Efficacy and Safety of Osilodrostat in Paraneoplastic Cushing Syndrome: A Real-World Multicenter Study in France

Abstract

Context: Prospective studies have demonstrated the efficacy of osilodrostat in Cushing disease. No study has evaluated osilodrostat in a series of patients with paraneoplastic Cushing syndrome/ectopic adrenocorticotropin syndrome (PNCS/EAS).

Objective: This work aimed to evaluate in France the real-world efficacy and safety of osilodrostat in patients with PNCS/EAS.

Methods: A total of 33 patients with PNCS/EAS with intense/severe hypercortisolism were involved in this retrospective, multicenter, real-world study. Patients received osilodrostat between May 2019 and March 2022 at a median initial dose (range) of 4 mg/day (1-60) and maximum dose, 20 mg/day (4-100), first under patient then cohort temporary authorizations and after marketing authorization. Regimens used titration (n = 6), block and replace (n = 16), or titration followed by block and replace (n = 11).

Results: In 11 patients receiving osilodrostat as first-line monotherapy, median 24-hour urinary free cortisol (24h-UFC) decreased dramatically (from 26 × upper limit of normal [ULN; 2.9-659] to 0.11 × ULN [0.08-14.9]; P < .001). In 9 of them, 24h-UFC normalization was achieved in 2 weeks (median). Thirteen additional patients were previously treated with classic steroidogenesis inhibitors but 10 of these 13 were not controlled. In these patients, osilodrostat monotherapy, used as second line, induced a significantly decreased of 24h-UFC (from 2.6 × ULN [1.1-144] to 0.22 × ULN [0.12-0.66]; P < .01). Nine additional patients received osilodrostat in combination with another anticortisolic drug, decreasing 24h-UFC from 11.8 × ULN (0.3-247) to 0.43 × ULN (0.33-2.4) (P < .01). In parallel, major clinical symptoms/comorbidities improved dramatically with improvement in blood pressure, hyperglycemia, and hypokalemia, allowing the discontinuation or dose reduction of patient treatments. Adrenal insufficiency (grade 3-4) was reported in 8 of 33 patients.

Conclusion: Osilodrostat is a rapidly efficient therapy for PNCS/EAS with severe/intense hypercortisolism. Osilodrostat was generally well tolerated; adrenal insufficiency was the main side effect.

Keywords: Cushing syndrome; adrenal insufficiency; corticotropin; ectopic adrenocorticotropic hormone syndrome; hypokalemia; neuroendocrine tumors; osilodrostat; paraneoplastic Cushing syndrome; steroidogenesis inhibitors.

Figure 1.

Urinary free cortisol (24-h [24h-UFC], × upper limit of normal [ULN]) before and during osilodrostat treatment in 33 patients with paraneoplastic Cushing syndrome/ectopic adrenocorticotropin syndrome. Each vertical set of data points is for 1 patient. Patients are shown in order of decreasing baseline 24h-UFC concentration. For each patient the time elapsed (wk) between the introduction of the osilodrostat and the 24h-UFC nadir is shown. Patients who received osilodrostat as first-line or second line monotherapy or those who received osilodrostat in combination with another anticortisolic drug (bitherapy) are detailed in Table 2. The numbers above vertical lines indicate both initial (upper) osilodrostat dosages (mg/d), and maximum dosages (lower number) either at nadir or closest to nadir of 24h-UFC.

Figure 2.

Time course of clinical parameters/comorbidities associated with hypercortisolism in patients with paraneoplastic Cushing syndrome/ectopic adrenocorticotropin syndrome treated by osilodrostat. A and B, Systolic (SBP) and diastolic blood pressure (DBP) at the time of osilodrostat introduction and during osilodrostat treatment after control of hypercortisolism, respectively. The median number of antihypertensive medications are indicated in blue. Dotted line indicates the upper limit of normal (European Society of Hypertension Guidelines). C, Evolution of the arbitrary clinical score of Cushing syndrome at the time of the introduction of osilodrostat and during osilodrostat treatment after control of hypercortisolism (see text). D, Change in body mass index (BMI) at the time of osilodrostat introduction and during osilodrostat treatment after control of hypercortisolism. **P less than .01; ***P less than .001; ****P less than .0001 (Wilcoxon matched-pairs signed rank test).

Figure 3.

Evolution of main biological disturbances associated with hypercortisolism in patients with paraneoplastic Cushing syndrome/ectopic adrenocorticotropin syndrome (PNCS/EAS) treated with osilodrostat. A, Individual circulating potassium levels in patients with PNCS/EAS, measured at diagnosis, at the time of introduction of osilodrostat (before osilodrostat) and after reaching nadir of urinary free cortisol (24h-UFC) (during osilodrostat) (see also Tables 1 and 2). Blue numbers indicate median spironolactone dosage (mg/d) and red numbers indicate median potassium dosage (g/d). Red dotted line indicates the lower limits of normal. B and C, Evolution of fasting blood glucose and glycated hemoglobin A_1c (HbA_1c), respectively, at time of the introduction of osilodrostat and after nadir of UFC. Dotted line indicates upper limit of normal in a nondiabetic French population. *P less than .05; ***P less than .001; ****P less than .0001 (Wilcoxon matched-pairs signed rank test).

Figure 4.

Proposed algorithm for practical use of osilodrostat in patients with paraneoplastic Cushing syndrome/ectopic adrenocorticotropin syndrome (PNCS/EAS): proposal in scenarios depending on the intensity of hypercortisolism, associated complications, and oncological status. These propositions are “expert advice” rather than being evidence based. ⁽¹⁾To convert ng/mL to nmol/L × 2.759 (1 ng/mL = 2.759 nmol/L); ⁽²⁾initial dose administered orally in 2 daily doses; ⁽³⁾ as reported in LINC studies ((24-26)); ⁽⁴⁾hospitalization so as to allow close monitoring and perform checklist as reported in (2) that allow to identification of major comorbidities/complications (severe hypokalemia, pulmonary embolism, heart failure, deep infection and/or sepsis, vertebral fractures);⁽⁵⁾prophylaxis for pneumocystis (trimethoprim/sulfamethoxazole) and thromboembolism (low-molecular-weight heparin); ⁽⁶⁾initial dose of osilodrostat can be personalized within the proposed range according to the intensity of hypercortisolism and/or severity of comorbidities and complications as well as the general condition and age of the patient; ⁽⁷⁾block and replace (B) strategy as soon as SC and/or 24h-UFC reach values below the upper limits of normal; ⁽⁸⁾B: hydrocortisone: 20 to 30 mg/d or prednisone: 4 to 7 mg/d or dexamethasone: 0.5 mg/d; ⁽⁹⁾locoregional and/or metastatic spread of responsible neuroendocrine cancer (NEC). ⁽¹⁰⁾In case of replacement therapy with hydrocortisone, stop this steroid 24 hours before and replace with dexamethasone or prednisolone before measuring SC and/or 24h-UFC; ⁽¹¹⁾if SC and 24h-UFC are still high, increase osilodrostat daily dose. In this case a combined therapy associating metyrapone or with ketoconazole can also be discussed. In case of confirmed low SC and/or UFC, a decrease of daily dose of osilodrostat can also be proposed. ⁽¹²⁾Potassium, spironolactone, insulin, oral antidiabetic, and antihypertensive drugs; 24h-UFC: 24-hour urinary free cortisol; SC: serum cortisol.