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).

1004 Background: For patients (pts) with ER-positive, HER2-negative MBC, CDK4/6 inhibitors + endocrine therapy (ET) is standard first-line treatment, with single-agent ET considered for second-line. Nevertheless, most pts progress. A novel therapeutic target is the antiapoptotic protein BCL2, which is overexpressed in ̃85% of primary ER-positive breast cancers. VEN is a potent, selective BCL2 inhibitor that has shown promising clinical activity in pts with ER-positive and BCL2-positive MBC who have received prior ET. We report the prespecified primary and updated (for overall survival [OS]) analysis of VERONICA (NCT03584009), a phase II study of VEN + F vs F in ER-positive, HER2-negative LA/MBC. Methods: Pts were ≥18-year-old women with ER-positive, HER2-negative LA/MBC, who received ≤2 prior lines of ET and no prior chemotherapy in the LA/MBC setting and experienced disease recurrence/progression during/after CDK4/6 inhibitor therapy (received ≥8 weeks prior). Pts were randomized 1:1 to VEN (oral; 800 mg daily) + F (intramuscular; 500 mg day 1 and 15 of cycle 1; day 1 of subsequent 28-day cycles) or F, and were treated until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end. Pts were stratified by prior lines of therapy in the LA/MBC setting (1 vs 2) and BCL2 status (high vs low). Primary endpoint was clinical benefit rate (CBR; complete response, partial response, and stable disease ≥24 weeks). Secondary endpoints included progression-free survival (PFS) and OS; safety and exploratory subgroup analyses were also conducted. Results: At primary analysis (cutoff: Aug 5, 2020), 103 pts had been randomized (intention-to-treat [ITT] population). Median age was 58.0 and 59.5 years in the VEN + F and F arms, respectively. CBR was similar between arms (VEN + F: 11.8% [n = 6/51; 95% confidence interval (CI) 4.44–23.87]; F: 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) in the VEN + F vs 1.94 months (1.84–3.55) in the F arm (stratified hazard ratio: 0.94 [95% CI 0.61–1.45]). Results for CBR and PFS were similar in the BCL2-high and -low subgroups vs the ITT population. More grade 3–4 adverse events (AEs) were observed in the VEN + F vs F arm (n = 13/50 [26%] vs 6/51 [11.8%]). AEs observed with VEN + F were consistent with their individual safety profiles. At updated analysis (cutoff: Oct 22, 2020), OS data were not mature (35.0% event/pt ratio); median OS was 16.99 months in the VEN + F vs not reached in the F arm (stratified hazard ratio: 2.06 [1.04–4.09]). Conclusions: From the primary analysis, VERONICA did not show an improved CBR or PFS with VEN + F, vs F alone, in pts with endocrine- and CDK4/6 inhibitor-refractory LA/MBC. Biomarker analysis is ongoing. Clinical trial information: NCT03584009 .