Vepdegestrant — Drug Monograph

Brand names: Veppanu

Drug class: Hormonal Agent

Mechanism of Action

Vepdegestrant is a first-in-class, orally bioavailable PROTAC (PROteolysis-TArgeting Chimera) estrogen receptor degrader — a heterobifunctional molecule that simultaneously binds the estrogen receptor (ER) and an E3 ubiquitin ligase (cereblon), tagging ER for ubiquitination and proteasomal degradation. Unlike oral SERDs (e.g., elacestrant), which competitively block and destabilize the receptor, vepdegestrant catalytically eliminates ER protein, producing deep receptor knockdown that retains activity against ESR1-mutant, endocrine-resistant disease.

FDA Indications

• Estrogen receptor (ER)-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer (detected by an FDA-authorized test) in adults with disease progression following at least one line of endocrine therapy

Common Side Effects

• Decreased white blood cell count (leukopenia)
• Increased AST
• Musculoskeletal pain
• Fatigue
• Decreased hemoglobin (anemia)
• Decreased neutrophils
• Increased ALT
• Nausea

Clinical Pearl

Vepdegestrant is the first PROTAC degrader approved in oncology — mechanistically distinct from oral SERDs like elacestrant. Rather than competitively antagonizing ER, it hijacks the cereblon E3 ubiquitin-ligase pathway to catalytically degrade the receptor, giving deep ER knockdown that stays active in ESR1-mutated, endocrine-resistant breast cancer. Its monitoring centers on hematologic (leukopenia/neutropenia/anemia) and hepatic (AST/ALT) parameters, and it carries distinct P-gp and UGT1A9…

Related Therapies & Mechanisms

• Anastrozole (Arimidex) — Hormonal Agent · Breast
• Exemestane (Aromasin) — Hormonal Agent · Breast
• Fulvestrant (Faslodex) — Hormonal Agent · Breast
• Goserelin (Zoladex) — Hormonal Agent · Breast