SAT-551 - Severe Insulin Resistance after Capivasertib, A Novel Targeted Therapy for Breast Cancer

Background
Capivasertib is a novel oral AKT inhibitor used in combination with fulvestrant for HR+/HER2- advanced breast cancer. By inhibiting the PI3K/AKT/mTOR pathway, the drug suppresses tumor growth but also disrupts downstream insulin signaling, leading to decreased glucose uptake and increased hepatic glycogen storage. We present a case of severe hyperglycemia occurring after Capivasertib initiation requiring high doses of insulin.

Clinical case
A 68-year-old female with metastatic breast cancer and prediabetes was admitted for dyspnea secondary to malignant pleural effusion. After chest pigtail insertion and antibiotic therapy, she was cleared to undergo Cycle 1 of Capivasertib and Fulvestrant. Capivasertib was started at a dose of 200mg/tablet 2 tablets twice a day. Within 24 hours of initiation, blood glucose levels increased from a baseline of 163–193 mg/dL on the first day of therapy to as high as 557 mg/dL hence referral to Endocrinology service. Hyperglycemic crises such as Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State were ruled out. The patient showed severe insulin resistance, requiring an insulin regular drip as high as 180 units/hour, together with subcutaneous glargine as high as 50 units and subcutaneous glulisine as high as 60 units three times a day. Metformin and Linagliptin were started however the patient experienced nausea and vomiting upon initiation of Metformin. Due to the pleural effusion, the insulin drip was concentrated at 1000 units per 250 mL of plain normal saline solution. Capivasertib was discontinued on the 3rd day of treatment, and the patient eventually achieved glycemic control 58 hours after discontinuation of the drug.

Discussion
The CAPItello-291 trial noted hyperglycemia in 16.3% of patients. The preferred treatment for PI3K inhibitor induced hyperglycemia is Metformin, but this was not tolerated by the patient, hence intensification of treatment with insulin therapy was needed. Two other case reports on Capivasertib induced Diabetic Ketoacidosis (Rodriguez et al, 2024) and Acute hyperglycemic hyperosmolar state associated with Capivasertib (Chu et al., 2024) describes onset between 10 to 16 days post-initiation.

Conclusion
This case is notable for its onset within 24 hours and the severity of insulin resistance. This case highlights the need for baseline metabolic risk stratification and readiness for aggressive insulin management in patients ongoing Capivasertib therapy. Collaboration between Endocrinology and Oncology is needed to manage these metabolic consequences.

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