participants With a BRCA or ATM Alteration Combined | From enrollment to completion of study (up to approximately 7 years) | Overall survival time is calculated as the time from randomization to death (by any cause) +1 day. Participants who have not died will be censored on the date the participants was last known to be alive. |
Countries
Australia, Belgium, Canada, Denmark, France, Germany, Ireland, Israel, Italy, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Rucaparib Oral rucaparib (monotherapy).
Rucaparib: Rucaparib will be administered daily. | 270 |
| Abiraterone Acetate or Enzalutamide or Docetaxel Oral abiraterone acetate (monotherapy, given in combination with prednisone). Oral enzalutamide (monotherapy). Intravenous docetaxel (monotherapy, given in combination with prednisone or prednisolone).
Abiraterone acetate or Enzalutamide or Docetaxel: Abiraterone acetate and enzalutamide will be administered daily.
Docetaxel will be administered every 3 weeks. | 135 |
| Total | 405 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Treatment Phase | Never initiated study drug | 0 | 5 | 0 |
Baseline characteristics
| Characteristic | Rucaparib | Abiraterone Acetate or Enzalutamide or Docetaxel | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 186 Participants | 103 Participants | 289 Participants |
| Age, Categorical Between 18 and 65 years | 84 Participants | 32 Participants | 116 Participants |
| Age, Continuous | 70 years | 71 years | 70 years |
| Baseline prostate specific antigen (PSA) | 26.9 ng/ml | 28.8 ng/ml | 27.8 ng/ml |
| ECOG Performance Status (at stratification) 0 | 132 Participants | 68 Participants | 200 Participants |
| ECOG Performance Status (at stratification) 1 | 138 Participants | 67 Participants | 205 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 4 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 216 Participants | 103 Participants | 319 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 51 Participants | 28 Participants | 79 Participants |
| Gene Alteration (at stratification) ATM | 69 Participants | 34 Participants | 103 Participants |
| Gene Alteration (at stratification) BRCA1 | 29 Participants | 15 Participants | 44 Participants |
| Gene Alteration (at stratification) BRCA2 | 172 Participants | 86 Participants | 258 Participants |
| Gleason score ≥8 at diagnosis | 173 Participants | 96 Participants | 269 Participants |
| Measurable Disease per Independent Radiological Review (IRR) | 106 Participants | 55 Participants | 161 Participants |
| Metastases site(s) by IRR Bone | 235 Participants | 114 Participants | 349 Participants |
| Metastases site(s) by IRR Nodal | 118 Participants | 60 Participants | 178 Participants |
| Metastases site(s) by IRR Visceral | 74 Participants | 46 Participants | 120 Participants |
| Prior Therapies for CRPC 0 | 48 Participants | 26 Participants | 74 Participants |
| Prior Therapies for CRPC ≥1 | 222 Participants | 109 Participants | 331 Participants |
| Prior therapy (2nd generation androgen receptor pathway inhibitor (ARPI) or docetaxel only) Abiraterone acetate | 150 Participants | 80 Participants | 230 Participants |
| Prior therapy (2nd generation androgen receptor pathway inhibitor (ARPI) or docetaxel only) Apalutamide | 8 Participants | 1 Participants | 9 Participants |
| Prior therapy (2nd generation androgen receptor pathway inhibitor (ARPI) or docetaxel only) Docetaxel for hormone-sensitive prostate cancer | 63 Participants | 28 Participants | 91 Participants |
| Prior therapy (2nd generation androgen receptor pathway inhibitor (ARPI) or docetaxel only) Enzalutamide | 119 Participants | 61 Participants | 180 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 4 Participants | 14 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 53 Participants | 27 Participants | 80 Participants |
| Race (NIH/OMB) White | 199 Participants | 103 Participants | 302 Participants |
| Region of Enrollment Australia | 10 participants | 3 participants | 13 participants |
| Region of Enrollment Europe | 141 participants | 73 participants | 214 participants |
| Region of Enrollment Israel | 8 participants | 3 participants | 11 participants |
| Region of Enrollment North America | 111 participants | 56 participants | 167 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 270 Participants | 135 Participants | 405 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 270 | 3 / 135 | 1 / 70 |
| other Total, other adverse events | 270 / 270 | 127 / 130 | 67 / 70 |
| serious Total, serious adverse events | 81 / 270 | 36 / 130 | 18 / 70 |
Outcome results
Primary
Radiographic Progression-free Survival (rPFS) by IRR in Participants With a BRCA Alteration
The primary efficacy endpoint for the study is rPFSirr, defined as the time from randomization to the first objective evidence of radiographic progression, or death due to any cause (whichever occurs first). Radiographic disease progression includes confirmed soft tissue disease progression and confirmed bone disease progression as per modified RECIST Version 1.1 (at least a 20% increase in the sum of the LD of target lesions or appearance of one or more new extra-skeletal lesions and/or unequivocal progression of existing nontarget lesions) or PCWG3 criteria Progression by bone is determined by PCWG3 criteria in which at least two new lesions appearing during the first 12-week flare window followed by 2 additional new lesions in the confirmatory scan appearing after the 12-week flare window, or after the 12-week flare window, at least 2 new lesions relative to the first post-treatment scan confirmed on a subsequent scan).
