Drug Update · Oncology

FDA Approves vepdegestrant for ESR1‑Mutated ER+ HER2‑ Breast Cancer; PFS HR 0.58 in VERITAC‑2

July 21, 2026

FDA approval date

2026-05-01

Trial

VERITAC-2

Primary efficacy (ESR1‑mutated subgroup)

Median PFS 5.0 vs 2.1 months; HR 0.58 (95% CI, 0.43 to 0.78); P<0.001

Overall population PFS

Median PFS 3.8 vs 3.6 months; HR 0.83 (95% CI, 0.69 to 1.01); P = 0.07

Recommended dose

200 mg orally once daily with food

Clinical Perspective

This FDA approval affects oncologists, breast‑cancer specialists, and advanced practice providers treating adults with ER‑positive, HER2‑negative advanced or metastatic breast cancer whose tumors harbor ESR1 mutations. The VERITAC-2 data support use of vepdegestrant in patients with disease progression following at least one line of endocrine therapy, specifically when an ESR1 mutation is detected by an FDA‑authorized test ^[1]^[4]. What remains unanswered is whether combinations with other targeted agents will further extend benefit in ESR1‑mutated disease?

Dr. Rahul Verma · Oncology

Vepdegestrant (VEPPANU) was approved by the FDA on 2026-05-01 for adults with ER-positive, HER2-negative, ESR1‑mutated advanced or metastatic breast cancer after progression on endocrine therapy, based on the phase 3 VERITAC-2 trial showing a progression‑free survival benefit in the ESR1‑mutated subgroup (median PFS 5.0 vs 2.1 months; HR 0.58; 95% CI, 0.43 to 0.78) ^[1]^[4]. The recommended dose is 200 mg orally once daily with food ^[2]^[4]. Clinicians should consult current prescribing information for complete dosing guidance.

Clinical Context

Vepdegestrant is an oral proteolysis-targeting chimera (PROTAC) estrogen receptor degrader developed by Arvinas Operations, Inc. that targets the estrogen receptor for ubiquitin-proteasome–mediated degradation ^[1]^[2]. It was evaluated as a comparator to fulvestrant in patients with ER‑positive, HER2‑negative advanced breast cancer who had prior endocrine therapy and prior CDK4/6 inhibitor exposure ^[1]. The regulatory submission focused on activity in tumors with activating ESR1 mutations detected in circulating tumor DNA; the FDA labeled the drug for ESR1‑mutated disease as detected by an FDA‑authorized test ^[4]^[2]. The approval adds an oral PROTAC ER degrader to treatment options for this biomarker‑defined population ^[4]^[2].

Key Findings

The pivotal evidence came from VERITAC-2, a randomized, open‑label, active‑controlled phase 3 trial that enrolled 624 patients and included a prespecified analysis of 270 patients with ESR1 mutations detected in plasma ^[1]. In that ESR1‑mutated subgroup, vepdegestrant achieved a median progression‑free survival of 5.0 months versus 2.1 months with fulvestrant (hazard ratio for progression or death, 0.58; 95% CI, 0.43 to 0.78; P<0.001) ^[1]. Objective response among patients with measurable disease in the ESR1‑mutated cohort was 19% with vepdegestrant versus 4% with fulvestrant ^[1]. In the overall randomized population, median PFS was 3.8 months with vepdegestrant and 3.6 months with fulvestrant (HR 0.83; 95% CI, 0.69 to 1.01; P = 0.07) ^[1]. The trial was the basis for the FDA indication restricted to ESR1‑mutated tumors detected by an FDA‑authorized test ^[1]^[4].

Safety & Tolerability

Adverse events of grade 3 or higher occurred in 23.4% of patients receiving vepdegestrant and in 17.6% of patients receiving fulvestrant in VERITAC-2 ^[1].
Adverse events led to treatment discontinuation in 2.9% of patients on vepdegestrant and 0.7% on fulvestrant ^[1].
The VEPPANU prescribing information lists the most common adverse reactions (≥10%, including laboratory abnormalities) as decreased white blood cells; increased aspartate aminotransferase (AST); musculoskeletal pain; fatigue; decreased hemoglobin; decreased neutrophils; increased alanine aminotransferase (ALT); increased alkaline phosphatase; nausea; decreased blood potassium; increased bilirubin; decreased appetite; electrocardiogram QT prolonged; decreased platelets; and constipation ^[2]^[3].
QTc interval prolongation was reported in 10% of patients in VERITAC-2; Grade 3 occurred in 1.6% of patients. QTc >500 msec occurred in 1.6% and an increase >60 msec from baseline occurred in 2.6% of patients; dose reduction for QTc prolongation was required in 0.3% of patients ^[2]^[3].

Study Design

VERITAC-2 was a phase 3, open‑label, randomized trial that enrolled 624 patients with ER‑positive, HER2‑negative advanced breast cancer who had prior CDK4/6 inhibitor therapy plus prior endocrine therapy; 313 patients were assigned to vepdegestrant and 311 to fulvestrant ^[1]. Randomization was 1:1 and stratified by ESR1‑mutation status and visceral disease; the primary endpoint was progression‑free survival assessed by blinded independent central review in the ESR1‑mutated subgroup and in the overall population ^[1]. The FDA approval for vepdegestrant (VEPPANU) is for adults with ESR1‑mutated disease detected by an FDA‑authorized test ^[4]^[2].

FAQ

What is vepdegestrant (VEPPANU) approved for?

VEPPANU is approved for the treatment of adults with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, 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 indication specifies selection by an FDA‑authorized ESR1 mutation assay and applies to patients after prior endocrine therapy.

How does vepdegestrant work?

Vepdegestrant is an oral heterobifunctional proteolysis‑targeting chimera (PROTAC) that induces ubiquitin‑proteasome degradation of the estrogen receptor, reducing ER protein levels in tumor cells. The PROTAC mechanism targets the ER for degradation rather than solely antagonizing its activity; this approach was evaluated in the randomized VERITAC‑2 trial comparing vepdegestrant with fulvestrant.

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. Dose reduction to 100 mg once daily is recommended for certain adverse reactions per the label. Patients should be selected based on ESR1 mutation status using an FDA‑authorized test, and clinicians should follow label guidance on dosing modifications for adverse events and drug interactions. Clinicians should consult current prescribing information for complete dosing guidance.

What are the common side effects of vepdegestrant?

The most common adverse reactions (≥10%, including laboratory abnormalities) observed with VEPPANU in VERITAC‑2 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. Grade 3 or higher adverse events occurred in 23.4% of patients on vepdegestrant versus 17.6% on fulvestrant; treatment discontinuation due to adverse events occurred in 2.9% of vepdegestrant patients. QTc prolongation was reported and ECG/electrolyte monitoring is recommended per the label.

FDA Approves vepdegestrant for ESR1‑Mutated ER+ HER2‑ Breast Cancer; PFS HR 0.58 in VERITAC‑2

FDA Approves vepdegestrant for ESR1‑Mutated ER+ HER2‑ Breast Cancer; PFS HR 0.58 in VERITAC‑2

Clinical Perspective

Clinical Context

Key Findings

Safety & Tolerability

Study Design

FAQ

References

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