Abstract LB273: HSK46575: A best-in-class, long lasting, small molecular CYP11A1 inhibitor for the treatment of castration-resistant prostate cancer (CRPC)
Authors: Lulin Huang, Meilin Qian, Ju Wang, Yao Li, Pingming Tang, Pangke Yan
Journal: Cancer Research (2025)

Abstract Background: Progression of prostate cancer highly depends on androgen. Approximately half of the castration-resistant prostate cancer (CRPC) patients will benefit from abiraterone or enzalutamide treatment initially. However, most relapse within 1 to 2 years due to enhanced AR activity, such as AR mutations, allowing higher affinity to more steroid ligands. CYP11A1 catalyzes the initial and rate-limiting step in steroid biosynthesis, converting cholesterol to pregnenolone. The first-in-class CYP11A1 inhibitor ODM-208 has successfully gain the proof-of-concept of CRPC treatment. However, due to its short T1/2, it needs to be given twice-daily (BID). HSK46575 is a best-in-class, potent, long-lasting and oral inhibitor of CYP11A1, supporting once-daily (QD) administration to halt the synthesis of steroid hormones and realize good anti-tumor activity in CRPC xenograft models. Methods: The potency of CYP11A1 inhibition was demonstrated by testing the production of pregnenolone (Preg) and testosterone (TE) in H295R cell line in vitro and in normal male rats in vivo by ELISA. The anti-tumor efficacy was studied in VCaP and LNCap castrated xenograft models. Animals were orally administered with HSK46575 once daily. Serum PSA concentration was detected by ELISA. Plasma concentrations of HSK46575 were measured with LS-MS/MS. Results: HSK46575 potently blocks the CYP11A1 enzymatic activity and the biosynthesis of Preg and TE at low nM concentrations in vitro. In normal male rats, the inhibition of both Preg and TE by HSK46575 was dose-dependent and long-lasting. In the LNCap (with AR-T877A) castrated xenograft model, HSK46575 significantly inhibited tumor growth and serum PSA level at a low dosage of 1 mg/kg/day. Notably, 2.5 mg/kg/day dosage of HSK46575 exhibited superior efficacy compared to Abiraterone (200 mg/kg/day) and ODM-208 (60 mg/kg/day). Additionally, in the VCaP castrated xenograft mice model carrying AR-wt, HSK46575 remarkably inhibited tumor growth at a dosage of 2.5 mg/kg/day, showing comparable efficacy to ODM-208 at 60 mg/kg/day. Moreover, HSK46575 displayed favorable PK profiles with good oral bioavailability in all studied animals, including higher plasma exposure, longer T1/2, and lower clearance ratios to support daily administration, versus BID of ODM-208. Moreover, HSK46575 was well tolerated with steroid hormone replacement and has favorable safety margin in rats and dogs. Discussion: The preclinical studies demonstrated that HSK46575 possesses promising anti-tumor efficacy, favorable PK properties, and an excellent safety profile, suggesting HSK46575 as a potential therapeutic agent for CRPC treatment. Clinical trials in patients with CRPC is ongoing in China. Citation Format: Lulin Huang, Meilin Qian, Ju Wang, Yao Li, Pingming Tang, Pangke Yan. HSK46575: A best-in-class, long lasting, small molecular CYP11A1 inhibitor for the treatment of castration-resistant prostate cancer (CRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB273.