Real-World Osilodrostat Effectiveness and Safety in Nonpituitary Cushing Syndrome

Context: Osilodrostat's clinical development program mostly enrolled Cushing disease patients. Data in nonpituitary Cushing syndrome (CS) patients are limited. Objective: This work aims to evaluate osilodrostat effectiveness and safety in nonpituitary CS in real-world practice in France. Methods: A retrospective, observational study (LINC 7; NCT05633953) was conducted in a multicenter institutional practice setting. Data for patients who initiated osilodrostat under the French Autorisation Temporaire d'Utilisation program or, once approved, in routine clinical practice were extracted retrospectively for 36 months or less (2019-2022). Participants included 103 adult nonpituitary CS patients: ectopic adrenocorticotropin secretion (EAS), n = 53; adrenocortical carcinoma (ACC), n = 19; adrenal adenoma (AA), n = 17; and bilateral adrenal nodular disease (BND), n = 14. Forty-three patients remained on osilodrostat throughout the observation period. Median (minimum-maximum) osilodrostat exposure and baseline dose were 177 days (1-1178 days) and 5.0 mg/day (1-60 mg/day), respectively. The main outcome measure was the proportion with mean urinary free cortisol (mUFC) less than or equal to the upper limit of normal (ULN) at Wk 12 (modified intention-to-treat [mITT] population: all enrolled patients with ≥12 weeks' follow-up, excluding patients without Wk 12 mUFC for nonsafety reasons). Results: Osilodrostat was initiated and titrated based on investigator judgment. Cortisol decreased by Wk 4, remaining stable thereafter. Twenty-three of 52 patients (mITT, 44.2%; 95% CI, 30.5%-58.7%) had mUFC less than or equal to the ULN at Wk 12 (missing values reported as nonresponders). Forty-five of 52 had Wk 12 mUFC available; the proportions with mUFC less than or equal to the ULN by etiology were as follows: EAS, n = 12/29 (41%); ACC, n = 4/6; AA, n = 1/3; and BND, n = 6/7. The most common (≥15%) treatment-emergent adverse events were adrenal insufficiency (28%) and hypokalemia (18%). Twenty-nine patients (EAS, n = 24; ACC, n = 5) died from adverse events (n = 1 assessed as osilodrostat related by investigator), most commonly neoplasm progression (n = 11). Conclusion: Osilodrostat is a suitable treatment for endogenous CS of various nonpituitary etiologies.