Background: The combination of PARP inhibitors (PARPi) with novel hormonal agents (NHAs) has recently demonstrated significant improvement in progression-free survival in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) compared with NHAs alone. AZD5305, a PARP1-selective inhibitor, has the potential for an improved safety profile and limited drug-drug interactions (DDIs) compared with first-generation PARPi. PETRANHA, an open-label nonrandomized study, is evaluating the safety and DDIs of AZD5305 with physician’s choice of NHA (enzalutamide [enza], abiraterone acetate [abi] or darolutamide [daro]) in pts with metastatic prostate cancer. Methods: Pts were aged ≥18 years with histologically confirmed mCRPC or metastatic castration-sensitive prostate cancer (mCSPC), suitable for NHA treatment, with or without HRR mutations in tumor tissue. Key exclusion criteria were previous PARPi, platinum chemotherapy, or targeted radioligand therapy for pts with mCRPC or mCSPC; and previous NHA or docetaxel in pts with mCSPC. Pts were assigned to receive AZD5305 60 mg once daily (OD; first dose level tested) and either enza 160 mg OD (Arm 1), abi 1000 mg + 5 mg prednisone OD (Arm 2), or daro 600mg twice daily (Arm 3) until disease progression or any intolerable adverse event (AE) occurred. Primary objectives were safety and tolerability. DDIs were evaluated for each combination. Results: At data cutoff (July 10, 2023), 48 pts were included in the interim safety analysis (Arm 1, n=11; Arm 2, n=19; Arm 3, n=18). In total, 32 (66.7%) pts had mCRPC, 16 (33.3%) pts had mCSPC, and 8 (16.7%) pts were pre-exposed to NHAs. Median duration of AZD5305 exposure was 6.3 months (range, 1.05–12.58) across all arms. Safety data are presented in the Table. The most common AEs were anemia (52.1%; Gr ≥3, 16.7%), fatigue (50.0%; Gr ≥3, 2.1%), and neutropenia (33.3%; Gr ≥3, 6.3%). No dose-limiting toxicities or AE-related deaths occurred in any arm; AEs leading to discontinuations were uncommon. No clinically significant DDIs were measured with any of the combinations. Conclusions: Initial safety, tolerability, and DDI data from the PETRANHA study indicates that AZD5305 can be safely combined with three individual NHAs with low rates of dose interruptions or reductions. The study is ongoing in Australia, Italy, UK, and USA. Clinical trial information: NCT05367440.

*Includes AZD5305 in combination with any NHA.