Discovery of BMS-986365, a first-in-class dual androgen receptor ligand-directed degrader (AR LDD) and antagonist, for the treatment of advanced prostate cancer.

BMS-986365, a heterobifunctional AR LDD, was designed as a potent cereblon-dependent degrader and competitive antagonist of AR to overcome resistance to ARPIs in metastatic prostate cancer (PC). In vitro impact of BMS-986365-induced AR degradation on AR activity and PC cell proliferation was evaluated. Intrinsic agonistic and antagonist activities of BMS-987365 were assessed. In vivo anti-tumor activity of BMS-986365 was compared with enzalutamide in cell line- or patient-derived PC models. BMS-986365 is a potent, rapid, and selective degrader of AR wildtype and most clinically relevant mutants. Degradation of both wildtype 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 PC cell lines. While enzalutamide increased AR protein in mCRPC 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 PC and advanced and/or therapy-resistant CRPC. Clinically, BMS-986365 reduced prostate‑specific antigen in patients with mCRPC post ARPI, including patients with wildtype 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 PC.