A Study of Rucaparib Versus Physician's Choice of Therapy in Participants With Metastatic Castration-resistant Prostate Cancer and Homologous Recombination Gene Deficiency

Study Overview
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Brief Summary
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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.

Official Title
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TRITON3: A Multicenter, Randomized, Open Label Phase 3 Study of Rucaparib Versus Physician's Choice of Therapy for Patients With Metastatic Castration Resistant Prostate Cancer Associated With Homologous Recombination Deficiency

Conditions
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Metastatic Castration Resistant Prostate Cancer

Intervention / Treatment
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* Drug: Rucaparib
* Drug: Abiraterone acetate or Enzalutamide or Docetaxel


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rucaparib<br>Oral rucaparib (monotherapy). | Drug: Rucaparib<br>* Rucaparib will be administered daily.<br>* Other names: CO-338;|
| Active Comparator: Abiraterone acetate or Enzalutamide or Docetaxel<br>Oral abiraterone acetate (monotherapy, given in combination with prednisone). Oral enzalutamide (monotherapy). Intravenous docetaxel (monotherapy, given in combination with prednisone or prednisolone). | Drug: Abiraterone acetate or Enzalutamide or Docetaxel<br>* Abiraterone acetate and enzalutamide will be administered daily. Docetaxel will be administered every 3 weeks.<br>* Other names: Zytiga (abiraterone acetate) or Xtandi (enzalutamide) or Taxotere (docetaxel);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | From enrollment to primary completion of study (Total follow-up was up to approximately 4 years) | 
| 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). | From enrollment to primary completion of study (Total follow-up was up to approximately 4 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Interim 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. | From enrollment to primary completion of study (up to approximately 5 years) | 
| Interim 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. | From enrollment to primary completion of study (up to approximately 5 years) | 
| 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. | From enrollment to primary completion of study (Total follow-up was up to approximately 4 years) | 
| 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. | From enrollment to primary completion of study (Total follow-up was up to approximately 4 years) | 
| 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. | From enrollment to primary completion of study (Total follow-up was up to approximately 4 years) | 
| 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. | From enrollment to primary completion of study (Total follow-up was up to approximately 4 years) | 
| 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. | From enrollment to primary completion of study (up to approximately 5 years) | 
| 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. | From enrollment to primary completion of study (up to approximately 5 years) | 
| 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. | From enrollment to 6 months | 
| 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. | From enrollment to 6 months | 
| 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. | From enrollment to primary completion of study (up to approximately 5 years) | 
| 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. | From enrollment to primary completion of study (up to approximately 5 years) | 
| 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. | From enrollment to up to approximately 25 weeks | 
| 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. | From enrollment to up to approximately 25 weeks | 
| 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. | From enrollment to up to approximately 25 weeks | 
| 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. | From enrollment to week 5 of dosing | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CRPC, PARP inhibitor, PARPi, BRCA, ATM, HRD, TRITON, homologous recombination, DNA repair, DNA defect, DNA anomaly, germline, somatic, mCRPC