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

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.

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.

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.

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.