FDA Approves Veppanu (Vepdegestrant): World's First PROTAC Drug for ESR1-Mutant Breast Cancer

The FDA granted full approval to vepdegestrant (brand name Veppanu), developed by Arvinas and Pfizer, for adults with estrogen receptor-positive, HER2-negative, ESR1-mutated locally advanced or metastatic breast cancer who progressed on at least one prior line of endocrine therapy. This marks the world's first FDA approval of a PROTAC (PROteolysis TArgeting Chimera) — a protein degrader drug — for any disease. Unlike traditional SERDs (selective estrogen receptor degraders) such as fulvestrant that block the estrogen receptor, Veppanu recruits the cell's own protein-disposal machinery (the ubiquitin-proteasome system) to destroy the ER protein entirely, potentially overcoming all ER-dependent resistance mechanisms simultaneously. The Phase 3 VERITAC-2 trial (270 patients with confirmed ESR1 mutation) demonstrated median progression-free survival of 5.0 months versus 2.1 months for fulvestrant (HR 0.57, p<0.0001), with an objective response rate of 19% vs. 4%. The FDA simultaneously approved the Guardant360 CDx as a companion diagnostic for ESR1 mutation testing. ESR1 mutations occur in approximately 30–40% of patients after aromatase inhibitor treatment and are a dominant acquired resistance mechanism in metastatic HR+/HER2- breast cancer. PROTAC technology represents a platform potentially applicable to androgen receptor-driven prostate cancer, BCL-2 in leukemia, and other oncoproteins.