Vepdegestrant
Vepdegestrant is an investigational oral proteolysis-targeting chimera compound that targets the estrogen receptor for protein degradation. It is being developed for the treatment of estrogen receptor-positive, HER2-negative breast cancer by Arvinas and Pfizer.
Mechanism of action
Vepdegestrant is designed as a PROTAC that recruits the ubiquitin-proteasome system to target the estrogen receptor for degradation. The compound contains both an E3 ubiquitin ligase-binding moiety and an estrogen receptor-binding domain, intended to bring these proteins into proximity to trigger ubiquitination and subsequent proteasomal degradation of the ER protein.In laboratory studies, vepdegestrant demonstrated ER degradation in ER-positive breast cancer cell lines with reported DC50 values of approximately 1-2 nM.
Clinical development
Phase I/II trials
Vepdegestrant has been evaluated in early-phase clinical trials as both monotherapy and in combination with other agents in patients with ER+/HER2- breast cancer. In a first-in-human Phase I/II study, vepdegestrant monotherapy was well tolerated and showed clinical activity in pretreated patients.Phase III VERITAC-2 trial
The Phase III VERITAC-2 trial is a randomized, open-label study comparing vepdegestrant to fulvestrant in patients with ER+/HER2- advanced breast cancer. The trial enrolled 624 patients at sites in 26 countries who had previously received treatment with a CDK4/6 inhibitor plus endocrine therapy.In March 2025, results were announced from the VERITAC-2 trial. According to company statements, the study met its primary endpoint in the ESR1-mutant patient population, showing improvement in progression-free survival compared to fulvestrant. However, the trial did not achieve statistical significance in the overall intent-to-treat population. Detailed results were presented at the 2025 American Society of Clinical Oncology Annual Meeting.
Preclinical studies
In preclinical studies, vepdegestrant achieved greater ER degradation in vivo compared with fulvestrant, which correlated with improved tumor growth inhibition. The compound showed high efficacy as monotherapy and demonstrated synergistic effects when combined with CDK4/6 inhibitors or PI3K/mTOR pathway inhibitors in preclinical ER+ breast cancer models.Regulatory status
The U.S. Food and Drug Administration granted Fast Track designation to vepdegestrant in February 2024 as a monotherapy for the treatment of adults with ER+/HER2- metastatic breast cancer.Following company-reported results from the VERITAC-2 trial, Arvinas stated it submitted a New Drug Application to the FDA in June 2025 for vepdegestrant in patients with ESR1-mutant ER+/HER2- advanced or metastatic breast cancer whose disease progressed following previous treatment.