Phase I/II Study of Bavdegalutamide, a Proteolysis-Targeting Chimera Androgen Receptor Degrader, in Metastatic Castration-Resistant Prostate Cancer

PURPOSE: This phase I/II study (which, to our knowledge, is the first such study in humans) evaluated the safety and efficacy of bavdegalutamide (ARV-110), a proteolysis-targeting chimera (PROTAC) androgen receptor (AR) degrader, in patients with metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: Eligible patients were adult (18 years and older) males with mCRPC previously treated with an AR pathway inhibitor (ARPI). In phase I, patients received escalating doses of oral bavdegalutamide to determine the recommended phase II dose (RP2D). In phase II, patients received bavdegalutamide at the RP2D in 28-day cycles. Antitumor activity, including prostate-specific antigen (PSA) response rate (≥50% [PSA₅₀] or ≥30% [PSA₃₀] decline from baseline) and radiographic progression-free survival (rPFS), was assessed in three AR molecular profile-defined subgroups and a less-pretreated (one prior ARPI without prior chemotherapy) subgroup. RESULTS: In phase I (N = 95), bavdegalutamide 420 mg once daily was the RP2D. In phase II, PSA₅₀ and PSA₃₀ rates, respectively, were 60.0% and 70.0% among patients with tumors 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 was 11.1, 4.2, and 5.1 months in the respective subgroups. Among less-pretreated patients (n = 42), the PSA₅₀ rate was 21.4%, the PSA₃₀ rate was 23.8%, and the median rPFS was 11.1 months. Among phase II patients (n = 144), 72.3% experienced grade 1/2 treatment-related adverse events (TRAEs) and 17.4% experienced grade 3 TRAEs; no grade ≥4 TRAEs occurred. TRAEs led to dose reduction and discontinuation in 11.8% and 11.1% of patients, respectively. CONCLUSION: Bavdegalutamide had a manageable safety profile and showed promising clinical activity in patients with mCRPC, particularly those with tumors harboring AR T878/H875 mutations.