Addition of the BCL2 inhibitor venetoclax to endocrine therapy does not improve clinical benefit in patients with ER-positive, HER2-negative, locally advanced/metastatic breast cancer, according to the primary analysis of the phase 2 VERONICA trial.  

For patients with ER-positive, HER2-negative metastatic breast cancer, CDK4/6 inhibitors combined with single-agent endocrine therapy is standard first-line treatment. Nevertheless, most patients progress. A potential novel therapeutic target is the antiapoptotic protein BCL2, which is overexpressed in ̃85% of primary ER-positive breast cancers.

Venetoclax is a potent, selective and oral BCL2 inhibitor, already approved in several haematological malignancies, that has shown promising clinical activity in patients with ER-positive and BCL2-positive metastatic breast cancer who have received prior endocrine therapy [1,2]. The VERONICA trial (NCT03584009) included 103 patients with ER-positive, HER2-negative, metastatic breast cancer who had progressive disease after ≤2 lines of treatment (including a CDK4/6 inhibitor). Participants were randomized 1:1 to receive venetoclax (800 mg daily) plus fulvestrant (500 mg day 1 and 15 of cycle 1; day 1 of subsequent 28-day cycles) or fulvestrant alone until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end.

Primary endpoint was clinical benefit rate (complete response, partial response, and stable disease ≥24 weeks). Prof. Geoff Lindeman (Peter McCallum Cancer Center, Australia) presented results from the primary analysis [3]. Clinical benefit rate was similar between arms: 11.8% and 13.7% for venetoclax plus fulvestrant and fulvestrant alone, respectively. Median progression-free survival was 2.69 months versus 1.94 months, respectively. Overall survival data were not mature. Based on the results of this primary analysis, venetoclax in second (or later) line does not seem to benefit patients with metastatic ER-positive, HER2-negative, metastatic breast cancer, Prof. Lindeman concluded. “However, it remains unclear whether a BCL2 inhibitor would be effective in an endocrine-responsive, CDK4/6 inhibitor-naïve setting.”

  1. Rozeboom B, et al. Am J Cancer Res. 2019; 9(12): 2821–2831.
  2. Lok SW, et al. Cancer Discov 2019; 9: 354-69.
  3. Lindeman GJ, et al. Results from VERONICA: A randomized, phase II study of second-/third-line venetoclax (VEN) + fulvestrant (F) versus F alone in estrogen receptor (ER)-positive, HER2-negative, locally advanced, or metastatic breast cancer (LA/MBC). ASCO 2021 Virtual Meeting, abstract 1004.