FDA Approves Vepdegestrant for ESR1-Mutated ER+/HER2− Advanced Breast Cancer

The US FDA has approved vepdegestrant (Veppanu) for the treatment of adults 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.¹ The approval marks a significant regulatory milestone: vepdegestrant is the first PROteolysis TArgeting Chimera (PROTAC) protein degrader to receive FDA approval for any indication.

Vepdegestrant is an orally bioavailable PROTAC ER degrader co-developed by Arvinas and Pfizer. The new drug application was supported by data from the phase 3 VERITAC-2 trial (NCT05654623), a global, randomized study evaluating vepdegestrant vs fulvestrant (Faslodex) in patients with ER+, HER2− advanced breast cancer whose disease had progressed after treatment with CDK4/6 inhibitors and endocrine therapy.

VERITAC-2 Efficacy Data

The trial enrolled 624 patients, 270 of whom had ESR1-mutated disease, at 213 sites across 25 countries. Patients were randomized 1:1 to receive either vepdegestrant once daily orally on a 28-day cycle or intramuscular fulvestrant.²

In the prespecified ESR1-mutated subgroup—the population for which approval was granted—results demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS). 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), median PFS was 5.0 months (95% CI, 3.7-7.4) vs 2.1 months (95% CI, 1.9-3.5), respectively (stratified HR, 0.57; 95% CI, 0.42–0.77; 2-sided P <.001). The 6-month PFS rates were 45.2% (95% CI, 36.1%-53.9%) and 22.7% (95% CI, 15.1%-31.2%), respectively.³

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).

In the overall trial population, which included patients with or without ESR1 mutations, those treated with vepdegestrant (n = 313) had 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), a difference that did not reach statistical significance. These findings reinforce the importance of ESR1 mutation testing to guide patient selection.

The VERITAC-2 data were presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting and simultaneously published in The New England Journal of Medicine.

Safety

The most common treatment-emergent adverse events (TEAEs) of any grade occurring in at least 10% of patients included fatigue (vepdegestrant, 27%; fulvestrant, 16%), increased alanine aminotransferase (ALT) levels (14%; 10%), increased aspartate aminotransferase (AST) levels (4%; 10%), nausea (13%; 9%), anemia (12%; 8%), neutropenia (12%; 5%), back pain (11%; 7%), arthralgia (11%; 11%), and decreased appetite (11%; 5%). Grade ≥3 events occurred in 23.4% of patients, and permanent discontinuations were rare at 2.9%. QTc prolongation was infrequent and was not associated with arrhythmias. No treatment-related deaths occurred in either arm.

“…[T]he vepdegestrant safety looked really encouraging. I like to look at dose reductions and discontinuations as an indication of how well patients really tolerate a drug. What we saw discontinuations with vepdegestrant were only 3% and reductions were only 2%. When we looked at what AEs were most frequent, fatigue was the most common. But this also stood out to me as this was any-grade fatigue, and only present in 27% of patients. So said another way, three-quarters of patients had no fatigue at all,” said Erika Hamilton, MD, director of breast cancer research at Sarah Cannon Research Institute, said in an interview with Targeted Oncology.

“Our second and third most common [AEs] were nausea and AST/ALT elevations, all-grade frequencies in the low teens, under 15%. Compared with some other oral SERDs that have more prominent gastrointestinal [AEs], what stood out to me was that vomiting and diarrhea were not on our AE table—because across all grades, they were present in only 6% of patients,” Hamilton continued.

Mechanism of Action and Clinical Context

Vepdegestrant represents a mechanistic departure from existing endocrine therapies. As a PROTAC, the molecule works by recruiting the intracellular ubiquitin-proteasome system to achieve targeted degradation of the ER protein, a distinct approach from selective ER degraders (SERDs) such as fulvestrant, which achieves only partial ER degradation and requires intramuscular administration. ESR1 mutations are a common mechanism of acquired endocrine resistance, identified in approximately 40% of patients in the second-line setting. These mutations arise primarily under selective pressure from CDK4/6 inhibitor–based endocrine therapy and reduce the activity of most available endocrine agents.

Regulatory Background

The FDA granted fast track designation to vepdegestrant in February 2024, based on its potential to address a serious condition and fill an unmet medical need in patients with ER+/HER2− locally advanced or metastatic breast cancer previously treated with endocrine-based therapy.⁴ Earlier clinical evaluation in the phase 1/2 VERITAC study (NCT04072952) established the 200 mg once-daily oral dose as the recommended phase 3 dose.

Clinical Context

ESR1 mutations remain a challenge—and one that is potentially growing—in breast cancer.

“We…think ESR1 mutations may be on the rise, because in the first-line setting with CDK4/6 inhibitors, patients are on aromatase inhibitors for a longer duration, which breeds ESR1 mutations. In [VERITAC-2], we saw that 43% of patients had an ESR1 mutation, so this is not a negligible population,” said Hamilton.

REFERENCES

1. FDA approves vepdegestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. News release. US Food and Drug Administration. May 1, 2026. Accessed May 1, 2026. https://tinyurl.com/zjm3x8rp

2. Arvinas announces FDA acceptance of the new drug application for vepdegestrant for the treatment of ESR1m, ER+/HER2− advanced breast cancer. News release. Arvinas, Inc. August 8, 2025. Accessed May 1, 2026. https://tinyurl.com/3u6csmv9

3. 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

4. Arvinas and Pfizer's vepdegestrant (ARV-471) receives FDA Fast Track designation for the treatment of patients with ER+/HER2− metastatic breast cancer. News release. Pfizer Inc. February 6, 2024. Accessed May 1, 2026. https://tinyurl.com/4e8uj25c