FDA Approves Vepdegestrant, First PROTAC Therapy for ESR1+ ER+/HER2- Advanced Breast Cancer

The U.S. Food and Drug Administration has approved VEPPANU™ (vepdegestrant) for estrogen receptor-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer whose disease has progressed after at least one line of endocrine therapy. The approval gives clinicians a new oral targeted option for a patient group in whom endocrine resistance remains a major therapeutic challenge.

The decision is notable not only for breast cancer treatment, but also for drug development more broadly. VEPPANU is the first FDA-approved PROteolysis TArgeting Chimera, or PROTAC, therapy. PROTACs are heterobifunctional protein degraders designed to eliminate disease-driving proteins rather than simply inhibit their activity. In this case, vepdegestrant targets estrogen receptor signaling, a central driver of ER-positive breast cancer and a key mechanism of treatment resistance when ESR1 mutations emerge.

The FDA also approved Guardant360 CDx as a companion diagnostic to identify patients with ESR1-mutated breast cancer who may be eligible for treatment with vepdegestrant.

A new option after endocrine resistance

ER-positive, HER2-negative breast cancer is the most common biological subtype of breast cancer. Endocrine therapy, often combined with a CDK4/6 inhibitor, remains a standard approach in advanced disease. However, ESR1 mutations can develop under treatment pressure and are associated with endocrine resistance, disease progression, and poorer outcomes. According to Arvinas, up to 40% to 50% of patients treated with endocrine therapy and a CDK4/6 inhibitor may develop ESR1 mutations.

“For patients living with ESR1 mutant, ER+/HER2 advanced breast cancer, there have been minimal second-line treatment options once standard therapies are no longer effective,” said Dr. Erika Hamilton, CDO, and Director, Breast Cancer Research, Sarah Cannon Research Institute, as well as a principal investigator of the VERITAC-2 trial. “The introduction of a new, targeted treatment is an encouraging development for this community and highlights meaningful innovation in the way this disease is treated. The approval of vepdegestrant gives clinicians another tool in the breast cancer treatment arsenal and brings renewed hope to individuals who need additional options.”

VEPPANU is indicated for patients whose ESR1 mutation is detected by an FDA-authorized test and whose disease has progressed after at least one line of endocrine-based therapy.

VERITAC-2 supports approval

The approval was based on results from VERITAC-2, a global, randomized, open-label, active-controlled, multicenter Phase 3 trial. The study enrolled 624 adults with ER-positive, HER2-negative advanced or metastatic breast cancer. Of these, 270 patients had tumors carrying ESR1 mutations. The major efficacy endpoint was progression-free survival assessed by blinded independent central review in both the ESR1-mutated population and the overall study population. Additional endpoints included overall survival and objective response rate.

In the ESR1-mutated population, vepdegestrant produced a statistically significant and clinically meaningful improvement in progression-free survival compared with fulvestrant. Median PFS was 5.0 months with vepdegestrant, compared with 2.1 months with fulvestrant. This corresponded to a 43% reduction in the risk of disease progression or death, with a hazard ratio of 0.57. The result was highly statistically significant, with a p value of 0.0001.

Objective response rate was also higher with vepdegestrant, reaching 19% compared with 4% for fulvestrant. Overall survival data remain immature, with deaths reported in 16% of patients in the ESR1-mutated population at the time of the PFS analysis.  

Safety profile and clinical considerations

Most adverse events reported with vepdegestrant were Grade 1 or 2. The most common adverse reactions, including laboratory abnormalities, were decreased white blood cells, increased AST, musculoskeletal pain, fatigue, decreased hemoglobin, decreased neutrophils, increased ALT, increased alkaline phosphatase, nausea, decreased blood potassium, increased bilirubin, decreased appetite, electrocardiogram QT prolonged, decreased platelets, and constipation.

“The approval of VEPPANU is an important milestone for patients, their caregivers, and physicians,” said Dr. Noah Berkowitz, Ph.D., Chief Medical Officer at Arvinas. “VEPPANU addresses an unmet need for patients with this aggressive form of breast cancer who have progressed on their initial therapy. Today’s approval provides a new oral treatment option that showed improved progression free survival when compared to the current standard of care, fulvestrant, which is administered via an intramuscular injection.”

First approved PROTAC therapy

Beyond its breast cancer indication, the approval represents a landmark for targeted protein degradation. Arvinas was founded on research from Yale University, where Professor Craig Crews, Ph.D., co-authored the first paper on PROTAC protein degraders. VEPPANU was discovered by Arvinas and jointly developed with Pfizer.

Arvinas and Pfizer said they intend to jointly identify and select a third-party partner to maximize the commercial potential of VEPPANU. The companies remain on track to announce that selection.