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.

Autor:	Rathkopf DE; Memorial Sloan Kettering Cancer Center, New York. Electronic address: rathkopd@mskcc.org., Patel MR; Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota., Choudhury AD; Dana-Farber Cancer Institute, Boston., Rasco D; START Center for Cancer Care, San Antonio., Lakhani N; START Midwest, Grand Rapids., Hawley JE; University of Washington, Fred Hutch Cancer Center, Seattle., Srinivas S; Stanford University Medical Center, Stanford., Aparicio A; UT MD Anderson Cancer Center, Houston., Narayan V; Abramson Cancer Center and Perelman School of Medicine, University of Pennsylvania, Philadelphia., Runcie KD; New York-Presbyterian/Columbia University Medical Center, New York., Emamekhoo H; Carbone Cancer Center, University of Wisconsin-Madison, Madison., Reichert ZR; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor., Nguyen MH; Bristol Myers Squibb, Princeton., Wells AL; Bristol Myers Squibb, San Francisco., Kandimalla R; Bristol Myers Squibb, Princeton., Liu C; Bristol Myers Squibb, Princeton., Suryawanshi S; Bristol Myers Squibb, Princeton., Han J; Bristol Myers Squibb, San Francisco., Wu J; Bristol Myers Squibb, Princeton., Arora VK; Bristol Myers Squibb, Princeton., Pourdehnad M; Bristol Myers Squibb, San Francisco., Armstrong AJ; Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University, Durham, USA.
Jazyk:	angličtina
Zdroj:	Annals of oncology : official journal of the European Society for Medical Oncology [Ann Oncol] 2025 Jan; Vol. 36 (1), pp. 76-88. Date of Electronic Publication: 2024 Sep 16.
DOI:	10.1016/j.annonc.2024.09.005
Abstrakt:	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. (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze:	MEDLINE
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