Vepdegestrant for the treatment of HR+/HER2– breast cancer

The treatment of advanced hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer has been improved through the development of endocrine therapy (ET) and targeted agents. However, resistance to ET, particularly caused by ESR1 mutations, has not been fully addressed. Vepdegestrant is a first-in-class, selective, and orally bioavailable PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader. Preclinical studies have suggested promising activity of vepdegestrant irrespective of ESR1 genotypes. Phase I and II clinical studies have revealed a favorable safety profile and encouraging efficacy of vepdegestrant as a single agent and in combination with other targeted agents. The results of the phase III VERITAC-2 study, comparing vepdegestrant with fulvestrant, are expected to be available in 2025, and will provide the first data on the true clinical significance of vepdegestrant. Several phase III studies of combinations with vepdegestrant including + atirimociclib (a cyclin-dependent kinase 4 inhibitor) have been or are planned to be conducted. The results of these may not only transform the treatment landscape for advanced HR+/HER2- breast cancer but may pave the way for PROTAC as a new class of anti-cancer drugs that may make previously undruggable targets druggable.