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Vepdegestrant for the treatment of HR+/HER2- breast cancer

Toru Mukohara1

  • 1Department of Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan.

Expert Opinion on Pharmacotherapy
|April 3, 2025
PubMed
Abstract

Insights

Vepdegestrant, a novel oral PROTAC ER degrader, shows promise for advanced HR+/HER2- breast cancer, especially with ESR1 mutations. Clinical trials are ongoing to confirm its efficacy and potential to overcome endocrine resistance.

Area of Science:

  • Oncology
  • Endocrinology
  • Pharmacology

Background:

  • Advanced hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer treatment improved with endocrine therapy (ET) and targeted agents.
  • Endocrine therapy resistance, particularly due to ESR1 mutations, remains a significant clinical challenge.

Purpose of the Study:

  • To evaluate vepdegestrant, a novel PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, for advanced HR+/HER2- breast cancer.
  • To assess the safety and efficacy of vepdegestrant, including its potential activity across different ESR1 genotypes.

Main Methods:

  • Vepdegestrant is a first-in-class, orally bioavailable PROTAC ER degrader.
  • Preclinical studies and Phase I/II clinical trials have been conducted to assess its activity, safety, and efficacy as a single agent and in combination therapies.

Main Results:

  • Preclinical data suggest vepdegestrant activity irrespective of ESR1 mutation status.
  • Phase I/II studies indicate a favorable safety profile and encouraging efficacy for vepdegestrant.

Conclusions:

  • Vepdegestrant demonstrates potential as a new therapeutic option for advanced HR+/HER2- breast cancer, addressing unmet needs in endocrine resistance.
  • Ongoing Phase III trials (VERITAC-2) will provide crucial data on vepdegestrant's clinical significance and its potential to establish PROTACs as a new class of anti-cancer drugs.
Keywords:
ARV-471Breast cancerHER2-negativePROTAChormone receptor-positivevepdegestrant

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