Rucaparib Trial Achieves Primary Endpoint in Metastatic Castration-Resistant Prostate Cancer With BRCA, ATM Mutations

Rucaparib is the only PARP inhibitor demonstrated to have better outcomes than a docetaxel-containing control arm, according to researchers.

Rucaparib (Rubraca; Clovis Oncology) monotherapy achieved improved radiographic progression-free survival (rPFS) compared with chemotherapy or second-line androgen deprivation therapy in patients with metastatic castration-resistant prostate cancer (mCRPC) with BRCA or ATM mutations, according to results from the TRITON3 trial.

The study enrolled 405 patients with a mutation in BRCA or ATM who were randomized to either the rucaparib or the control group, which consisted of physician’s choice of docetaxel, abiraterone acetate, or enzalutamide. Approximately 55% of patients in the control arm received docetaxel, according to the study. The primary endpoint was rPFS in patients with mutations in BRCA1, BRCA2, or ATM.

Participants were required to have disease progression after treatment with 1 prior next-generation AR-targeted therapy, as well as deleterious mutation in BRCA or ATM. Following a protocol amendment, participants were permitted to have received a qualifying AR-targeted therapy in either the hormone-sensitive or castration-resistant setting. As a result, approximately 18% of patients in TRITON3 had received prior AR-targeted therapy in the metastatic hormone-sensitive setting only.

“Men with this type of metastatic prostate cancer want to get their genetically targeted therapy as early as possible, and this trial clearly shows the value of rucaparib as a treatment for these men,” said Alan H. Bryce, MD, chair of the Division of Hematology and Medical Oncology at the Mayo Clinic and principal investigator of TRITON3, in a press release. “A key point is that rucaparib can replace chemotherapy in this setting. The current standard of care for these men is chemotherapy with docetaxel, and rucaparib is the only PARP inhibitor which has beaten a docetaxel-containing control arm in a clinical trial.”

The benefit of rucaparib was observed in both primary efficacy analyses of patients with chemotherapy-naïve mCRPC, including those with BRCA mutations and the overall intent-to-treat population. The rucaparib arm achieved statistical significance over the control arm for rPFS with a hazard ratio of 0.50. According to the study, the median PFS for the population of patients with BRCA mutations treated with rucaparib was 11.2 months versus 6.4 months among those receiving physician’s choice.

Rucaparib also showed statistical significance in all 405 patients randomized in the TRITON3 study. The rucaparib arm (n=270) successfully achieved statistical significance over the control arm (n=135) for the primary endpoint of rPFS with a hazard ratio of 0.61. The median PFS for all patients enrolled in the trial and treated with rucaparib was 10.2 months versus 6.4 months among those who received physician’s choice.

Investigators also conducted an exploratory analysis in a subgroup of patients with ATM mutations. They found that the hazard ratio for rPFS was 0.97. Median rPFS in the rucaparib arm was 8.1 months versus 6.8 months in the control arm.

Overall survival was a secondary endpoint in the BRCA and intent-to-treat population. The hazard ratio in the interim analysis for this secondary endpoint is not yet mature, but favored rucaparib.

“This trial demonstrates the potential for rucaparib to treat men with early-stage metastatic castration-resistant prostate cancer,” said Karim Fizazi, MD, PhD, principal investigator of the TRITON3 trial, in the press release. “To my knowledge, this is the first time in 2 decades that a potential new treatment, rucaparib, has shown in a randomized controlled trial radiographic PFS efficacy over an investigator’s choice control arm that included docetaxel chemotherapy, a long-standing standard of care for men with metastatic castration-resistant prostate cancer, and this is excellent news for patients.”

The safety profile was also consistent with rucaparib labeling. The most common treatment-emergent grade 3 or higher adverse events (TEAEs) among all patients treated with rucaparib in the TRITON3 study were anemia (23.7%), neutropenia (7.4%), asthenia (7%), thrombocytopenia (5.9%), and increased alanine transaminase (5.2%). The discontinuation rate for TEAEs was 14.8% for rucaparib-treated patients and 21.5% for the control arm.

Based on these findings, Clovis Oncology plans to submit a supplemental new drug application to the FDA for the BRCA subgroup of patients and intends to discuss a submission for the broader intent-to-treat population in the first quarter of 2023.

“We believe that the positive results from TRITON3 further demonstrate the important role that Rubraca can play as a treatment option for men with metastatic castration-resistant prostate cancer associated with homologous recombination deficiency, and we look forward to submitting these data to the regulatory authorities in the [United States] during [quarter 1] of 2023,” said Patrick J. Mahaffy, president and CEO of Clovis Oncology, in the release. “Not only does this provide a potential treatment option for eligible men with earlier stage disease, but it is the first and only PARP inhibitor that has demonstrated superior radiographic PFS compared to chemotherapy, which is the standard of care for these patients.”


TRITON3 phase 3 trial of Rubraca (Rucaparib) achieves primary endpoint in men with metastatic castration-resistant prostate cancer with BRCA or ATM mutations. News release. Clovid Oncology. October 3, 2022. Accessed October 6, 2022.