HRS-1167 (M9466), a PARP1 inhibitor, combined with abiraterone acetate and prednisone in metastatic castration-resistant prostate cancer: A phase 1b/2 study.

5036 Background: PARP inhibitors combined with novel hormonal agents (NHAs) have shown improved progression-free survival in metastatic prostate cancer compared to NHA alone. HRS-1167 (M9466) is a novel highly selective PARP1 inhibitor with established antitumor activity in advanced solid tumors. This multicenter, open-label, dose-finding and efficacy expansion phase 1b/2 study assessed the safety, tolerability and preliminary efficacy of HRS-1167 combined with AA-P in mCRPC (ClinicalTrials.gov, NCT06689163). Methods: Chinese adult mCRPC patients with homologous recombination repair mutations who were previously treated were enrolled. Eligible patients received oral HRS-1167 at 30 mg QD or 50 mg QD, combined with AA-P (abiraterone acetate 300 mg QD; prednisone 5 mg BID). Primary objectives were safety and tolerability. Results: As of Oct 31, 2025, 58 patients were enrolled and treated (HRS-1167 30 mg, n = 33; HRS-1167 50 mg, n = 25; prior NHA, 100%; BRCA mutation, 44.8%). Median follow-up was 3.0 months and 6.2 months in the 30 mg and 50 mg cohorts. Preliminary efficacy was summarized in the Table. Among patients with evaluable efficacy (n = 47), prostate-specific antigen response (PSA50) rate was 36.4% (8/22) in the 30 mg cohort and 52.0% (13/25) in the 50 mg cohort. Confirmed objective response rate (cORR) was 37.5% and 14.3%, and disease control rate (DCR) was 81.8% and 92.0%, respectively. HRS-1167 plus AA-P demonstrated particularly encouraging efficacy in patients with BRCA mutations: PSA50 rate was 100% (6/6) in the 30 mg cohort and 81.8% (9/11) in the 50 mg cohort, and cORR was 100% (2/2) and 33.3% (1/3), respectively. DCR was 100% in the BRCA -mutated subgroup. Treatment-emergent adverse events (TEAEs) were reported by 26 (78.8%) and 25 (100%) patients in the 30 mg and 50 mg cohorts (grade ≥3, 18.2% and 44.0%; serious, 9.1% and 32.0%). There were no TEAEs leading to death. The most common (≥5% of patients) grade ≥3 TEAEs were hematologic toxicities (anemia, 9.1% and 24.0%; decreased platelet count, 6.1% and 8.0%; decreased white blood cell count, 0% and 12.0%; decreased neutrophil count, 3.0% and 8.0%). Conclusions: HRS-1167 combined with AA-P showed promising efficacy in patients with mCRPC, especially those with BRCA mutations. The combination was well-tolerated with no new safety signals identified. Clinical trial information: NCT06689163 . Overall BRCA m 30 mg (N = 22) 50 mg (N = 25) 30 mg (N = 6) 50 mg (N = 11) PSA50, n (%) 8 (36.4) 13 (52.0) 6 (100) 9 (81.8) Time to PSA progression, months, median (95% CI) NR (3.7, NR) 6.5 (5.5, NR) NR (4.6, NR) 6.5 (3.8, NR) cORR, n/N* (%) 3/8 (37.5) 1/7 (14.3) 2/2 (100) 1/3 (33.3) DCR, n (%) 18 (81.8) 23 (92.0) 6 (100) 11 (100) N = efficacy evaluable patients; N* = patients with target lesions at baseline. PSA and tumor responses were confirmed. PSA, prostate-specific antigen; cORR, confirmed objective response rate; DCR, disease control rate; NR, not reached.