Abstract LB262: HSK38008: An oral AR-V7 degrader for metastatic castration-resistant prostate cancer

Abstract The androgen deprivation therapy (ADT) alone and its combination with hormone therapy that block AR signaling (e.g., enzalutamide or abiraterone) are effective treatments for advanced prostate cancer. Unfortunately, patients with truncated AR splice variants which lacking the ligand-binding domain still developed resistance to these AR-targeting compounds. The truncated AR splice variant 7 (AR-V7), which is the most clinically relevant variants, remains constitutively active as a transcription factor in 75% of the patients with mCRPC, associated with shorter PFS and OS with abiraterone or enzalutamide treatment. Therefore, AR-V7 has become a promising target for mCRPC.As a novel oral AR-V7 degrader with favorable bioavailability, HSK38008 could degrade the AR-V7 protein with DC50 of 136 nM and achieve the maximum degradation at 24h at 10 μM. In the meanwhile, HSK38008 also degrade AR with weaker IC50 of 110 nM and the maximum degradation at 48hrs at 10 μM. By validation of protease inhibitor MG341, HSK38008 could not degrade ARV7 and AR at high concentration. Compared with enzalutamide and ARV-110, HSK38008 could block the AR-V7 pathway and AR pathway in luciferase report assay with IC50 of 400 nM and 1913 nM respectively. Importantly, HSK38008 also showed significant inhibition of AR mutants (AR-T878A/S889G, T878S, H875Y, T878A) in luciferase assay but not ARV110 and enzalutamide. HSK38008 significantly inhibit the cell proliferation in AR-V7 positive cell line, e.g., 22RV1, but weak antiproliferation in AR and ARV7 positive cell line such as VCAP However, when combination with enzalutamide there is synergistic effect for the anti-proliferation in VCAP. It means the potential to use the compounds in a broader population of mCRPC.In the xenograft model, the mice which were orally given HSK38008 showed 22RV1 tumor growth inhibition in a dose-dependent manner, with the TGI = 89.8% at 10 mpk and the intratumoral AR-V7 protein degradation rate was 73%. 30 mpk of HSK38008 showed completely tumor regression. At the same time, abiraterone and ARV-110 did not show significantly tumor growth inhibition at 30 mpk. There is no influence on mice body weight at all HSK38008 dose groups, while 3 mice in the 30 mpk of ARV-110 group died during the experiment. These results indicated that HSK38008 achieved better therapeutic effects than enzalutamide and ARV-110 did in AR-V7 positive 22RV1 xenograft model.Rats were dosed with 10, 30 and 60 mg/kg HSK38008 once daily for up to 28 days via oral gavage and main study animals were necropsied on Day 29 or Day 57. No animal was found dead or moribund and no test article-related changes in clinical signs, body weights, food consumption, ophthalmologic examinations, clinical pathology parameters, sperm analysis, urinalysis, organ weights, histopathology. In conclusion, HSK38008 is a promising oral AR-V7 degrader with better efficacy than enzalutamide and ARV-110 in AR and AR-V7 positive, and potential AR mutants mCRPC. Citation Format: Ju Wang, Meilin Qian, Pangke Yan, Linli Li, Chen Zhang, Yan Yu, Lihua Tao, Pingming Tang, Yuting Liao, Xiaogang Chen, Xinfan Cheng, Jinxiong Xu, Xuemei Wan, Luchan Deng, Hongjiao Dong, Haixian Zhang, Maotao He. HSK38008: An oral AR-V7 degrader for metastatic castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB262.