First-in-class Protein Degrader Approved for ESR1-mutated Breast Cancer
Vepdegestrant is the first PROTAC approved for any cancer indication.
The U.S. Food and Drug Administration (FDA) approved vepdegestrant (Veppanu) for adults with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, advanced or metastatic breast cancer with a mutation in the gene ESR1 that has progressed after at least one prior line of endocrine therapy.
Concurrently, the FDA approved the Guardant360 CDx as a companion diagnostic device to identify patients whose tumors carry ESR1 mutations.
Vepdegestrant is a proteolysis-targeting chimera (PROTAC), a type of two-headed molecule that promotes destruction of a target protein. The first head of the PROTAC binds to the target—in vepdegestrant’s case, the ER—and the second head binds to the E3 ubiquitin ligase, a protein that marks proteins for degradation. By actively promoting the degradation of ER, vepdegestrant treatment leads to reduced levels of this breast cancer-driving protein. ESR1 is the gene that codes for the production of one of the two main ERs, and mutations in ESR1 can cause ER to remain active even in the absence of estrogen, leading to resistance to many of the endocrine therapies used to treat ER-positive breast cancers.
This is the first FDA approval for vepdegestrant, which is the first PROTAC to be approved by the FDA for any cancer type.
Vepdegestrant’s in vitro efficacy was reported in Clinical Cancer Research, a journal of the American Association for Cancer Research (AACR), in 2024.
The approval was based on VERITAC-2, a randomized, open-label, phase III trial that enrolled 270 adults with ER-positive, HER2-negative advanced or metastatic breast cancer who had progressed on one or two prior lines of therapy (at least one of which was a CDK4/6 inhibitor) and whose tumors harbored ESR1 mutations. The patients were randomly assigned 1:1 to receive either vepdegestrant in an oral 200 mg dose daily or 500 mg of intramuscular fulvestrant once every 28 days.
After a median follow-up of 7.4 months in the vepdegestrant group and 6 months in the fulvestrant group, patients who received vepdegestrant were 43% less likely to experience disease progression than the patients who received fulvestrant. Median progression-free survival for patients in the vepdegestrant group was 5 months compared with 2.1 months in the fulvestrant group. These results were reported at the San Antonio Breast Cancer Symposium 2025, which is co-organized by the AACR.
The objective response rate was also significantly higher in the vepdegestrant group at 19% than in the fulvestrant group at 4%.
The recommended dosage of vepdegestrant is a daily 200 mg oral dose, to be taken with food, that should be continued until disease progression or unacceptable toxicity.
Breast cancer is the most common cancer diagnosed in women in the United States, excluding skin cancers, and roughly 70% of cases are hormone-receptor-positive and HER2-negative. According to federal statistics, it was estimated that 321,910 individuals would be diagnosed with breast cancer and 42,140 patients would die of the disease in the United States in 2026.
The FDA rendered its decision on May 1, 2026. Check this resource for updated information on all therapeutics regulated by the FDA.