OXFORD
ENDOCRINE SOCIETY
International real-world study on osilodrostat efficacy and safety in adrenal Cushing syndrome
Marta Araujo-Castro (D 1,2, Irina Bancos @D3, Mario Detomas 04, Martin Reincke DD 5, Salehi Mahdi3, Haibo Lu6, Barbara Altieri 0D 4, Markus Kroiss5, Matthias Oettle5, Fernando Guerrero-Pérez7,8, Felicia A. Hanzu9, Rogelio García-Centeno1º, Laura Gonzalez-Fernandez1º, María Pasarón11, Paola Gracia Gimeno12, Lucía Manzano Valero13, Ana Castro Luna13, Ana Irigaray Echarri14, María Dolores Ollero Garcia-Argullo14, and Wilfredo Antonio Rivera Martinez D 15
1Endocrinology and Nutrition Department, Hospital Universitario Ramón y Cajal, Madrid 28034, Spain
2Instituto de Investigación Biomédica Ramón y Cajal (IRYCIS), Madrid 28034, Spain
3Division of Endocrinology, Diabetes, and Nutrition, Mayo Clinic, Rochester, MN 55905, USA
4Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, Würzburg 97080, Germany 5Department of Medicine IV, LMU University Hospital, LMU Munich, Munich 81377, Germany
6Luoyang Key Laboratory of Clinical Multiomics and Translational Medicine, Key Laboratory of Hereditary Rare Diseases of Health Commission of Henan Province, Henan Key Laboratory of Rare Diseases, Endocrinology and Metabolism Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China
7Department of Endocrinology and Nutrition, Bellvitge University Hospital-IDIBELL, L’Hospitalet de Llobregat, Barcelona 08907, Spain
8Biomedical Research Institute of Bellvitge (IDIBELL), L’Hospitalet de Llobregat, Barcelona 08907, Spain
9 Endocrinology and Nutrition Department and Institut de Investigacions Biomediques Pi I Sunyer Barcelona, Hospital Clínic of Barcelona, University Barcelona, Barcelona 08036, Spain
10Endocrinology and Nutrition Department, Hospital Universitario Gregorio Marañón, Madrid 28007, Spain
11Endocrinology and Nutrition Department, Hospital Universitario de Cabueñes, Gijón (Asturias) 33203, Spain
12Endocrinology and Nutrition Department, Hospital Universitario Royo Villanova, Zaragoza 50015, Spain
13Endocrinology and Nutrition Department, Hospital Universitario Toledo, Toledo 45007, Spain
14Endocrinology and Nutrition Department, Hospital Universitario Navarra, Pamplona 31008, Spain
15Endocrinology Department, Clínica Imbanaco, Cali 760042, Colombia
Correspondence: Marta Araujo-Castro, MD, PHD, Endocrinology and Nutrition Department, Hospital Universitario Ramón y Cajal, Colmenar Viejo Street km 9, Madrid 28034, Spain. Email: marta.araujo@salud.madrid.org; or Wilfredo Antonio Rivera Martínez, MD, Endocrinology Department, Clínica Imbanaco, Carrera 38 Bis No. 5B2-04, Cali, Valle del Cauca 760042, Colombia. Email: antonioriveramartinez@gmail.com.
Abstract
Context Most of the patients included in the clinical trials and real-world studies with osilodrostat only include patients with adrenocorticotropic hormone dependent Cushing syndrome (CS), while data on the efficacy and safety of osilodrostat in patients with adrenal CS is scarce.
Objective To assess the efficacy and safety of osilodrostat in adrenal CS.
Methods International study of patients with adrenal CS: patients treated with osilodrostat at any time were enrolled in the safety evaluation and those treated for longer than 4 weeks, in the efficacy evaluation. Patients were classified as responders if they experienced a reduction in urinary free cortisol (UFC) >50% (complete responders when UFC levels were below the upper limit of normal [ULN] and partial responders if there was a reduction >50% but not normalization).
