Abstract ND02: Discovery of BMS-986365, a ligand-directed androgen receptor degrader (AR LDD) with a dual mechanism-of-action and best-in-class potential, for the treatment of advanced prostate cancer

Abstract The androgen receptor (AR) is a key driver of the cellular processes that contribute to the pathology of prostate cancers at most stages, and drugs that inhibit the activity of this receptor or interfere with androgen biosynthesis have become the cornerstone of treatments for prostate cancer. While both types of therapy have had a significant positive impact on disease progression and overall survival, de novo and acquired resistance remains an impediment to a durable clinical response in patients with metastatic castration-resistant prostate cancer (mCRPC). The mechanisms underlying drug resistance are complex and multifactorial, being attributable to AR overexpression, point mutations in the receptor that alter drug pharmacology, and to the upregulation of receptor-associated coregulators, which render AR less dependent on an activating ligand. Regardless, absolute inhibition of AR signaling remains the objective of contemporary approaches to treat prostate cancer. Recently, there has been specific interest in the development of approaches to eliminate AR proteins using drugs that enable targeted degradation of AR in cancer cells.This puts in context the significance of our discovery of BMS-986365 (also known as CC-94676), a heterobifunctional ligand-directed degrader (LDD) that enables the CRL4CRBN E3 ligase-dependent ubiquitination and degradation of AR (DC50 10 to 40 nM, Ymin 7 to 19%). BMS-986365 is a highly potent and selective AR degrader that induces rapid and deep degradation of both wildtype and mutant forms of the receptor residing in either the cytoplasmic or nuclear compartments of the cell. The drug is ~100-fold more potent than enzalutamide (ENZ) at inhibiting androgen-stimulated transcription of AR target genes, and 10 to 120-fold more potent than ENZ at inhibiting AR-dependent proliferation of multiple prostate cancer cell lines in vitro. In animal models of advanced prostate cancer, BMS-986365 demonstrates on-target activity, degrading AR, suppressing AR signaling, and inhibiting tumor growth. Indeed, tumor volume reductions of 63-92% were achieved by BMS-986365 in validated models of advanced CRPC and therapy resistant patient-derived xenografts, including those with acquired resistance to ENZ. Collectively our preclinical data suggest that the AR degrader BMS-986365 is superior to standard-of-care AR antagonists, such as ENZ, in both preclinical and disease-relevant animal models, and support its clinical development for treatment of prostate cancer. BMS-986365 has advanced into clinical studies where it has demonstrated encouraging clinical activity in patients with mCRPC. Citation Format: Shuichan Xu, Surendra Nayak, John D. Norris, Massimo Ammirante, Emyly Rychak, Suzanne E. Wardell, Toshiya Tsuji, Ken Liu, Joseph Meiring, Joseph R. Piccotti, Deepak Dalvie, Debbie Liao, Raju Kandimalla, Nadia Guerrero, Lisa Sapinoso, Jennifer G. Baker, Yeeun Bae, Joshua Baughman, Brandon Toyama, Celia Fontanillo Fontanillo, Stephen Norris, Evan J. Horn, Veronique Plantevin-Krenitsky, Deborah Mortensen, Brian Cathers, Marie Hong Nguyen, Joshua D. Hensen, Lawrence G. Hamann, Donald P. McDonnell, Rama Krishna Narla, Mark Rolfe. Discovery of BMS-986365, a ligand-directed androgen receptor degrader (AR LDD) with a dual mechanism-of-action and best-in-class potential, for the treatment of advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr ND02.