Abstract P5-13-06: Exploratory biomarker analysis in VERONICA, a phase 2 study of venetoclax + fulvestrant versus fulvestrant in patients with estrogen receptor (ER)-positive HER2-negative metastatic breast cancer (mBC)

Abstract BACKGROUND: Venetoclax (VEN) is a potent and selective inhibitor of the anti-apoptotic protein, BCL2. Preclinical studies have implicated the BCL2 family members, BCLXL and MCL1, in VEN resistance, and clinical studies in hematological malignancies have demonstrated subgroups with high ratios of BCL2/BCLXL and BCL2/MCL1 have the greatest VEN antitumor activity. The randomized phase 2 VERONICA study (NCT03584009) evaluated VEN in combination with fulvestrant (F) vs F alone in ER-positive, HER2-negative MBC pts who experienced disease recurrence/progression during or after a CDK4/6 inhibitor. Previously reported results from VERONICA (Lindeman et al. ASCO 2021) did not show an improved clinical benefit rate or progression-free survival (PFS) with VEN+F vs F alone. Here we present exploratory biomarker analyses of the expression of BCL2 family members and genomic alterations in circulating tumor DNA (ctDNA) and association with clinical outcomes from VEN+F vs F. METHODS: Tumor specimens were obtained during screening from 103 patients enrolled in the study, and expression levels of BCL2, BCLXL and MCL1 were analyzed by IHC. Baseline plasma-derived ctDNA was evaluated using the FoundationOne® Liquid assay. Expression of BCL2, BCLXL, MCL1 and mutations in ctDNA were correlated with PFS from VEN+F vs F based on the primary analysis (cutoff: Aug 5, 2020). RESULTS: In the overall population, protein levels of BCL2, BCLXL and MCL1 were similar between the VEN+F vs F arms. Patients whose tumors were BCL2 3+ trended towards having the greatest difference in median (m) PFS (3.9 months [mo] in VEN+F vs 1.7 mo in F; hazard ratio [HR] 0.38 [95% CI 0.09, 1.62]) albeit in a small sample size (n=13). Similarly, subgroup analysis suggested a trend for increasing mPFS and improved HR in VEN+F vs F alone in patients with the lowest BCLXL expression. mPFS in patients with a BCL2/BCLXL ratio ≥1 was 3.7 mo for VEN+F vs 1.8 mo for F (HR 0.67 [95% CI 0.3-1.49]) whereas patients with a BCL2/BCLXL ratio <1 had no difference in mPFS between the arms (2.0 mo in both arms, HR 1.21 [95% CI 0.7-2.1]). In the ctDNA-evaluable population, ESR1 (42.6%), TP53 (41.5%) and PIK3CA (35%) were the most prevalent genomic alterations observed and well-controlled between arms. PFS was similar between the ESR1 wildtype (wt) and mutant (mut) subgroups. TP53 mut status was a poor prognostic factor in both treatment arms. The PIK3CA wt subgroup had increased mPFS with VEN+F vs F alone (HR 0.66 [95% 0.38-1.17]) compared to PIK3CA mut (HR 1.59 [95% 0.74-3.34]). Patients with PIK3CA wt and BCL2 high tumors had the largest difference in mPFS between VEN+F (3.7 mo) vs F alone (1.9 mo) (HR 0.58 [95%CI 0.28-1.19]), compared to PIK3CA wt-BCL2 low tumors (2.4 vs 1.9 mo; HR 0.67 [95%CI 0.26-1.72]). CONCLUSION: Our data suggest that a high ratio of BCL2 to BCLXL conferred a trend towards a greater benefit to VEN+F compared to F alone, consistent with other clinical studies evaluating VEN. These analyses highlight the need to profile BCL2 and its family members to identify the VEN-sensitive subgroups, especially in indications where high expression of BCLXL or MCL1 may be observed. The ctDNA profile of VERONICA patients indicate a heavily pretreated patient population. The benefit observed in PIK3CA wt patients from VEN+F suggest increased dependence on BCL2 in this subgroup, while PIK3CA mut tumors likely rely on PI3K/AKT/mTOR survival programs or other BCL2 family members to evade apoptosis. Exploratory biomarker analyses are ongoing to further understand the VERONICA patient population. Citation Format: Geoffrey J. Lindeman, Tharu M. Fernando, Rebecca Bowen, Ching-Wei Chang, Rupal Desai, Kushagra Gupta, Aulde Fléchais, Timothy R. Wilson, Aditya Bardia. Exploratory biomarker analysis in VERONICA, a phase 2 study of venetoclax + fulvestrant versus fulvestrant in patients with estrogen receptor (ER)-positive HER2-negative metastatic breast cancer (mBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-06.