Drug Update · Oncology

Vepdegestrant Approved for ESR1‑Mutant Breast Cancer; PFS HR 0.58

July 14, 2026

VERITAC-2 randomized patients

624 patients randomized; 313 to vepdegestrant, 311 to fulvestrant [1]

PFS in ESR1-mutant subgroup

Median PFS 5.0 months vs 2.1 months (HR 0.58; 95% CI 0.43-0.78) [1]

PFS in overall population

Median PFS 3.8 months vs 3.6 months (HR 0.83; 95% CI 0.69-1.01; P = 0.07) [1]

Grade 3+ adverse events

23.4% with vepdegestrant vs 17.6% with fulvestrant [1]

Discontinuation for adverse events

2.9% with vepdegestrant vs 0.7% with fulvestrant [1]

Approved indication

Adults with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer after progression on at least one line of endocrine therapy [11][12]

Recommended dose

200 mg orally once daily with food (label) [11][12]

Clinical Perspective

This approval affects oncologists and advanced practice clinicians treating adult patients with ER-positive, HER2-negative advanced or metastatic breast cancer whose tumors carry ESR1 mutations and who have disease progression following at least one line of endocrine therapy ^[2]^[3]. The VERITAC-2 data support selecting vepdegestrant for patients with ESR1-mutant disease after prior endocrine therapy (and typically following CDK4/6 inhibitor exposure), where it produced a median PFS of 5.0 months versus 2.1 months with fulvestrant in that subgroup ^[1]^[2]. What remains to be defined is how best to sequence vepdegestrant relative to other approved and emerging therapies in ESR1-mutant disease and which patients derive the largest overall survival benefit?

Dr. Meera Pillai · Oncology

The FDA approved vepdegestrant (VEPPANU) for adults with estrogen receptor (ER)-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer on 2026-05-01 based on results from the randomized VERITAC-2 trial ^[2]^[3]. In the VERITAC-2 subgroup with ESR1 mutations, vepdegestrant prolonged progression-free survival: median 5.0 months versus 2.1 months with fulvestrant (hazard ratio, 0.58; 95% CI, 0.43-0.78) ^[1]^[2].

Clinical Context

Vepdegestrant is an oral heterobifunctional protein degrader (PROTAC) that targets the estrogen receptor and directs it to the ubiquitin-proteasome system for degradation; the mechanism and PROTAC class are described in the VERITAC-2 background and prescribing information ^[1]^[2]. The agent is developed and marketed by Arvinas Operations, Inc. as VEPPANU, and the FDA approval covers adults with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer after progression on prior endocrine therapy ^[2]^[3]. The pivotal trial population had previously received at least one line of CDK4/6 inhibitor therapy plus endocrine therapy, reflecting the contemporary post–CDK4/6 setting in which clinicians will consider a targeted oral ER degrader after progression ^[1]^[2].

Key Findings

The VERITAC-2 trial showed that vepdegestrant reduced the risk of progression by 42% versus fulvestrant in the subgroup with ESR1 mutations (hazard ratio, 0.58; 95% CI, 0.43-0.78); median progression-free survival was 5.0 months with vepdegestrant versus 2.1 months with fulvestrant ^[1].
In the overall randomized population, median progression-free survival was 3.8 months with vepdegestrant and 3.6 months with fulvestrant (hazard ratio, 0.83; 95% CI, 0.69-1.01; P = 0.07) ^[1].
The trial randomized 624 patients (313 to vepdegestrant, 311 to fulvestrant) and stratified by ESR1-mutation status and visceral disease; efficacy was assessed by blinded independent central review using RECIST 1.1 ^[1]^[2].

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 vepdegestrant-treated patients and 0.7% of fulvestrant-treated patients ^[1].
The VERITAC-2 safety profile and the VEPPANU prescribing information list common adverse reactions and laboratory abnormalities; the most frequently reported adverse reactions (including laboratory abnormalities) 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 ^[2].

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 received one prior line of CDK4/6 inhibitor therapy plus one line of endocrine therapy (and up to one additional line of endocrine therapy); patients were randomized 1:1 to vepdegestrant 200 mg orally once daily or fulvestrant 500 mg intramuscularly with stratification by ESR1-mutation status and visceral disease ^[1]^[2]. Clinicians should consult current prescribing information for full dosing guidance. The primary end point was progression-free survival assessed by blinded independent central review among patients with ESR1 mutations and in the overall randomized population ^[1]^[2]. The FDA approved VEPPANU for the ESR1-mutant indication on 2026-05-01 with label details and monitoring guidance published in the prescribing information ^[2]^[3].

FAQ

Q1 What is vepdegestrant (VEPPANU) approved for?

A1 Vepdegestrant (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 approval is based on VERITAC-2, a phase 3 randomized trial comparing vepdegestrant with fulvestrant in this setting.

Q2 How does vepdegestrant work?

A2 Vepdegestrant is an oral heterobifunctional protein degrader (PROTAC) that targets the estrogen receptor and harnesses the ubiquitin-proteasome system to induce ER degradation. The mechanism is described in the trial background and drug prescribing information; VEPPANU is characterized as a PROTAC estrogen receptor degrader in the NEJM report and the prescribing information.

Q3 What is the recommended dose of vepdegestrant (VEPPANU)?

A3 The recommended dosage of VEPPANU is 200 mg taken orally once daily with food until disease progression or unacceptable toxicity, with tablet strength and administration guidance provided in the prescribing information. Dose reduction to 100 mg once daily is specified for certain adverse reactions, and the label provides drug-interaction–based modifications for strong CYP3A inhibitors or inducers. Clinicians should consult current prescribing information for complete dosing guidance.

Q4 What are the most common side effects of vepdegestrant?

A4 The most frequently reported adverse reactions and laboratory abnormalities 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 vepdegestrant-treated patients versus 17.6% with fulvestrant; adverse-event–driven discontinuation occurred in 2.9% versus 0.7%.

Vepdegestrant Approved for ESR1‑Mutant Breast Cancer; PFS HR 0.58

Vepdegestrant Approved for ESR1‑Mutant Breast Cancer; PFS HR 0.58

Clinical Perspective

Clinical Context

Key Findings

Safety & Tolerability

Study Design

FAQ

References

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