Use of osilodrostat is effective at controlling hypercortisolism in one of three (66.7 percent) patients with adrenal Cushing's Syndrome (CS) treated for longer than 4 weeks and in nearly four of five (87.5 percent) individuals treated for more than 12 weeks, a real-world study has shown. It also displays a positive impact on blood pressure and body weight.
Moreover, “[p]atients who received osilodrostat after previous steroidogenesis inhibitors had a higher probability of response to osilodrostat,” the investigators said.
Twenty-eight patients with adrenal CS were enrolled in this study, of whom 16 had adrenocortical carcinoma (ACC) and 12 had benign disease. Twenty-two patients used osilodrostat in monotherapy and six in combination with metyrapone. [J Clin Endoc Metab 2026;111:2180-2189]
In 21 participants treated for more than 4 weeks, 66.7 percent showed response to osilodrostat (28.6 percent with complete response and 38.1 percent with partial response). Treatment for more than 12 weeks increased the rate of response to 87.5 percent. Notably, osilodrostat used as a nonfirst-line therapy appears predictive of response (odds ratio, 15.0; p=0.010).
Furthermore, the study drug significantly reduced both body weight and systolic blood pressure (p<0.05). With regard to safety, nine patients had one or more adverse events, five of whom (56 percent) led to treatment discontinuation.
Frequent use
“One of the most important findings of our study is that the use of osilodrostat after the use of other previous adrenal steroidogenesis inhibitors (ie, as a second-/third- or fourth-line therapy vs first line) might be a potential predictor of response to osilodrostat,” the investigators said.
“The higher efficacy of osilodrostat when it was used in a nonfirst-line therapy may be related to the more frequent use of osilodrostat as first-line therapy in patients with ACC than with benign adrenal CS and a tendency to a higher proportion of patients treated with concomitant mitotane in the group of nonfirst-line therapy in comparison with the first-line therapy group,” they added.
While the differences did not reach statistical significance, these findings reveal worse hypercortisolism control among patients with ACC than those with benign adrenal CS. Patients with ACC who received concomitant mitotane also showed a higher rate of response than those who did not receive mitotane.
“The lack of statistically significant differences may be due to a type II error or a small sample size among the comparators, especially considering the relationship that we found between ACC and severe hypercortisolism, a predictor of lower response found in the statistical analysis,” the investigators said.
Study details
In this international real-world study, adrenal CS patients treated with osilodrostat at any time were enrolled in the safety evaluation, while those treated for longer than 4 weeks were included in the efficacy evaluation.
The investigators classified participants as responders if they experienced a reduction in urinary free cortisol (UFC) >50 percent (complete responders when UFC levels were below the upper limit of normal and partial responders if there was a reduction >50 percent but not normalization).
“Endogenous CS is a severe endocrine disorder caused by chronic exposure to hypercortisolism and is associated with a wide range of metabolic, cardiovascular, immune, thrombotic, and neuropsychiatric morbidities,” the investigators said. [Lancet Diabetes Endocrinol 2016;4:611-629]
“Based on the underlying mechanism, CS can be broadly classified into two main etiological categories: adrenocorticotropic hormone (ACTH)-dependent CS, which results from excessive secretion of ACTH, and ACTH-independent CS, in which cortisol excess arises directly from the adrenal gland,” they added. [Nat Rev Dis Primers 2025;11:4]