What are the alternative treatment options for a patient with Cushing's disease who is not a suitable candidate for Korlym (mifepristone) or has not responded adequately to this medication?

Alternatives to Korlym (Mifepristone) for Cushing's Disease

Adrenal steroidogenesis inhibitors—specifically osilodrostat, ketoconazole, or metyrapone—should be used as first-line alternatives to mifepristone, given their reliable effectiveness and ability to monitor cortisol levels biochemically. 1

First-Line Alternative Agents

Osilodrostat (Preferred for Most Patients)

• Osilodrostat demonstrates the highest efficacy among medical therapies, with 77-86% of patients achieving urinary free cortisol (UFC) normalization, compared to other available agents 1, 2
• Provides rapid cortisol reduction within hours, making it ideal for patients requiring prompt disease control 1
• Does not cause hypogonadism in men, unlike ketoconazole 3
• Key adverse effects include hypokalemia, QTc prolongation, and hyperandrogenism in women requiring careful monitoring 1

Ketoconazole

• Achieves approximately 70% UFC normalization in retrospective studies 1
• Easier to dose-titrate compared to other steroidogenesis inhibitors 1
• Requires gastric acid for absorption (avoid proton pump inhibitors) and liver function monitoring 1
• Causes hypogonadism in men, which may be a limiting factor 3
• Response typically seen within days 1

Metyrapone

• Demonstrates approximately 70% UFC normalization in retrospective studies and 47% at week 12 in prospective trials 1
• Provides rapid cortisol reduction within hours 1
• Requires dosing every 6-8 hours (500 mg/day to 6 g/day) 1
• Adverse effects include hyperandrogenism (hirsutism in women), hypertension, and hypokalemia due to increased mineralocorticoid precursors 1
• May be considered with precautions in pregnant women desiring treatment, using a higher cortisol target of 1.5 × upper limit of normal 1

Tumor-Directed Therapies

Pasireotide LAR

• FDA-approved specifically for Cushing's disease when pituitary surgery is not an option or has not been curative 4
• Achieves 40% UFC normalization in phase 3 studies 1
• Offers potential tumor shrinkage benefit for patients with visible residual tumor 1
• Critical limitation: high risk of hyperglycemia and new-onset diabetes (requires careful patient selection and glucose monitoring) 1
• Recommended initial dose is 10 mg intramuscularly every 28 days, with potential titration to 40 mg maximum 4

Cabergoline

• Achieves approximately 40% UFC normalization in retrospective studies 1
• Less effective with slower onset of action, but requires less frequent dosing 1
• May decrease tumor volume in up to 50% of patients initially, though 25-40% experience treatment escape 1
• Should not be used in patients with history of bipolar disorder or impulse control disorders 1
• May be preferred in young women desiring pregnancy 1

Treatment Selection Algorithm

For Mild Disease (No Visible Tumor on MRI)

• Start with ketoconazole, osilodrostat, or metyrapone 1
• Cabergoline may be used but is less effective 1

For Mild-to-Moderate Disease (Residual Tumor Present)

• Consider cabergoline or pasireotide for tumor shrinkage potential 1
• Pasireotide requires critical assessment of glucose tolerance before initiation 1

For Severe Disease

• Rapid cortisol normalization is the primary goal 1
• Use osilodrostat or metyrapone (response within hours) or ketoconazole (response within days) 1
• Etomidate (0.04-1 mg/kg/h IV) for hospitalized patients unable to take oral medications 1
• Combination therapy with multiple steroidogenesis inhibitors may be necessary 1
• If severe hypercortisolism remains unresponsive to optimized medical therapy including combinations, bilateral adrenalectomy should be considered to avoid worsening outcomes 1, 2

Combination Therapy Strategies

When monotherapy fails to normalize cortisol:

• Ketoconazole plus metyrapone to maximize adrenal blockade 1
• Ketoconazole plus cabergoline (steroidogenesis inhibitor plus tumor-targeting agent), especially with visible tumor 1
• Triple therapy: cabergoline, pasireotide, plus ketoconazole 1
• Monitor for overlapping toxicities, particularly QTc prolongation, with all combinations 1

Critical Monitoring Parameters

• Regular UFC measurements (except with mifepristone), morning cortisol, and/or late-night salivary cortisol 1
• Clinical features: weight, blood pressure, glycemic control 1
• ACTH levels with adrenal-targeting agents (significant elevations may indicate tumor growth) 1
• MRI typically 6-12 months after initiating treatment, then every few years 1
• Consider treatment change if cortisol remains persistently elevated after 2-3 months on maximum tolerated doses 1

Why Mifepristone Is Not First-Line

Mifepristone should only be used by clinicians with extensive Cushing's disease experience and is not recommended as first-line therapy 5, 3:

• No reliable biochemical markers exist for monitoring cortisol levels or detecting adrenal insufficiency 5, 3
• Increased risk of unrecognized adrenal insufficiency requiring clinical assessment only 5
• Worsens hypokalemia and hypertension 1, 5
• Long half-life requires several days of stress-dose glucocorticoid (preferably dexamethasone) if adrenal insufficiency develops 1, 3
• Extensive drug-drug interactions requiring careful medication review 1, 3