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. Author manuscript; available in PMC: 2026 Jul 14.
Published in final edited form as: Trends Pharmacol Sci. 2026 Jul 10;47(8):940–941. doi: 10.1016/j.tips.2026.06.009

Vepdegestrant for ESR1-mutated breast cancer

Ryan S MacLeod 1,2, Chuan-Ju Liu 1,*
PMCID: PMC13360994  NIHMSID: NIHMS2191737  PMID: 42431763

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STRUCTURE:

Vepdegestrant is an orally bioavailable heterobifunctional PROTAC estrogen receptor degrader with molecular formula C45H49N5O4 and molecular weight 723.90 g/mol. The molecule combines an estrogen receptor-binding ligand derived from an aryltetralin/tetrahydronaphthalene scaffold, a linker, and a cereblon-binding glutarimide-phthalimide moiety. This modular architecture enables simultaneous binding of ER alpha and cereblon, promoting formation of a productive ternary complex that drives ubiquitination and proteasomal degradation of the receptor.

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MECHANISM OF ACTION:

Estrogen receptor alpha (ER alpha), encoded by ESR1, is a central transcriptional driver of hormone receptor-positive breast cancer. Standard endocrine therapies, including aromatase inhibitors, selective estrogen receptor modulators, and selective estrogen receptor degraders, suppress ER signaling, but resistance often emerges through ligand-binding-domain ESR1 mutations such as Y537S and D538G that sustain receptor activity despite estrogen deprivation. Vepdegestrant differs from conventional antagonists because it is a targeted protein degrader rather than a simple occupancy-based inhibitor. The molecule links an ER-binding ligand to a cereblon-recruiting ligand, bringing ER alpha into proximity with the CRL4-CRBN E3 ubiquitin ligase complex and triggering receptor ubiquitination followed by proteasomal destruction. Loss of ER protein suppresses estrogen-responsive transcriptional programs, cell-cycle progression, and survival signaling in ER-dependent tumor cells, including models harboring clinically relevant ESR1 mutations. Preclinical studies showed deep ER degradation, inhibition of proliferation, and antitumor activity alone and in combinations with CDK4/6 or PI3K/mTOR pathway inhibitors. Clinical development advanced after early studies demonstrated pharmacodynamic ER degradation and manageable safety, and the pivotal VERITAC-2 trial supported use in tumors with ESR1 mutations, where degradation of mutant ER offers a rational strategy to overcome acquired endocrine resistance in HER2-negative metastatic endocrine-resistant ER-positive breast cancer. The results from VERITAC-2 add vepdegestrant to the expanding treatment armamentarium for ER+HER2− endocrine-resistant breast cancer, raising new questions regarding the optimal choice, combinations and sequencing of therapies.

NAME:

Vepdegestrant (also known as ARV-471 and PF-07850327); brand name is Veppanu.

DRUG CLASS:

Vepdegestrant is a first-in-class oral heterobifunctional protein degrader, or proteolysis-targeting chimera (PROTAC), that targets estrogen receptor alpha (ER alpha).

CLINICAL USE:

Veppanu is indicated to treat adult patients with estrogen receptor-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer, who have received at least one prior endocrine therapy and have disease progression. The recommended dosage is 200 mg taken orally once daily with food.

DEVELOPED BY:

Arvinas Operations, Inc., co-developed with Pfizer Inc.

ADVERSE EFFECTS:

The Veppanu label warnings include QTc interval prolongation and embryo-fetal toxicity. During clinical trials, serious adverse reactions occurred in 9% of patients who received vepdegestrant. Common adverse reactions or laboratory abnormalities (≥10%) include decreased white blood cells (33%), increased AST (31%) and ALT (22%), musculoskeletal pain (30%), fatigue (29%), anemia (24%), neutropenia (23%), nausea (12%), hypokalemia (14%), increased bilirubin (14%), decreased appetite (11%), QT prolongation (10%), thrombocytopenia (10%), and constipation (10%).

TIMELINE:

2018: Preclinical ARV-471 degrader data reported. 2019: First-in-human phase I/II development initiated. 2021: Arvinas-Pfizer collaboration announced. 2024: FDA Fast Track designation reported. 2025: VERITAC-2 met its primary endpoint in the ESR1-mutated subgroup; NDA submitted. May 1, 2026: FDA approval of Veppanu with Guardant360 CDx as companion diagnostic.

Acknowledgments

This work was partly supported by NIH research grants R01AR078035, R01AR062207, R01AR076900 and R01NS070328. Mechanism of action figure created using https://BioRender.com.

Footnotes

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