As reported in The New England Journal of Medicine by Karim Fizazi, MD, PhD, and colleagues, the phase III TRITON3 trial has shown significantly improved progression-free survival with rucaparib vs physician-selected single-agent therapy in the entire population of patients with metastatic castration-resistant prostate cancer with BRCA- or ATM-altered disease, and in the subgroup with BRCA-mutant disease. These findings were also presented at the 2023 ASCO Genitourinary Cancers Symposium (Abstract 18).

In May 2020, rucaparib was granted accelerated approval for the treatment of patients with a deleterious BRCA mutation (germline and/or somatic)-associated metastatic castration-resistant prostate cancer who have been treated with androgen receptor–directed therapy and taxane-based chemotherapy, on the basis of response rate and duration observed in the phase II TRITON2 trial.

Karim Fizazi, MD, PhD

Study Details

The open-label trial included 450 patients from sites in 12 countries who had a deleterious (germline or somatic) BRCA alteration or an ATM alteration, disease progression after a second-generation androgen receptor pathway inhibitor, and had received no chemotherapy for metastatic disease. They were randomly assigned 2:1 between February 2017 and February 2022 to receive rucaparib at 600 mg twice daily (n = 270) or physician’s choice of treatment (n = 135); options consisted of docetaxel (n = 75) or one of the second-generation androgen receptor pathway inhibitors abiraterone acetate (n = 28) or enzalutamide (n = 32), to which patients had no prior exposure. The primary outcome measure was imaging-based progression-free survival according to independent review.

Progression-Free Survival

At 62 months, median progression-free survival in the intent-to-treat (ITT) population was 10.2 months (95% confidence interval [CI] = 8.3–11.2 months) in the rucaparib group vs 6.4 months (95% CI = 5.6–8.2 months) in the control group (hazard ratio [HR] = 0.61, 95% CI = 0.47–0.80,  P < .001). Among 201 vs 101 patients with BRCA alterations, median progression-free survival was 11.2 months (95% CI = 9.2–13.8 months) in the rucaparib group vs 6.4 months (95% CI = 5.4–8.3 months) in the control group (HR = 0.50, 95% confidence interval [CI] = 0.36–0.69, P < .001).

In an exploratory analysis in the BRCA subgroup, median progression-free survival with rucaparib (11.2 months) was longer than that with docetaxel (8.3 months; HR = 0.53, 95% CI = 0.37–0.77) and that with abiraterone acetate or enzalutamide (4.5 months; HR = 0.38, 95% CI = 0.25–0.58).

In an exploratory analysis in the subgroup of patients with ATM alterations, median progression-free survival was 8.1 months (95% CI = 5.5–8.3 months) among 69 patients in the rucaparib group vs 6.8 months (95% CI = 4.0–10.4 months) among 34 patients in the control group (HR = 0.95, 95% CI = 0.59–1.52).

Adverse Events

Grade ≥ 3 adverse events occurred in 60% of patients in the rucaparib group vs 53% of the control group; the most common in the rucaparib group were anemia (24%), fatigue (7%), and neutropenia (7%). Serious adverse events occurred in 29% vs 28% of patients. Adverse events led to discontinuation of treatment in 15% vs 22% of patients. No cases of myelodysplastic syndrome or acute myeloid leukemia were reported. Interstitial lung disease was reported in one patient in the rucaparib group, and pneumonitis was reported in two patients receiving docetaxel in the control group. Pulmonary embolism occurred in nine patients (3%) vs nine patients (7%); deep-vein thrombosis was reported in three patients (1%) vs one patient (1%). Adverse events led to death in five patients (2%) in the rucaparib group and three patients (2%) in the control group. None of the deaths were considered related to treatment.

The investigators concluded, “The duration of imaging-based progression-free survival was significantly longer with rucaparib than with a control medication among patients who had metastatic, castration-resistant prostate cancer with a BRCA alteration.”

Dr. Fizazi, of Gustave Roussy Institute, Paris-Saclay University, Villejuif, is the corresponding author for The New England Journal of Medicine article.

Disclosure: The study was funded by Clovis Oncology. For full disclosures of the study authors, visit nejm.org.