U.S. Food and Drug Administration approve VEPPANU (vepdegestrant), the first PROTAC therapy, for ESR1-mutated ER+/HER2- advanced breast cancer, showing improved PFS vs fulvestrant.
Written By: Sana Khan, BPharm
Reviewed By: Pharmacally Editorial Team
The U.S. Food and Drug Administration has approved VEPPANU (vepdegestrant) for the treatment of adults with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-), ESR1-mutated advanced or metastatic breast cancer who have progressed after at least one line of endocrine therapy.
The therapy is the first approved PROTAC (proteolysis targeting chimera), establishing a new class of targeted protein degrader treatments in oncology. The approval applies to patients whose tumors harbor ESR1 mutations, identified through an FDA-authorized diagnostic test.
These mutations are a key mechanism of resistance to endocrine therapy and are observed in approximately 40–50% of patients treated with endocrine therapy and CDK4/6 inhibitors, often leading to disease progression and limited treatment options after first-line therapy. VEPPANU is an oral estrogen receptor degrader designed to selectively target and degrade the estrogen receptor, addressing a central driver of resistance in this patient population.
The approval was based on results from the Phase 3 VERITAC-2 trial (NCT05654623), a global, randomized, open-label study comparing vepdegestrant with fulvestrant in patients with ER+/HER2- advanced or metastatic breast cancer. Among patients with ESR1 mutations (n=270), vepdegestrant demonstrated a statistically significant improvement in progression-free survival, reducing the risk of disease progression or death by 43% compared with fulvestrant. Median progression-free survival was 5.0 months with vepdegestrant versus 2.1 months with fulvestrant (hazard ratio 0.57; 95% CI: 0.42–0.77; p=0.0001).
Overall survival data remain immature, with 16% of events reported at the time of analysis. The safety profile was generally manageable, with most adverse events reported as Grade 1 or 2. Common adverse reactions included hematologic abnormalities such as decreased white blood cells, neutrophils, hemoglobin, and platelets; elevated liver enzymes; fatigue; musculoskeletal pain; nausea; decreased appetite; and QT interval prolongation.
Randy Teel, PhD, President and Chief Executive Officer of Arvinas, described the approval as a milestone for both the company and the field, highlighting it as the first PROTAC therapy to reach approval and evidence that targeted protein degradation can deliver meaningful clinical outcomes, while also noting plans to accelerate patient access through a commercialization partner.
Erika Hamilton, principal investigator of the VERITAC-2 trial, emphasized the limited second-line options for patients with ESR1-mutated ER+/HER2- advanced breast cancer and noted that the approval introduces a new targeted treatment approach that expands available options for clinicians and patients.
VEPPANU was discovered and developed by Arvinas in collaboration with Pfizer under a global partnership established in 2021. The companies plan to select a third-party partner to support commercialization and expand access.
Reference
About the Writer
Sana Jamil Khan is a B. Pharm graduate with a strong interest in medical writing and scientific communication. Her work focuses on interpreting clinical research, exploring developments in pharmaceutical science, and presenting complex medical information in a clear and accessible manner. She is particularly interested in topics related to human clinical studies, drug safety observations, and emerging therapeutic research.