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

Abstract

Purpose: Despite promising activity in hematopoietic malignancies, efficacy of the B-cell lymphoma 2 (BCL) inhibitor venetoclax in solid tumors is unknown. We report the prespecified VERONICA primary results, a randomized phase 2 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. Patients and Methods: Pre-/postmenopausal females {greater than or equal to}18 years were randomized 1:1 to venetoclax (800 mg oral 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: progression-free survival (PFS), overall survival, and safety. Exploratory biomarker analyses included BCL2 and BCL extra-large (BCLXL) tumor expression, and PIK3CA ctDNA mutational status. Results: 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: -16.86-12.94]). 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 hazard ratio 0.94 [95% CI: 0.61-1.45]; P = 0.7853). Overall survival data were not mature. A non-significant improvement of CBR and PFS was observed in patients whose tumors had strong BCL2 expression (immunohistochemistry 3+), a BCL2/BCLXL Histoscore ratio {greater than or equal to}1, or PIK3CA-wildtype status. Conclusions: 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.