(UroToday.com) The 2026 American Society of Clinical Oncology (ASCO) Annual Meeting hosted a prostate, testicular, and penile cancers poster session. Dr. Valentina Boni presented safety and preliminary efficacy data from Module 3 of the phase 1 DDRiver 501 study evaluating M9466 (HRS-1167), a next-generation PARP1-selective inhibitor, in combination with abiraterone acetate plus prednisone/prednisolone (AA+P) in patients with metastatic prostate cancer.
PARP inhibitor combinations with androgen receptor pathway inhibition have become an increasingly important therapeutic strategy in metastatic prostate cancer, particularly among patients with homologous recombination repair (HRR)-altered disease.1-4 However, currently available PARP inhibitors are associated with hematologic toxicities that may limit treatment tolerability. M9466 (HRS-1167) is a highly potent and selective next-generation PARP1 inhibitor designed to maintain antitumor activity while potentially improving tolerability through selective PARP1 targeting. The DDRiver 501 study evaluated the safety, pharmacokinetics, molecular activity, and preliminary efficacy of M9466 combined with AA+P in patients with metastatic hormone-sensitive prostate cancer (mHSPC) or metastatic castration-resistant prostate cancer (mCRPC).
DDRiver 501 Module 3 was an open-label, global multicenter phase 1 study (NCT06421935) enrolling patients with mCRPC or mHSPC regardless of prior anticancer therapy exposure. Patients received M9466 at either 50 mg or 100 mg once daily in combination with AA+P until disease progression. The primary objective was safety, while secondary objectives included objective response rate (ORR), PSA50 response rate, pharmacokinetics, molecular response assessments using circulating tumor DNA (ctDNA), and tumor genomic profiling.
As of the November 21, 2025, data cutoff, enrollment was complete with 21 treated patients, including 10 in the 50 mg cohort and 11 in the 100 mg cohort. Most patients had mCRPC (n=20), while one patient had mHSPC. All patients had received prior androgen receptor pathway inhibitor therapy, and none had previously received a PARP inhibitor. HRR gene mutations were identified in 62% of patients, including BRCA1/2 alterations in 19%, based on ctDNA analysis. Median treatment duration was 18.1 weeks in the 50 mg cohort and 26.9 weeks in the 100 mg cohort.
The combination demonstrated a favorable preliminary safety profile. Importantly, no dose-limiting toxicities or serious treatment-related adverse events were observed. Treatment-emergent adverse events (TEAEs) occurred in 90% and 100% of patients in the 50 mg and 100 mg cohorts, respectively, while grade ≥3 TEAEs occurred in 40% and 45.5%.
The most common TEAEs were hematologic, particularly anemia, which occurred in 70% and 81.8% of patients in the 50 mg and 100 mg cohorts, respectively. Fatigue was reported in 60% and 18.2%, while decreased platelet counts occurred in 20% and 45.5%. Grade ≥3 anemia occurred in 20% of patients receiving 50 mg and 45.5% receiving 100 mg. Grade ≥3 thrombocytopenia and neutropenia were each observed in approximately 10% of patients across cohorts.
Treatment discontinuation due to M9466-related TEAEs was uncommon, occurring in none of the patients in the 50 mg cohort and one patient (9.1%) in the 100 mg cohort, secondary to anemia. Dose reductions and interruptions were more common and occurred in 20% and 40% of patients in the 50 mg cohort, respectively, versus 36.4% for both in the 100 mg cohort.
Preliminary antitumor activity was also observed. Among patients with RECIST-measurable disease at baseline, the confirmed ORR was 18.8% (3/16; 95% CI 4.0–45.6). Notably, two of the three responders harbored RAD50 loss-of-function mutations. Among patients with baseline PSA ≥2 ng/mL, 17.6% (3/17) achieved a confirmed PSA50 response. Molecular response and pharmacokinetic analyses were also planned for presentation.
The investigators concluded that preliminary findings from DDRiver 501 Module 3 demonstrate that M9466 combined with AA+P is generally well tolerated and shows early evidence of antitumor activity in ARPI-pretreated patients with metastatic prostate cancer.
These findings are clinically relevant as they further support the development of selective PARP1 inhibition strategies in metastatic prostate cancer. Although this remains an early phase study with a limited sample size, the absence of dose-limiting toxicities and encouraging preliminary activity in a heavily pretreated population suggest that M9466 may represent a potentially promising next-generation PARP inhibitor platform. Additional follow-up and larger expansion cohorts will be important to better define efficacy, biomarker-selected activity, and whether selective PARP1 inhibition may ultimately improve the therapeutic index of PARP-based combination strategies in prostate cancer.
Presented by: Valentina Boni, MD, PhD, Director of Clinical Cancer Research, Next Oncology Madrid, Madrid, Spain
Written by: Rashid K. Sayyid, MD, MSc, Assistant Professor, Urologic Oncologist, Department of Urology at The University of Arizona and Banner University Medical Center, Tucson, AZ – @rksayyid on X during the American Society of Clinical Oncology Genitourinary (ASCO) Annual Meeting held in Chicago, IL between May 29th and June 1st, 2026
References:
- U.S. Food and Drug Administration. FDA Approves Olaparib and Rucaparib for Metastatic Castration-Resistant Prostate Cancer. National Cancer Institute Cancer Currents Blog. Published May 27, 2020. Accessed June 1, 2026. National Cancer Institute Cancer Currents Blog
- U.S. Food and Drug Administration. FDA Approves Niraparib and Abiraterone Acetate Plus Prednisone for BRCA-Mutated Metastatic Castration-Resistant Prostate Cancer. Published August 11, 2023. Accessed June 1, 2026. FDA Drug Approval Announcement
- U.S. Food and Drug Administration. FDA Approves Talazoparib With Enzalutamide for HRR Gene-Mutated Metastatic Castration-Resistant Prostate Cancer. Published June 20, 2023. Accessed June 1, 2026. FDA Drug Approval Announcement
- U.S. Food and Drug Administration. FDA Approves Olaparib With Abiraterone and Prednisone (or Prednisolone) for BRCA-Mutated Metastatic Castration-Resistant Prostate Cancer. Published May 31, 2023. Accessed June 1, 2026. FDA Drug Approval Announcement