TRITON3: Rucaparib improves rPFS in BRCA-altered mCRPC

Treatment with rucaparib significantly improved radiographic progression-free survival (rPFS) in patients with metastatic castration-resistant prostate cancer (mCRPC), particularly those with BRCA alterations, compared with the physician’s choice of therapy of docetaxel or a second-generation ARPI*, according to the TRITON3 trial presented at ASCO GU 2023.

“TRITON3 showed that rucaparib is superior to the physician's choice of therapy for improving the primary endpoint of radiographic progression or death,” said lead author Dr Alan Bryce from Mayo Clinic in Phoenix, Arizona, US. [ASCO GU 2023, abstract 18]

In a subgroup of patients with BRCA-altered mCRPC, those who received rucaparib had a significantly improved median rPFS than those who received physician’s choice of therapy (11.2 vs 6.4 months; hazard ratio [HR], 0.50; log-rank p<0.0001).

In the intention-to-treat (ITT) population, representing both subgroups of patients with either BRCA or ATM alterations, the median rPFS remained significantly longer in the rucaparib group vs the physician’s choice group (10.2 vs 6.4 months; HR, 0.61; log-rank p=0.0003).

However, there was no significant difference between rucaparib and physician’s choice of therapy in terms of median rPFS among those with ATM alterations (8.1 vs 6.8 months; HR, 0.95; log-rank p=0.84). “This is consistent with results seen in prior randomized controlled trials of PARP** inhibitors in mCRPC,” Bryce noted.

“Taken together, the benefit with respect to imaging-based PFS in the rucaparib group was reported both in the BRCA subgroup and in the ITT population, but with the greatest benefit in the BRCA subgroup,” the researchers reported in a recently published paper. [N Engl J Med 2023;388:719-732]

“The PARP inhibitor rucaparib received accelerated approval in the US for the treatment of BRCA-altered mCRPC in patients previously treated with second-generation ARPI and taxane-based chemotherapy,” Bryce noted.

FDA approval for rucaparib was based on data from the multicentre, single-arm TRITON2 clinical trial involving patients with mCRPC and a deleterious BRCA mutation. [https://news.cancerconnect.com/prostate-cancer/parp-inhibitors-effective-in-men-with-brca-mutant-prostate-cancer]

The current phase III, multicentre, open-label trial analysed 405 patients with chemotherapy-naïve mCRPC who had received ≥1 prior second-generation ARPI therapy. The majority of patients had a BRCA1/2 alteration (n=302), while the remaining 103 patients had an ATM alteration. Participants were randomized to receive either oral rucaparib 600 mg twice daily (n=270, mean age 70 years) or physician’s choice of therapy (docetaxel or second-generation ARPI [abiraterone acetate or enzalutamide]; n=135, mean age 71 years). Seventy-five percent of the patients in the physician’s choice group crossed over to rucaparib upon progression.

Even when stratifying by physician’s choice of therapy, median rPFS in the BRCA subgroup remained significantly longer with rucaparib than with docetaxel (11.2 vs 8.3 months; HR, 0.53; log-rank p=0.0009) and second-generation ARPI (11.2 vs 4.5 months; HR, 0.38; log-rank p<0.0001).

Median rPFS also favoured rucaparib over docetaxel (10.2 vs 8.3 months; HR, 0.64; log-rank p=0.0066) and second-generation ARPI (10.2 vs 4.5 months; HR, 0.47; log-rank p<0.0001) in the ITT population.

There was a trend toward improved median overall survival (OS) with rucaparib compared with physician’s choice in the BRCA subgroup (24.3 vs 20.8 months; HR, 0.81; log-rank p=0.21) and the ITT population (23.6 vs 20.9 months; HR, 0.94; log-rank p=0.67). However, these results are still immature at the time of this analysis, said Bryce.

In terms of safety profile, asthenia/fatigue was the most common treatment-emergent adverse event of any grade in both arms (61 percent [rucaparib] and 63 percent [docetaxel or second-generation ARPI]). “The rest of the toxicities are in line with all previously published studies,” Bryce noted.

“The TRITON3 trial met its primary endpoint of improving rPFS by the use of rucaparib vs the physician’s choice of therapy,” said Bryce.

“This study clearly demonstrates the value of rucaparib for treating BRCA1- or BRCA2-altered mCRPC after disease progression on an ARPI,” Bryce said in an interview. [https://dailynews.ascopubs.org/do/triton-3-validates-rucaparib-monotherapy-after-prior-arpi-but-before-chemotherapy-brca-]

*ARPI: Androgen receptor pathway inhibitor