Abstract P137: SGLT2 inhibition improves BYL719-induced hyperglycemia and hyperinsulinemia in rat pre-clinical models

Abstract

Abstract Background In phase III SOLAR-1 trial (NCT02437318), the PI3K alpha selective inhibitor alpelisib (ALP) + fulvestrant significantly improved progression-free survival vs. fulvestrant alone in patients with HR+/HER2- advanced breast cancer with PIK3CA mutations. Hyperglycemia is an on-target adverse effect of ALP that led to 6% of patient discontinuation in the ALP arm. Recently, Sodium-glucose co-transporter 2 (SGLT2) inhibition was reported to reduce PI3K inhibition-induced glucose and insulin increase. For 6 SOLAR-1 patients, the addition of an SGLT2 inhibitor to metformin (MET) and ALP stabilized blood glucose levels, allowing them to continue ALP treatment. Methods Brown Norway (BN) rat and Rat1-myr-p110α tumor bearing nude rat in vivo models were used to further investigate the degree of glucose and insulin control achievable upon treatment with ALP and a SGLT2 inhibitor dapagliflozin (DAPA) +/- MET and effects on ALP tolerability and efficacy. Results In both rat models tested, the addition of DAPA to ALP nearly suppressed ALP-induced hyperglycemia, was associated with insulin level reduction and insulin sensitivity improvement and no signs for ketoacidosis upon single agent (S.A) nor combination were observed under fed conditions. ALP S.A efficacy in the Rat1-myr-p110α tumor bearing nude rats was maintained when used in combination with DAPA and there was no influence of DAPA on ALP-induced body weight loss (BWL). In BN rats, when combining MET with ALP, a delay in blood glucose reduction was observed vs. DAPA + ALP combination. The triple combination of MET + DAPA + ALP improved further blood glucose levels reduction with the same kinetic as DAPA + ALP. MET + DAPA + ALP triple combination was more effective in reducing plasma insulin levels when compared to MET + ALP or DAPA + ALP double combinations. All combinations tested with MET slightly increased BYL719-induced BWL in BN rats. Conclusions SGLT2 inhibitors such as DAPA significantly reduced hyperglycemia and improved hyperinsulinemia induced by ALP in rat models without further BWL induced by ALP. These results warrant further clinical investigation of adding SGLT2 inhibitors +/- metformin to treat ALP-induced hyperglycemia. Citation Format: Christian R. Schnell, Daniel Wyss, Walter Tinetto, Thomas Ferrat, Jiaping Gao, Panza Darrell, Josh Gold, Valerie Beaulieu, John Diener, Christine Fritsch. SGLT2 inhibition improves BYL719-induced hyperglycemia and hyperinsulinemia in rat pre-clinical models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P137.