Rucaparib vs docetaxel (DTX) or second-generation androgen pathway inhibitor (ARPI) therapy for metastatic castration-resistant prostate cancer (mCRPC): TRITON3 final overall survival (OS) and safety.
Authors: Bryce Alan Haruo , McDermott Raymond S. , Piulats Josep M. , Reaume M. Neil , Ostler Peter James , Gingerich Joel Roger , Pintus Elias , Sridhar Srikala S. , Bambury Richard Martin , Emmenegger Urban , Lindberg Henriette , Morris David , Nole Franco , Staffurth John Nicholas , Abida Wassim , Caunt Lisa , Despain Darrin , Ryan Charles J. , Fizazi Karim , Chowdhury Simon 
Published: February 2025

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Background:
Primary results from the randomized, multicenter, open-label, phase 3 TRITON3 (NCT02975934) study of rucaparib, a poly(ADP-ribose) polymerase inhibitor (PARPi) in patients with chemotherapy-naive mCRPC and
BRCA1/2
(BRCA) vs the control arm of physician’s choice of DTX or ARPI (abiraterone acetate [ABI] or enzalutamide [ENZ]) demonstrated that rucaparib significantly improved radiographic progression-free survival (rPFS, primary efficacy endpoint) vs physician’s choice. Here, we report final OS and safety results from TRITON3.
Methods:
Patients with disease progression after 1 prior second-generation ARPI in any setting were randomized 2:1 to rucaparib 600 mg BID or physician’s choice of DTX, ABI, or ENZ (control). OS was a key secondary endpoint tested initially in the BRCA subgroup, followed by the intent-to-treat (ITT) population in an ordered step-down multiple-comparisons procedure. Crossover from placebo to rucaparib was allowed after radiographic progression was confirmed by independent radiology review.
Results:
As of March 1, 2024 (final analysis data cutoff),patients with BRCA (N = 302) and
ATM
(N = 103) alterations were randomized (ITT, N = 405). After an overall median follow-up of 44.0 months, median OS in the BRCA subgroup in the rucaparib arm was 23.2 months vs 21.2 months for the physician’s choice control arm (HR, 0.91 [95% CI, 0.68–1.20];
P
= 0.5044; Table). Hierarchical testing did not continue due to lack of statistical significance. No OS benefit was observed in the ITT population or
ATM
subgroup (Table). Median duration of treatment in rucaparib and physician’s choice arms was 8.3 and 5.1 months, respectively. The most frequent any-grade treatment emergent adverse event (TEAE) in the rucaparib (n = 270) and physician’s choice (n = 130) arms was asthenia/fatigue (61.5% and 63.1%, respectively). The most frequent grade ≥3 TEAE was anemia (23.7%) with rucaparib, and asthenia/fatigue (9.2%) with physician’s choice. Of the 135 patients in the physician’s choice arm, 77 patients had radiographic progression and 70 crossed over to rucaparib.
Conclusions:
Rucaparib remains the only PARPi to show improved rPFS vs a DTX-containing control arm and has a similar OS even when most patients cross over to rucaparib. Safety was consistent with prior reports. These data support rucaparib as a treatment option for patients with BRCA-mutated mCRPC. Clinical trial information:
NCT02975934
.

Median OS at final analysis.

Group
Rucaparib, n
Physician's choice, n
Rucaparib, months
Physician's choice, months

HR (95% CI)
a

BRCA
201
101
23.2
21.2
0.91 (0.68–1.20)

ITT
270
135
22.8
21.7
0.99 (0.78–1.26)

ATM
69
34
18.4
22.1
1.21 (0.77–1.90)

a
Calculated by stratified Cox proportional hazard model.