Phase Ib Trial of Bavdegalutamide (ARV-110) in Combination with Abiraterone for Metastatic Prostate Cancer.

PURPOSE: Resistance to androgen receptor (AR) pathway inhibitors necessitates the development of regimens to improve outcomes in metastatic prostate cancer (mPC). This phase Ib clinical trial evaluated the safety/tolerability and pharmacokinetics of bavdegalutamide, an oral proteolysis-targeting chimera AR degrader, combined with abiraterone in patients with mPC experiencing prostate-specific antigen (PSA) progression on abiraterone.

PATIENTS AND

METHODS

Patients received bavdegalutamide 420 mg, abiraterone ≤1,000 mg, and corticosteroid daily. Assessments included safety [dose-limiting toxicities (DLT); treatment-emergent adverse events (TEAE)], pharmacokinetics, PSA control rate, ≥50% PSA decline (PSA50), and radiographic progression-free survival (rPFS).

RESULTS

Forty-five patients were treated; seven had AR ligand-binding domain (LBD) mutations. The median duration of exposure was 35.7 weeks; 13 patients were continuing bavdegalutamide at the 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 II 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%). The PSA control rate was 48.9% [95% confidence interval (CI), 33.7-64.2]. The PSA50 response rate was 24.4% (95% CI, 12.9-39.5), including in five out of seven patients with AR LBD mutations. The median time to PSA progression was 2.8 months (95% CI, 1.5-6.5). The median rPFS was 16.3 months (95% CI, 8.2-not calculable).

CONCLUSIONS

Bavdegalutamide combined with abiraterone demonstrated a manageable safety profile with no major drug-drug interactions and evidence of clinical activity in mPC.