The findings supported the accelerated approval of rucaparib for the treatment of men with metastatic castration-resistant prostate cancer who have a deleterious BRCA mutation and who have previously received androgen receptor-directed therapy and taxane-based chemotherapy.
Results from the ongoing, international, open-label, phase 2 TRITON2 trial indicated that rucaparib (Rubraca) has antitumor activity in patients with metastatic castration-resistant prostate cancer (mCRPC) and a deleterious BRCA alteration, along with a manageable safety profile consistent with that reported in other solid tumor types.
The findings, published in the Journal of Clinical Oncology, supported the FDA accelerated approval of rucaparib for the treatment of men with mCRPC who have a deleterious BRCA mutation (germline and/or somatic) and who have previously received androgen receptor-directed therapy and taxane-based chemotherapy.
“Data from TRITON2 illustrate the importance of genomic screening to identify men who may benefit from treatment with a PARP inhibitor,” the authors wrote. “TRITON2 patients with mCRPC associated with a BRCA alteration who received rucaparib had substantially higher RECIST and PSA response rates than those typically observed with other treatments in an unselected population, including responses in clinically relevant subgroups.”
Patients who progressed after 1 or 2 lines of next-generation androgen receptor-directed therapy and 1 taxane-based chemotherapy for mCRPC were enrolled in the study. Overall, efficacy and safety populations included 115 patients with a deleterious BRCA alteration who received at least 1 dose of rucaparib.
The co-primary end points for the study were objective response rate (ORR) per RECIST/Prostate Cancer Clinical Trials Working Group 3 in patients with measurable disease as assessed by blinded, independent radiology review and by investigators, and locally assessed prostate-specific antigen (PSA) response (≥ 50% decrease from baseline) rate.
As of the visit cutoff, median treatment duration was 6.5 months (range, 0.5-26.7 months), and median follow up was 13.7 months (range, 4.2-28.2 months). Confirmed ORRs per independent radiology review and investigator assessment were 43.5% (95% CI, 31.0%-56.7%) and 50.8% (95% CI, 38.1%-63.4%), respectively. Moreover, the confirmed PSA response rate was 54.8% (95% CI, 45.2%-64.1%).
Notably, ORRs were similar for patients with a germline or somatic BRCA alteration and for patients with a BRCA1 or BRCA2 alteration, while a higher PSA response rate was observed in patients with a BRCA2 alteration.
“Our results are consistent with those from other studies demonstrating the clinical activity of PARP inhibitors (Olaparib [Lynparza], niraparib [Zejula], and talazoparib [Talzenna]) in patients with mCRPC and a BRCA alteration who received prior [androgen receptor]-directed therapy,” the authors wrote. “Although there are important differences in the study designs for these trials (eg, differences in the method of determining genomic alteration, type of alterations eligible for enrollment, assessment of response by RECIST, PSA decrease, or a composite that includes changes in circulating tumor cell count), these studies reinforce the potential benefit of PARP inhibitors in patients with mCRPC associated with a BRCA alteration.”
A treatment-emergent adverse event (TEAE) of any grade occurred in 114 patients (99.1%), and a grade 3 or greater TEAE was reported in 70 patients (60.9%). The most frequent TEAEs of any grade were asthenia/fatigue (61.7%), nausea (52.2%), and anemia/decreased hemoglobin (43.5%). Further, the most frequent grade 3 or higher TEAE was anemia (25.2%; 29 of 115 patients).
Currently, the phase 3 TRITON3 study (NCT02975934) is ongoing to define the clinical benefit of rucaparib in an earlier disease setting among patients with mCRPC associated with a BRCA or ATM alteration who have progressed after 1 next-generation androgen receptor-directed therapy and who have not received taxane-based chemotherapy in the mCRPC setting. In the study, rucaparib is being compared with physician’s choice of next-generation androgen receptor-directed therapy or docetaxel (Taxotere) and is designed provide additional evidence of the effects of rucaparib treatment in men with mCRPC.
Abida W, Patnaik A, Campbell D, et al. Rucaparib in Men With Metastatic Castration-Resistant Prostate Cancer Harboring a BRCA1 or BRCA2 Gene Alteration. Journal of Clinical Oncology. doi:10.1200/JCO.20.01035