A Study of Rucaparib in Patients 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 patients with metastatic castration-resistant prostate cancer, and evidence of a homologous recombination gene deficiency, respond to treatment with rucaparib.

Official Title
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TRITON2: A Multicenter, Open-label Phase 2 Study of Rucaparib in 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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be 18 years old at the time the informed consent form is signed Have a histologically or cytologically confirmed adenocarcinoma or poorly differentiated carcinoma of the prostate Be surgically or medically castrated, with serum testosterone levels of ≤ 50 ng/dL (1.73 nM) Experienced disease progression after having received at least 1 but no more than 2 prior next-generation androgen receptor-targeted therapies, and 1 prior taxane-based chemotherapy, for castration-resistant disease Have a deleterious mutation in BRCA1/2 or ATM, or molecular evidence of other homologous recombination deficiency 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, mitoxantrone, cyclophosphamide or any platinum-based chemotherapy 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 rucaparib

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
Intervention Model: Single Group 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;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed Objective Response Rate (ORR) by Gene in Patients With Measurable Disease at Baseline Per Central Independent Radiology Review (IRR) | The primary efficacy endpoint is confirmed radiographic ORR by central IRR. ORR is defined as the percentage of patients with a confirmed CR (complete response) or PR (partial response) by mRECIST (modified Response Evaluation Criteria in Solid Tumors) v1.1/PCWG3 (Prostate Cancer Working Group 3) criteria. The confirmed response is defined as a CR or PR on subsequent tumor assessment at least 28 days after first response documentation in the absence of confirmed progression in bone. 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 diameters. | Assessments every 8 weeks from study day 1 for the first 24 weeks, and then every 12 weeks until disease progression, death, or initiation of subsequent treatment. Total follow-up was up to approximately 3 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed Objective Response Rate (ORR) by Gene in Patients With Measurable Disease at Baseline Per Investigator (INV) | A supportive efficacy endpoint is confirmed radiographic ORR by INV. ORR is defined as the percentage of patients with a confirmed CR (complete response) or PR (partial response) by mRECIST (modified Response Evaluation Criteria in Solid Tumors) v1.1/PCWG3 (Prostate Cancer Working Group 3) criteria. The confirmed response is defined as a CR or PR on subsequent tumor assessment at least 28 days after first response documentation in the absence of confirmed progression in bone. 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. | Assessments every 8 weeks from study day 1 for the first 24 weeks, and then every 12 weeks until disease progression, death, or initiation of subsequent treatment. Total follow-up was up to approximately 3 years. | 
| Duration of Response (DOR) by Gene in Patients With Confirmed Response Per Central Independent Radiology Review (IRR) | A secondary efficacy endpoint is DOR by central IRR. The DOR is defined as the time from the date that a confirmed response per modified RECIST Version 1.1/PCWG3 is first reported to the time that progressive disease (PD) is first documented. Progressive disease is defined using RECIST v1.1, as at least a 20% increase in the sum of the diameters of target lesions, or an unequivocal increase in non-target lesions, or the appearance of new lesions. PCWG3 criteria is used to document evidence of disease progression in bone lesions. | Assessments every 8 weeks from study day 1 for the first 24 weeks, and then every 12 weeks until disease progression, death, or initiation of subsequent treatment. Total follow-up was up to approximately 3 years. | 
| Duration of Response (DOR) by Gene in Patients With Confirmed Response Per Investigator | A secondary efficacy endpoint is DOR as assessed by the investigator. The DOR is defined as the time from the date that a confirmed response per modified RECIST Version 1.1/PCWG3 is first reported to the time that progressive disease (PD) is first documented. Progressive disease is defined using RECIST v1.1, as at least a 20% increase in the sum of the diameters of target lesions, or an unequivocal increase in non-target lesions, or the appearance of new lesions. PCWG3 criteria is used to document evidence of disease progression in bone lesions. | Assessments every 8 weeks from study day 1 for the first 24 weeks, and then every 12 weeks until disease progression, death, or initiation of subsequent treatment. Total follow-up was up to approximately 3 years. | 
| Confirmed PSA Response (≥ 50% Decrease) by Gene as Assessed by Local Laboratory | A secondary endpoint is confirmed PSA (prostate-specific antigen) response (≥ 50% reduction) as assessed by local laboratory. Confirmed PSA response is analyzed for all patients who had PSA value at baseline and is defined as the percentage of patients having 2 consecutive PSA values (at least 3 weeks apart) that are at least 50% lower than baseline and that occur prior to PSA progression. PSA progression is defined as a ≥ 25% increase and absolute increase of ≥ 2 ng/mL above the nadir in PSA. | PSA assessments were done at baseline, Week 5, Week 9, every 4 weeks thereafter, and at Treatment Discontinuation. Total follow-up was up to approximately 39 months. | 
