Resistance to androgen receptor pathway inhibitors (ARPIs) necessitates development of regimens to improve outcomes in metastatic prostate cancer (mPC). This phase 1b clinical trial evaluated safety/tolerability and pharmacokinetics of bavdegalutamide, an oral PROteolysis TArgeting Chimera (PROTAC) androgen receptor (AR) degrader, combined with abiraterone in patients with mPC experiencing prostate-specific antigen (PSA) progression on abiraterone.
Patients received bavdegalutamide 420 mg, abiraterone ≤1000 mg, and corticosteroid daily. Assessments included safety (dose-limiting toxicities [DLTs]; treatment-emergent adverse events [TEAEs]), pharmacokinetics, PSA control rate, ≥50% PSA decline (PSA50), and radiographic progression-free survival (rPFS).
Forty-five patients were treated; seven had AR ligand-binding domain (LBD) mutations. Median duration of exposure was 35.7 weeks; 13 patients were continuing bavdegalutamide at data cutoff. No DLTs were observed. There were no clinically significant effects of bavdegalutamide on abiraterone pharmacokinetics. Bavdegalutamide 420 mg daily was selected as the recommended phase 2 dose. TEAEs were mostly grade 1/2 (82.2%), and 17.8% were grade 3. Dose modifications or discontinuations due to TEAEs occurred in 48.9% and 13.3% of patients, respectively. The most common bavdegalutamide-related TEAEs were fatigue (48.9%) and nausea (46.7%). PSA control rate was 48.9% (95% confidence interval [CI], 33.7‒64.2). PSA50 response rate was 24.4% (95% CI, 12.9‒39.5), including in 5/7 patients with AR LBD mutations. Median time to PSA progression was 2.8 months (95% CI, 1.5‒6.5). Median rPFS was 16.3 months (95% CI, 8.2‒not calculable).
Bavdegalutamide combined with abiraterone demonstrated a manageable safety profile with no major drug-drug interaction and evidence of clinical activity in mPC.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2026 Jun 02 [Epub ahead of print]
Martin Smoragiewicz, Alice Bernard-Tessier, Mark Linch, John Shen, Neal D Shore, Omi Parikh, Kim N Chi, Alexandra O Sokolova, Stephane Culine, Meredith McKean, Martin Gleave, Michael E Devitt, Eric Zhi, Jiachang Gong, Sean Landrette, Meghan Colasanto, Vaibhav Patel, Xin Gao
Sunnybrook Health Science Centre Toronto Canada., Institut Gustave Roussy Villejuif France., University College London Cancer Institute London United Kingdom., UCLA Jonsson Comprehensive Cancer Center United States., Carolina Urologic Research Center Myrtle Beach, SC United States., Lancashire Teaching Hospitals NHS Foundation Trust Preston United Kingdom., BC Cancer Foundation Vancouver, British Columbia Canada., Oregon Health & Science University Portland, OR United States., Hôpital Saint-Louis Paris France., Sarah Cannon Nashville, TN United States., University of British Columbia Vancouver, BC Canada., University of Virginia Charlottesville, Virginia United States., Arvinas (United States) New Haven United States., Arvinas United States., Arvinas (United States) New Haven, CT United States., Boehringer Ingelheim Ridgefield, CT United States., Massachusetts General Hospital Boston, Massachusetts United States.