The PROTAC milestone: FDA approval of vepdegestrant (ARV-471) for ESR1-mutated breast cancer.

The 2026 FDA approval of vepdegestrant (ARV-471), an oral proteolysis-targeting chimera (PROTAC) that targets the estrogen receptor α (ERα), represents a historic milestone for targeted protein degradation. Unlike selective estrogen receptor degraders that operate via occupancy-driven destabilization, vepdegestrant catalytically recruits the CRBN E3 ligase to ERα, inducing its ubiquitination and proteasomal degradation. In the Phase III VERITAC-2 trial, vepdegestrant significantly improved progression-free survival versus fulvestrant in ESR1-mutated, endocrine-resistant breast cancer. This milestone approval validates the PROTAC modality as a therapeutic platform, redefining oral beyond-Rule-of-5 design principles and opening new frontiers for induced-proximity medicines.