Time frame: From enrollment to primary completion of study (Total follow-up was up to approximately 4 years)
Population: ITT Population with BRCA mutated mCRPC.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rucaparib | Radiographic Progression-free Survival (rPFS) by IRR in Participants With a BRCA Alteration | 11.2 months |
| Abiraterone Acetate or Enzalutamide or Docetaxel | Radiographic Progression-free Survival (rPFS) by IRR in Participants With a BRCA Alteration | 6.4 months |
p-value: <0.00195% CI: [0.36, 0.69]Log Rank
Primary
Radiographic Progression-free Survival (rPFS) by IRR in Participants With a BRCA or ATM Alteration Combined
The primary efficacy endpoint for the study is rPFSirr, defined as the time from randomization to the first objective evidence of radiographic progression, or death due to any cause (whichever occurs first). Radiographic disease progression includes confirmed soft tissue disease progression and confirmed bone disease progression as per modified RECIST Version 1.1 (at least a 20% increase in the sum of the LD of target lesions or appearance of one or more new extra-skeletal lesions and/or unequivocal progression of existing nontarget lesions) or PCWG3 criteria (Progression by bone is determined by PCWG3 criteria in which at least two new lesions appearing during the first 12-week flare window followed by 2 additional new lesions in the confirmatory scan appearing after the 12-week flare window, or after the 12-week flare window, at least 2 new lesions relative to the first post-treatment scan confirmed on a subsequent scan).
Time frame: From enrollment to primary completion of study (Total follow-up was up to approximately 4 years)
Population: ITT Population included all randomized participants (participants with BRCA mutated mCRPC and participants with ATM mutated mCRPC).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rucaparib | Radiographic Progression-free Survival (rPFS) by IRR in Participants With a BRCA or ATM Alteration Combined | 10.2 months |
| Abiraterone Acetate or Enzalutamide or Docetaxel | Radiographic Progression-free Survival (rPFS) by IRR in Participants With a BRCA or ATM Alteration Combined | 6.4 months |
p-value: <0.00195% CI: [0.47, 0.8]Log Rank
Secondary
Change in Patient-reported Outcome (PRO) in Participants With a BRCA Alteration: BPI-SF
Changes in health and pain status from baseline to week 25 using: Brief Pain Inventory-Short Form (BPI-SF) questionnaire (on a scale of 1 to 10, from mild to severe, for pain and pain-interference scores). A decrease indicates less severe pain/interference. Assessments completed during screening, at study treatment visits (Day 1, Day 15, Day 29, Day 43, Day 57, and every 29 days thereafter) (during the Treatment Phase, the Treatment Discontinuation Visit, and during the Follow-up Phase.
