Vepdegestrant
Chemical compound
From Wikipedia, the free encyclopedia
Vepdegestrant (developmental code name ARV-471) is an investigational oral proteolysis-targeting chimera (PROTAC) compound that targets the estrogen receptor for protein degradation. It is being developed for the treatment of estrogen receptor-positive, HER2-negative (ER+/HER2-) breast cancer by Arvinas and Pfizer.[1][2][3]
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| Other names | ARV-471 |
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| Formula | C45H49N5O4 |
| Molar mass | 723.918 g·mol−1 |
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Mechanism of action
Vepdegestrant is designed as a PROTAC that recruits the ubiquitin-proteasome system to target the estrogen receptor for degradation.[4] 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.[5] In laboratory studies, vepdegestrant demonstrated ER degradation in ER-positive breast cancer cell lines with reported DC50 values of approximately 1-2 nM.[6]
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.[7]
Phase III VERITAC-2 trial
The Phase III VERITAC-2 trial (NCT05654623) is a randomized, open-label study comparing vepdegestrant to fulvestrant in patients with ER+/HER2- advanced breast cancer.[8] The trial enrolled 624 patients at sites in 26 countries who had previously received treatment with a CDK4/6 inhibitor plus endocrine therapy.[9]
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.[9] However, the trial did not achieve statistical significance in the overall intent-to-treat population.[10] Detailed results were presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.[11]
Preclinical studies
In preclinical studies, vepdegestrant achieved greater ER degradation in vivo compared with fulvestrant, which correlated with improved tumor growth inhibition (TGI).[12] 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.[12]
Regulatory status
The U.S. Food and Drug Administration (FDA) granted Fast Track designation to vepdegestrant in February 2024 as a monotherapy for the treatment of adults with ER+/HER2- metastatic breast cancer.[13][14]
Following company-reported results from the VERITAC-2 trial, Arvinas stated it submitted a New Drug Application (NDA) 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.[15]