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The FDA on May 1, 2026 approved Veppanu (vepdegestrant) for adults with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer whose disease has progressed after at least one line of endocrine therapy.
Vepdegestrant is a heterobifunctional degrader: one end binds the estrogen receptor, the other an E3 ligase, and the receptor is tagged for destruction by the proteasome. Fulvestrant, the incumbent, degrades the receptor too but is given by monthly intramuscular injection and limited by poor solubility. The mechanism has been described in the literature since the early 2000s.
VERITAC-2 (NCT05654623) randomized 624 patients 1:1 to oral vepdegestrant 200 mg daily or fulvestrant 500 mg intramuscularly, 270 of them carrying ESR1 mutations detected in circulating tumor DNA. All had progressed on one or two prior lines of endocrine therapy including a CDK4/6 inhibitor. In the ESR1-mutated group, median progression-free survival by blinded independent review was 5.0 months against 2.1 months, a hazard ratio of 0.57. Confirmed objective response rate was 19% versus 4%. Overall survival was immature, with deaths in 16% of the group.
QTc prolongation carries a warning, and most reactions above 10% were laboratory findings.
Arvinas and Pfizer developed the drug and held the application at approval. Rigel Pharmaceuticals licensed global rights on May 12, 2026, paying $70 million upfront, and describes Veppanu as the first and only FDA-approved PROTAC.
Clinically, it adds an oral option after endocrine therapy fails, in the labeled ESR1-mutated population.
Sources: FDA prescribing information; Drugs@FDA, NDA 219835; Rigel press release; VERITAC-2 (NCT05654623); Nature Reviews Drug Discovery
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