Abstract Background: PIK3CA mutations are found in up to 40% of hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancers (MBC). Alpelisib is an orally bioavailable PIK3CA inhibitor approved in combination with fulvestrant based on the SOLAR-1 study. However, uptake has been limited due to toxicity concerns, most commonly hyperglycemia (grade ≥3 was 37% in SOLAR-1 and 28% in the BYLieve study, which evaluated alpelisib after progression on a CDK 4/6 inhibitor). Patients with uncontrolled type 2 diabetes (T2DM) were excluded from both studies [defined as fasting plasma glucose (FPG) level >140 mg per deciliter, or a glycosylated hemoglobin (HgbA1C) level of >6.4%]. Of note, both trials enrolled a majority of non-Hispanic White (NHW) patients. Disparities regarding prevalence of diabetes has been reported among Hispanics (H). The Centers for Disease Control and Prevention reports that H are more likely to have T2DM than NHW (approximately 17% vs 8% respectively). Our study aims to characterize the incidence and management of hyperglycemia in H MBC patients treated with alpelisib. Methods: A retrospective chart review was performed to include patients with HR+ HER2- MBC with a documented PIK3CA mutation treated with alpelisib in combination with fulvestrant at Miami Cancer Institute from 2019-2022. Patients were identified using pharmacy records and the COTA real-world database (RWD, an analytics platform enabling investigation of longitudinal RWD). Cases were excluded where the start date was unclear, or treatment was given for a diagnosis other than breast cancer. Based on available data in the medical record, patients were categorized as H or NH. Descriptive statistics were used to describe variables in both groups of patients. Results: Of 46 patients identified, 34 were included in the final analysis (17 H and 17 NH). The median age was 63 y (range 32-87). The most common PIK3CA mutation identified was H1047R (41.2% of H and 23.5% of NH; p > 0.05). Starting body mass index (BMI) was higher in H compared to NH (29.9 vs 24.8; p < 0.05). Starting FPG was the same for both groups (115 mg/dL), and within the first two weeks on treatment the highest FPG was higher in H vs NH (250 mg/dL vs 157 mg/dL; p > 0.05). H also had the highest peak glucose when compared to NH (333.8 mg/dL vs 217.8 mg/dL; p < 0.05). Furthermore, by the end of treatment H had a higher FBG than NH (247.4 mg/dL vs 118.0 mg/dL; p < 0.05). Overall, any grade hyperglycemia occurred in 70.6% (82.4% H, 58.8% NH; p > 0.05, with high rates of grade 3/4 hyperglycemia in both groups (53% H 41% NH; p > 0.05). A higher percentage of H patients required more than one anti-hyperglycemic medication as compared to NH (41% vs 12%; p > 0.05). Hispanics time on treatment was shorter compared to NH (151 vs 240 days; p > 0. 05). Disease progression was the most frequent reason for treatment discontinuation in both groups 52.9%. However, more H patients discontinued alpelisib due to hyperglycemia (23.5% vs 5.9%; p > 0.31). Conclusions: Despite starting treatment with similar FPG levels, H had a higher peak plasma glucose level compared to NH. Although not statistically significant, likely due to a small sample size, the rates of hyperglycemia within two weeks of treatment was higher in H than NH. Furthermore, H required the use of more antiglycemic medications and had higher discontinuation rates. Therefore, there is a heightened need to increase education and awareness of glucose monitoring in H during treatment with alpelisib. Further prospective studies are warranted to better define the optimal management of hyperglycemia in H patients. Citation Format: Yolcar Chamorro, Reshma Mahtani, Shanada Monestime, Manmeet Ahluwalia, Muni Rubens, Natasha Harpalani, Ana Sandoval-Leon. Hyperglycemia in Hispanic MBC patients treated with alpelisib: single institution retrospective study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-08-11.