FDA Receives NDA for Vepdegestrant in ESR1-Mutated, ER+/HER2– Metastatic Breast Cancer

June 6, 2025

The FDA received an NDA for vepdegestrant in ER-positive, HER2-negative advanced breast cancer with an ESR1 mutation.

A new drug application (NDA) has been submitted to the FDA seeking the approval of vepdegestrant for the treatment of patients with estrogen receptor (ER)–positive, HER2-negative advanced or metastatic breast cancer harboring an ESR1 mutation who were previously treated with endocrine-based therapy.1

The NDA is supported by data from the phase 3 VERITAC-2 trial (NCT05654623). Findings from the study presented at the 2025 ASCO Annual Meeting showed that in patients harboring ESR1 mutations, vepdegestrant (n = 136) generated a median progression-free survival (PFS) of 5.0 months (95% CI, 3.7-7.4) compared with 2.1 months (95% CI, 1.9-3.5) for fulvestrant (Faslodex; n = 134; HR, 0.57; 95% CI, 0.42-0.77; 2-sided P < .001).2

In the overall trial population, which included patients with or without ESR1 mutations, those treated with vepdegestrant (n = 313) experienced a median PFS of 3.7 months (95% CI, 3.6-5.3) compared with 3.6 months (95% CI, 2.2-3.8) for fulvestrant (n = 311; HR, 0.83; 95% CI, 0.68-1.02; 2-sided P = .07).

“We look forward to the NDA review and to the first ever FDA-approved, proteolysis-targeting chimera ER degrader potentially being available to patients who could benefit from a much needed, new treatment option,” John Houston, PhD, chairperson, chief executive officer, and president at Arvinas, stated in a news release.1

VERITAC-2 Overview

The global, randomized study enrolled patients at least 18 years of age with ER-positive, HER2-negative advanced or metastatic breast cancer who received 1 line of therapy with a CDK4/6 inhibitor plus endocrine therapy; were given no more than 1 additional line of endocrine therapy; received their most recent endocrine therapy for at least 6 months; were not previously exposed to a selective ER degrader such as fulvestrant or elacestrant (Orserdu); and were naive to chemotherapy in the advanced or metastatic settings.2 Radiological disease progression during or after the most recent line of therapy was required.

Patients were randomly assigned 1:1 to receive 200 mg of oral vepdegestrant once per day or 500 mg of intramuscular fulvestrant on days 1 and 15 of cycle 1, then on day 1 of subsequent cycles. Key stratification factors included ESR1 mutation status (yes vs no) and visceral disease (yes vs no).

PFS per blinded independent central review (BICR) in both the ESR1-mutated population and overall population served as the trial’s primary end point. Overall survival (OS) was a key secondary end point, and other objectives included clinical benefit rate (CBR), overall response rate (ORR), and safety.

Further Efficacy and Safety Findings

An investigator assessment showed that in the ESR1-mutated population, the median PFS was 5.4 months (95% CI, 3.7-6.4) in the vepdegestrant arm vs 2.8 months (95% CI, 2.0-3.5) in the fulvestrant arm (HR, 0.52; 95% CI, 0.39-0.70; P < .001). The median PFS in the overall population was 3.9 months (95% CI, 3.7-5.4) and 3.6 months (95% CI, 2.8-5.0), respectively (HR, 0.83; 95% CI, 0.69-1.01; P = .06).

OS data were immature at the time of this interim analysis.

Within the ESR1-mutated population, the ORR was 18.6% for vepdegestrant (n = 97) compared with 4.0% for fulvestrant (n = 100; odds ratio [OR], 5.45; 95% CI, 1.69-22.73; P = .001). The CBRs were 42.1% for vepdegestrant (n = 121) and 20.2% for fulvestrant (n = 119; OR, 2.88; 95% CI, 1.57-5.39; P < .001).

In the overall population, the ORR was 10.9% for vepdegestrant (n = 221) vs 3.6% for fulvestrant (n = 222; OR, 3.23; 95% CI, 1.38-8.71; P = .003). The CBRs were 34.3% for vepdegestrant (n = 274) and 28.7% for fulvestrant (n = 272; OR, 1.29; 95% CI, 0.89-1.91; P = .16).

Regarding safety, the rates of any-grade treatment-emergent adverse effects (TEAEs) were 87% in the vepdegestrant arm (n = 312) and 81% in the fulvestrant arm (n = 307). The respective rates of grade 3 or higher TEAEs were 23% and 18%. Serious TEAEs occurred in 10% of patients in the experimental arm vs 9% of those in the control arm. Any-grade treatment-related AEs (TRAEs) were reported in 57% and 40% of patients, respectively. The respective rates of grade 3 or higher TRAEs were 8% and 3%.

TEAEs led to treatment discontinuation in 3% of patients in the vepdegestrant group vs 1% of patients in the fulvestrant cohort. TEAEs led to dose reductions in 2% of patients treated with vepdegestrant.

The most common any-grade TEAEs reported in at least 10% of patients included fatigue (vepdegestrant, 27%; fulvestrant, 16%), increased alanine aminotransferase levels (14%; 10%), increase aspartate aminotransferase levels (14%; 10%), nausea (13%; 9%), anemia (12%; 8%), neutropenia (12%; 5%), back pain (11%; 7%), arthralgia (11%; 11%; and decreased appetite (11%; 5%).

References

Arvinas announces submission of new drug application to U.S. FDA for vepdegestrant for patients with ESR1-mutated ER+/HER2- advanced or metastatic breast cancer. News release. Arvinas. June 6, 2025. Accessed June 6, 2025. https://ir.arvinas.com/news-releases/news-release-details/arvinas-announces-submission-new-drug-application-us-fda
Hamilton EP, De Laurentiis M, Jhaveri KL, et al. Vepdegestrant, a PROTAC estrogen receptor (ER) degrader, vs fulvestrant in ER-positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer: results of the global, randomized, phase 3 VERITAC-2 study. J Clin Oncol. 2025;43(suppl 17):LBA1000. doi:10.1200/JCO.2025.43.17_suppl.LBA1000