VERONICA: Randomized Phase II Study of Fulvestrant and Venetoclax in ER-Positive Metastatic Breast Cancer Post-CDK4/6 Inhibitors - Efficacy, Safety, and Biomarker Results.

in Clinical cancer research : an official journal of the American Association for Cancer Research by Geoffrey J Lindeman, Tharu M Fernando, Rebecca Bowen, Katarzyna J Jerzak, Xinni Song, Thomas Decker, Frances Boyle, Steve McCune, Anne Armstrong, Catherine Shannon, Gianfilippo Bertelli, Ching-Wei Chang, Rupal Desai, Kushagra Gupta, Timothy R Wilson, Aulde Flechais, Aditya Bardia

TLDR

  • The study aimed to determine if the B-cell lymphoma 2 (BCL2) inhibitor venetoclax is effective in treating solid tumors, specifically in estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer that has progressed after treatment with cyclin-dependent kinase (CDK) 4/6 inhibitors. The study used a randomized phase II clinical trial design, where participants were randomly assigned to receive either venetoclax plus fulvestrant or fulvestrant alone. The primary endpoint was the clinical benefit rate (CBR), which measures how much the treatment improved the patient's condition. Secondary endpoints included progression-free survival (PFS), overall survival, and safety. The study also looked at biomarkers, such as BCL2 and BCL extra-large (BCLXL) tumor expression and PIK3CA circulating tumor DNA mutational status, to see if they could predict how well the treatment worked. At the primary analysis, the study found that venetoclax did not significantly improve CBR, median PFS, or overall survival data were not mature. However, a nonsignificant improvement of CBR and PFS was observed in patients whose tumors had strong BCL2 expression, a BCL2/BCLXL Histoscore ratio ≥1, or PIK3CA-wild-type status. The study suggests that venetoclax plus fulvestrant may not be effective in treating endocrine therapy-resistant, CDK4/6 inhibitor-refractory metastatic breast tumors, but it may increase dependence on BCLXL in this setting.

Abstract

Despite promising activity in hematopoietic malignancies, efficacy of the B-cell lymphoma 2 (BCL2) inhibitor venetoclax in solid tumors is unknown. We report the prespecified VERONICA primary results, a randomized phase II clinical trial evaluating venetoclax and fulvestrant in estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer, post-cyclin-dependent kinase (CDK) 4/6 inhibitor progression. Pre-/postmenopausal females ≥18 years were randomized 1:1 to venetoclax (800 mg orally daily) plus fulvestrant (500 mg intramuscular; cycle 1: days 1 and 15; subsequent 28-day cycles: day 1) or fulvestrant alone. The primary endpoint was clinical benefit rate (CBR); secondary endpoints were progression-free survival (PFS), overall survival, and safety. Exploratory biomarker analyses included BCL2 and BCL extra-large (BCLXL) tumor expression, and PIK3CA circulating tumor DNA mutational status. At primary analysis (cutoff: August 5, 2020; n = 103), venetoclax did not significantly improve CBR [venetoclax plus fulvestrant: 11.8% (n = 6/51; 95% confidence interval (CI), 4.44-23.87); fulvestrant: 13.7% (7/51; 5.70-26.26); risk difference -1.96% (95% CI, -16.86 to 12.94)]. Median PFS was 2.69 months (95% CI, 1.94-3.71) with venetoclax plus fulvestrant versus 1.94 months (1.84-3.55) with fulvestrant (stratified HR, 0.94; 95% CI, 0.61-1.45; P = 0.7853). Overall survival data were not mature. A nonsignificant improvement of CBR and PFS was observed in patients whose tumors had strong BCL2 expression (IHC 3+), a BCL2/BCLXL Histoscore ratio ≥1, or PIK3CA-wild-type status. Our findings do not indicate clinical utility for venetoclax plus fulvestrant in endocrine therapy-resistant, CDK4/6 inhibitor-refractory metastatic breast tumors, but suggest possible increased dependence on BCLXL in this setting.

Overview

  • The study aims to evaluate the efficacy of the B-cell lymphoma 2 (BCL2) inhibitor venetoclax in solid tumors, specifically in estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer post-cyclin-dependent kinase (CDK) 4/6 inhibitor progression. The study is a randomized phase II clinical trial that randomized pre-/postmenopausal females ≥18 years to venetoclax (800 mg orally daily) plus fulvestrant (500 mg intramuscular; cycle 1: days 1 and 15; subsequent 28-day cycles: day 1) or fulvestrant alone. The primary endpoint was clinical benefit rate (CBR), and secondary endpoints were progression-free survival (PFS), overall survival, and safety. Exploratory biomarker analyses included BCL2 and BCL extra-large (BCLXL) tumor expression, and PIK3CA circulating tumor DNA mutational status. At primary analysis (cutoff: August 5, 2020; n = 103), venetoclax did not significantly improve CBR, median PFS, or overall survival data were not mature. A nonsignificant improvement of CBR and PFS was observed in patients whose tumors had strong BCL2 expression, a BCL2/BCLXL Histoscore ratio ≥1, or PIK3CA-wild-type status. The study does not indicate clinical utility for venetoclax plus fulvestrant in endocrine therapy-resistant, CDK4/6 inhibitor-refractory metastatic breast tumors, but suggests possible increased dependence on BCLXL in this setting.

Comparative Analysis & Findings

  • The study compared the outcomes observed under two experimental conditions: venetoclax plus fulvestrant versus fulvestrant alone. The primary endpoint was clinical benefit rate (CBR), and secondary endpoints were progression-free survival (PFS), overall survival, and safety. At primary analysis (cutoff: August 5, 2020; n = 103), venetoclax did not significantly improve CBR, median PFS, or overall survival data were not mature. A nonsignificant improvement of CBR and PFS was observed in patients whose tumors had strong BCL2 expression, a BCL2/BCLXL Histoscore ratio ≥1, or PIK3CA-wild-type status. The study suggests that venetoclax plus fulvestrant does not have clinical utility in endocrine therapy-resistant, CDK4/6 inhibitor-refractory metastatic breast tumors, but it may increase dependence on BCLXL in this setting.

Implications and Future Directions

  • The study's findings suggest that venetoclax plus fulvestrant does not have clinical utility in endocrine therapy-resistant, CDK4/6 inhibitor-refractory metastatic breast tumors. However, the study suggests that BCLXL may play a role in this setting, and further research is needed to explore this possibility. The study's limitations include a small sample size and the fact that overall survival data were not mature. Future research should focus on larger studies with longer follow-up to assess the long-term efficacy and safety of venetoclax plus fulvestrant in this setting. Additionally, studies should explore the role of BCLXL in this setting and identify potential biomarkers to predict response to venetoclax plus fulvestrant.
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