The TRITON clinical trial programme: evaluation of the PARP inhibitor rucaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) associated with homologous recombination deficiency (HRD)

      Background: Recent data have shown that ≈20% of patients (pts) with mCRPC have a germline or somatic alteration in either BRCA1, BRCA2 or ATM (homologous recombination [HR] genes) (Robinson et al. Cell. 2015;161:1215-28), suggesting these molecular markers may be used to select pts with mCRPC for targeted treatment with a poly(ADP-ribose) polymerase inhibitor (PARPi). PARPis have demonstrated preliminary evidence of antitumour activity in pts with sporadic mCRPC and an HR gene mutation (Mateo et al. N Engl J Med. 2015;373:1697-708). These results provide a strong rationale for investigating rucaparib in pts with mCRPC associated with HRD.
      Methods: TRITON2 (EudraCT 2016-003162-13, NCT02952534) is a phase 2 study evaluating rucaparib 600 mg BID in pts (n≈160) with mCRPC who have a deleterious germline or somatic BRCA1, BRCA2 or ATM mutation (per local and/or central testing). Pts with tumours harbouring an alteration in any of 12 other prespecified HR genes (eg, RAD51C, RAD51D or PALB2) will also be enrolled in an exploratory cohort. Pts must have progressed on androgen receptor (AR) signalling-directed therapy (eg, abiraterone or enzalutamide) and 1 prior taxane-based chemotherapy for mCRPC. The primary endpoint of TRITON2 is response rate (modified RECIST v1.1/PCWG3 in pts with soft-tissue disease and prostate-specific antigen response in pts with nonmeasurable disease). TRITON3 (NCT02975934) is a randomised phase 3 study evaluating rucaparib 600 mg BID vs physician’s choice of treatment (abiraterone, enzalutamide or docetaxel) in pts (n≈400) with mCRPC and a deleterious germline or somatic BRCA1, BRCA2 or ATM mutation (per local and/or central testing). Pts must have progressed on AR signalling-directed therapy for mCRPC; prior chemotherapy for mCRPC and prior PARPi are exclusions. Pts will be randomised 2:1 to rucaparib or physician’s choice; the latter group may cross over to rucaparib after radiographic progression confirmed by independent radiology review (IRR). The primary endpoint of TRITON3 is IRR-confirmed radiographic progression-free survival (modified RECIST v1.1/PCWG3 criteria). Pretreatment blood samples collected from all pts in both trials will enable development of a plasma-based companion diagnostic that predicts rucaparib sensitivity.
      Results: Both TRITON2 and TRITON3 are currently enrolling pts.
      Conclusions: The TRITON programme will assess the efficacy and safety of rucaparib treatment in pts with mCRPC associated with HRD.