Background: Breast cancer is the most common malignancy among women in the U.S. and is a leading cause of cancer-related death. Among women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, 45% harbor activating mutations in the PIK3CA gene, which induces hyperactivation of phosphatidylinositol 3-kinase (PI3K) and drives cell growth and survival. The SOLAR-1 trial found that the combination of alpelisib, a PI3K inhibitor, and fulvestrant, an endocrine therapy, significantly improved progression-free survival compared to fulvestrant alone, leading to Food and Drug Administration approval in PIK3CA-mutated metastatic breast cancer. While PI3K inhibition induces apoptosis of cancer cells, inhibition of this pathway in the liver and skeletal muscle impairs physiologic insulin signaling leading to hyperglycemia. This affects > 60% of patients, results in grade 3-4 hyperglycemia in 36% of patients, and is a major cause of interrupted/reduced dosing or discontinuation. In preclinical models, application of a very low carbohydrate (ketogenic) diet or a sodium-glucose cotransporter 2 inhibitor (SGLT2i), a commonly used diabetes medication, minimized hyperglycemia and improved the anti-tumor efficacy of PI3K inhibition. These interventions are safe and feasible in cancer patients but have not been studied for the prevention of PI3K inhibitor-associated hyperglycemia. Methods: We are conducting a multicenter phase II clinical trial (NCT05090358) in patients receiving standard-of-care alpelisib plus fulvestrant to test the efficacy of three interventions (n = 106): 1) ketogenic diet, 2) low-carbohydrate diet, or 3) canagliflozin (a SGLT2i) in preventing alpelisib-associated hyperglycemia. The goal of this study is to mitigate a major toxicity of PI3K inhibitors and maximize their clinical efficacy. Eligible patients must be postmenopausal and have histologically confirmed HR-positive, HER2-negative metastatic breast cancer, ≥1 activating PIK3CA mutations, measurable disease per RECIST v1.1 or at least one predominantly lytic bone lesion, recurrence or progression during or after endocrine-based therapy, ECOG performance status of 0-1, hemoglobin A1c < 8%, and fasting blood glucose < = 140mg/dL. Prior CDK4/6 inhibitor use is allowed. The primary endpoint is the grade 3-4 hyperglycemia-free rate at 12 weeks. Secondary endpoints include the 6- and 12-month overall response rate, 6- and 12-month progression-free survival, alpelisib adherence, changes in systemic hormones and metabolites related to glucose homeostasis, changes in body composition, and quality of life. The first patient was enrolled on October 15, 2021. Participating sites include Memorial Sloan Kettering Cancer Center, Weill Cornell Medical Center, and the Ohio State University Wexner Medical Center. Clinical trial information: NCT05090358.