HSK46575，一种强效CYP11A1抑制剂，在治疗去势抵抗性前列腺癌（CRPC）中展示出有前景的单药疗效及与标准治疗（SOC）的协同疗效

Background: HSK46575 is a novel, selective CYP11A1 inhibitor that suppresses production of all steroid hormones and precursors, showing significant antitumor efficacy in CRPC models and is now in clinical studies. A CYP11A1 inhibitor, ODM-208, showed a decrease in prostate-specific antigen levels of 50% (PSA50) in about 50% patients with AR LBD mutation (AR-mut), but lower response in CRPC patients with wild type AR (AR-wt) in phase1/2 studies. Given that the majority of CRPC patients harboring AR-wt, the monotherapy may face limitations following different AR status and also inevitably encounter drug resistance, evaluating the synergistic potential of HSK46575 and other mechanistic therapies holds promise for benefiting more patients. Methods: In vivo combination efficacy was assessed in CRPC xenograft models. Model mice were treated with HSK46575 and/or other mechanic drugs, including PARP inhibitor (Olaparib), docetaxel or EZH2 inhibitor. Tumor growth inhibition (TGI) was compared between combination and respective monotherapy groups. In the phase 1 dose-escalation study, patients with advanced prostate cancer received HSK46575 (3 to 30 mg). Study objectives were safety and preliminary efficacy assessed by PSA and standard safety measures. Results: In the Vcap (AR-amp) castrated xenograft model, the combo of HSK46575 (1 mg/kg) and docetaxel (5 mg/kg) showed synergistic efficacy (TGI: 117.78% for combo vs. 21.94% for HSK46575 monotherapy, P≤0.0001; vs. 103.93% for docetaxel monotherapy, P≤0.05). In LNCaP (AR-mut) models, the combo of HSK46575 (0.15 mg/kg) plus olaparib (100 mg/kg) significantly elevated TGI (79.9% for combo vs. 42.0% for HSK46575, P≤0.05; vs. 29.0% for olaparib, P≤0.01). Similarly, HSK46575 plus an EZH2 inhibitor also demonstrated synergistic antitumor activity, and the combo achieved TGI of 82.1%, significantly better than HSK46575 monotherapy (53.7%, P≤0.01) or EZH2 inhibitor monotherapy (51.1%, P≤0.0001). All monotherapy or combinations were well-tolerated. In addition, clinically, at data cut-off (Oct 27, 2025), 27 patients were treated with HSK46575. Patients with AR-wt or AR-mut, among all dose-escalation cohorts, showed a PSA50 response of 30.8% (8/26). Encouragingly, patients with AR-mut gained much higher PSA responses. HSK46575 exhibited favorable clinical safety during dose escalation, with treatment-related adverse events (TRAEs) rate of 63.0%, while only 7.4% experiencing Grade ≥3 TRAEs, date cut-off (Sep 9, 2025), and no dosing limited toxicity or treatment-related deaths occurred. Conclusion: Preliminary clinical data confirm the manageable safety profile and promising antitumor activity of HSK46575, particularly in patients harboring AR-LBD mutations. Furthermore. HSK46575 exhibits strong synergistic efficacy when combined with docetaxel or targeted agents (PARPi or EZH2i) in CRPC xenograft models. These results support the further clinical development of HSK46575, both as monotherapy and in rational combinations, for prostate cancer treatment.