Rucaparib has ‘meaningful’ antitumor activity in BRCA-mutated mCRPC
medwireNews: Phase 2 TRITON2 study data suggest that men with metastatic castration-resistant prostate cancer (mCRPC) harboring a BRCA1 or BRCA2 mutation may benefit from treatment with the PARP inhibitor rucaparib.
“For men with mCRPC with disease progression after next-generation AR [androgen receptor]-directed therapy and taxane-based chemotherapy, response to previously approved therapies has been historically poor,” say Wassim Abida, from Memorial Sloan Kettering Cancer Center in New York, USA, and colleagues.
They therefore investigated the use of rucaparib 200 mg twice daily in 115 men with mCRPC who had deleterious germline (n=44) or somatic (n=71) alterations in BRCA1 (n=13) or BRCA2 (n=102), and had progressed on 1–2 lines of next-generation AR-directed therapy and one prior taxane-based chemotherapy.
During a median 17.1 months of follow-up, the objective response rate (ORR) was 43.5% among the 62 patients who were assessed by independent radiology review and 50.8% among the 65 patients who underwent investigator assessment.
ORRs by independent radiology review were comparable for men with germline or somatic mutations, at 42.9% and 43.9%, respectively, and for those with a BRCA1 or BRCA2 mutation, at 33.3% versus 45.3%.
But the researchers note that the same could not be said for prostate-specific antigen (PSA) responses. Overall, the PSA response rate was 54.8%, but such responses occurred at a higher rate among patients with biallelic alterations (75.0%) and/or homozygous loss (81.0%) compared with the overall population.
The median radiographic progression-free survival in the total study cohort was 9.0 months by independent radiographic review and 8.5 months by investigator assessment.
In addition to showing “meaningful antitumor activity,” rucaparib had “a manageable safety and tolerability profile,” comment Abida et al in the Journal of Clinical Oncology. Treatment-emergent adverse events (TEAEs) of grade 3 or higher occurred in 60.9% of study participants, with anemia being the most common (25.2%).
A total of 56.5% of patients required a treatment interruption due to TEAEs, while 40.9% needed a dose reduction and 7.8% discontinued treatment. Three deaths were attributed to TEAEs, including one case of acute respiratory distress syndrome that was deemed related to the study drug.
“Our results are consistent with those from other studies demonstrating the clinical activity of PARP inhibitors (olaparib, niraparib, and talazoparib) in patients with mCRPC and a BRCA alteration who received prior AR-directed therapy,” say Abida and colleagues.
“[T]hese studies reinforce the potential benefit of PARP inhibitors in patients with mCRPC associated with a BRCA alteration,” and highlight “the importance of genomic screening to identify men who may benefit from treatment with a PARP inhibitor,” they add.
The investigators note that the ongoing phase 3 TRITON3 study aims to investigate the use of rucaparib in an earlier disease setting among mCRPC patients with BRCA or ATM alterations.
Specifically, the agent “is being compared with physician’s choice of next-generation AR-directed therapy or docetaxel” in men who have received just one prior AR-directed agent and no taxane-based chemotherapy for metastatic castration-resistant disease, they conclude.
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