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

  • Clin Cancer Res. 2025 Aug 11. doi: 10.1158/1078-0432.CCR-25-0471.
Surendra Nayak  1 ,  John D Norris  2 ,  Massimo Ammirante  3 ,  Emily Rychak  3 ,  Suzanne E Wardell  4 ,  Debbie Liao  3 ,  Brandon Toyama  3 ,  Raju Kandimalla  1 ,  Andy Christoforou  3 ,  Toshiya Tsuji  3 ,  Ken Liu  3 ,  Minerva Tran  3 ,  Joseph Meiring  3 ,  Samantha Reiss  1 ,  Joseph R Piccotti  3 ,  Joshua M Baughman  3 ,  Celia Fontanillo  3 ,  Marwa Khater  3 ,  Deborah S Mortensen  1 ,  Brian Cathers  3 ,  Neil Bence  3 ,  Daniel W Pierce  3 ,  Veronique Plantevin-Krenitsky  3 ,  Dana Rathkopf  5 ,  Joshua D Hansen  3 ,  Lawrence G Hamann  3 ,  Rama Krishna Narla  1 ,  Vivek K Arora  6 ,  Donald P McDonnell  4 ,  Mark Rolfe  3 ,  Shuichan Xu  3
Affiliations
  • 1. Bristol-Myers Squibb (United States), San Diego, CA, United States.
  • 2. Duke University, Durham, North Carolina, United States.
  • 3. Bristol Myers Squibb, San Diego, CA, United States.
  • 4. Duke University, Durham, NC, United States.
  • 5. Memorial Sloan Kettering Cancer Center, New York, New York, United States.
  • 6. Washington University in St. Louis, St. Louis, MO, United States.
PMID: 40788283 DOI: 10.1158/1078-0432.CCR-25-0471
Abstract

Purpose: 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).

Experimental design: 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.

Results: 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.

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 PC.

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