Vepdegestrant (ARV-471): A Comprehensive Clinical and Strategic Analysis of a First-in-Class PROTAC Estrogen Receptor Degrader

I. Executive Summary

Vepdegestrant (developmental code: ARV-471) represents a paradigm shift in endocrine therapy for breast cancer, emerging as the first orally bioavailable PROteolysis TArgeting Chimera (PROTAC) protein degrader to demonstrate clinical benefit in a Phase III trial.[1] Developed by Arvinas, Inc., in collaboration with Pfizer Inc., Vepdegestrant is designed to harness the body's natural protein disposal machinery to selectively and efficiently eliminate the estrogen receptor (ER), a key driver of the most common subtype of breast cancer.[4] This report provides a comprehensive analysis of Vepdegestrant, detailing its novel mechanism of action, the full arc of its clinical development, its position within the competitive landscape, and the strategic decisions shaping its future.

The cornerstone of Vepdegestrant's clinical validation is the pivotal Phase III VERITAC-2 trial, which evaluated its efficacy and safety against the current standard-of-care selective estrogen receptor degrader (SERD), fulvestrant.[1] The trial met its primary endpoint in the prespecified population of patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced or metastatic breast cancer harboring an activating mutation in the estrogen receptor 1 gene (

ESR1).[2] In this high-need patient group, Vepdegestrant demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS), more than doubling the median PFS from 2.1 months with fulvestrant to 5.0 months.[6]