| Confirmed PSA Response (≥ 90% Decrease) by Gene as Assessed by Local Laboratory | A secondary endpoint is confirmed PSA (prostate-specific antigen) response (≥ 90% reduction) as assessed by local laboratory. Confirmed PSA response is analyzed for all patients who had PSA value at baseline and is defined as the percentage of patients having 2 consecutive PSA values (at least 3 weeks apart) that are at least 90% lower than baseline and that occur prior to PSA progression. PSA progression is defined as a ≥ 25% increase and absolute increase of ≥ 2 ng/mL above the nadir in PSA. | PSA assessments were done at baseline, Week 5, Week 9, every 4 weeks thereafter, and at Treatment Discontinuation. Total follow-up was up to approximately 39 months. | 
| Radiologic Progression-free Survival (rPFS) by Gene in All Patients Per Central Independent Radiology Review (IRR) | A secondary efficacy endpoint is Radiologic Progression-free Survival (rPFS) assessed by IRR. rPFS is defined as the time from first dose of rucaparib to the date of first objective evidence of radiographic progression (soft tissue or bone lesion) or death due to any cause, whichever occurs first, plus 1 day. Radiographic disease progression includes confirmed bone disease progression and soft tissue disease progression adjudicated by IRR using the PCWG3 guidelines for bone disease and modified RECIST Version 1.1 for soft tissue disease. | Assessments every 8 weeks from study day 1 for the first 24 weeks, and then every 12 weeks until disease progression, death, or initiation of subsequent treatment. Total follow-up was up to approximately 3 years. | 
| Radiologic Progression-free Survival (rPFS) by Gene in All Patients Per Investigator | A secondary efficacy endpoint is Radiologic Progression-free Survival (rPFS) assessed by Investigator. rPFS is defined as the time from first dose of rucaparib to the date of first objective evidence of radiographic progression (soft tissue or bone lesion) or death due to any cause, whichever occurs first, plus 1 day. Radiographic disease progression includes confirmed bone disease progression and soft tissue disease progression using the PCWG3 guidelines for bone disease and modified RECIST Version 1.1 for soft tissue disease. | Assessments every 8 weeks from study day 1 for the first 24 weeks, and then every 12 weeks until disease progression, death, or initiation of subsequent treatment. Total follow-up was up to approximately 3 years. | 
| Overall Survival (OS) by Gene | A secondary efficacy endpoint is Overall Survival (OS). OS is defined as the date from first dose of rucaparib to the date of death due to any cause, +1 day. | From date of first dose until event, loss to follow-up, withdrawal of consent, or study closure: an overall median of approximately 33.1 months | 
| Clinical Benefit Rate (CBR) by Gene Per Central Independent Radiology Review (IRR) | A secondary efficacy endpoint is Clinical Benefit Rate (CBR) assessed by IRR. CBR is defined as the number of patients without radiographic progression (defined by modified RECIST Version 1.1/ PCWG3 criteria) who were continuing with study drug treatment through the given time interval divided by the number of patients who had the given amount of follow-up. Clinical benefit rates are summarized at 6 and 12 months. | Assessments every 8 weeks from study day 1 for the first 24 weeks, and then every 12 weeks until disease progression, death, or initiation of subsequent treatment. Total follow-up was up to approximately 3 years. | 
| Clinical Benefit Rate (CBR) by Gene Per Investigator | A secondary efficacy endpoint is Clinical Benefit Rate (CBR) assessed by Investigator. CBR is defined as the number of patients without radiographic progression (defined by modified RECIST Version 1.1/ PCWG3 criteria) who were continuing with study drug treatment through the given time interval divided by the number of patients who had the given amount of follow-up. Clinical benefit rates are summarized at 6 and 12 months. | Assessments every 8 weeks from study day 1 for the first 24 weeks, and then every 12 weeks until disease progression, death, or initiation of subsequent treatment. Total follow-up was up to approximately 3 years. | 
| Time to PSA Progression by Gene | A secondary efficacy endpoint is time to PSA progession. Time to PSA progression is defined as the time from first dose of rucaparib to the date that a ≥ 25% increase and absolute increase of ≥ 2 ng/mL above the nadir (or baseline if there was no PSA decline after baseline) in PSA was measured, plus 1 day. The increase must be confirmed by a second consecutive assessment conducted at least 3 weeks later (unless the PSA progression occurred at the last recorded PSA assessment). If confirmed, the date used for time of PSA progression is the earlier of the 2 PSA dates. | PSA assessments were done at baseline, Week 5, Week 9, every 4 weeks thereafter, and at Treatment Discontinuation. Total follow-up was up to approximately 39 months. | 
| Steady State Trough (Cmin) Level Rucaparib Concentrations | Trough (Cmin) concentrations of rucaparib are summarized for all patients with at least one PK sample collected. The absolute values of rucaparib plasma concentration at each time point are presented by gene. | Participants were assessed at Study Day 29, Day 57, Day 85 and Day 113 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RAD51B, CRPC, PARP inhibitor, PARPi, BRCA, ATM, HRD, TRITON, homologous recombination, DNA repair, DNA defect, DNA anomaly, BARD1, BRIP1, CDK12, CHEK2, FANCA, NBN, PALB2, RAD51, RAD51C, RAD51D, RAD54L, germline, somatic, mCRPC