FDA Approves Vepdegestrant for ER+/HER2– Advanced Breast Cancer With an ESR1 Mutation

The FDA has approved vepdegestrant (Veppanu) for the treatment of adult patients with estrogen receptor (ER)–positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer, as detected by an FDA-authorized test, with disease progression following at least 1 line of endocrine therapy.^1,2

The approval was backed by data from the phase 3 VERITAC-2 trial (NCT05654623), which demonstrated that patients harboring ESR1 mutations treated with vepdegestrant (n = 136) experienced 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 those treated with fulvestrant (Faslodex; n = 134; HR 0.57; 95% CI, 0.42-0.77; P = 0.0001).^1,3 The overall response rates (ORRs) in these respective groups were 19% (95% CI, 12%-27%) and 4% (95% CI, 1.6%-10%).¹

The overall study population included 624 patients with ER-positive, HER2-negative, advanced or metastatic breast cancer, including 270 with tumors harboring ESR1 mutations.

“Vepdegestrant is an oral selective ER degrader [SERD], but it’s got a different mechanism from some of the other ones,” Kelly E. McCann, MD, PhD, an associate professor at the University of California San Diego, said in an interview with OncLive^®. “It is a molecule that brings together the ER with an E3 ubiquitin ligase to cause degradation through ubiquitination and proteasome system. And then after that happens, the molecule can be released to cause another cycle of degradation. It’s an interesting drug. The approval, like [with] the other oral SERDs, is currently based on [the presence of] ESR1 mutations, which are activating mutations in the ER that develop as a resistance mutation to aromatase inhibitors. Now we have yet another oral SERD that is tied down to ESR1 mutations.”

What data have been presented from VERITAC-2?

Findings presented at the 2025 American Society of Clninical Oncology (ASCO) Annual Meeting demonstrated that among the overall trial population, those treated with vepdegestrant (n = 313) achieved 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 patients treated with fulvestrant (n = 311; HR, 0.83; 95% CI, 0.68-1.02; P = .07).³

Overall survival (OS) data were immature at the data cutoff.

How was the VERITAC-2 trial designed?

The global study enrolled patients at least 18 years of age with ER-positive, HER2-negative advanced or metastatic breast cancer who had received 1 prior line of endocrine therapy plus a CDK4/6 inhibitor and no more than 1 additional endocrine therapy. Patients needed to have received their most recent endocrine therapy for at least 6 months, and no prior treatment with a selective ER degrader was permitted. Prior chemotherapy in the advanced or metastatic setting was allowed. Patients were also required to have had radiological progression during or after their most recent line of therapy.

Patients were randomly assigned 1:1 to receive vepdegrestrant at 200 mg once per day or fulvestrant at 500 mg 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 served as the trial’s primary end point. Secondary end points comprised OS, clinical benefit rate, ORR, and safety.

What safety data were reported for vepdegestrant?

Safety data presented at ASCO 2025 showed that any-grade treatment-emergent adverse effects (TEAEs) occurred in 87% of patients treated with vepdegestant (n = 312) compared with 81% of patients treated with fulvstrant (n = 307). The rates of grade 3 or higher TEAEs were 23% and 18%, respectively, and the rates of serious TEAEs were 10% and 9%, respectively.

TEAEs led to treatment discontinuation in 3% of patients in the vepdegestrant arm vs 1% of patients in the fulvstrant arm. Two percent of patients in the experimental arm received dose reductions due to TEAEs.

Any-grade treatment-related AEs (TRAEs) were reported in 57% of patients in the vepdegrestant group and 40% of patients in the fulvestrant group. The respective rates of grade 3 or higher TRAEs were 8% and 3%.

The most common any-grade TEAEs reported in at least 10% of patients in either arm included fatigue (vepdegrestant, 27%; fulvestrant, 16%), increased alanine aminotransferase levels (14%; 10%), increased 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%).

What is the recommended dose of vepdegestrant?

The recommended dose of vepdegestrant is 200 mg given orally once per day with food, with treatment continued until disease progression or unacceptable toxicity.¹

“For patients living with ESR1-mutant, ER-positive/HER2-negative advanced breast cancer, there have been minimal second-line treatment options once standard therapies are no longer effective,” Erika Hamilton, MD, chief development officer, late phase, and director of breast cancer research at Sarah Cannon Research Institute in Nashville, Tennessee, and a principal investigator of the VERITAC-2 trial, stated in a news release.² “The introduction of a new, targeted treatment is an encouraging development for this community and highlights meaningful innovation in the way this disease is treated. The approval of vepdegestrant gives clinicians another tool in the breast cancer treatment arsenal and brings renewed hope to individuals who need additional options.”

References

1. FDA approves vepdegestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. FDA. May 1, 2026. Accessed May 1, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-vepdegestrant-er-positive-her2-negative-esr1-mutated-advanced-or-metastatic-breast
2. Arvinas announces FDA approval of Veppanu (vepdegestrant) for the treatment of ESR1m, ER+/HER2- advanced breast cancer. News release. Arvinas. May 1, 2026. Accessed May 1, 2026. https://ir.arvinas.com/news-releases/news-release-details/arvinas-announces-fda-approval-veppanu-vepdegestrant-treatment
3. Hamilton E, De Laurentiis M, Jhaveri K, 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