Background
In a phase 2 study, rucaparib, an inhibitor of poly(ADP-ribose) polymerase (PARP), showed a high level of activity in patients who had metastatic, castration-resistant prostate cancer associated with a deleterious BRCA alteration. Data are needed to confirm and expand on the findings of the phase 2 study.
Methods
In this randomized, controlled, phase 3 trial, we enrolled patients who had metastatic, castration-resistant prostate cancer with a BRCA1, BRCA2, or ATM alteration and who had disease progression after treatment with a second-generation androgen-receptor pathway inhibitor (ARPI). We randomly assigned the patients in a 2:1 ratio to receive oral rucaparib (600 mg twice daily) or a physician’s choice control (docetaxel or a second-generation ARPI [abiraterone acetate or enzalutamide]). The primary outcome was the median duration of imaging-based progression-free survival according to independent review.
Results
Of the 4855 patients who had undergone prescreening or screening, 270 were assigned to receive rucaparib and 135 to receive a control medication (intention-to-treat population); in the two groups, 201 patients and 101 patients, respectively, had a BRCA alteration. At 62 months, the duration of imaging-based progression-free survival was significantly longer in the rucaparib group than in the control group, both in the BRCA subgroup (median, 11.2 months and 6.4 months, respectively; hazard ratio, 0.50; 95% confidence interval [CI], 0.36 to 0.69) and in the intention-to-treat group (median, 10.2 months and 6.4 months, respectively; hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001 for both comparisons). In an exploratory analysis in the ATM subgroup, the median duration of imaging-based progression-free survival was 8.1 months in the rucaparib group and 6.8 months in the control group (hazard ratio, 0.95; 95% CI, 0.59 to 1.52). The most frequent adverse events with rucaparib were fatigue and nausea.
Conclusions
The duration of imaging-based progression-free survival was significantly longer with rucaparib than with a control medication among patients who had metastatic, castration-resistant prostate cancer with a BRCA alteration. (Funded by Clovis Oncology; TRITON3 ClinicalTrials.gov number, NCT02975934.).
Among patients with metastatic castration resistant prostate cancer (mCRPC), one in four patients have somatic and/or germline alterations in homologous recombination repair genes (HRR+). PARP inhibitors (PARPi) have therefore been evaluated in this setting. Olaparib was approved by the European Medicine Agency in 2020 as a treatment option in patients with mCRPC previously treated with at least one androgen-receptor pathway inhibitor (ARPI) if they were harbouring a somatic or germline BRCA1/2 alteration, based on the findings of the PROFOUND study.
Recently, another trial (TRITON-3) reported on efficacy of a PARP inhibitor rucaparib in this setting. TRITON-3 is a phase III trial that enrolled 405 patients with mCRPC and BRCA1/2 or ATM mutations, which have been previously treated with ARPI. Patients were randomised 2:1 between rucaparib (600 mg twice daily) or a physician’s choice treatment (docetaxel or ARPI) and stratified on genetic alteration (BRCA or ATM), ECOG (0 or 1) and liver metastasis. A statistical benefit was observed in favour of rucaparib in terms of radiographic progression-free survival (PFS) (10.6 vs 6.4 months, HR 0.61; 95% CI, 0.47 to 0.80; p<0.001), regardless of the physician’s choice of treatment (rucaparib compared to docetaxel 11.2 vs 8.3 months, HR 0.53; 95%CI, 0.37-0.77; rucaparib compared to ARPI 11.2 vs 4.1 months, HR 0.38, 95%CI, 0.25-0.58). However, the subgroup analysis showed that only patients with BRCA alterations demonstrated a benefit for rucaparib (11.2 vs 6.4 months; HR, 0.50; 95%CI, 0.36 to 0.69), while no difference was observed between rucaparib and control arm in the ATM population (8.1 vs 6.8 months, HR 0.95; 95% CI, 0.59 to 1.52). A trend for overall survival benefit was observed in favour of rucaparib but data are presently immature. Rucaparib was well tolerated with fatigue (61% all grade, 7% grade ≥3), nausea (50% all grade, 3% ≥ grade 3) and anaemia (47% all grade, 24%≥ grade 3) being the main adverse events.
This trial confirms data previously reported in the PROFOUND trial: PARPi improves rPFS in mCRPC patients with BRCA1/2 but not in ATM alteration. Moreover, TRITON-3 suggests that PARPi is probably a more preferable second line treatment in mCRPC with BRCA1/2 mutations than docetaxel, based on the subgroup analysis conducted in the trial.