1. Fuerst, Mark L.

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First-line therapy with rucaparib significantly improves radiographic progression-free survival (rPFS) over physician's choice of therapy in patients with metastatic castration-resistant prostate cancer (mCRPC) harboring BRCA1/2 or ATM alterations.

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For patients with a BRCA alteration, median rPFS was 11.2 months for those who received rucaparib versus 6.4 months for patients who received physician's choice of therapy (HR: 0.50), which was either docetaxel or another second-generation androgen receptor pathway inhibitor (ARPI). In the overall intention-to-treat (ITT) population, median rPFS was 10.2 months with rucaparib versus 6.4 months with physician's choice of treatment (HR: 0.61).


"Rucaparib is superior to all existing standard therapies for patients with BRCA-mutant mCRPC who have already been treated with at least one modern ARPI, and it is the first drug to ever beat a docetaxel-containing control arm for mCRPC. In the long term, this study validates rucaparib as a superior treatment option for patients with BRCA-mutated mCRPC," said lead author Alan Bryce, MD, Medical Director of the Genomic Oncology Clinic at the Mayo Clinic in Phoenix.


Bryce presented the results of the randomized, open-label, Phase III TRITON-3 trial at the 2023 ASCO Genitourinary Cancers Symposium (Abstract 18). The results were published simultaneously in the New England Journal of Medicine (2023; doi: 10.1056/NEJMoa2214676).


The PARP inhibitor rucaparib has received accelerated FDA-approval for the treatment of BRCA-altered mCRPC in patients previously treated with a second-generation ARPI and taxane-based chemotherapy. The new study's results may lead to label expansion that allows treatment in patients who are chemotherapy-naive.


Study Details

TRITON-3 enrolled 405 patients with mCRPC who were naive to chemotherapy in the CRPC setting and had received at least one prior second-generation ARPI. They received either 600 mg of oral rucaparib twice daily or docetaxel, abiraterone acetate, or enzalutamide. Of the 135 patients who received physician's choice therapy, 75 received docetaxel and 60 received the ARPI.


Three-quarters of patients had BRCA1/2-mutated disease and one-quarter had disease with ATM alterations. The median age of patients was about 70 years. All patients had an Eastern Cooperative Oncology Group performance status score of 0-1. Patients who progressed by radiographic assessment on the physician's choice arm were given the choice to cross over to rucaparib; three-quarters of eligible patients elected to receive rucaparib after progression.


"In the BRCA subgroup, TRITON-3 showed that rucaparib is superior to the physician's choice of therapy for improving the primary endpoint of radiographic progression or death, with a 50 percent reduction in events," Bryce stated. "Looking at the rPFS by the choice of control arm therapy, you see the comparison of rucaparib to docetaxel yielded a median rPFS of 8.3 months (HR: 0.53) favoring rucaparib. Compared to the second-generation ARPI, rucaparib was again superior (rPFS: 11.2 months vs. 4.5 months)."


The ATM results show no significant difference between rucaparib and physician's choice of therapy, which is consistent with prior randomized controlled trials of PARP inhibitors in mCRPC, he noted.


Interim median overall survival (OS) data are immature, but a trend favors rucaparib, despite the fact that the majority of patients crossed over from the control arm to receive rucaparib. Median OS, a key secondary endpoint, reached 24.3 months with rucaparib versus 20.8 months with physician's choice of treatment among the subgroup of patients with BRCA-altered disease (HR: 0.81). In the ITT population, median OS was 23.6 months with rucaparib versus 20.9 months with physician's choice of treatment (HR: 0.94).


Common adverse events in the rucaparib arm were fatigue, nausea, and anemia or decreased hemoglobin, and the most common Grade 3 or higher adverse events were anemia or decreased hemoglobin, neutropenia or decreased neutrophil count, and fatigue. Common adverse events in the physician's choice arm were fatigue, diarrhea, and neuropathy, and the most common Grade 3 or higher adverse events were fatigue and neutropenia or a decreased neutrophil count.


"Looking at the treatment-emergent adverse events, the primary toxicity that was more prevalent in the rucaparib group was anemia, with 29 percent of rucaparib arm patients receiving at least one blood transfusion versus 2 percent of those receiving physician's choice therapy," Bryce noted. There were not any reported cases of MDS or AML. The rest of the toxicities are in line with all previously published studies for these agents, he said.


"This study clearly demonstrates the value of rucaparib for treating BRCA1- or BRCA2-altered mCRPC after disease progression on an ARPI," Bryce concluded.


Mark L. Fuerst is a contributing writer.