Abstract 2849: The oral SERD Elacestrant in combination with the PI3K inhibitor MEN1611 inhibits tumor growth in ER+/HER2- breast cancer in vitro and in PDX models

Abstract In estrogen receptor (ER)+/HER2-breast cancer(BC), the addition of CDK4/6 inhibitors (CDK4/6i) to endocrine therapies (ET) leads to a significant increase in progression-free survival. Nevertheless, clinical resistance emerges. The upregulation of the PI3K/AKT/mTOR signaling pathway is one of the multiple acquired mechanisms of resistance to the CDK4/6i and ET combination. Thus, the extensive crosstalk between the PI3K/AKT/mTOR and ER pathways underlines the importance of targeting both pathways to overcome drug resistance in ER+/HER2- BC. Here we have evaluated the antitumor activity of Elacestrant, the oral selective estrogen receptor degrader (SERD) and antagonist, in combination with the σ-sparing PI3K inhibitor MEN1611, in vitro and in vivo in different clinically relevant BC Patient-Derived Xenograft (PDX) models, resistant to CDK4/6i and to ET, harboring mutations in PIK3CA and/or ESR1 genes. In cell-based proliferation assays, the combination of Elacestrant and MEN1611 showed a synergistic effect in inhibiting the growth of ER+ BC cell lines. In vivo data in MCF7- and patient-derived xenograft models showed compelling antitumor activity using the combination at tolerable and clinically relevant doses, compared to the single agents. In the PDX HBxC-3, wild-type for PIK3CA and ESR1 genes, the Tumor Volume-Inhibition (TVI) was 56.2%, 48.7% and 71.7% for MEN1611, Elacestrant and the combination group, respectively. In this model, the combination showed improved anti-tumor activity in comparison to the single agent treatments. In the PDX models HBxC-19 and CTG-2308, wild-type for ESR1 gene, but harboring a PIK3CA mutation, the TVI of the combination was 94.6% and 61.4%, respectively. In the latter model the combination was significantly superior to the single agents. In the PDX model CTG-1260, with PIK3CA and ESR1 mutations, MEN1611 and Elacestrant single agent treatment showed tumor growth inhibition with TVIs of 63.2% and 52.3%, while the combination showed a significant TVI of 86.9%. Overall, in all the tested in vivo models the combination of Elacestrant and MEN1611 was superior in comparison to the single agents by overcoming resistance to ER inhibition potentially driven by PI3K pathway activation in PIK3CA mutated tumors. The current data support the use of Elacestrant, the first oral SERD with positive phase III results in the EMERALD trial (Bidard et al.; JCO 2022), in combination with the PI3K inhibitor MEN1611, in ER+/HER2- mBC patients harboring PIK3CA mutations and who progressed to CDK4/6i plus ET. Citation Format: Giuseppe Merlino, Alessio Fiascarelli, Simone Talucci, Patrizia Tunici, Mario Bigioni, Alessandro Bressan, Monica Binaschi. The oral SERD Elacestrant in combination with the PI3K inhibitor MEN1611 inhibits tumor growth in ER+/HER2- breast cancer in vitro and in PDX models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2849.