Previously, the TRITON2 trial showed that the PARP inhibitor rucaparib was effective in treating patients with metastatic, castration-resistant prostate cancer with a deleterious BRCA alteration who previously received a second-generation androgen-receptor pathway inhibitor and taxane-based chemotherapy. Recently published in The New England Journal of Medicine, the results of TRITON3 confirmed these promising observations, with rucaparib significantly improving imaging-based progression-free survival in these patients.
While recent approvals have improved treatment options for castration-sensitive prostate cancer, metastatic prostate cancer remains to be incurable. Poly(ADP-ribose) polymerase (PARP) inhibitors have shown clinical efficacy in patients with metastatic, castration-resistant prostate cancer with alterations in genes encoding DNA damage response, with the best results seen in those with BRCA alterations. In the phase 2 TRITON2 study, the PARP inhibitor rucaparib showed a high level of activity in metastatic, castration-resistant prostate cancer associated with a deleterious BRCA alteration in patients who had received previous treatment with a second-generation androgen-receptor pathway inhibitor (ARPI) and taxane-based chemotherapy. TRITON3 was conducted to confirm and solidify the promising results from TRITON2.
The phase 3 TRITON3 trial enrolled patients with metastatic, castration-resistant prostate cancer harbouring a BRCA1, BRCA2, or ATM alteration with disease progression after treatment with a second-generation androgen receptor pathway inhibitor (ARPI). In total, 405 patients were randomly assigned (2:1) to receive oral rucaparib (600 mg twice daily) or a physician’s choice control (docetaxel or a second-generation ARPI, i.e., abiraterone acetate or enzalutamide) (N=270 and 135, respectively). In the two groups, 201 patients and 101 patients, respectively, had a BRCA alteration. The primary outcome was the median duration of imaging-based progression-free survival according to independent review.
After 62 months, the imaging-based PFS was significantly longer in the rucaparib group compared to the control group (median: 10.2 vs. 6.4 months, respectively; HR[95%CI]: 0.61[0.47-0.80], p<0.001). In the BRCA subgroup, rucaparib also significantly improved the imaging-based PFS (median: 11.2 vs. 6.4 months, respectively; HR[95%CI]: 0.50[0.36-0.69]; p<0.001). In an exploratory analysis focussing on patients with an ATM mutation, the median duration of imaging-based PFS was reported at 8.1 and 6.8 months with rucaparib and control treatment, respectively (HR[95%CI]: 0.95[0.59-1.52]). At 62 months, an interim analysis in the BRCA population reported a median OS of 24.3 vs. 20.8 months in the rucaparib and control groups, respectively. This difference did however not cross the threshold for statistical significance (p=0.21).
The most frequent adverse events with rucaparib were fatigue (61 vs. 63% in the control group), nausea (50 vs. 19%) and anaemia or decreased haemoglobin (47 vs. 18%). The most common grade ≥3 adverse events were anaemia or a decreased haemoglobin level (24% vs. 1%), neutropenia or a decreased neutrophil count (7 vs. 8%), and fatigue (7 vs. 9%).
In conclusion, the use of rucaparib resulted in a longer duration of the imaging-based PFS than physician’s choice of docetaxel or a second-generation ARPI in patients with metastatic, castration-resistant prostate cancer harbouring a BRCA mutation who failed on an ARPI.
Fizazi K, Piulats JM, Reaume MN, et al. Rucaparib or Physician’s Choice in Metastatic Prostate Cancer. N Engl J Med. 2023;388(8):719-732.