MON-102 Osilodrostat for Ectopic Cushing's Syndrome: A Superior Off-Label Option After Failure of Other Therapies - A Case Report

Abstract Disclosure: T. Abu Samaan: None. F. Erenler: None. Background: Ectopic Cushing's syndrome (CS) is a challenging disease to manage due to the aggressive nature of the primary tumor, which is often metastasized at diagnosis. This increases the disease burden and exacerbates elevated cortisol levels. Controlling cortisol production is the cornerstone of treatment. We present a case of ectopic CS managed with multiple medications, including metyrapone and pasireotide, with successful control ultimately achieved using osilodrostat. Clinical Case: A 76-year-old male presented with uncontrolled, new-onset diabetes mellitus (A1c: 13.5%). His wife suggested evaluation for CS. A 1 mg dexamethasone suppression test (DST) revealed elevated ACTH (85 pg/mL), cortisol (16.4 µg/dL), and DHEA-S (62 µg/dL). An 8 mg DST showed cortisol at 15.1 µg/dL and ACTH at 78 pg/mL, confirming ectopic CS.Chest and abdomen CT revealed a 3.5 cm right perihilar mass, 1.8 cm and 0.8 cm left lower lobe lung masses, and pancreatic body bulkiness with calcifications. Brain MRI was negative for pituitary masses. A 24-hour urinary free cortisol (UFC) test was elevated at 541.6 µg/24h. PET scan showed FDG uptake in the pancreatic uncinate process and lung masses. Biopsies confirmed small-cell lung cancer (chromogranin-positive) and a high-grade pancreatic neuroendocrine tumor (NET) with strong SSTR5 but weak, patchy SSTR2 expression.The patient was initiated on metyrapone, gradually increased to 3000 mg/day over four months, with UFC reaching a nadir of 46 µg/24h after six months but with frequent elevations. Pasireotide (10 mg/day, up to 30 mg/day) was added to target SSTR5 and reduce tumor burden. UFC briefly improved (nadir of 5.4 µg/24h), but tapering metyrapone led to increases in UFC, and the tumor continued to grow. To reduce polypharmacy, both medications were discontinued. Osilodrostat (5 mg BID) was initiated due to its simplicity and lower pill burden, achieving control within four days (cortisol: 2.5 µg/dL; ACTH: 37 pg/mL; UFC: 2.3 µg/24h). QTc and serum potassium were closely monitored. Appetite loss was managed with dexamethasone (1-1.5 mg), and KCl supplementation controlled hypokalemia. The patient remained stable on this regimen but passed away six months later. Conclusion: Osilodrostat, though off-label, is an effective and user-friendly option for managing ectopic CS, allowing for straightforward monitoring and improved patient adherence Presentation: Monday, July 14, 2025