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 1 multicenter study of BMS-986365 in patients with progressive mCRPC.
Patients who progressed on androgen deprivation therapy, ≥ 1 ARPI, 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 (BID). Primary objectives were safety, tolerability, and to define maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). Key secondary endpoints included decline in prostate-specific antigen ≥50% (PSA50) and radiographic progression-free survival (rPFS).
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 (TRAEs) were asymptomatic prolonged corrected QT interval (47%) and bradycardia (34%). Part A MTD was not reached and RP2D selection is ongoing. Across Part B three highest doses (400-900 mg BID, n = 60), PSA50 was 32% (n = 19), including 50% (n = 10/20) at 900 mg; median rPFS (95% CI) was 6.3 months (5.3-12.6), including 8.3 months (3.8-16.6) at 900 mg; and rPFS was longer in patients without versus with prior chemotherapy: 16.5 months (5.5-not evaluable) versus 5.5 months (2.7-8.3), respectively. Efficacy was observed in patients with AR ligand binding domain (LBD) WT or with AR LBD mutations.
BMS-986365 was well tolerated, with a manageable safety profile, and demonstrated activity in heavily pretreated patients with potentially higher benefit in chemotherapy-naïve patients. These data show BMS-986365's potential to overcome resistance to current ARPIs, regardless of AR LBD mutation status.
Annals of oncology : official journal of the European Society for Medical Oncology. 2024 Sep 10 [Epub ahead of print]
D Rathkopf, M R Patel, A D Choudhury, D Rasco, N Lakhani, J E Hawley, S Srinivas, A Aparicio, V Narayan, K D Runcie, H Emamekhoo, Z R Reichert, M H Nguyen, A L Wells, R Kandimalla, C Liu, S Suryawanshi, J Han, J Wu, V K Arora, M Pourdehnad, A J Armstrong
Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: rathkopd@mskcc.org., Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, FL, USA., Dana-Farber Cancer Institute, Boston, MA, USA., START Center for Cancer Care, San Antonio, TX, USA., START Midwest, Grand Rapids, MI, USA., University of Washington, Fred Hutch Cancer Center, Seattle, WA, USA., Stanford University Medical Center, Stanford, CA, USA., UT MD Anderson Cancer Center, Houston, TX, USA., Abramson Cancer Center and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., New York-Presbyterian/Columbia University Medical Center, New York, NY, USA., Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA., Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA., Bristol Myers Squibb, Princeton, NJ, USA., Bristol Myers Squibb, San Francisco, CA, USA., Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University, Durham, NC, USA.