Combination Osilodrostat and Cabergoline in Cushing's Disease

Summary

Cushing disease remains a challenging endocrine disorder in which persistent or recurrent hypercortisolism often requires medical therapy after surgery or when surgery is not feasible. Combination medical therapy has emerged as a rational strategy to improve biochemical control through complementary mechanisms while potentially reducing treatment escape and dose-related toxicity. Cabergoline exerts pituitary D2-receptor-mediated inhibition of ACTH secretion and may provide partial cortisol control in selected patients, although treatment escape and variable durability remain important limitations. Osilodrostat is a potent 11β-hydroxylase inhibitor that produces rapid and often substantial reductions in cortisol secretion, with clinical improvement in metabolic and cardiovascular features of hypercortisolism. The osilodrostat-cabergoline combination is mechanistically attractive because it pairs central ACTH suppression with peripheral blockade of cortisol synthesis, but published evidence remains limited to small real-world experiences and does not yet define optimal sequencing, dosing, or long-term benefit. Safety considerations include adrenal insufficiency from overtreatment, osilodrostat-associated hypertension from mineralocorticoid precursor accumulation, and hyperandrogenism due to steroid precursor shunting. Combination medical therapy in Cushing disease is a promising individualized approach, and the osilodrostat-cabergoline pairing is biologically plausible and potentially effective, but current literature is insufficient to support firm recommendations regarding efficacy, safety, or patient selection. The study aims to evaluate whether a combination can result in rapid, more control of Cushing's disease (clinically and biochemically)? Can cabergoline reduces Osilodrostat dose requirement, reduces Osilodrostat related mineralocorticoid and hyperandrogenism side effects?

Timeline

Start

2026-05-11

Primary completion

2028-06

Completion

2028-08

Publications

• Background Ferriere A, Cortet C, Chanson P, Delemer B, Caron P, Chabre O, Reznik Y, Bertherat J, Rohmer V, Briet C, Raingeard I, Castinetti F, Beckers A, Vroonen L, Maiter D, Cephise-Velayoudom FL, Nunes ML, Haissaguerre M, Tabarin A. Cabergoline for Cushing's disease: a large retrospective multicenter study. Eur J Endocrinol. 2017 Mar;176(3):305-314. doi: 10.1530/EJE-16-0662. Epub 2016 Dec 22.
• Background Giustina A, Uygur MM, Frara S, Barkan A, Biermasz NR, Chanson P, Freda P, Gadelha M, Haberbosch L, Kaiser UB, Lamberts S, Laws E, Nachtigall LB, Popovic V, Schilbach K, Lely AJV, Wass JAH, Melmed S, Casanueva FF. Medical management pathways for Cushing's disease in pituitary tumors centers of excellence (PTCOEs). Pituitary. 2025 Jan 29;28(1):23. doi: 10.1007/s11102-024-01485-x.
• Background Gadelha M, Bex M, Feelders RA, Heaney AP, Auchus RJ, Gilis-Januszewska A, Witek P, Belaya Z, Yu Y, Liao Z, Ku CHC, Carvalho D, Roughton M, Wojna J, Pedroncelli AM, Snyder PJ. Randomized Trial of Osilodrostat for the Treatment of Cushing Disease. J Clin Endocrinol Metab. 2022 Jun 16;107(7):e2882-e2895. doi: 10.1210/clinem/dgac178.
• Background Vilar L, Naves LA, Machado MC, Bronstein MD. Medical combination therapies in Cushing's disease. Pituitary. 2015 Apr;18(2):253-62. doi: 10.1007/s11102-015-0641-x.

Drugs

Indications