Time frame: From enrollment to up to approximately 25 weeks
Population: ITT Population with BRCA mutated mCRPC. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure. 'Number analyzed' = participants evaluable for specified category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rucaparib | Change in Patient-reported Outcome (PRO) in Participants With a BRCA Alteration: BPI-SF | BPI-SF Pain Score | -0.32 units on a scale | Standard Error 0.139 |
| Rucaparib | Change in Patient-reported Outcome (PRO) in Participants With a BRCA Alteration: BPI-SF | BPI-SF Interference Score | -0.28 units on a scale | Standard Error 0.147 |
| Abiraterone Acetate or Enzalutamide or Docetaxel | Change in Patient-reported Outcome (PRO) in Participants With a BRCA Alteration: BPI-SF | BPI-SF Pain Score | 0.14 units on a scale | Standard Error 0.285 |
| Abiraterone Acetate or Enzalutamide or Docetaxel | Change in Patient-reported Outcome (PRO) in Participants With a BRCA Alteration: BPI-SF | BPI-SF Interference Score | 0.65 units on a scale | Standard Error 0.302 |
Secondary
Change in Patient-reported Outcome (PRO) in Participants With a BRCA Alteration: EQ-5D-5L
Changes in health and pain status from baseline to week 25 using: EuroQol-5D-5L Visual Analogue Scale (EQ-5D-5L VAS; on a scale from 100 to 0, from best to worst health status). The greater the increase in score (including more negative) from baseline to week 25 the greater the increase in health status. Assessments completed during screening, at study treatment visits (Day 1, Day 15, Day 29, Day 43, Day 57, and every 29 days thereafter) during the Treatment Phase, the Treatment Discontinuation Visit, and during the Follow-up Phase.
Time frame: From enrollment to up to approximately 25 weeks
Population: ITT Population with BRCA mutated mCRPC. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Rucaparib | Change in Patient-reported Outcome (PRO) in Participants With a BRCA Alteration: EQ-5D-5L | 2.4 units on a scale | Standard Error 1.23 |
| Abiraterone Acetate or Enzalutamide or Docetaxel | Change in Patient-reported Outcome (PRO) in Participants With a BRCA Alteration: EQ-5D-5L | 1.8 units on a scale | Standard Error 2.39 |
Secondary
Change in Patient-reported Outcome (PRO) in Participants With a BRCA Alteration: FACT-P
Changes in health and pain status from baseline to week 25 using: Functional Assessment of Cancer Therapy-Prostate questionnaire (FACT-P total score, on a scale of 0 to 156 where a higher score is better quality of life). The greater the decrease in score (ie more negative) from baseline to week 25 the greater the decrease in health status. Assessments completed during screening, at study treatment visits (Day 1, Day 15, Day 29, Day 43, Day 57, and every 29 days thereafter) (during the Treatment Phase, the Treatment Discontinuation Visit, and during the Follow-up Phase.
Time frame: From enrollment to up to approximately 25 weeks
Population: ITT Population with BRCA mutated mCRPC. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Rucaparib | Change in Patient-reported Outcome (PRO) in Participants With a BRCA Alteration: FACT-P | -0.8 units on a scale | Standard Error 1.13 |
| Abiraterone Acetate or Enzalutamide or Docetaxel | Change in Patient-reported Outcome (PRO) in Participants With a BRCA Alteration: FACT-P | -3.9 units on a scale | Standard Error 2.23 |
Secondary
Clinical Benefit Rate (CBR) by IRR at 6 Months in Participants With a BRCA Alteration
Defined as the percentage of participants with a complete response (CR), partial response (PR), and stable disease (SD) according to modified RECIST Version 1.1 with no progression in bone per PCWG3 criteria.
Time frame: From enrollment to 6 months
Population: The Safety Population included all participants with BRCA mutated mCRPC who received at least one dose of protocol-specified treatment and had 6 months of follow-up prior to the data cutoff.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rucaparib | Clinical Benefit Rate (CBR) by IRR at 6 Months in Participants With a BRCA Alteration | 63.0 percentage of participants |
| Abiraterone Acetate or Enzalutamide or Docetaxel | Clinical Benefit Rate (CBR) by IRR at 6 Months in Participants With a BRCA Alteration | 22.7 percentage of participants |
Secondary
Clinical Benefit Rate (CBR) by IRR at 6 Months in Participants With a BRCA or ATM Alteration Combined
Defined as the percentage of participants with a Complete Response (CR), Partial Response (PR), and Stable Disease (SD), according to Modified RECIST Version 1.1 with no progression in bone per PCWG3 Criteria.
Time frame: From enrollment to 6 months
Population: The Safety Population included all participants who received at least one dose of protocol-specified treatment and had 6 months of follow-up prior to the data cutoff.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rucaparib | Clinical Benefit Rate (CBR) by IRR at 6 Months in Participants With a BRCA or ATM Alteration Combined | 57.6 percentage of participants |
| Abiraterone Acetate or Enzalutamide or Docetaxel | Clinical Benefit Rate (CBR) by IRR at 6 Months in Participants With a BRCA or ATM Alteration Combined | 25.4 percentage of participants |
Secondary
Duration of Response (DOR) by IRR in Participants With a BRCA Alteration
DOR is defined as the time from the first confirmed response (CR or PR by modified RECIST Version 1.1 in participants with nodal or visceral ± nodal disease) until the first date that Progressive Disease (PD) (using the same criteria) is documented.
