Safety and preliminary efficacy of M9466 (HRS-1167) in combination with abiraterone acetate and prednisone/prednisolone (AA-P) in patients (pts) with metastatic prostate cancer in the phase 1 DDRiver 501 study.

Abstract

5038 Background: M9466 (HRS-1167) is a highly potent, selective next-generation PARP1 inhibitor being investigated in pts with locally advanced/metastatic solid tumors. Here we report safety and preliminary efficacy data from Module 3 of the DDRiver 501 study, a Phase 1, open-label, global multicenter study, evaluating M9466 with AA-P in pts with metastatic prostate cancer (NCT06421935). Methods: DDRiver 501 Module 3 enrolled eligible pts with metastatic castration-resistant prostate cancer (mCRPC) or metastatic hormone-sensitive prostate cancer (mHSPC), irrespective of prior anticancer therapy received. Pts received M9466 (either 50 or 100 mg once-daily) with AA-P until disease progression. Primary objective was safety. Additional objectives included efficacy (objective response rate [ORR], PSA50 [confirmed decrease in prostate-specific antigen levels of >50% from baseline]), pharmacokinetics (PK), molecular responses (e.g. >50% reduction from baseline of methylation-based tumor fraction in circulating tumor DNA [ctDNA]) and tumor genetic profiling. Results: As of Nov 21, 2025, Module 3 enrolment was complete (N=21; M9466 50 mg n=10, 100 mg n=11; mHSPC n=1, mCRPC n=20; prior treatment included: PARP inhibitors n=0, androgen receptor pathway inhibitors [ARPI] n=21). Thirteen (62%) pts carried HRR gene mutations, including four (19.0%) with BRCA1/2 mutations, by ctDNA analysis. Pts received M9466 for a median (range) of 18.1 (6.0–30.1) and 26.9 (6.0–42.0) weeks (50 and 100 mg arms respectively). Safety outcomes are presented (table). No dose-limiting toxicities or serious treatment-related adverse events to any study intervention were observed. Across pts with baseline RECIST measurable disease, confirmed ORR was 18.8% (3/16, 95% CI: 4.0, 45.6). Two of the three responders had RAD50 loss of function mutations. In pts with baseline PSA ≥2 ng/mL, 3/17 (17.6%) achieved a PSA50 response. Molecular response and PK data will also be presented. Conclusions: Preliminary data from DDRiver 501 Module 3 demonstrate M9466 with AA-P is generally well tolerated and demonstrates antitumor activity in ARPI-pretreated pts with mHSPC/mCRPC. Clinical trial information: NCT06421935 . Safety overview. n (%) M9466 50 mg (n=10) M9466 100 mg (n=11) Any TEAE 9 (90.0) 11 (100) TEAEs (>25% of total pts) Anemia Fatigue Platelet count decreased Neutrophil count decreased 7 (70.0)6 (60.0)2 (20.0)3 (30.0) 9 (81.8)2 (18.2)5 (45.5)3 (27.3) Any ≥Grade 3 TEAE 4 (40.0) 5 (45.5) ≥Grade 3 TEAEs (≥n=2 of total pts) Anemia Platelet count decreased Neutrophil count decreased 2 (20.0)1 (10.0)1 (10.0) 5 (45.5)1 (9.1)1 (9.1) M9466-related TEAEs leading to: Discontinuation Reduction Interruption 02 (20.0)4 (40.0) 1 (9.1)*4 (36.4)4 (36.4) *Due to anemia. TEAE, treatment-emergent adverse events.