Background: AZD5305 is a potent and selective oral PARP inhibitor (PARPi) that specifically targets and traps PARP1, in contrast to approved PARPis which target both PARP1 and PARP2. Preclinical data suggest that PARP1 inhibition confers antiproliferative effects, while PARP2 inhibition is a major driver of hematological toxicity. Thus, AZD5305 may have an improved therapeutic index with less toxicity. The Phase 3 PROpel study showed that first-line olaparib plus abiraterone (abi) significantly improved radiographic progression-free survival (rPFS) over abi alone in pts with metastatic castration-resistant prostate cancer (mCRPC) enrolled irrespective of homologous recombination repair (HRR) gene mutations (Clarke et al, NEJM Evidence 2022). There is a need for better understanding of the benefit of adding PARPi to NHA and the potential synergy between them in early treatment of mPC. The PETRANHA study (NCT05367440) is evaluating the combination of AZD5305 with physician’s choice of NHA including abi, darolutamide, and enzalutamide, in pts with mPC. Methods: This is a multi-arm, open-label, nonrandomized dose-escalation phase study. Key eligibility criteria include age ≥18 years, histologically confirmed mPC (mCRPC or metastatic castration-sensitive prostate cancer [mCSPC], suitability for NHA treatment, ECOG PS 0–1, and life expectancy ≥16 wks. HRR gene mutation status is assessed at screening by testing blood, tumor or circulating tumor (ct) DNA; however, an identified mutation is not required for study entry. Key exclusion criteria for pts with mCRPC include previous PARPi, platinum chemotherapy, or targeted radioligand therapy. For pts with mCSPC, key exclusion criteria are the same, plus previous NHA or docetaxel in the mCSPC setting. Treatment continues until disease progression, starting an alternative anticancer therapy, or unacceptable toxicity. The primary objectives are to assess the safety and tolerability of AZD5305 in combination with NHAs, in terms of adverse events (AEs), serious AEs, and dose-limiting toxicities. Key secondary objectives include characterization of pharmacokinetics, changes in tumor size and prostate-specific antigen level, and assessment of preliminary antitumor activity by objective response rate, rPFS, and time to and duration of response by RECIST v1.1 and Prostate Cancer Clinical Trials Working Group 3 criteria. Exploratory endpoints include evaluating the role of predictive biomarkers including longitudinal assessment of ct cells and ctDNA, prostate-specific membrane antigen positron emission tomography (PET) and fluorodeoxyglucose PET. Enrollment began on June 23, 2022, in Melbourne, Australia; additional sites are planned in Australia, USA, and Europe. Clinical trial information: NCT05367440.