Bevdegalutamide active in heavily pretreated metastatic prostate cancer
SAN FRANCISCO — Bavdegalutamide demonstrated clinical activity among heavily pretreated men with metastatic castration-resistant prostate cancer who received novel hormonal agents, according to study results presented at ASCO Genitourinary Cancers Symposium.
The agent conferred the greatest benefit to men with androgen receptor (AR) T878 or H875 mutations, suggesting this is a particularly AR-dependent, bavdegalutamide-sensitive population.
“Bavdegalutamide merits further investigation [among] men with metastatic castration-resistant prostate cancer,” Xin Gao, MD, medical oncologist at Massachusetts General Hospital Cancer Center, said during a presentation.
Treatment options are limited for men with metastatic castration-resistant prostate cancer because tumors exhibit decreasing androgen receptor dependence after successive therapies.
Bavdegalutamide (ARV-110, Arvinas) is a novel proteolysis targeting chimera protein degrader that selectively targets the androgen receptor.
At ASCO GU, Gao reported findings from an ongoing phase 1/phase 2 study.
The phase 1 portion included 67 men with metastatic castration-resistant prostate cancer who experienced disease progression after two or more therapies, including enzalutamide (Xtandi; Astellas, Pfizer) or abiraterone acetate (Zytiga, Janssen).
Men received ARV-110 orally once or twice daily in sequential cohorts. Doses ranged from 35 mg to 700 mg daily, or 210 mg to 420 mg twice daily.
Safety and selection of the recommended phase 2 dose served as primary objectives.
Researchers chose 420 mg daily as the recommended phase 2 dose based on safety, efficacy and pharmacokinetics.
Phase 1 data showed ARV-110 had clinical activity among heavily pretreated men with metastatic prostate cancer. Those findings also suggested enhanced activity among men with specific molecular profiles, including AR T878 and H875 mutations.
Researchers conducted a phase 2 expansion in hopes of better characterizing the agent among biomarker-defined subgroups.
Phase 2 included 106 men with metastatic castration-resistant disease who received one or two prior novel hormonal agents with no more than one prior chemotherapy regimen each for castration-sensitive and castration-resistant disease.
Researchers assigned these men to one of three biomarker-defined subgroups: presence of AR T878A/S and/or H875Y mutations; presence of AR L702H mutation or AR-V7 (including co-occurring T878X/H875Y variants); or wild-type AR or other AR alterations.
A fourth subgroup included men with less prior therapy — specifically no more than one therapy for metastatic castration-resistant disease, receipt of one novel hormonal agent and no prior chemotherapy.
PSA response rate, RECIST response rate, PFS and radiographic PFS served as primary endpoints. Secondary endpoints included duration of response, OS, adverse events and laboratory abnormalities.
Gao presented an analysis of complete phase 1 data (n = 71) and interim phase 2 data (n = 124), based on data cutoff of Dec. 20, 2021.
Baseline characteristics appeared consistent with what is expected for a population of patients with refractory metastatic castration-resistant disease, Gao said. Approximately 35% of all patients had visceral disease. Median number of prior therapies was six (range, 2-14) for the phase 1 population and four (range, 1-11) for the phase 2 population.
Twenty-eight men had tumors that harbored AR T878X/H875Y mutations. Twelve (43%) received bavdegalutamide for at least 24 weeks.
A higher percentage of men with those mutations than without achieved PSA declines of at least 50% (46% vs. 10%) or at least 30% (58% vs. 23%).
Two of seven men with AR T878X/H875Y mutations achieved confirmed partial responses per RECIST. Six of those seven exhibited tumor shrinkage, and three remained on therapy.
No grade 4 or higher treatment-related adverse events occurred among men who received the recommended phase 2 dose. Eleven men (8%) treated at this dose level experienced treatment-related adverse events that led to dose reduction, and 12 (9%) experienced events that led to discontinuation.
The most frequently reported treatment-related adverse events at the recommended phase 2 dose included nausea (any grade, 48%; grade 3, 1%), fatigue (any grade, 36%; grade 3, 1%), vomiting (any grade, 26%; grade 3, 1%), decreased appetite (any grade, 25%; grade 3, 1%) and diarrhea (any grade, 20%; grade 3, 2%).
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Gao X, et al. Abstract 17. Presented at: ASCO Genitourinary Cancers Symposium; Feb. 17-19, 2022; San Francisco.