Rucaparib for the Treatment of Metastatic Castration-resistant Prostate Cancer Associated with a DNA Damage Repair Gene Alteration: Final Results from the Phase 2 TRITON2 Study

Wassim Abida ,Melanie Dowson ,Éric Voog ,Akash Patnaik ,Josep María Piulats ,Vinod Ganju ,Darrin Despain ,Jingsong Zhang ,Karim Fizazi ,Charles J Ryan ,Albert Font ,Gedske Daugaard ,Andrew Simmons ,Axel S Merseburger ,Ray Mcdermott ,David Campbell ,Simon P Watkins ,Elias Pintus ,Anne‐Claire Hardy‐Bessard ,Dominique Spaëth ,Brieuc Sautois ,Axel Heidenreich ,Richard Bambury ,Jowell Go ,John M Burke ,Alan H Bryce ,Jeremy Shapiro ,Daniel Castellano ,Andrea Loehr ,Simon Chowdhury

doi:10.1016/j.eururo.2023.05.021

Abstract

BackgroundInitial TRITON2 (NCT02952534) results demonstrated the efficacy of rucaparib 600 mg BID in patients with metastatic castration-resistant prostate cancer (mCRPC) associated with a BRCA1 or BRCA2 (BRCA) or other DNA damage repair (DDR) gene alteration. ObjectiveTo present the final data from TRITON2. Design, setting, and participantsTRITON2 enrolled patients with mCRPC who had progressed on one or two lines of next-generation androgen receptor–directed therapy and one taxane-based chemotherapy. Outcome measurements and statistical analysisThe primary endpoint was objective response rate (ORR; as per the modified Response Evaluation Criteria in Solid Tumor Version 1.1/Prostate Cancer Clinical Trials Working Group 3 criteria in patients with measurable disease by independent radiology review [IRR]); prostate-specific antigen (PSA) response rate (≥50% decrease from baseline [PSA50]) was a key secondary endpoint. Results and limitationsAs of July 27, 2021 (study closure), TRITON2 had enrolled 277 patients, grouped by mutated gene: BRCA (n = 172), ATM (n = 59), CDK12 (n = 15), CHEK2 (n = 7), PALB2 (n = 11), or other DDR gene (Other; n = 13). ORR by IRR was 46% (37/81) in the BRCA subgroup (95% confidence interval [CI], 35–57%), 100% (4/4) in the PALB2 subgroup (95% CI, 40–100%), and 25% (3/12) in the Other subgroup (95% CI, 5.5–57%). No patients within the ATM, CDK12, or CHEK2 subgroups had an objective response by IRR. PSA50 response rates (95% CI) in the BRCA, PALB2, ATM, CDK12, CHEK2, and Other subgroups were 53% (46–61%), 55% (23–83%), 3.4% (0.4–12), 6.7% (0.2–32%), 14% (0.4–58%), and 23% (5.0–54%), respectively. ConclusionsThe final TRITON2 results confirm the clinical benefit and manageable safety profile of rucaparib in patients with mCRPC, including those with an alteration in BRCA or select non-BRCA DDR gene. Patient summaryAlmost half of TRITON2 patients with BRCA-mutated metastatic castration-resistant prostate cancer had a complete or partial tumor size reduction with rucaparib; clinical benefits were also observed with other DNA damage repair gene alterations.

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