Multicenter phase 1-2 trial of bavdegalutamide for metastatic castration-resistant prostate cancer

Bavdegalutamide (ARV-110) is a proteolysis-tagering chimera androgen receptor (AR) degrader. A multicenter phase 1-2 trial in the USA evaluated safety and efficacy of bavdegalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with an AR pathway inhibitor (ARPI). In phase 1, patients received escalating doses of oral bavdegalutamide to determine the recommended phase 2 dose (RP2D). In phase 2, patients received bavdegalutamide at the RP2D. Antitumor activity, including PSA response rate (≥ 50% or ≥ 30% decline from baseline; PSA₅₀ and PSA₃₀) and radiographic progression-free survival (rPFS) was assessed in three AR molecular profile-defined subgroups and one less-pretreated subgroup (one prior ARPI without prior chemotherapy). In phase 1 (n=95), bavdegalutamide 420 mg once daily was the RP2D. In phase 2, PSA₅₀ and PSA₃₀ rates, respectively, were 60.0% and 70.0% among patients among patients harboring AR T878 and or H875 mutations (n=20), 4.3% and 6.5% among those with wild-type AR or other AR alterations (n=46), and 3.1% and 6.3% among those with AR L702H mutations or AR splice variant 7 expression (n=32); the median rPFS in these three subgroups was 11.1, 4.2, and 5.1 months. In the less-pretreated subgroup (n=42), the PSA₅₀ rate was 21.4% while the PSA₃₀ rate was 23.8% and the median rPFS was 11.1 months. Among phase 2 patients (n=144), 72.3% experienced grade 1-2 treatment-related adverse events (TRAEs), and 17.4% experienced grade 3 TRAEs; no grade 4 or 5 TRAEs occurred. TRAEs led to dose reduction in 11.8% of patients and to discontinuation in 11.1%. The authors conclude that bavdegalutamide had a manageable safety profile and showed promising clinical activity in patients with mCRPC, particularly those with tumors harboring AR T878/H875 mutations.