Discovery of BMS-986365, a First-in-Class Dual Androgen Receptor Ligand-Directed Degrader and Antagonist, for the Treatment of Advanced Prostate Cancer.

PURPOSE: BMS-986365, a heterobifunctional androgen receptor (AR) ligand-directed degrader, was designed as a potent cereblon-dependent degrader and competitive antagonist of the AR to overcome resistance to AR pathway inhibition (ARPI) in metastatic prostate cancer. EXPERIMENTAL DESIGN: The in vitro impact of BMS-986365-induced AR degradation on AR activity and prostate cancer cell proliferation was evaluated. Intrinsic agonistic and antagonist activities of BMS-986365 were assessed. The in vivo antitumor activity of BMS-986365 was compared with enzalutamide in multiple cell line- or patient-derived prostate cancer models. RESULTS: BMS-986365 is a potent, rapid, and selective degrader of AR wild-type (WT) and most of the clinically relevant mutants. Degradation of both WT and mutant AR is the key driver of BMS-986365 efficacy, with additional antagonism of residual AR activity enabled through occupancy of its ligand-binding domain. Compared with enzalutamide, BMS-986365 more efficiently inhibits AR target gene transcription and AR-dependent proliferation of prostate cancer cell lines. Whereas enzalutamide increased AR protein in metastatic castration-resistant prostate cancer (CRPC) models, BMS-986365 maintained low levels of AR protein despite increased AR transcript levels. In vivo, BMS-986365 demonstrated on-target activity, degrading AR, suppressing AR signaling, and inhibiting growth in validated cell line- and patient-derived xenograft models of castration-sensitive prostate cancer and advanced and/or therapy-resistant CRPC. Clinically, BMS-986365 reduced PSA in patients with metastatic CRPC after ARPI, including patients with WT AR. CONCLUSIONS: The preclinical observations, coupled with clinical data, strongly support the potential for BMS-986365 to overcome ARPI-resistant disease regardless of AR mutational status. These findings establish BMS-986365 as a first-in-class dual AR degrader and competitive antagonist, likely to emerge as an important tool in the armamentarium to treat prostate cancer. See related commentary by Nyquist and Nelson, p. 13.

Duke Scholars

Author John David Norris Pharmacology & Cancer Biology

Author Suzanne E Wardell Pharmacology & Cancer Biology

Author Donald Patrick McDonnell Pharmacology & Cancer Biology