Insights Into Vepdegestrant (ARV-471): The First-in-Class Estrogen Receptor Proteolysis-Targeting Chimera Approaching Food and Drug Administration Approval for Breast Cancer.

This publication is a concise review of vepdegestrant (ARV-471), an orally bioavailable PROTAC-based estrogen receptor (ER) degrader being developed for advanced or metastatic ER-positive, HER2-negative breast cancer, particularly in tumors with ESR1 mutations.

The article outlines:

• Drug concept and design: Vepdegestrant was generated through rational medicinal chemistry optimization as a proteolysis-targeting chimera (PROTAC) that binds ER and recruits the ubiquitin–proteasome system to drive ER degradation rather than simple antagonism.
• Mechanism of action: As a PROTAC, it functions by inducing targeted ER degradation via the ubiquitin–proteasome pathway, offering a mechanistically distinct approach from traditional endocrine therapies and SERDs.
• Preclinical pharmacology: The review summarizes nonclinical work supporting its ability to degrade ER and its potential activity in models of ER-positive disease, including those with ESR1 mutations.
• Clinical development status: It highlights that an NDA was submitted to the U.S. FDA on June 6, 2025, underscoring its status as one of the most clinically advanced ER-targeting PROTAC degraders.
• Broader implications: The authors discuss how oral PROTAC-based ER degraders could expand treatment options in breast cancer, especially in endocrine-resistant settings, and consider the future prospects of this drug class in clinical oncology.