FDA Receives Vepdegestrant NDA for ESR1-Mutated Breast Cancer
A new FDA application for vepdegestrant offers hope for advanced breast cancer patients with ESR1 mutations, showcasing promising trial results.
Breast cancer, female anatomy: © peterschreiber.media - stock.adobe.com
A new drug application (NDA) has been submitted to the FDA for vepdegestrant (ARV-471), an investigational agent proposed for the treatment of patients with estrogen receptor (ER)-positive, HER2-negative (ER+/HER2–) ESR1-mutated advanced or metastatic breast cancer who have previously undergone endocrine-based therapy.1
The NDA submission is supported by the data from the pivotal phase 3 VERITAC-2 clinical trial (NCT05654623). Results from this global, randomized study were recently presented at the 2025 American Society for Clinical Oncology (ASCO) Annual Meeting, where they garnered attention, including selection for a late-breaking oral presentation, an ASCO press briefing, and recognition in "Best of ASCO." Concurrently, detailed findings from VERITAC-2 were published in The New England Journal of Medicine.
“This milestone comes after an exciting presentation at the American Society of Clinical Oncology’s Annual Meeting,” said John Houston, PhD, chairperson, chief executive officer, and president at Arvinas, in a press release. “We look forward to the NDA review and to the first-ever FDA-approved [PROteolysis TArgeting Chimera (PROTAC)] ER degrader potentially being available to patients who could benefit from a much-needed, new treatment option.”
About VERITAC-2
VERITAC-2 was designed to evaluate the efficacy and safety of vepdegestrant as a monotherapy in comparison with fulvestrant in the specified patient population. The trial enrolled 624 patients across 25 countries, all of whom had a history of treatment with a CDK4/6 inhibitor in conjunction with endocrine therapy.
Patients were randomly assigned 1:1 to receive either oral vepdegestrant daily on a continuous 28-day schedule or intramuscular fulvestrant. Notably, approximately 43% of the enrolled patients (n = 270) were identified as having ESR1 mutations, a key subset of interest given vepdegestrant’s mechanism of action.
The primary end point of the study was progression-free survival (PFS) as determined by blinded independent central review, assessed in both the ESR1-mutant and intent-to-treat populations. Overall survival is a designated key secondary end point.
“Vepdegestrant is the first PROTAC to be evaluated in a phase 3 study,” Erika Hamilton, MD, said during a presentation of the VERITAC-2 data during the ASCO 2025 meeting.2 “These results support vepdegestrant as a potential treatment option for previously treated [patients with] ESR1-mutant ER-positive, HER2-negative advanced breast cancer.”
At a median follow-up of 7.4 months in the vepdegestrant arm (n = 136) and 6.0 months in the fulvestrant arm (n = 134), the median progression-free survival (PFS) was 5.0 months (95% CI, 3.7-7.4) and 2.1 months (95% CI, 1.9-3.5), respectively (stratified HR, 0.57; 95% CI, 0.42-0.77; 2-sided P <.001). At the time of the analysis, 58% of PFS events had occurred in the vepdegestrant arm vs 71% in the fulvestrant arm; treatment was ongoing in 33% and 12% of patients, respectively. The 6-month PFS rates with vepdegestrant and fulvestrant were 45.2% (95% CI, 36.1%-53.9%) and 22.7% (95% CI, 15.1%-31.2%), respectively.
About Vepdegestrant
Vepdegestrant represents a novel therapeutic approach as an orally bioavailable PROTAC protein degrader.1 It is specifically engineered to target and degrade ER, which is a critical driver in ER+/HER2– breast cancer. This targeted degradation strategy aims to overcome resistance mechanisms that can develop with traditional endocrine therapies, particularly in the context of ESR1 mutations, which are known to confer resistance to standard endocrine treatments.
The FDA had previously granted vepdegestrant fast track designation as a monotherapy for this patient population, underscoring the potential for this agent to address an unmet medical need. The oncology community anticipates the FDA's review of this NDA, as vepdegestrant holds promise as a potential new treatment option for patients with ESR1-mutated ER+/HER2- advanced or metastatic breast cancer.
