Beyond Mifepristone: Enzyme Inhibitors, Pituitary-targeted Agents, and Emerging Therapies

In this segment, Richard Auchus, MD, broadens the discussion beyond mifepristone to review other medical therapies targeting cortisol synthesis and pituitary drivers of Cushing syndrome. He begins with metyrapone, a relatively weak 11β-hydroxylase inhibitor that has been used off label for many years. Metyrapone requires high total daily doses (often 1–3 g or more) divided three or four times a day, making it more suitable for inpatient settings where rapid titration and close monitoring are feasible. The newer 11β-hydroxylase inhibitor osilodrostat is highlighted as approximately 1000 times more potent, dosed once or twice daily in milligram rather than gram quantities, but with an attendant risk of overtreatment and adrenal insufficiency if not carefully managed—considerations that make endocrinology oversight essential.

Dr Auchus then reviews steroidogenesis inhibitors that have been used chronically, including ketoconazole and levoketoconazole. Ketoconazole, long employed off label for Cushing syndrome, is limited by a black box warning regarding hepatotoxicity and by the risk of QT prolongation. Levoketoconazole, the more potent 2S,4R stereoisomer, allows roughly half the dose and twice-daily rather than three-times-daily dosing, potentially improving tolerability and adherence. For pituitary-dependent Cushing disease, pasireotide—a somatostatin analog targeting somatostatin receptor subtype 5—can be useful, but is ineffective in ACTH-independent forms such as adrenal adenomas, reinforcing the importance of accurate etiologic classification before selecting therapy.

Finally, Ralph DeFronzo, MD, and Dr Auchus discuss emerging and investigational therapies. Relacorilant, a selective glucocorticoid receptor modulator that does not significantly block progesterone receptors, has completed major trials (GRACE and GRADIENT) and may avoid some gynecologic adverse effects seen with mifepristone, such as endometrial thickening and bleeding. Additional pipeline agents include ACTH receptor antagonists (eg, agents targeting melanocortin 2 receptor) for ACTH-dependent disease. Together, these agents expand the therapeutic landscape, providing multiple pharmacologic “Plan A, B, C, and D” options for patients who are not surgical candidates, have persistent or recurrent disease after surgery, or have non-neoplastic hypercortisolism. The segment underscores that, unlike in past decades, clinicians now have a diverse toolkit to tailor therapy to disease etiology, severity, and patient-specific risk profiles.