As reported in the Journal of Clinical Oncology by Wassim Abida, MD, PhD, of Memorial Sloan Kettering Cancer Center, and colleagues, the phase II TRITON2 trial has shown that the poly (ADP-ribose) polymerase (PARP) inhibitor rucaparib produced durable responses in patients with previously treated metastatic castration-resistant prostate cancer with deleterious BRCA1 or BRCA2 alterations.¹ The trial supported the May 2020 accelerated approval of rucaparib in this setting.

Wassim Abida, MD, PhD

Study Details

The international study included 115 patients with or without measurable disease that progressed 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 Response Evaluation Criteria in Solid Tumors/Prostate Cancer Clinical Trials Working Group 3 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).

Among the 115 patients, median age was 72 years (range = 50–88 years), 74% were White, and 98% had an Eastern Cooperative Oncology Group performance status of 0 (32%) or 1. Median baseline PSA level was 61.1 ng/mL (range = 0–4,782 ng/mL), 67% of patients had a Gleason score of at least 8 at diagnosis. The median number of therapies for castration-resistant prostate cancer was two (range = 1–8). Next-generation androgen receptor–directed therapy included enzalutamide in 71% and abiraterone in 64%, 94% received docetaxel in the castration-resistant setting and 15% in the castration-sensitive setting, and 54% had independent radiology review–assessed measurable disease.

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 (43.5%, 95% confidence interval [CI] = 31.0%–56.7%) with measurable disease on independent radiology review assessment, including a complete response in 7 (11.3%), and in 33 of 65 patients (50.8%, 95% CI = 38.1%–63.4%) with measurable disease on investigator assessment, including a complete response in 4 (6.2%). An additional 28 (45.2%) and 25 (38.5%) patients had stable disease. Median durations of response were not reached (95% CI = 6.4 months to not reached) on independent radiology review assessment and at 6.4 months (95% CI = 5.5–11.7 months) on investigator assessment. On independent radiology review, 15 of 27 patients (55.6%) with an objective response had responses within at least 6 months; 3 patients with ongoing responses were followed for less than 6 months from the onset of response.

PSA response was observed in 63 of 115 patients (54.8%, 95% CI = 45.2%–64.1%). The median time to PSA response was 1.9 months (95% CI = 1.3–1.9 months), and the median time to PSA progression was 6.5 months (95% CI = 5.9–7.8 months). Overall, 60% of patients exhibited a single best PSA reduction ≥ 50% from baseline.

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

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, the most common being anemia (25.2%), thrombocytopenia (9.6%), asthenia/fatigue (8.7%), and increased levels of ALT/AST (5.2%). At least one red blood cell transfusion was required for 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 levels of 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.” 

DISCLOSURE: The study was funded by Clovis Oncology. Dr. Abida has received honoraria from Caret; has served as a consultant or advisor to Clovis Oncology, Daiichi Sankyo, Janssen, MORE Health, and Oric Pharmaceuticals; has received institutional research funding from AstraZeneca, Clovis Oncology, GlaxoSmithKline, Zenith Epigenetics, the National Cancer Institute, the Department of Defense Prostate Cancer Research Program, and the Prostate Cancer Foundation; and has been reimbursed for travel, accommodations, or other expenses by Clovis Oncology, GlaxoSmithKline, and Oric Pharmaceuticals.

REFERENCE

1. Abida W, Patnaik A, Campbell D, et al: Rucaparib in men with metastatic castration-resistant prostate cancer harboring a BRCA1 or BRCA2 gene alteration. J Clin Oncol. August 14, 2020 (early release online).