Safety and clinical activity of BMS-986365 (CC-94676), a dual androgen receptor ligand-directed degrader and antagonist, in heavily pretreated patients with metastatic castration-resistant prostate cancer

  • Ann Oncol. 2024 Sep 16:S0923-7534(24)04001-8. doi: 10.1016/j.annonc.2024.09.005.
D E Rathkopf  1 ,  M R Patel  2 ,  A D Choudhury  3 ,  D Rasco  4 ,  N Lakhani  5 ,  J E Hawley  6 ,  S Srinivas  7 ,  A Aparicio  8 ,  V Narayan  9 ,  K D Runcie  10 ,  H Emamekhoo  11 ,  Z R Reichert  12 ,  M H Nguyen  13 ,  A L Wells  14 ,  R Kandimalla  13 ,  C Liu  13 ,  S Suryawanshi  13 ,  J Han  14 ,  J Wu  13 ,  V K Arora  13 ,  M Pourdehnad  14 ,  A J Armstrong  15
Affiliations
  • 1. Memorial Sloan Kettering Cancer Center, New York. Electronic address: [email protected].
  • 2. Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota.
  • 3. Dana-Farber Cancer Institute, Boston.
  • 4. START Center for Cancer Care, San Antonio.
  • 5. START Midwest, Grand Rapids.
  • 6. University of Washington, Fred Hutch Cancer Center, Seattle.
  • 7. Stanford University Medical Center, Stanford.
  • 8. UT MD Anderson Cancer Center, Houston.
  • 9. Abramson Cancer Center and Perelman School of Medicine, University of Pennsylvania, Philadelphia.
  • 10. New York-Presbyterian/Columbia University Medical Center, New York.
  • 11. Carbone Cancer Center, University of Wisconsin-Madison, Madison.
  • 12. Rogel Cancer Center, University of Michigan Medical School, Ann Arbor.
  • 13. Bristol Myers Squibb, Princeton.
  • 14. Bristol Myers Squibb, San Francisco.
  • 15. Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University, Durham, USA.
PMID: 39293515 DOI: 10.1016/j.annonc.2024.09.005
Abstract

Background: Metastatic castration-resistant prostate Cancer (mCRPC) that progresses on Androgen Receptor pathway inhibitors (ARPIs) may continue to be driven by AR signaling. BMS-986365 is an orally administered ligand-directed degrader targeting the AR via a first-in-class dual mechanism of AR degradation and antagonism. CC-94676-PCA-001 (NCT04428788) is a phase I multicenter study of BMS-986365 in patients with progressive mCRPC.

Patients and methods: Patients who progressed on androgen deprivation therapy, one or more ARPIs, and taxane chemotherapy (unless declined/ineligible) were enrolled. The study included dose escalation (part A) and expansion (part B) of BMS-986365 up to 900 mg twice daily. Primary objectives were safety and tolerability, and to define maximum tolerated dose and/or recommended phase II dose. Key secondary endpoints included decline in prostate-specific antigen ≥50% (PSA50) and radiographic progression-free survival (rPFS).

Results: Parts A and B enrolled 27 and 68 patients, respectively. In part B, the median number of prior therapies was 4 (range 2-11). The most common treatment-related adverse events were asymptomatic prolonged corrected QT interval (47%) and bradycardia (34%). Part A maximum tolerated dose was not reached and recommended phase II dose selection is ongoing. Across part B three highest doses (400-900 mg twice daily, n = 60), PSA50 was 32% (n = 19), including 50% (n = 10/20) at 900 mg; median rPFS (95% confidence interval) was 6.3 months (5.3-12.6 months), including 8.3 months (3.8-16.6 months) at 900 mg; and rPFS was longer in patients without versus with prior chemotherapy: 16.5 months (5.5 months-not evaluable) versus 5.5 months (2.7-8.3 months), respectively. Efficacy was observed in patients with mCRPC with AR ligand binding domain (LBD) WT or with AR LBD mutations.

Conclusions: BMS-986365 was well tolerated, with a manageable safety profile, and demonstrated activity in heavily pretreated patients with mCRPC with potentially higher benefit in chemotherapy-naive patients. These data show the potential of BMS-986365 to overcome resistance to current ARPIs, regardless of AR LBD mutation status.

Keywords
androgen receptor antagonist; androgen receptor pathway inhibitor; ligand binding domain; ligand-directed degrader; mCRPC; protein degradation.
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