Vepdegestrant Boosts Progression-Free Survival in ESR1-Mutant ER+/HER2- Breast Cancer

Arvinas, Inc. and Pfizer Inc. have released significant findings from the Pivotal Phase 3 VERITAC-2 clinical trial, which assesses the efficacy of vepdegestrant as a treatment for patients with advanced or metastatic estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) breast cancer. This trial focuses on patients who have experienced disease progression following treatment with cyclin-dependent kinase (CDK) 4/6 inhibitors and endocrine therapy.

Presented at the American Society of Clinical Oncology (ASCO) meeting and published in the New England Journal of Medicine, the trial results showed that vepdegestrant significantly improved progression-free survival (PFS) in patients with an estrogen receptor 1 (ESR1) mutation. Compared to fulvestrant, vepdegestrant reduced the risk of disease progression or death by 43%. The median PFS with vepdegestrant was 5.0 months, compared to 2.1 months with fulvestrant, as independently reviewed. The benefits of vepdegestrant were consistently observed across all predefined patient subgroups with ESR1 mutations.

Dr. Erika P. Hamilton, a principal investigator of the VERITAC-2 trial, highlighted the significance of these results, emphasizing the potential of vepdegestrant to provide a new treatment option for patients with ESR1 mutation-driven resistance to existing therapies. The trial indicated that vepdegestrant was well tolerated with minimal gastrointestinal side effects, making it a promising candidate for patients who face challenges with current treatment options.

Importantly, the trial noted that the overall survival data is still maturing, with less than a quarter of the necessary events recorded at the time of analysis. However, secondary endpoints such as clinical benefit rate (CBR) and objective response rate (ORR) also favored vepdegestrant over fulvestrant. In the ESR1 mutation subgroup, the CBR was 42.1% with vepdegestrant versus 20.2% for fulvestrant, and the ORR was 18.6% versus 4.0%, respectively.

John Houston, CEO and President at Arvinas, expressed optimism about vepdegestrant's potential as a leading monotherapy for patients with second-line ESR1-mutant breast cancer. He emphasized the company's intention to advance discussions with regulatory authorities to make the treatment available to healthcare providers and patients swiftly.

The overall survival data, an important secondary endpoint, is still being collected, with subsequent analyses planned. Vepdegestrant, developed as an oral PROTAC ER degrader, is designed to utilize the body's protein degradation system specifically targeting the estrogen receptor. Arvinas and Pfizer plan to submit a New Drug Application (NDA) to the U.S. Food & Drug Administration in the latter half of 2025.

Dr. Johanna Bendell from Pfizer highlighted the importance of these findings in addressing ESR1 mutation-induced resistance to endocrine therapy in patients with metastatic breast cancer. With an estimated 2.3 million new global breast cancer diagnoses in 2022, and predictions of around 320,000 new cases in the United States by 2025, the development of effective treatments like vepdegestrant is crucial.

In July 2021, Arvinas and Pfizer entered into a global collaboration to co-develop and co-commercialize vepdegestrant. This investigational drug, designed for ER+/HER2- advanced or metastatic breast cancer with ESR1 mutations, has been granted Fast Track designation by the FDA for adults who previously received endocrine-based therapy. The recent VERITAC-2 trial results were first announced in March 2025, and the companies are eager to continue discussions with regulatory bodies regarding the introduction of vepdegestrant to the medical community.