The novel androgen receptor degrader bavdegalutamide demonstrated a manageable safety profile and antitumor activity in patients with metastatic castration–resistant prostate cancer previously treated with androgen receptor pathway inhibitors, particularly those with tumors harboring specific androgen receptor mutations, according to findings from a phase I/II study reported by Gao et al in the Journal of Clinical Oncology.
Study Details
The open-label, phase I/II study (ClinicalTrials.gov identifier NCT03888612) enrolled 239 patients at 20 U.S. sites. Eligible patients had metastatic castration–resistant prostate cancer and had previously received at least one androgen receptor pathway inhibitor. The investigators evaluated bavdegalutamide (ARV-110), a proteolysis-targeting chimera (PROTAC) designed to promote androgen receptor degradation through recruitment of an E3 ubiquitin ligase.
In phase I, 95 patients (median age = 71 years, range = 45–85 years) received escalating oral doses of bavdegalutamide to assess safety and tolerability, estimate the maximum tolerated dose, and select the recommended phase II dose. In phase II, 144 patients (median age = 73 years, range = 48–91 years) received the recommended dose of 420 mg once daily in 28-day cycles, with the primary objective of evaluating antitumor activity in prespecified molecular subgroups.
Efficacy was assessed in three subgroups based on androgen receptor alterations: T878 and/or H875 mutations; wild-type androgen receptor or other alterations; and L702H mutations or androgen receptor splice variant 7 expression.
A separate less-pretreated subgroup included patients who had received one prior androgen receptor pathway inhibitor without chemotherapy. Efficacy assessments included prostate-specific antigen (PSA) responses and radiographic progression-free survival.
Key Results
In phase II, patients with T878 and/or H875 mutations had the highest PSA response rates. Among 20 evaluable patients, 60.0% achieved a PSA reduction of at least 50%, and 70.0% achieved a reduction of at least 30%. Corresponding rates were 4.3% and 6.5% in the wild-type/other subgroup (n = 46), 3.1% and 6.3% in the L702H/splice variant 7 subgroup (n = 32), and 21.4% and 23.8% among less-pretreated patients (n = 42).
Median radiographic progression-free survival was 11.1 months (95% confidence interval [CI] = 3.61–not reached) in the T878/H875 subgroup, 4.2 months (95% CI = 3.58–8.28) in the wild-type/other subgroup, and 5.1 months (95% CI = 3.02–8.28) in the L702H/splice variant 7 subgroup. It was also 11.1 months (95% CI = 3.75–22.11) among less-pretreated patients.
In phase II, grade 1 or 2 treatment-related adverse events occurred in 72.2% of patients and grade 3 events occurred in 17.4% (no grade 4 or higher events were observed). The most common treatment-related adverse events were nausea (56.3%), fatigue (36.1%), vomiting (34.0%), decreased appetite (27.8%), and diarrhea (24.3%). Treatment-related adverse events prompted dose reductions in 11.8% of patients and discontinuation in 11.1%.
The authors concluded: “Bavdegalutamide had a manageable safety profile and showed promising clinical activity in patients with [metastatic castration–resistant prostate cancer], particularly those with tumors harboring [androgen receptor] T878/H875 mutations.”
Daniel P. Petrylak, MD, of Smilow Cancer Center, Yale School of Medicine, New Haven, Connecticut, is the corresponding author for the Journal of Clinical Oncology article.
DISCLOSURE: The study was supported by Arvinas Androgen Receptor, Inc. For full disclosures of the study authors, visit ascopubs.org.