Time frame: From enrollment to primary completion of study (Total follow-up was up to approximately 4 years)
Population: ITT Population with BRCA mutated mCRPC and measurable disease at baseline. 'Overall number of participants analyzed' = participants with objective response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rucaparib | Duration of Response (DOR) by IRR in Participants With a BRCA Alteration | 7.4 months |
| Abiraterone Acetate or Enzalutamide or Docetaxel | Duration of Response (DOR) by IRR in Participants With a BRCA Alteration | 7.4 months |
Secondary
Duration of Response (DOR) by IRR in Participants With a BRCA or ATM Alteration Combined
DOR is defined as the time from the first confirmed response (CR or PR by modified RECIST Version 1.1 in participants with nodal or visceral ± nodal disease) until the first date that Progressive Disease (PD) (using the same criteria) is documented.
Time frame: From enrollment to primary completion of study (Total follow-up was up to approximately 4 years)
Population: ITT Population included all randomized participants (participants with BRCA mutated mCRPC and participants with ATM mutated mCRPC) with measurable disease at baseline. 'Overall number of participants analyzed' = participants with objective response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rucaparib | Duration of Response (DOR) by IRR in Participants With a BRCA or ATM Alteration Combined | 7.4 months |
| Abiraterone Acetate or Enzalutamide or Docetaxel | Duration of Response (DOR) by IRR in Participants With a BRCA or ATM Alteration Combined | 7.4 months |
Secondary
Objective Response Rate (ORR) by IRR in Participants With a BRCA Alteration
ORR is defined as the percentage of participants with a confirmed best response of Complete response (CR) or Partial Response (PR) in participants with measurable disease at study entry. Modified RECIST Version 1.1 criteria is used to determine ORR (ie, CR or PR by IRR assessment and no progression in bone per PCWG3 by IRR assessment). CR is disappearance of all target and non-target lesions; any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.
Time frame: From enrollment to primary completion of study (Total follow-up was up to approximately 4 years)
Population: ITT Population with BRCA mutated mCRPC and measurable disease at baseline.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rucaparib | Objective Response Rate (ORR) by IRR in Participants With a BRCA Alteration | 37 Participants |
| Abiraterone Acetate or Enzalutamide or Docetaxel | Objective Response Rate (ORR) by IRR in Participants With a BRCA Alteration | 7 Participants |
Secondary
Objective Response Rate (ORR) by IRR in Participants With a BRCA or ATM Alteration Combined
ORR is defined as the percentage of participants with a confirmed best response of Complete response (CR) or Partial Response (PR) in participants with measurable disease at study entry. Modified RECIST Version 1.1 criteria is used to determine ORR (ie, CR or PR by IRR assessment and no progression in bone per PCWG3 by IRR assessment). CR is disappearance of all target and non-target lesions; any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.
Time frame: From enrollment to primary completion of study (Total follow-up was up to approximately 4 years)
Population: ITT Population included all randomized participants (participants with BRCA mutated mCRPC and participants with ATM mutated mCRPC) with measurable disease at baseline.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rucaparib | Objective Response Rate (ORR) by IRR in Participants With a BRCA or ATM Alteration Combined | 37 Participants |
| Abiraterone Acetate or Enzalutamide or Docetaxel | Objective Response Rate (ORR) by IRR in Participants With a BRCA or ATM Alteration Combined | 9 Participants |
Secondary
Overall Survival in Participants With a BRCA Alteration
Overall survival time is calculated as the time from randomization to death (by any cause) +1 day. Participants who have not died will be censored on the date the participant was last known to be alive.
Time frame: From enrollment to completion of study (up to approximately 7 years)
Population: ITT Population with BRCA mutated mCRPC.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rucaparib | Overall Survival in Participants With a BRCA Alteration | 23.2 months |
| Abiraterone Acetate or Enzalutamide or Docetaxel | Overall Survival in Participants With a BRCA Alteration | 21.2 months |
p-value: 0.504495% CI: [0.68, 1.2]Log Rank
Secondary
Overall Survival in Participants With a BRCA or ATM Alteration Combined
Overall survival time is calculated as the time from randomization to death (by any cause) +1 day. Participants who have not died will be censored on the date the participants was last known to be alive.
