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VERONICA: Randomized Phase II Study of Fulvestrant and Venetoclax in ER-Positive Metastatic Breast Cancer Post-CDK4/6

Geoffrey J Lindeman1,2,3, Tharu M Fernando4, Rebecca Bowen5

  • 1Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|May 18, 2022
PubMed
Abstract

Insights

Venetoclax (BCL2 inhibitor) did not improve outcomes for metastatic breast cancer patients post-CDK4/6 inhibitor therapy. Further research is needed to explore its potential in specific patient subgroups.

Area of Science:

  • Oncology
  • Pharmacology

Background:

  • The B-cell lymphoma 2 (BCL2) inhibitor venetoclax shows promise in hematologic cancers, but its efficacy in solid tumors remains unestablished.
  • Estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer often becomes resistant to endocrine therapy and cyclin-dependent kinase (CDK) 4/6 inhibitors.

Purpose of the Study:

  • To evaluate the efficacy of venetoclax combined with fulvestrant in patients with ER-positive, HER2-negative metastatic breast cancer following progression on CDK4/6 inhibitors.
  • To assess clinical benefit rate (CBR) and progression-free survival (PFS) as primary and secondary endpoints.

Main Methods:

  • A randomized phase II clinical trial (VERONICA) enrolled pre-/postmenopausal women with advanced breast cancer.
  • Participants were randomized to receive either venetoclax plus fulvestrant or fulvestrant alone.
  • Exploratory analyses included tumor BCL2 and BCL extra-large (BCLXL) expression and PIK3CA mutational status.

Main Results:

  • Venetoclax did not significantly improve the clinical benefit rate (CBR) compared to fulvestrant alone (11.8% vs 13.7%).
  • Median progression-free survival (PFS) was similar between arms (2.69 months vs 1.94 months).
  • A trend towards benefit was observed in patients with high BCL2 expression, a high BCL2/BCLXL ratio, or wild-type PIK3CA.

Conclusions:

  • Venetoclax plus fulvestrant does not demonstrate clinical utility in endocrine therapy-resistant, CDK4/6 inhibitor-refractory metastatic breast cancer.
  • The results suggest a potential compensatory dependence on BCLXL in this patient population, warranting further investigation.

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