The poly (ADP-ribose) polymerase (PARP) inhibitor rucaparib prolonged imaging-based progression-free survival vs physician’s choice of therapy in patients with metastatic castration-resistant prostate cancer whose tumors harbored BRCA or ATM alterations. These results of the phase III TRITON3 study were presented at the 2023 ASCO Genitourinary (GU) Cancers Symposium by Alan Haruo Bryce, MD, of the Mayo Clinic, Phoenix, and published simultaneously in TheNew England Journal of Medicine.1,2
All patients enrolled in the study had experienced disease progression after treatment with a second-generation androgen receptor pathway inhibitor. Median follow-up was 62 months.
“Rucaparib reduced the risk of imaging-based disease progression or death by half in patients with BRCA alterations.”— Alan Haruo Bryce, MD
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Among those whose cancers had a BRCA alteration, the median imaging-based progression-free survival was 11.2 months with rucaparib vs 6.4 months with physician’s choice of therapy, which included either docetaxel or another second-generation androgen receptor signaling inhibitor—abiraterone or enzalutamide (P < .001). In the -intention-to-treat population—which also included patients with ATM alterations—the rucaparib-treated arm had a median imaging-based progression-free survival of 10.2 months compared with 6.4 months in the control group (P < .001).
“Rucaparib reduced the risk of imaging-based disease progression or death by half in patients with BRCA alterations and improved [imaging-based] progression-free survival vs both docetaxel and second-generation androgen receptor signaling inhibition in the BRCA subgroup and the intention-to-treat population,” stated Dr. Bryce.
The phase III TRITON3 trial enrolled 405 patients with metastatic castration-resistant prostate cancer and a BRCA1, BRCA2, or ATM alteration and whose disease progressed after treatment with a second-generation androgen receptor pathway inhibitor. They were randomly assigned in a 2:1 ratio to receive oral rucaparib at 600 mg twice daily (n = 270) or physician’s choice of docetaxel or abiraterone acetate or enzalutamide (n = 135). In the two treatment arms, 201 patients and 101 patients, respectively, had a BRCA alteration. The primary outcome was the median duration of imaging-based progression-free survival according to independent review.
Median patient age in the rucaparib group was comparable in both arms: 70 and 71, respectively. About three-quarters of the patients in both arms were White. All patients had an Eastern Cooperative Oncology Group performance status score of 0 or 1.
Imaging-based progression-free survival was evaluated according to separate therapies in the control arm (physician’s choice). In the BRCA subgroup, imaging-based progression-free survival was shorter with docetaxel compared with rucaparib in the BRCA subgroup, at 8.3 vs 11.2 months (P = .0009) and was also shorter with abiraterone acetate and enzalutamide at 4.5vs 11.2 months with rucaparib (hazard ratio = 0.38; P < .0001). In an exploratory analysis of the ATM subgroup, median imaging-based progression-free survival did not significantly differ between the rucaparib and control groups (8.1 vs 6.8 months, respectively). Median overall survival was immature and was 24.3 months with rucaparib vs 20.8 months with physician’s choice.
The most common adverse events in the rucaparib group were fatigue, nausea, and anemia or decreased hemoglobin, and the most common grade ≥ 3 adverse events were anemia or decreased hemoglobin, neutropenia or a decreased neutrophil count, and fatigue. The most common adverse events in the control group were fatigue, diarrhea, and neuropathy, and the most common grade ≥ 3 adverse events were fatigue and neutropenia or a decreased neutrophil count.
Adverse events leading to treatment discontinuation were reported in 15% of patients in the rucaparib group and 22% in the control group. Death caused by an adverse event during treatment occurred in five patients in the rucaparib group and three patients in the control group. No cases of myelodysplastic syndrome or acute myeloid leukemia were reported.
ASCO expert Robert Dreicer, MD, Deputy Director of the University of Virginia Comprehensive Cancer Center, noted TRITON3 was limited to patients with metastatic castration-resistant prostate cancer with BRCA1/2 or ATM alterations. “This trial provides the clinician with prospective evidence to aid in making treatment decisions in patients with these molecular alterations as it compared rucaparib vs administration of either the alternate pathway inhibitor (abiraterone or enzalutamide) or, importantly, docetaxel.
Robert Dreicer, MD
“The survival data are immature, but the study does provide compelling evidence of improved image-based progression-free survival in patients with BRCA1/2 alterations when treated with rucaparib in lieu of either docetaxel or the alternative pathway inhibitor. The study also provides some additional data to suggest that patients with ATM alterations may be no more responsive to rucaparib than the other therapies tested.
“This study is important because it provides sequence data in a select group of patients with advanced prostate cancer, improving the clinician’s ability to make better informed choices regarding therapy sequence. This trial informs clinical practice, although rucaparib is not yet approved in this setting. In patients with metastatic castration-resistant prostate cancer who have BRCA1 or BRCA2 alterations and have not received prior docetaxel and who have experienced disease progression on an androgen receptor pathway inhibitor have improved progression-free survival with rucaparib instead of an alternative androgen receptor pathway inhibitor,” he stated.
DISCLOSURE: The trial was supported by Clovis Oncology. Dr. Bryce reported financial relationships with Bayer HealthCare Pharmaceuticals, Foundation Medicine, Janssen, Merck, Myovant Sciences, Pfizer, and Novartis; holds a patent for therapeutic targeting of patients with cancer who have NRG1 rearrangements; and has received reimbursement for travel, accommodations, and expenses from Clovis Oncology and Phosplatin Therapeutics. Dr. Dreicer has served as a consultant or advisor to Astellas, AstraZeneca, Aveo, Bayer, EMD Serono, Exelixis, Gilead Sciences, Hinova, Hengrui, Janssen, Merck, Myovant, Pfizer, Seagen, Sanofi Genzyme, and Tavanta Therapeutics; has received royalties from MSN Pharmaceuticals; and has received grant or research support from Exelixis, Arvinas, Seagen, and Gilead Sciences.
1. Bryce AH, Piulats JM, Reaume MN, et al: Rucaparib for metastatic castration-resistant prostate cancer: TRITON3 interim overall survival and efficacy of rucaparib vs docetaxel or second-generation androgen pathway inhibitor therapy. 2023 ASCO GU Cancers Symposium. Abstract 18. Presented February 16, 2023.
2. Fizazi K, Piulats JM, Reaume MN, et al: Rucaparib or physician’s choice in metastatic prostate cancer. N Engl J Med. February 16, 2023 (early release online).
Elena Castro, MD, PhD
Formal discussant of the TRITON3 trial, Elena Castro, MD, PhD, of the Hospital Universitario 12 de Octubre, Madrid, noted that the study helps to answer several questions raised by the PROfound trial.
In the PROfound trial, a cohort of patients with at least one...