Time frame: From enrollment to completion of study (up to approximately 7 years)
Population: ITT Population included all randomized participants (participants with BRCA mutated mCRPC and participants with ATM mutated mCRPC).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rucaparib | Overall Survival in Participants With a BRCA or ATM Alteration Combined | 22.8 months |
| Abiraterone Acetate or Enzalutamide or Docetaxel | Overall Survival in Participants With a BRCA or ATM Alteration Combined | 21.7 months |
p-value: 0.936895% CI: [0.78, 1.26]Log Rank
Secondary
PSA Response in Participants With a BRCA Alteration
Confirmed PSA response is defined as ≥ 50% reduction in PSA from baseline on at least two assessments conducted at least 3 weeks apart. PSA response is calculated for all participants with PSA values at baseline and at least one post-baseline assessment. PSA is assessed by a local laboratory.
Time frame: From enrollment to primary completion of study (up to approximately 5 years)
Population: ITT Population with BRCA mutated mCRPC.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rucaparib | PSA Response in Participants With a BRCA Alteration | 54.7 percentage of participants |
| Abiraterone Acetate or Enzalutamide or Docetaxel | PSA Response in Participants With a BRCA Alteration | 26.7 percentage of participants |
Secondary
PSA Response in Participants With a BRCA or ATM Alteration Combined
Confirmed PSA response is defined as ≥ 50% reduction in PSA from baseline on at least two assessments conducted at least 3 weeks apart. PSA response is calculated for all participants with PSA values at baseline and at least one post-baseline assessment. PSA is assessed by a local laboratory.
Time frame: From enrollment to primary completion of study (up to approximately 5 years)
Population: ITT Population included all randomized participants (participants with BRCA mutated mCRPC and participants with ATM mutated mCRPC).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rucaparib | PSA Response in Participants With a BRCA or ATM Alteration Combined | 41.9 percentage of participants |
| Abiraterone Acetate or Enzalutamide or Docetaxel | PSA Response in Participants With a BRCA or ATM Alteration Combined | 26.7 percentage of participants |
Secondary
Time to Prostate Specific Antigen (PSA) Progression in Participants With a BRCA Alteration
Time to PSA progression is defined as the time from randomization to the date that a ≥ 25% increase and absolute increase of ≥ 2 ng/mL above the nadir (or baseline value for participants who did not have a decline in PSA) in PSA was measured. The increase must be confirmed by a second consecutive assessment conducted at least 3 weeks later.
Time frame: From enrollment to primary completion of study (up to approximately 5 years)
Population: ITT Population with BRCA mutated mCRPC.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rucaparib | Time to Prostate Specific Antigen (PSA) Progression in Participants With a BRCA Alteration | 6.6 months |
| Abiraterone Acetate or Enzalutamide or Docetaxel | Time to Prostate Specific Antigen (PSA) Progression in Participants With a BRCA Alteration | 3.8 months |
Secondary
Time to Prostate Specific Antigen (PSA) Progression in Participants With a BRCA or ATM Alteration Combined
Time to PSA progression is defined as the time from randomization to the date that a ≥ 25% increase and absolute increase of ≥ 2 ng/mL above the nadir (or baseline value for participants who did not have a decline in PSA) in PSA was measured. The increase must be confirmed by a second consecutive assessment conducted at least 3 weeks later.
Time frame: From enrollment to primary completion of study (up to approximately 5 years)
Population: ITT Population included all randomized participants (participants with BRCA mutated mCRPC and participants with ATM mutated mCRPC).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rucaparib | Time to Prostate Specific Antigen (PSA) Progression in Participants With a BRCA or ATM Alteration Combined | 5.7 months |
| Abiraterone Acetate or Enzalutamide or Docetaxel | Time to Prostate Specific Antigen (PSA) Progression in Participants With a BRCA or ATM Alteration Combined | 3.6 months |
Secondary
Trough Plasma PK (Cmin) of Rucaparib Based on Sparse Sampling
Mean trough PK plasma concentration over time in the safety population with at least one PK sample collected at timepoints week 5, 9, 13 and 17; only Week 5 data presented.
Time frame: From enrollment to week 5 of dosing
Population: Safety Population with at least 1 PK sample collected.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rucaparib | Trough Plasma PK (Cmin) of Rucaparib Based on Sparse Sampling | 1310 ng/mL |