MON-625 Comparison of PI3K Inhibitor Versus AKT Inhibitor on Hyperglycemia with Continuous Glucose Monitoring in Metastatic Breast Cancer

Abstract Disclosure: J.A. Aurora: None. S. Majrashi: None. R. Yan: None. A.G. Pittas: None. Background: Phosphatidylinositol-3-kinase (PI3K) inhibitors, such as alpelisib, are targeted therapies used in the management of metastatic breast cancer. While effective for cancer treatment, these agents can induce metabolic side effects, including severe hyperglycemia due to decreased glucose transport, increased gluconeogenesis, and increased glycogenolysis. Protein kinase B (AKT) inhibitors, such as capivasertib, are alternatives agents to PI3K inhibitors due to a lower risk of hyperglycemia; however, there are no direct comparison studies. AKT inhibitors may have a more favorable glycemia profile due to their downstream effects in the PI3K/AKT/mTOR signaling pathway. We present a case of a patient with type 2 diabetes mellitus (T2DM) who developed severe hyperglycemia attributed to alpelisib and subsequent improvement of glycemia when switched to capivasertib. Clinical Case: A 59-year-old woman with a history of T2DM, diastolic heart failure, and metastatic breast cancer (ER+, PR+, HER2+), was started on alpelisib 250 mg daily in combination with fulvestrant after a liquid biopsy analyzing tumor biomarkers confirmed a PIK3CA (H1047R) mutation. Her diabetes was previously well-managed with metformin extended release, yielding a glucose management indicator (GMI) of 5.6%. Within one week of initiating alpelisib, the patient developed Grade 3 hyperglycemia (BG 251-500 mg/dL) with symptoms of polydipsia and polyuria. Continuous glucose monitoring (CGM) while on alpelisib revealed average glucose level of 284 mg/dL (GMI 10.1%) with multiple readings over 350 mg/dL. Alpelisib was stopped and empagliflozin 10 mg daily was started, and glycemia normalized four days later (average glucose of 120 mg/dL). Due to her severe alpelisib-induced hyperglycemia, she was transitioned to a subtherapeutic dose of capivasertib 200 mg twice daily for four consecutive day cycles to reduce the degree of hyperglycemia. Following the switch to capivasertib, average glycemia improved significantly, 141 mg/dL (GMI 6.7%) on days when taking capivasertib and 126 mg/dL (GMI 6.3%), while off it. Conclusion: This case underscores the pronounced hyperglycemic effects of alpelisib, emphasizing the need for diligent monitoring and management of glycemia. Options to manage hyperglycemia from PI3K inhibitors are limited as medications binding to the insulin receptor can activate the PI3K tissue proliferation cascade. The transition to capivasertib improved her glycemic control and highlights the importance of individualized cancer treatment strategies. CGM played a critical role in guiding timely interventions and understanding pharmacokinetics of alpelisib and capivasertib, specifically time to peak and half-life. Additionally, a multidisciplinary approach is essential for optimizing care in this patient population. Presentation: Monday, July 14, 2025