As reported in the Journal of Clinical Oncology by Abida and colleagues, the phase II TRITON2 trial has shown that rucaparib produces durable responses in patients with metastatic castration-resistant prostate cancer with deleterious BRCA1 or BRCA2 alterations. The trial supported the May 2020 accelerated approval of rucaparib in this setting.

Study Details

The international study included 115 patients with or without measurable disease who had disease progression after one or two lines of next-generation androgen receptor–directed therapy and one line of taxane-based chemotherapy. Patients were enrolled by May 2019. Cutoff dates were in September 2019 for safety analyses and December 2019 for efficacy analyses, to permit more complete assessment (≥ 32 weeks of follow-up) of efficacy endpoints.

Patients received a starting dose of rucaparib at 600 mg twice daily; dose reductions in decrements of 100 mg were permitted for grade ≥ 3 or persistent grade 2 adverse events. The main efficacy endpoints were objective response rate on modified Response Evaluation Criteria in Solid Tumors and Prostate Cancer Clinical Trials Working Group 3 criteria among patients with measurable disease as assessed by independent radiology review and by investigators and locally assessed prostate-specific antigen (PSA) response (≥ 50% decrease from baseline).

Responses

Median treatment duration was 8.1 months, and median follow-up was 17.1 months. An objective response was observed in 27 of 62 patients with measurable disease on independent radiology review assessment (43.5%, 95% confidence interval [CI] = 31.0%–56.7%), including a complete response in 7 (11.3%), and in 33 of 65 patients with measurable disease on investigator assessment (50.8%, 95% CI = 38.1%–63.4%), including a complete response in 4 (6.2%). An additional 28 (45.2%) and 25 (38.5%) patients, respectively, had stable disease.

Median durations of response were not reached (95% CI = 6.4 months to not reached) on independent radiology review assessment and 6.4 months (95% CI = 5.5–11.7 months) on investigator assessment. PSA response was observed in 63 of 115 patients (54.8%, 95% CI = 45.2%–64.1%).

On independent radiology review, objective responses were observed in 3 (33.3%) of 9 patients with BRCA1 alteration, 24 (45.3%) of 53 with BRCA2 alteration, 9 (42.9%) of 21 with germline BRCA alteration, and 18 (43.9%) of 41 with somatic BRCA alteration. PSA response was observed in 2 (15.4%) of 13 patients with BRCA1 alteration, 61 (59.8%) of 102 with BRCA2 alteration, 27 (61.4%) of 44 with germline alteration, and 36 (50.7%) of 71 with somatic alteration.

Median radiographic progression-free survival was 9.0 months (95% CI = 8.3–13.5 months) on independent radiology review assessment and 8.5 months (95% CI = 8.1–11.2 months) on investigator assessment. Overall survival data were not mature at the time of analysis; the Kaplan-Meier estimate of 12-month overall survival was 73.0%.

Adverse Events

The most common adverse events of any grade were asthenia/fatigue (61.7%), nausea (52.2%), anemia (43.5%), and increased alanine transaminase (ALT)/aspartate transaminase (AST; 33.0%). Grade ≥ 3 adverse events occurred in 60.9% of patients, with the most common being anemia (25.2%), thrombocytopenia (9.6%), asthenia/fatigue (8.7%), and increased ALT/AST (5.2%). At least one red blood cell transfusion was required in 27.8% of patients.

Treatment interruption due to an adverse event occurred in 56.5% of patients, most commonly due to anemia (21.7%), thrombocytopenia (13.9%), and asthenia/fatigue (9.6%). Dose reduction due to adverse events occurred in 40.9%, most commonly due to anemia (13.0%), asthenia/fatigue (9.6%), and thrombocytopenia (7.0%). Adverse events led to discontinuation of treatment in nine patients (7.8%), with causes consisting of acute respiratory distress syndrome; increased ALT/AST; anemia; balance disorder; cardiac failure; decreased appetite, fatigue, and weight decrease; leukopenia and neutropenia; pneumonia; and prolonged QT interval in one patient each. Adverse events led to death in three patients; one each was due to pneumonia and prolonged QT interval, with both considered unrelated to rucaparib, and one was due to acute respiratory distress syndrome, considered related to treatment.

The investigators concluded: “Rucaparib has antitumor activity in patients with [metastatic castration-resistant prostate cancer] and a deleterious BRCA alteration, but with a manageable safety profile consistent with that reported in other solid tumor types.”

Wassim Abida, MD, PhD, of Memorial Sloan Kettering Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was funded by Clovis Oncology and by the National Cancer Institute, Department of Defense Prostate Cancer Research Program, and Prostate Cancer Foundation awards. For full disclosures of the study authors, visit ascopubs.org.