A Case of Severe Cushing Syndrome Due to Metastatic Adrenocortical Carcinoma Treated with Osilodrostat

Introduction:
Osilodrostat is a newer treatment for Cushing disease. We present a case in which osilodrostat was used in a block-and-replace strategy to treat severe Cushing syndrome secondary to metastatic adrenocortical carcinoma (ACC).

Case Description:
A 70-year-old female presented with abdominal pain and was found to have a right adrenal mass. Hypercortisolism noted with morning cortisol 31.8 mcg/dL which was nonsuppressible at 29 mcg/dL after 1 mg dexamethasone. After right adrenalectomy, pathology revealed low-grade ACC with negative margins. Morning cortisol on post-operative day 3 was 18.9 mcg/dL. Three months after surgery, hypercortisolism recurred and a PET CT scan showed metastases to liver and bone. Traditional chemotherapy and mitotane were initiated. Mitotane therapy was complicated by hemolytic anemia, and was replaced by osilodrostat 2 mg twice daily (BID) with peak 24-hour urinary free cortisol 1,856 µg/L. Dosage was titrated to 7 mg BID over 10 weeks at which time the patient presented with fatigue and hypotension. Morning cortisol was 4.7 mcg/dL, consistent with adrenal insufficiency. Sick-day hydrocortisone was initiated, 30 mg AM and 15 mg PM. After 10 days of sick day dosing, osilodrostat was titrated to 8 mg BID for complete blockade, and hydrocortisone replacement decreased to 20 mg AM and 10 mg PM. After 3 weeks on this regimen her 24-hour urinary free cortisol was 59 µg/L.

Discussion:
ACC is a rare but devastating cause of Cushing syndrome. While surgical resection has curative potential, 40-70% of patients have recurrence, requiring adjuvant treatment. While Mitotane, with or without chemotherapy, has been a mainstay of adjuvant therapy for high-risk and metastatic ACC, up to 75% cases develop metastatic disease that is refractory to treatment. Osilodrostat, a recently developed steroidogenesis inhibitor, may provide another option for controlling hypercortisolism by inhibiting 11β-hydroxylase and aldosterone synthase. It was FDA approved to treat Cushing disease in patients unresponsive to pituitary surgery and non-surgical candidates. It has been used off-label effectively in select cases of Cushing syndrome. The FDA recommends dosing to target a normal cortisol level, but block-and-replace dosing may be reasonable to avoid adrenal insufficiency in situations resulting in variable cortisol production, such as cyclic Cushing’s syndrome, metastatic disease refractory to traditional therapies, or continued treatment with chemotherapy that may unpredictably reduce biochemical tumor activity.