Endocrine Abstracts

Introduction: Osilodrostat is the newest approved steroidogenic inhibitor drug for the treatment of Cushing’s syndrome (CS). In this presentation, we describe 3 patients who experienced an unexpectedly prolonged adrenal insufficiency following interruption of this treatment.

Methods: A monocentric retrospective analysis (October 2019 to January 2023) of ACTH-dependent CS patients controlled with Osilodrostat was performed to identify patients with proven adrenal blockade persisting at least 4 weeks after cessation of Osilodrostat. Hormonal evaluation included basal serum cortisol, and DHEA-S as well plasma ACTH, aldosterone and renin levels determination. Stimulation test results with ACTH 250mcg and CRH 100mcg injection were also analyzed, when available.

Results: We identified 25 CS patients controlled by Osilodrostat and 5 among them experienced an unplanned treatment interruption due to adverse events or drug intolerance. Persistence of adrenocortical blockade was observed in 3 of those patients and lasted from 6 weeks to 9 months depending on cases. The reasons for Osilodrostat interruption were either a skin eruption (case 1) or a severe adrenal insufficiency secondary to infectious episodes (cases 2 and 3), requiring mineralocorticoid supplementation in the most acutely ill patient (case 3). Osilodrostat daily doses were 2, 4 and 10 mg/day at the time of interruption, respectively. Total Osilodrostat treatment duration before cessation did not seem to predict the severity of this outcome. On their latest hormonal evaluation, every patient showed an insufficient serum cortisol peak response to ACTH stimulation test, although 2/3 patients had a normal basal cortisol serum value > 250 mmol/l. Basal ACTH was high (>13 pmol/l) in the 3 patients. DHEA-S values were suppressed in all cases under Osilodrostat treatment and remained low during all the follow-up duration after cessation. At the latest available follow-up, Fludrocortisone supplementation was still necessary in the patient with mineralocorticoid deficit (case 3). CRH test was performed in 2 patients showing a significant response of ACTH but not of cortisol.

Conclusion: The duration of adrenal blockade in these 3 patients is hardly explained by the drug’s half-life (~4h) and remains to be elucidated. Additional research is also needed to identify predictors of this long-term effect on adrenal function. This highlights the importance of monitoring adrenal function and preventing adrenal crisis in patients at risk even after Osilodrostat interruption.