UPDATE: Bavdegalutamide Shows Stronger Activity in Prostate Cancers With Specific AR Mutations

New phase 1/2 results published in the Journal of Clinical Oncology provide further evidence of the clinical activity of bavdegalutamide (ARV-110), an experimental androgen receptor (AR) degrader, in patients with metastatic castration-resistant prostate cancer (mCRPC). The findings suggest that specific AR mutations may help identify patients most likely to benefit from this treatment.

Unlike conventional androgen receptor inhibitors, bavdegalutamide is a PROTAC (proteolysis-targeting chimera) designed to trigger the destruction of the androgen receptor itself, rather than simply blocking its activity. The drug recruits the cell’s protein-degradation machinery to eliminate the receptor, potentially overcoming certain mechanisms of resistance to existing hormonal therapies.

The open-label study enrolled 239 patients previously treated with at least one androgen receptor pathway inhibitor, including 95 in phase 1 and 144 in phase 2. The recommended dose was established at 420 mg orally once daily. Phase 2 evaluated treatment activity in subgroups defined by their AR molecular profile.

The strongest results were observed in patients whose tumours carried AR T878 and/or H875 mutations. In this subgroup of 20 patients, 60% achieved a PSA reduction of at least 50% (PSA50), while 25% achieved a reduction of at least 90%. Median radiographic progression-free survival (rPFS) was 11.1 months.

By comparison, the PSA50 rate was only 4.3% among 46 patients with wild-type AR or other alterations, and 3.1% among 32 patients with AR L702H mutations or AR-V7 expression. Median rPFS was 4.2 and 5.1 months, respectively. In a separate group of 42 less heavily pretreated patients, the PSA50 rate was 21.4%, with a median rPFS of 11.1 months.

In phase 2, treatment-related grade 3 adverse events occurred in 17.4% of patients, with no grade 4 or higher treatment-related events reported. The most common side effects included nausea, fatigue, vomiting, reduced appetite and diarrhoea. Treatment-related adverse events led to dose reductions in 11.8% of patients and treatment discontinuation in 11.1%.

These findings suggest that bavdegalutamide’s activity may depend substantially on the molecular characteristics of the androgen receptor, highlighting the potential importance of genomic profiling in selecting patients for AR-targeted protein degradation.

Source.