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 (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.

Patients and methods: 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.

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 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.

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.

Figure 1.

Primary and secondary endpoints in the ITT population. CBR (A), PFS (B), OS (C; August 5, 2020 cutoff date), and OS (D; June 23, 2021 cutoff date). BCL2, B-cell lymphoma 2; CBR, clinical benefit rate; CI, confidence interval; CR, complete response; ITT, intention-to-treat; NE, not evaluable; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease. ^aCBR included CR, PR, and SD ≥24 weeks. ^bOne patient did not report measurable disease at baseline. ^cStratified by prior line of therapy in the locally advanced or metastatic breast cancer setting (one versus two) and BCL2 status (high versus low).

Figure 2.

PFS in the BCL2-high subgroup (A), the BCL2-low subgroup (B), and tumors with a BCL2/BCLXL ratio ≥1 and <1 (C). BCL2, B-cell lymphoma 2; BCLXL, B-cell lymphoma extra-large; CI, confidence interval; PFS, progression-free survival.

Figure 3.

PFS in the PIK3CA-wild-type subgroup (A) and PIK3CA-mutant subgroup (B). CI, confidence interval; ITT, intention-to-treat; PFS, progression-free survival; SV, short variant. ^aAnalysis is based on known or likely pathogenic PIK3CA SVs detected from samples evaluable for plasma ctDNA only.