1597MO - Clinical activity of BMS-986365 (CC-94676), a dual androgen receptor (AR) ligand-directed degrader and antagonist, in heavily pretreated patients (pts) with metastatic castration-resistant prostate cancer (mCRPC)

Background

The majority of mCRPC remains AR-dependent even if resistant to AR pathway inhibitors (ARPI) such as enzalutamide (ENZ) and abiraterone (ABI). BMS-986365 is a heterobifunctional, oral therapy designed to inhibit AR activity via a first-in-class dual mechanism of AR degradation and antagonism. We report updated results from CC-94676-PCA-001 (NCT04428788), the first-in-human, multicenter study of BMS-986365 in pts with progressive mCRPC.

Methods

Pts with mCRPC who progressed on antiandrogen therapy including ≥ 1 ARPI (eg, ENZ, ABI) were enrolled. Pts had prior taxane chemotherapy (CT) unless ineligible or declined. Data reported are from the Part B dose expansion at 400, 600, or 900 mg BID (n = 20 each). PSA data are best changes from baseline.

Results

Of 60 pts, prior therapy included CT (n = 28; 47%), ENZ (n = 45; 75%), and ABI (n = 39; 65%); 45% received both ENZ and ABI. As of Feb 1, 2024, 48% achieved PSA30 and 32% PSA50; median rPFS was 6.3 mo. PSA30 and rPFS increased with dose (Table). PSA responses were seen both in pts with AR WT (including AR amplification) and ligand binding domain mutations (LBD mut). Pts with (n = 28) vs without (n = 32) prior CT had median rPFS of 5.5 vs 16.5 mo, respectively. There were no ≥ G4 treatment-related adverse events (TRAE) or discontinuations due to TRAE. The most common TRAE were prolonged QTc (asymptomatic) (47%; G3 10%), bradycardia (37%; G3 0%), and fatigue (22%; G3 0%). G3 QTc prolongation was successfully managed by dose reduction.

Conclusions

BMS-986365 demonstrated activity in heavily pretreated pts post-ARPI, especially encouraging durability in pts with no prior CT, and was well tolerated, with a manageable safety profile. These data show potential of BMS-986365 to overcome resistance to current ARPI in a large segment of pts regardless of AR genomic status. Table: 1597MO

Data by dose

BID, twice a day; PSA, prostate-specific antigen; PSAXX, ≥ XX% decline in PSA (locally assessed, best % change, either confirmed or unconfirmed, from baseline); NE, not estimable; rPFS, radiographic progression-free survival.

Clinical trial identification

NCT04428788.

Editorial acknowledgement

Writing and editorial assistance were provided by Benjamin Levine, PhD, and Tina Allen, BSc, of Spark (a division of Prime, New York, USA).

Legal entity responsible for the study

Bristol Myers Squibb.

Funding

Bristol Myers Squibb.

