Phase 1, multicenter, open-label study of HSK46575 in patients with metastatic castration-resistant prostate cancer progressing after next-generation hormonal agents and chemotherapy.

5047 Background: The development and progression of prostate cancer are regulated by steroid hormones. HSK46575 Tablet is a novel oral small-molecule inhibitor of cytochrome P450 11A1 (CYP11A1), which can block the production of all downstream steroid hormones and their precursors, thereby reducing the activation of the androgen receptor (AR) signaling pathway and inhibiting tumor progression. Herein, we report the safety and efficacy of HSK46575 in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: This multicenter, open - label Phase I clinical trial had two parts: Phase Ia (dose escalation and expansion) and Phase Ib (dose optimization). Eligible patients were mCRPC patients who failed at least one NHA treatment and either failed, were intolerant to, or refused at least one line of chemotherapy. Phase Ia's dose escalation used a "3 + 3" design to explore four doses (3 mg, 10 mg, 30 mg, 60 mg), and dose expansion was done at 30 mg due to good safety and preliminary efficacy.The primary endpoints were safety and the recommended Phase II dose (RP2D). Results: As of November 4, 2025, 27 subjects were enrolled, with a median follow-up of 3.7 months and a median age of 68 years (range: 51-82 years). Among them, 15 (55.6%) had AR ligand -binding domain (AR-LBD) mutations, and 12 (44.4%) had received taxane-based chemotherapy before. No dose-limiting toxicities were observed in any dose group. Treatment-related adverse events (TRAEs) occurred in 18 subjects (66.7%), most of which were Grade 1-2. The most common TRAEs were alanine aminotransferase elevation (18.5%), sinus bradycardia (11.1%), and nausea (11.1%).No adverse events leading to permanent treatment discontinuation or death were observed. Prostate-specific antigen (PSA) assessment was available for 26 subjects, with PSA response rates confirmed after at least 3 weeks. The PSA 30 and PSA 50 response rates were 42.3% and 34.6% in the total population, 71.4% and 57.1% in AR-LBD mutant subjects (n = 14), and 75% and 58.3% in the 30 mg dose group with AR-LBD mutations (n = 12). The PSA 50 response rate was 12.5% (1/8) in the 30 mg dose group with AR-LBD wild-type. Fourteen subjects were eligible for soft tissue assessment, 8 of whom had AR-LBD mutations. One partial response (PR) was seen during treatment in an AR-LBD mutant patient in the 30 mg dose group, leading to an objective response rate (ORR) of 14.3% in this population. . The radiographic progression-free survival (rPFS) has not been reached. The 6-month rPFS rates were 67.5% in the total population and 76.2% in the AR - LBD mutation population. Conclusions: HSK46575 shows a manageable safety profile and preliminary antitumor activity, especially in the population with AR - LBD mutations. These findings support further exploration in the mCRPC population. Clinical trial information: NCT07007910 .