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

The FDA has accepted a new drug application (NDA) seeking the approval of vepdegestrant for the treatment of patients with estrogen receptor (ER)–positive/HER2-negative, ESR1-mutated advanced or metastatic breast cancer who have previously received endocrine-based therapy.1

The target action date for the NDA under the Prescription Drug User Fee Act (PDUFA) is June 5, 2026.

The application is supported by data from the phase 3 VERITAC-2 trial (NCT05654623), which were presented at the 2025 ASCO Annual Meeting. Findings demonstrated 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 The median follow-ups were 7.4 months and 6.0 months, respectively. The 6-month PFS rate was 45.2% (95% CI, 36.1%-53.9%) for vepdegestrant vs 22.7% (95% CI, 15.1%-31.2%) for fulvestrant.

In the trial’s overall population, patients 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 those given fulvestrant (n = 311; HR, 0.83; 95% CI, 0.68-1.02; 2-sided P = .07).

“Patients often face limited treatment options after first-line treatment, and vepdegestrant demonstrated improved PFS in patients with ESR1-mutated ER-positive/HER2-negative advanced breast cancer,” John Houston, PhD, chair, CEO, and president of Arvinas, stated in a news release.1 “With the efficacy and favorable tolerability seen in VERITAC-2, we believe vepdegestrant, if approved, has potential to be a best-in-class treatment option for patients in the second-line ESR1-mutant setting. We look forward to working alongside Pfizer and with the FDA to pursue vepdegestrant’s approval and to ensure this important treatment option is made available to patients as rapidly as possible.”

VERITAC-2 Background

In the phase 3 study of the selective, oral PROTAC ER degrader, investigators enrolled patients 18 years and older with ER-positive, HER2-negative advanced or metastatic breast cancer who received first-line treatment with a CDK4/6 inhibitor plus endocrine therapy, received no more than 1 additional line of endocrine therapy, and had radiological disease progression during or after their most recent line of therapy.2 Patients’ most recent line of endocrine therapy needed to be given for at least 6 months. Additionally, prior treatment with a selective ER degrader was not permitted; chemotherapy in the advanced or metastatic setting was also not allowed.

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

PFS in the ESR1-mutated and overall populations served as the trial’s primary end point. Overall survival (OS) was a key secondary end point, with other objectives including clinical benefit rate, overall response rate, and safety.

Additional Data

OS data were immature at the time of the analysis presented at the 2025 ASCO Annual Meeting.

Within the ESR1-mutated population, the ORR was 18.6% for vepdegestrant (n = 97) compared with 4.0% for fulvestrant (n = 100; OR, 5.45; 95% CI, 1.69-22.73; P = .001). The clinical benefit rates 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).

Any-grade treatment-emergent adverse effects (TEAEs) occurred at a rate of 87% in the vepdegestrant arm (n = 312) and 81% in the fulvestrant arm (n = 307). Grade 3 or higher TEAEs were reported in 23% and 18% of patients, respectively; the respective rates of serious TEAEs were 10% and 9%. 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 arm vs 1% of patients in the fulvestrant arm; 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%, respectively), 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

1. Arvinas announces FDA acceptance of the new drug application for vepdegestrant for the treatment of ESR1m, ER+/HER2- advanced breast cancer. News release. Arvinas. August 8, 2025. Accessed August 9, 2025. https://ir.arvinas.com/news-releases/news-release-details/arvinas-announces-fda-acceptance-new-drug-application
2. 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