Veppanu (vepdegestrant): FDA approval, pivotal trial and safety
Approved
Type
New molecular entity · Oral
FDA-approved use
To treat estrogen receptor-positive, human epidermal growth factor receptor 2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapyWording from FDA's list of novel approvals.
FDA review
Standard review
Company
Arvinas
Application
NDA 219835
Specialty
Oncology
At a glance
Veppanu (vepdegestrant) is an oral estrogen receptor degrader approved for adults with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer that has progressed after at least one line of endocrine therapy. In VERITAC-2, patients with ESR1 mutations had a median progression-free survival of 5.0 months versus 2.1 months with fulvestrant (hazard ratio 0.57). The main safety concern is QTc interval prolongation; there is no boxed warning.
What it is and how it works
Vepdegestrant is a heterobifunctional protein degrader, a PROTAC. It binds both an E3 ubiquitin ligase and the estrogen receptor. This triggers ubiquitination of the receptor and its breakdown by the proteasome. Fulvestrant is also a receptor degrader but is given by intramuscular injection, while vepdegestrant is taken by mouth. Aromatase inhibitors lower estrogen production, and CDK4/6 inhibitors act on the cell cycle, so both work differently.
Randomized, open-label, active-controlled, multicenter phase 3 trial, 1:1, stratified by ESR1 status and visceral metastasis.
Patients
624 adults with ER-positive, HER2-negative advanced or metastatic breast cancer after a CDK4/6 inhibitor plus endocrine therapy; 270 had ESR1-mutated tumors (136 vepdegestrant, 134 fulvestrant).
Compared with
Fulvestrant given intramuscularly.
Primary endpoint
Progression-free survival by blinded independent central review, in the ESR1-mutated group and in all randomized patients.
Result
In the ESR1-mutated group, median PFS was 5.0 months (95% CI 3.7 to 7.4) with vepdegestrant versus 2.1 months (95% CI 1.9 to 3.5) with fulvestrant. Hazard ratio 0.57 (95% CI 0.42 to 0.77); one-sided P=0.0001 per the label. The publication reported a hazard ratio of 0.58 (95% CI 0.43 to 0.78; P<0.001). In all patients, median PFS was 3.8 versus 3.6 months (hazard ratio 0.83; 95% CI 0.69 to 1.01; P=0.07), not significant.
Other results
Confirmed objective response rate in ESR1-mutated patients with measurable disease was 19% (95% CI 12 to 27) with vepdegestrant versus 4% (95% CI 1.6 to 10) with fulvestrant. All responses were partial. Overall survival was immature, with 16% of deaths at the PFS analysis.
Safety in the trial
Grade 3 or higher adverse events occurred in 23.4% with vepdegestrant and 17.6% with fulvestrant. Discontinuation for adverse events was 2.9% versus 0.7%. Serious adverse reactions occurred in 9% and fatal ones in 1.0% with vepdegestrant. QTc prolongation was reported in 10%.
How does Veppanu (vepdegestrant) compare with the alternatives (Fulvestrant, Elacestrant, Aromatase inhibitors) for estrogen receptor-positive, human epidermal growth factor receptor 2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy? Summarize head-to-head and indirect evidence, efficacy, safety and where each fits, with citations.
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Safety signals
There is no boxed warning. The label warns of QTc interval prolongation, which was reported in 10% of patients in VERITAC-2, with grade 3 in 1.6%. Check an ECG and electrolytes before starting, correct low potassium and magnesium, do not start if QTc is above 470 msec, and repeat the ECG about 4 weeks in. Avoid strong CYP3A inhibitors and other QTc-prolonging drugs where possible. The drug can cause fetal harm, so patients need counseling on effective contraception. Common adverse reactions, including lab changes, were decreased white cells, raised AST and ALT, musculoskeletal pain, fatigue, anemia, and nausea. Serious adverse reactions occurred in 9%, including fractures.
What it competes with
After progression on endocrine therapy, patients with ER-positive, HER2-negative advanced breast cancer are often given a different endocrine agent, frequently with a targeted partner. Choice depends on prior therapy, mutation status, and how quickly disease progressed.
FulvestrantIntramuscular selective estrogen receptor degrader and the comparator in VERITAC-2.
ElacestrantOral selective estrogen receptor degrader also used in ESR1-mutated disease after endocrine therapy.
Aromatase inhibitorsLower estrogen production; often used earlier, and ESR1 mutations are linked to resistance to them.
Everolimus with endocrine therapymTOR inhibitor combination used after progression, with notable mucosal and metabolic toxicity.
Capivasertib with fulvestrantOption for tumors with certain pathway alterations after endocrine therapy.
Bottom line for clinicians
Veppanu suits adults with ESR1-mutated disease, confirmed by an FDA-authorized test, who have progressed after endocrine therapy and a CDK4/6 inhibitor. The benefit was seen only in the ESR1-mutated group and not in the overall trial population. Overall survival data were immature. Weigh the oral route against the need for ECG and electrolyte monitoring and QTc drug interactions.
Dosing, contraindications and full warnings are in the prescribing information.
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Last updated October 28, 2026 by 2 Minute Medicine.
For healthcare professionals. A summary of public FDA documents and published trials, not medical advice. Check the full prescribing information before prescribing.
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