As reported in The New England Journal of Medicine by Karim Fizazi, MD, PhD, of Gustave Roussy Institute, Paris-Saclay University, 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 BRCA- or ATM-altered metastatic castration-resistant prostate cancer and in the subgroup with BRCA-mutant disease.1
Dr. Fizazi commented to The ASCO Post: “The control arm of docetaxel is being beaten for the first time in 2 decades.”
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, based on response rate and duration observed in the phase II TRITON2 trial.2
Karim Fizazi, MD, PhD
In the open-label trial, 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 no chemotherapy for metastatic disease were randomly assigned on a 2:1 basis between February 2017 and February 2022 to receive rucaparib at 600 mg twice daily (n = 270) or physician’s choice of treatment (control group; 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. Patients in the control group could cross over to receive rucaparib upon disease progression.
The primary outcome measure was imaging-based progression-free survival according to independent review.
At 62 months, median progression-free survival in the intent-to-treat 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 an ATM alteration, 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).
Subsequent treatment was received by 60% of the rucaparib group and 67% of the control group, including 47% of patients in the control group who crossed over to receive rucaparib. A total of 60% of the control group received poly (ADP-ribose) polymerase inhibitor therapy, and 15% of the rucaparib group received platinum therapy. Interim analysis of overall survival in the BRCA subgroup (54% data maturity) showed medians of 24.3 months (95% CI = 19.9–25.7 months) in the rucaparib group and 20.8 months (95% CI = 16.3–23.1 months) in the control group (HR = 0.81, 95% CI = 0.58–1.12, P = .21). In the intent-to-treat population (59% data maturity), medians were 23.6 months (95% CI = 19.7–25.0 months) in the rucaparib group and 20.9 months (95% CI = 17.5–24.4 months) in the control group (HR = 0.94, 95% CI = 0.72–1.23).
Grade ≥ 3 adverse events occurred in 60% of 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 (because of cardiac failure, esophageal perforation, myocardial ischemia, sepsis, and a combination of lower respiratory tract infection and ventricular fibrillation) and three patients (2%) in the control group (because of COVID-19, pneumonia, and an unknown cause). 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.”
DISCLOSURE: The study was funded by Clovis Oncology. Dr. Fizazi has served as a consultant for Amgen, Astellas, AstraZeneca, Bayer, Clovis Oncology, CureVac, Daiichi Sankyo, Janssen Biotech, MSD, Novartis, Orion, Pfizer, and Sanofi-Aventis.
1. Fizazi K, Piulats JM, Reaume MN, et al: Rucaparib or physician’s choice in metastatic prostate cancer. N Engl J Med 388:719-732, 2023.
2. 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 38:3763-3772, 2020.