Introduction: Cushing's syndrome (CS) is a rare, chronic condition caused by prolonged exposure to elevated levels of circulating cortisol, and characterized by high morbidity and mortality. The primary treatment option for CS is surgery; however, medical therapy may be useful when surgery is unsuitable, refused, or has not been curative, or a rapid control of hypercortisolism is required. While osilodrostat and metyrapone are two treatments for controlling cortisol levels, they have not been compared directly in a clinical trial. This study evaluated the comparative efficacy and tolerability of osilodrostat versus metyrapone for the treatment of CS using indirect treatment comparison methods.
Methods: Unanchored matching-adjusted indirect comparison was used to synthesize relative treatment effects by reweighting patient-level data from two clinical trials for osilodrostat to published aggregate data for metyrapone. Efficacy endpoints included complete response (CR), defined as mean urinary free cortisol ≤ 1.0 × the upper limit of normal, at Weeks 12, 24, and 36. Tolerability endpoints included all-cause treatment discontinuation and treatment discontinuation due to lack of efficacy (LoE) or adverse events (AEs).
Results: The base case analysis demonstrated that osilodrostat provides increased odds of CR versus metyrapone at Week 12 [odds ratio (OR) 2.75; 95% confidence interval (CI) 1.29, 5.88], Week 24 (OR 3.28; 95% CI 1.58, 6.84) and Week 36 (OR 10.50; 95% CI 1.84, 59.96), implying a greater proportion of patients experience normalized cortisol levels at these time-points. Although the base case analysis showed that the odds of all-cause discontinuation and discontinuation due to LoE or AEs were numerically lower for osilodrostat, the evidence was insufficient to show a statistically significant difference.
Conclusion: These analyses show that osilodrostat increases the odds of achieving CR at Weeks 12, 24, and 36 versus metyrapone, demonstrating that osilodrostat is a more efficacious treatment option for normalizing cortisol levels in CS patients.
Keywords: Cushing’s disease (CD); Cushing’s syndrome (CS); Hypercortisolism; Indirect treatment comparison (ITC); Matching-adjusted indirect comparison (MAIC); Metyrapone; Osilodrostat.
Osilodrostat and metyrapone are two treatment options for patients with endogenous Cushing’s syndrome when surgery is ineffective, unsuitable, or refused, or a rapid control of hypercortisolism is required. Cushing’s syndrome is caused by prolonged exposure to excess cortisol levels, and the primary goal of therapy is to normalize cortisol secretion. The current analysis compared osilodrostat's and metyrapone’s ability to normalize cortisol levels after 12, 24, and 36 weeks of treatment, and the likelihood of stopping treatment during this time. Data from three clinical trials were used, two for osilodrostat and one for metyrapone. The trials recorded the number of patients with normal cortisol levels after 12, 24, and 36 weeks of treatment, and the number of patients stopping treatment and the reason for stopping. These data were used to compare treatments via matching-adjusted indirect comparison, an established statistical method used when treatments are not compared directly in a single trial. The results showed that patients treated with osilodrostat were around 2.8 times more likely to have normal cortisol levels after 12 weeks of treatment, 3.3 times after 24 weeks of treatment, and 10.5 times after 36 weeks of treatment. There was insufficient evidence to show a difference in the likelihood of stopping treatment for any reason or because of treatment failure or adverse events before 24 or 36 weeks. The analysis demonstrates that treatment with osilodrostat increases the chance of having normal cortisol levels after 12, 24, and 36 weeks compared with metyrapone.
© 2025. The Author(s), under exclusive licence to Springer Healthcare Ltd., part of Springer Nature.