Efficacy and Safety of Osilodrostat in Adrenal Cushing Syndrome: Insights from an International Real-World Study

Highlight

• Osilodrostat effectively reduces hypercortisolism in patients with adrenal Cushing syndrome (CS), achieving biochemical response in up to 87.5% of patients treated longer than 12 weeks.
• Patients previously treated with other steroidogenesis inhibitors show a significantly higher likelihood of responding to osilodrostat.
• Osilodrostat therapy is associated with improvements in clinical parameters such as systolic blood pressure and body weight.
• Adverse events are common, leading to treatment discontinuation in over half of affected patients, emphasizing the need for careful monitoring.

Study Background

Cushing syndrome (CS) is a clinical condition characterized by chronic exposure to excessive cortisol levels, which can result from multiple etiologies including adrenocorticotropic hormone (ACTH)-dependent and adrenal causes. While ACTH-dependent CS is more commonly studied, adrenal CS—caused by adrenal adenomas, carcinomas, or hyperplasia—remains a clinical challenge, particularly when surgery is not feasible or when malignancy is present.

Management of adrenal CS involves reducing cortisol production or blocking its effects to mitigate morbidity and mortality associated with hypercortisolism. Osilodrostat, a potent inhibitor of 11β-hydroxylase involved in cortisol synthesis, has been largely investigated in ACTH-dependent CS but less so in adrenal CS. This creates an unmet need for robust data on efficacy and safety of osilodrostat in this subgroup.

Study Design

This international real-world observational study enrolled 28 patients diagnosed with adrenal CS. Participants included 16 patients with adrenocortical carcinoma and 12 with benign adrenal disease. Osilodrostat was administered either as monotherapy (n=22) or combined with metyrapone (n=6), another steroidogenesis inhibitor.

For efficacy evaluation, patients treated with osilodrostat for more than four weeks (n=21) were assessed. Treatment response was defined by urinary free cortisol (UFC) reduction: complete responders had UFC reduced to below the upper limit of normal (ULN), partial responders had >50% UFC reduction but no normalization.

Safety assessments included monitoring of adverse events and impacts on clinical parameters.

Key Findings

Biochemical response was encouraging, with 66.7% of patients achieving either complete or partial response after four weeks of treatment. Among those treated beyond 12 weeks, response rates increased to 87.5%, reflecting improved efficacy with longer therapy duration.

Complete responses (normalized UFC) were observed in 28.6%, whereas partial responders comprised 38.1% of patients.

Multivariate analysis identified the use of osilodrostat as a second-line or later therapy after other steroidogenesis inhibitors as a significant predictor of response (odds ratio 15.0, P = .010), suggesting prior steroidogenesis modulation may enhance therapeutic efficacy.

Clinically, osilodrostat treatment was associated with significant improvements in systolic blood pressure and body weight (P < .05), important surrogate markers of hypercortisolism's systemic effects.

Regarding safety, 9 patients experienced adverse events, with over half (56%) necessitating treatment discontinuation. Adverse events were diverse, underscoring the need for vigilant monitoring.

Expert Commentary

This study addresses a critical gap in the literature by focusing on adrenal CS, a population underrepresented in previous osilodrostat investigations. The high response rates, particularly with prolonged treatment and in patients previously exposed to other inhibitors, suggest osilodrostat is a viable option in this challenging cohort.

However, the notable rate of adverse events and discontinuations highlights the drug’s risk profile. Clinicians must balance efficacy and safety and consider patient-specific factors when initiating therapy. The real-world design offers pragmatic insights but also introduces variability in treatment regimens and monitoring protocols.

Biologically, osilodrostat’s targeted inhibition of 11β-hydroxylase aligns with the pathophysiology of adrenal CS, making it mechanistically plausible as an effective intervention. Further studies may clarify optimal dosing, combination strategies, and long-term safety.

Conclusion

This international real-world study demonstrates that osilodrostat is effective in controlling hypercortisolism among patients with adrenal Cushing syndrome, with response rates improving over treatment duration. Prior exposure to steroidogenesis inhibitors positively influences response, suggesting a potential sequential therapeutic approach. Osilodrostat also favorably impacts clinical parameters such as blood pressure and body weight, addressing key complications of CS.

Adverse events remain a significant concern, necessitating cautious patient selection and close follow-up. Future randomized controlled trials should aim to further define the role of osilodrostat in adrenal CS management, optimize treatment protocols, and elucidate long-term safety.

Overall, this study adds valuable evidence supporting osilodrostat’s use in adrenal CS, expanding therapeutic options for a complex disease subset.

Funding and Trial Registration

The study details did not specify funding sources or clinical trial registration numbers. Further transparency in these areas would strengthen study appraisal.

References

1. Araujo-Castro M, Bancos I, Detomas M, et al. International real-world study on osilodrostat efficacy and safety in adrenal Cushing syndrome. J Clin Endocrinol Metab. 2026;111(8):2180-2189. PMID: 41824768.

2. Fleseriu M, Biller BMK, Findling JW, et al. Metyrapone for treatment of Cushing’s disease: a review. Endocrine. 2021;72(2):289-298.

3. Nieman LK, Biller BMK, Findling JW, et al. Treatment of Cushing’s Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015;100(8):2807-2831.