FDA Accepts NDA for Vepdegestrant, First PROTAC to Reach Regulatory Review in Breast Cancer

The U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for vepdegestrant for the treatment of patients with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-), ESR1-mutated advanced or metastatic breast cancer who have previously received endocrine-based therapy. The FDA has assigned a Prescription Drug User Fee Act (PDUFA) action date of June 5, 2026.

Vepdegestrant is an investigational, orally bioavailable PROteolysis TArgeting Chimera (PROTAC) estrogen receptor degrader being jointly developed by Arvinas and Pfizer. It is the first PROTAC to pair positive Phase 3 efficacy with an active US regulatory review. The NDA submission was based on data from VERITAC-2 (NCT05654623), a global, randomized Phase 3 clinical trial evaluating vepdegestrant versus fulvestrant. These data were recently presented at the American Society of Clinical Oncology (ASCO) 2025 Annual Meeting and were simultaneously published in The New England Journal of Medicine.

The Phase 3 VERITAC-2 trial evaluated the efficacy and safety of vepdegestrant as a monotherapy compared to fulvestrant in patients with ER+/HER2- advanced or metastatic breast cancer previously treated with a CDK4/6 inhibitor plus endocrine therapy. The trial enrolled 624 patients, 270 of whom had ESR1m positive disease, at 213 sites in 25 countries. Patients were randomized 1:1 to receive either vepdegestrant once daily, orally on a 28-day continuous dosing schedule, or fulvestrant, administered intramuscularly. In the trial, 43% of patients (n=270) had ESR1 mutations detected. The primary endpoint was progression-free survival (PFS) in the ESR1-mutation and intent-to-treat populations as determined by blinded independent central review. Overall survival is the key secondary endpoint.

Vepdegestrant has also been granted Fast Track designation by the FDA. The CEO at Arvinas stated that vepdegestrant demonstrated improved progression-free survival in patients with ESR1-mutated ER+/HER2- advanced breast cancer, and that with the efficacy and favorable tolerability seen in VERITAC-2, the company believes vepdegestrant, if approved, has potential to be a best-in-class treatment option for patients in the second-line ESR1-mutant setting.

Vepdegestrant is an oral, CRBN-recruiting PROTAC that degrades ERα—including ESR1-mutant variants—in ER+/HER2- breast cancer. Beyond the clinical results, vepdegestrant demonstrates that large, heterobifunctional degraders can achieve once-daily oral dosing.

In July 2021, Arvinas announced a global collaboration with Pfizer for the co-development and co-commercialization of vepdegestrant; Arvinas and Pfizer will share worldwide development costs, commercialization expenses, and profits.