Disclosure

D. Rathkopf: Financial Interests, Trial Chair: Janssen; Financial Interests, Steering Committee Member: Janssen; Financial Interests, Institutional, Research Grant, Clinical Trial Grant: Genentech; Non-Financial Interests, Advisory Role: Janssen, Genentech, AstraZeneca, Myovant, Bayer, BMS; Non-Financial Interests, Principal Investigator: Janssen, Genentech, Promontory, BMS, BMS. M.R. Patel: Financial Interests, Personal, Advisory Board: Daiichi Sankyo, Janssen, Accutar; Financial Interests, Institutional, Local PI, institution received research funding: Daiichi Sankyo. A.D. Choudhury: Financial Interests, Personal, Advisory Role: Bayer, Lilly, Blackstone, Astellas Pharma, Astra, Bayer, Blue Earth Diagnostics, Janssen Oncology, Tolmar, Sanofi/Aventis, Pfizer; Financial Interests, Personal, Other, Honoraria: OncLive, Bayer, Targeted Oncology, Apititude Health, Journal of Clinical Pathways/Oncology Learning Network, Cancer Network, Clinical Care Options, Great Debates and Updates, Pfizer, Springer, Lantheus Medical Imaging, Wiley, Color Genomics, Physicians' Education Resource; Financial Interests, Institutional, Research Funding: Janssen, Bayer, Pfizer. D. Rasco: Financial Interests, Institutional, Funding, Research funding to my institution: Bristol Myers Squibb. N.J. Lakhani: Financial Interests, Personal, Advisory Board: Innovent Biologics; Financial Interests, Personal, Advisory Board, Participation in Ad Board: Ikena, SK Life Sciences; Financial Interests, Institutional, Local PI: ALX Therapeutics, Ascentage, Constellation Pharma, Alpine Biosciences, Forty Seven, Merck, Pfizer, Regeneron, Symphogen, InhibRx, Seagen, Sapience Therapeutics, Jounce, Northern Biologics, Odonate, Loxo/Lilly, Ikena, Mersana Therapeutics, Astellas, Celgene, Helsinn, Shattuck Labs, Samumed, GSK, Alkermes, Samumed, Tizona Therapeutics, Gilead, Repare Therapeutics, Alkermes, InhibRx, Janssen, cytomX, KSQ Therapeutics, Repare Therapeutics, Arcus Bio, Artios, Revolution Medicines, Volastra; Financial Interests, Institutional, Coordinating PI: Servier. J. Hawley: Financial Interests, Personal, Advisory Board: Seagen, Daiichi Sankyo, Immunity Bio; Financial Interests, Institutional, Local PI: Bristol Myers Squibb, AstraZeneca, Vaccitech, Crescendo Biologics, Macrogenics, Amgen, J&J Innovative Medicine; Non-Financial Interests, Institutional, Other, Data and analysis of correlative studies from completed trials: Dendreon. S. Srinivas: Financial Interests, Personal, Advisory Board: Janssen, Novartis; Financial Interests, Local PI: Seagen; Financial Interests, Institutional, Local PI: Novartis, REGN, Merck. A. Aparicio: Financial Interests, Personal, Advisory Board: Genzyme, Janssen Pharmaceuticals, Pfizer, Sanofi. V. Narayan: Financial Interests, Personal, Advisory Role: Merck, AstraZeneca, Janssen Oncology, Pfizer/EMD Serono, Myovant Sciences, Regeneron, Amgen; Financial Interests, Personal, Advisory Board: Exelixis; Financial Interests, Personal, Other, Honoraria: Pfizer; Financial Interests, Institutional, Research Funding: Pfizer, Bristol Myers Squibb, Merck; Financial Interests, Institutional, Advisory Board: Janssen, Tmunity Therapeutics, Inc., Regeneron. K. Runcie: Financial Interests, Personal, Other, Virtual round table discussing updates in kidney cancer from ASCO 2024: VJ Oncology; Financial Interests, Personal and Institutional, Steering Committee Member: Janssen; Financial Interests, Institutional, Local PI: Exelixis, Inc., Bristol Myers Squibb, Xencor, Trisalus Life Sciences, Amgen, Novartis. H. Emamekhoo: Financial Interests, Personal, Advisory Board: Janssen, Aveo, Cardinal Health, Eisai, BMS. Z. Reichert: Financial Interests, Personal, Advisory Board: Huff Powell Bailey, AstraZeneca; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Celgene. H. Nguyen: Financial Interests, Personal, Full or part-time Employment: FogPharma; Financial Interests, Personal, Stocks/Shares: BMS. A. Wells: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb; Financial Interests, Personal, Other, Travel, accommodations expenses: Bristol Myers Squibb. S. Suryawanshi, V. Arora, M. Pourdehnad: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. J. Wu: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb. A.J. Armstrong: Financial Interests, Personal, Other, Consultant: Astellas; Financial Interests, Personal, Advisory Board: Pfizer, AstraZeneca, Merck, Bayer, Janssen, Myovant, Telix, Z Alpha; Financial Interests, Institutional, Coordinating PI: Pfizer, Janssen, BMS, Bayer, Astellas, Pathos; Financial Interests, Institutional, Local PI: Merck, Amgen; Financial Interests, Institutional, Steering Committee Member: AstraZeneca. All other authors have declared no conflicts of interest.