Drug Update · Oncology

FDA Approves vepdegestrant for ER‑positive, HER2‑negative, ESR1‑mutated advanced or metastatic breast cancer: PFS HR 0.57 in VERITAC-2

August 24, 2026

Indication

Adults with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer after ≥1 line of endocrine therapy [1][4]

VERITAC-2 ESR1-mutated PFS median

5.0 months (vepdegestrant) vs 2.1 months (fulvestrant) [10][4]

Hazard ratio (PFS)

0.57 (95% CI: 0.42, 0.77) [10][4]

Confirmed ORR (ESR1-mutated)

19% (vepdegestrant) vs 4% (fulvestrant) [10]

Recommended dose

200 mg orally once daily with food [1][10]

Clinical Perspective

Clinicians treating adults with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer now have an FDA-approved oral heterobifunctional protein degrader option for patients with disease progression after at least one line of endocrine therapy ^[1]^[3]. The approval is supported by VERITAC-2 data showing improved progression-free survival and higher objective response rate versus fulvestrant in the ESR1-mutated population, and US prescribing information specifies patient selection by an FDA-authorized ESR1 test and a recommended dose of 200 mg orally once daily with food ^[1]^[3]^[5]. Will vepdegestrant improve overall survival in this ESR1-mutated population?

Dr. Rahul Verma, MBBS, MD (General Medicine), DM (Medical Oncology) · Oncology

Vepdegestrant (Veppanu) was approved by the U.S. Food and Drug Administration on May 1, 2026, for adults with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy ^[3]^[1]. Approval was based on the randomized VERITAC-2 trial in which vepdegestrant demonstrated improved progression-free survival compared with fulvestrant in the ESR1-mutated population (median 5.0 vs 2.1 months; HR 0.57; 95% CI: 0.42, 0.77) ^[3]^[5].

Clinical Context

Vepdegestrant (brand name Veppanu, Arvinas Operations, Inc.) is described in FDA materials as a heterobifunctional protein degrader and a PROTAC estrogen receptor degrader that targets ER for proteasomal degradation ^[3]^[1]. The FDA approval includes selection of patients based on an FDA-authorized test to detect ESR1 mutations and the approval of the Guardant360 CDx as a companion diagnostic for ESR1 mutation detection ^[3]. The approved population is adults with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer who have disease progression after at least one line of endocrine therapy ^[1]^[3]. The FDA prescribing information lists recommended dosing, warnings including QTc interval prolongation and embryo-fetal toxicity, and required postmarketing commitments ^[1]^[2].

Key Findings

VERITAC-2 was a randomized, open-label, active-controlled, multicenter trial in which vepdegestrant reduced the risk of progression or death versus fulvestrant in patients with ESR1-mutated tumors (Hazard ratio 0.57; 95% CI: 0.42, 0.77) with median progression-free survival 5.0 months versus 2.1 months ^[3]^[5].
In the ESR1-mutated cohort, confirmed objective response rate (ORR) by blinded independent central review was 19% (95% CI: 12, 27) with vepdegestrant versus 4% (95% CI: 1.6, 10) with fulvestrant ^[5]^[3].
Overall survival was immature at the time of the PFS analysis, with 16% of deaths reported in the ESR1-mutated population at that analysis ^[3]^[5].

Safety & Tolerability

The most common (≥10%) adverse reactions, including laboratory abnormalities, reported with VEPPANU included decreased white blood cells, increased AST, musculoskeletal pain, fatigue, decreased hemoglobin, decreased neutrophils, increased ALT, increased alkaline phosphatase, nausea, decreased blood potassium, increased bilirubin, decreased appetite, electrocardiogram QT prolonged, decreased platelets, and constipation ^[1].
In VERITAC-2, serious adverse reactions occurred in 9% of patients who received VEPPANU; fatal adverse reactions occurred in 1.0% of patients who received VEPPANU and included dyspnea, cerebral ischemia, and unknown cause (one patient each) ^[1].
QTc interval prolongation was reported in 10% of patients in VERITAC-2; Grade 3 QTc prolongation occurred in 1.6% of patients, QTc >500 msec was observed in 1.6% of patients, and an increase from baseline QTc >60 msec occurred in 2.6% of patients ^[1].

Study Design

VERITAC-2 (NCT05654623) was a randomized, open-label, active-controlled, multicenter trial that enrolled 624 adult patients with ER-positive, HER2-negative advanced or metastatic breast cancer, of whom 270 had tumors carrying ESR1 mutations; randomization was 1:1 to vepdegestrant versus fulvestrant and was stratified by ESR1 mutation status and visceral metastasis ^[3]^[5]. The major efficacy outcome was progression-free survival by blinded independent central review using RECIST v1.1; additional outcomes included overall survival and objective response rate ^[5]. Patients were treated until disease progression or unacceptable toxicity ^[5]^[1].

FAQ

What is vepdegestrant (Veppanu) approved for?

Vepdegestrant (Veppanu) is approved for the treatment of adults with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, estrogen receptor-1 (ESR1)-mutated advanced or metastatic breast cancer, as detected by an FDA-authorized test, with disease progression following at least one line of endocrine therapy. The approval specifies selecting patients based on ESR1 mutation detection by an FDA-authorized test and includes the Guardant360 CDx as a companion diagnostic.

How does vepdegestrant work?

Vepdegestrant is described in FDA materials as a heterobifunctional protein degrader and an oral PROTAC estrogen receptor degrader that binds an E3 ligase and the estrogen receptor to trigger ubiquitination and proteasomal degradation of ER, thereby reducing ER protein levels. The mechanism is summarized in the prescribing information and in phase 1/2 trial publications referenced by the sponsors and FDA.

What is the recommended dose of vepdegestrant?

The recommended dosage of VEPPANU is 200 mg taken orally once daily with food until disease progression or unacceptable toxicity; tablets are available in 100 mg and 200 mg strengths and should be swallowed whole. Dosage modifications are provided in the prescribing information for adverse reactions and for drug interactions with strong CYP3A inhibitors or inducers. Clinicians should consult current prescribing information for full dosing guidance.

What are the most common side effects of vepdegestrant?

The most common (≥10%) adverse reactions, including laboratory abnormalities, reported with VEPPANU were decreased white blood cells, increased AST, musculoskeletal pain, fatigue, decreased hemoglobin, decreased neutrophils, increased ALT, increased alkaline phosphatase, nausea, decreased blood potassium, increased bilirubin, decreased appetite, electrocardiogram QT prolonged, decreased platelets, and constipation. Serious adverse reactions occurred in 9% of patients; fatal adverse reactions occurred in 1.0% of patients in VERITAC-2.

Clinicians should consult current prescribing information for full dosing guidance.

Clinicians should consult current prescribing information for complete dosing guidance.

FDA Approves vepdegestrant for ER‑positive, HER2‑negative, ESR1‑mutated advanced or metastatic breast cancer: PFS HR 0.57 in VERITAC-2

Direct Clinical Takeaway & Evidence Summary

FDA Approves vepdegestrant for ER‑positive, HER2‑negative, ESR1‑mutated advanced or metastatic breast cancer: PFS HR 0.57 in VERITAC-2

Clinical Perspective

Clinical Context

Key Findings

Safety & Tolerability

Study Design

FAQ

References

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