Rucaparib Sustains Safety in BRCA-Positive mCRPC in TRITON3 Update

A detailed safety analysis of the phase 3 TRITON3 trial provides a comprehensive characterization of the tolerability profile of rucaparib (Rubraca) in patients with BRCA-mutated metastatic castration-resistant prostate cancer (mCRPC), reinforcing that most adverse events are manageable through dose adjustments and supportive care and that treatment discontinuation due to toxicity remains uncommon.¹

The safety data, which were shared at the 2026 American Urological Association Annual Meeting, complement a well-established efficacy profile that includes a significant radiographic progression-free survival (rPFS) benefit and similar overall survival (OS) between treatment arms despite high crossover. These earlier findings supported the FDA's 2025 conversion of rucaparib's accelerated approval to full approval in this setting.²

TRITON3 Trial Design

TRITON3 (NCT02975934) is an international, multicenter, randomized, open-label phase 3 trial that enrolled 405 chemotherapy-naive patients with mCRPC and BRCA1/2 or ATM gene alterations who had experienced disease progression on a prior second-generation androgen receptor pathway inhibitor (ARPI).³ Patients were randomized 2:1 to receive rucaparib 600 mg orally twice daily or physician's choice of docetaxel or a second-generation ARPI (abiraterone acetate or enzalutamide). The primary end point was radiographic progression-free survival; OS was a key secondary endpoint. Crossover from physician's choice to rucaparib was permitted following confirmed radiographic progression by independent radiology review.

AUA Safety Analysis

The safety analysis presented at the AUA meeting focused on the 298 patients in the TRITON3 safety population who had confirmed BRCA tumor mutations, which comprised 201 patients randomized to rucaparib and 97 patients randomized to physician's choice (57 received docetaxel and 40 received an ARPI).¹

Any-grade treatment-emergent adverse events (TEAEs) occurred in all patients in both the rucaparib arm (n = 201; 100%) and the total physician's choice arm (n = 97; 100%). Grade 3 or higher TEAEs were somewhat more frequent with rucaparib than with physician's choice (59% vs 50%). Dose reductions due to TEAEs were required nearly twice as often in the rucaparib arm compared with physician's choice (36% vs 21%), as were dose interruptions (53% vs 22%).

Despite the higher rates of dose modifications with rucaparib, the rate of study drug discontinuation due to TEAEs was lower with rucaparib than with physician's choice (14% vs 22%). Deaths due to TEAEs occurred at the same rate in both arms (2% each); in the rucaparib arm, these included one death each due to cardiac failure, myocardial ischemia, and sepsis, while in the physician's choice arm they included one death due to COVID-19 and one of unknown origin. All deaths assessed by investigators were determined to be unrelated to study drug.

Regarding specific toxicities, the most common any-grade TEAE in the rucaparib arm was fatigue or asthenia, occurring in 60.7% of patients, with 7.0% being grade 3 or higher. This compared with 64.9% any-grade and 10.3% grade 3 or higher in the physician's choice arm. Musculoskeletal pain occurred in 53.2% of rucaparib patients (7.0% grade ≥3) versus 56.7% in the physician's choice arm (8.2% grade ≥3). ALT or AST elevations were observed in 27.4% of rucaparib patients (5.5% grade ≥3) versus 3.1% in the physician's choice arm. Anemia or hemoglobin decreased occurred in 45.8% of rucaparib patients, with a notably high grade ≥3 rate of 23.9%, compared with 19.6% any-grade and 1.0% grade ≥3 in the physician's choice arm.

Nausea was reported in 50.7% of rucaparib patients (2.0% grade ≥3) compared with 21.6% in the physician's choice arm (1.0% grade ≥3). Decreased appetite was reported in 34.3% of rucaparib patients (0.5% grade ≥3) versus 28.9% with physician's choice. Diarrhea and constipation each occurred in 30.8% of rucaparib patients (1.5% grade ≥3 each) compared with 16.5% for constipation in the physician's choice arm.

“Rucaparib has a well-defined and manageable safety profile in patients with BRCA-mutated prostate cancer in TRITON3. There was a low rate of discontinuation due to TEAEs suggesting that supportive care and dose adjustments are effective strategies for mitigating TEAEs,” said presenting author Alan H. Bryce, MD. Bryce is chief clinical officer at City of Hope Cancer Center Phoenix and Professor of Molecular Medicine at the Translational Genomics Research Institute, also part of City of Hope.

TRITON3 Efficacy Data

Primary efficacy results from TRITON3, published in the New England Journal of Medicine in 2023 at a data cutoff of August 25, 2022, demonstrated that rucaparib significantly improved rPFS compared with physician's choice in the BRCA1/2-mutated population.³ Median rPFS was 11.2 months (95% CI, 9.2-13.8) with rucaparib versus 6.4 months (95% CI, 5.4-8.3) with physician's choice (HR, 0.50; 95% CI, 0.36-0.69; P <.0001). The rPFS benefit was observed versus both docetaxel and second-generation ARPI comparators individually.

Final OS data from TRITON3 showed that OS was similar between the 2 treatment arms in the BRCA1/2 population.⁴ Median OS was 23.2 months (95% CI, 19.1-25.2) with rucaparib compared with 21.2 months (95% CI, 18.0-23.1) with physician's choice (HR, 0.91; 95% CI, 0.68-1.20). The absence of a statistically significant OS advantage was attributed in large part to the high rate of crossover from the physician's choice arm to rucaparib following radiographic progression; of the 135 patients in the physician's choice arm of the intent-to-treat population, 94 were eligible to cross over to rucaparib.

Clinical Implications

Taken together, the TRITON3 safety and efficacy data presented at AUA 2026, in the context of the final OS and primary rPFS results, reinforce rucaparib as a treatment with a well-characterized, manageable tolerability profile and meaningful clinical benefit in patients with BRCA-mutated mCRPC. These data support rucaparib's role as an established option in the post-ARPI, pre-chemotherapy mCRPC setting for BRCA-mutated patients.

REFERENCES

1. Gingerich JR, Bryce AH, Fizazi K, et al. Safety of rucaparib vs docetaxel or second-generation androgen receptor pathway inhibitor therapy for patients with metastatic castration-resistant prostate cancer and a BRCA mutation in TRITON3. J Urol. 2026;215(5 suppl):e712. doi:10.1097/01.JU.0001191680.76138.83.15

2. RUBRACA (rucaparib) prescribing information. Pfizer Inc; 2025.

3. Fizazi K, Piulats JM, Reaume MN, et al. Rucaparib or physician's choice in metastatic prostate cancer. N Engl J Med. 2023;388(8):719-732. doi:10.1056/NEJMoa2214676

4. Bryce AH, McDermott R, Piulats J, et al. Rucaparib versus docetaxel or second-generation androgen pathway inhibitor therapy for metastatic castration-resistant prostate cancer: TRITON3 final overall survival and safety. J Clin Oncol. 2025;43(5 suppl):155. doi:10.1200/JCO.2025.43.5_suppl.155