Vepdegestrant Enhances Progression-Free Survival in ESR1-Mutant Advanced Breast Cancer

NEW HAVEN, CT and NEW YORK, NY, USA I May 31, 2025 I Arvinas, Inc. and Pfizer Inc. have released significant findings from the Phase 3 VERITAC-2 clinical trial. This study evaluated the efficacy of vepdegestrant as a standalone treatment compared to fulvestrant in adults with advanced or metastatic breast cancer that is estrogen receptor-positive and human epidermal growth factor receptor 2-negative (ER+/HER2-). These patients had not responded to previous treatments involving cyclin-dependent kinase (CDK) 4/6 inhibitors and endocrine therapy. The detailed results, highlighted at an American Society of Clinical Oncology (ASCO) press briefing and chosen for Best of ASCO, were presented today in a late-breaking oral presentation and have been simultaneously published in the New England Journal of Medicine.

The VERITAC-2 trial demonstrated that vepdegestrant significantly and meaningfully improved progression-free survival (PFS) in patients with estrogen receptor 1 (ESR1) mutations. It reduced the risk of disease progression or death by 43% compared to fulvestrant. Specifically, the median PFS was 5.0 months for vepdegestrant, compared to 2.1 months for fulvestrant, as assessed by blinded independent central review. Investigator assessments were consistent with these findings. The trial showed that the PFS benefit of vepdegestrant over fulvestrant was consistent across all pre-specified subgroups with ESR1 mutations. However, in the broader intent-to-treat population, the improvement was not statistically significant.

Dr. Erika P. Hamilton, a principal investigator of the trial and Director of Breast Cancer Research at the Sarah Cannon Research Institute, noted the potential of vepdegestrant to provide a new treatment option for patients with ER+/HER2- metastatic breast cancer, particularly those with ESR1 mutations that drive resistance to standard therapies. She emphasized the low incidence of serious gastrointestinal side effects, which can significantly impact patients' quality of life.

Vepdegestrant was generally well tolerated, showing a safety profile similar to previous studies, with mostly low-grade treatment-emergent adverse events (TEAEs). Gastrointestinal side effects such as nausea and diarrhea were relatively low. Fatigue, increased alanine transaminase (ALT), and increased aspartate aminotransferase (AST) were the most common TEAEs observed. A small percentage of patients discontinued the treatment due to adverse effects.

John Houston, Ph.D., Chairperson, CEO, and President of Arvinas, expressed confidence in vepdegestrant’s potential as a leading monotherapy treatment for patients with ESR1 mutations. He emphasized the company’s commitment to engaging with regulatory authorities to expedite bringing this treatment to patients.

The trial's secondary endpoints, including overall survival (OS), clinical benefit rate (CBR), and objective response rate (ORR), were also promising. Although the OS data were immature at the time of analysis, less than a quarter of the required events had occurred. In patients with an ESR1 mutation, CBR and ORR were significantly higher with vepdegestrant compared to fulvestrant.

Dr. Johanna Bendell of Pfizer highlighted the critical role vepdegestrant could play in addressing treatment resistance in patients with ESR1 mutations, often associated with rapid disease progression on existing therapies.

Breast cancer remains a prevalent global health issue, with approximately 2.3 million new cases reported in 2022. ER+/HER2- breast cancer constitutes about 70% of these cases, and resistance to current treatments frequently leads to disease progression. ESR1 mutations are present in about 40% of patients in the second-line setting.

Vepdegestrant, an investigational oral PROTAC ER degrader developed by Arvinas and Pfizer, aims to specifically target and degrade the estrogen receptor. Following the promising results of the VERITAC-2 trial, the companies plan to submit a New Drug Application (NDA) to the U.S. Food & Drug Administration (FDA) in the latter half of 2025.