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)

Abstract

Background: Poly(ADP-ribose) polymerase (PARP) inhibitors have demonstrated preliminary evidence of antitumour activity in patients with mCRPC and a homologous recombination (HR) gene mutation (Mateo et al.NEnglJMed. 2015;373:1697-1708). These data provide a compelling rationale for evaluating rucaparib in patients with mCRPC associated with HRD. Methods: TRITON2 (NCT02952534) is a phase II study evaluating rucaparib (600 mg BID) in patients (n≈160) with mCRPC harbouring a deleterious germline or somatic BRCA1, BRCA2, or ATM mutation (by local and/or central testing). An exploratory cohort will enrol patients with an alteration in any of 12 other prespecifiedHRgenes (eg, RAD51C, RAD51D, or PALB2). Patients must have progressed on androgen receptor (AR) signalling-directed therapy and 1 prior taxanebased chemotherapy for mCRPC. The primary endpoint of TRITON2 is response rate (per modified RECIST v1.1/PCWG3 in patients with soft-tissue disease and prostate-specific antigen response in patients with nonmeasurable disease). TRITON3 (NCT02975934) is a randomised phase III study evaluating rucaparib vs physician's choice of abiraterone, enzalutamide, or docetaxel in patients (n = 400) with mCRPC harbouring a deleterious germline or somatic BRCA1, BRCA2, or ATM mutation (by local and/or central testing). Patients must have progressed on AR signalling-directed therapy for mCRPC; prior chemotherapy for mCRPC or prior PARP inhibitor treatment are exclusions. Patients 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 (per modified RECIST v1.1/PCWG3). Pretreatment blood samples collected from all patients in both trials will enable development of a plasma-based companion diagnostic to select patients for rucaparib treatment. Summary: The TRITON programme is actively recruiting and will assess the efficacy and safety of rucaparib treatment in patients with mCRPC associated with HRD.