Results Twenty-eight patients with adrenal CS were enrolled: 16 with adrenocortical carcinoma and 12 with benign disease. Osilodrostat was used in monotherapy in 22 patients and in combination with metyrapone in 6 cases. In those patients treated for longer than 4 weeks (n = 21), 66.7% were classified as responders (28.6% with complete response and 38.1% with partial response), and for those treated for longer than 12 weeks, the rate of response increased to 87.5% The use of osilodrostat as a nonfirst-line therapy (odds ratio 15.0, P = . 010) was a predictor of response. Osilodrostat led to a significant decrease in systolic blood pressure and body weight (P <. 05). Nine patients developed one or more adverse events and in 56% (n = 5) led to osilodrostat discontinuation.
Conclusion Osilodrostat controls hypercortisolism in 66.7% of patients with adrenal CS treated for longer than 4 weeks and in 87.5% of cases treated for longer than 12 weeks, with a positive impact on blood pressure and body weight. Patients who received osilodrostat after other previous steroidogenesis inhibitors have a higher probability of response.
Keywords adrenocortical carcinoma, osilodrostat, urinary free cortisol, Cushing syndrome, adrenal adenoma
Endogenous Cushing syndrome (CS) is a severe endocrine dis- order caused by chronic exposure to hypercortisolism and is as- sociated with a wide range of metabolic, cardiovascular, immune, thrombotic, and neuropsychiatric morbidities (1). Based on the underlying mechanism, CS can be broadly classi- fied into 2 main etiological categories: adrenocorticotropic hor- mone (ACTH)-dependent CS, which results from excessive secretion of ACTH, and ACTH-independent CS, in which cortisol excess arises directly from the adrenal gland (2).
The cornerstone of treatment for adrenal CS is surgical re- moval of the cortisol-secreting adrenal lesion (3). However, medical therapy also plays an important role in several clinical situations, including patients who are not candidates for sur- gery, those who decline surgical treatment, cases in which com- plete tumor resection cannot be achieved because of metastatic disease or residual tumor, and situations in which temporary control of hypercortisolism is required while await- ing surgery (4). Several steroidogenesis inhibitors are currently available for the medical management of CS (5). Nevertheless, some patients do not tolerate these treatments, and others pre- sent with severe hypercortisolism that requires rapid and ef- fective reduction of cortisol levels. In such situations, additional therapeutic options are needed to achieve adequate biochemical control of hypercortisolism (6). Osilodrostat is an oral imidazole derivative that inhibits 116-hydroxylase, the en- zyme responsible for the final step of cortisol synthesis in the adrenal cortex. By inhibiting this enzyme, osilodrostat effective- ly suppresses cortisol production (7). Most clinical studies evaluating osilodrostat have focused on patients with ACTH-dependent CS, particularly those with Cushing disease (CD) (7-13), while data on the efficacy and safety of osilodrostat in patients with adrenal CS are scarce (12, 14-16). Only a small number of reports have evaluated the use of osilodrostat in ad- renal CS, and the response rates described in these studies ap- pear to be lower than those reported in patients with ACTH-dependent disease (12, 14-16). More recently, the LINC 7 study analyzed the efficacy and safety of osilodrostat in pa- tients with adrenocortical carcinoma (ACC, n = 19), adrenal ad- enomas (n = 17), and bilateral adrenal nodular disease (n = 14), being the largest series reported until the current date, with a total of 50 cases included (17). However, in the intention to treat evalu- ation (efficacy of the treatment after 12 weeks of osilodrostat ther- apy), only 19 patients with adrenal CS were analyzed, and the reported efficacy of osilodrostat was quite lower than the de- scribed in previous studies (67% of the patients with ACC, 33% with adrenal adenomas, and 86% with bilateral adrenal disease had a complete biochemical response). These observations raise the question of whether the efficacy and safety profile of osilodro- stat differs between ACTH-dependent and ACTH-independent forms of CS.
Therefore, the aim of the present study was to evaluate the efficacy and safety of osilodrostat in patients with adrenal
CS, including both benign and malignant etiologies, and to ex- plore potential predictors of treatment response in this population.
Materials and methods
Study design and definitions
This was a multicenter, retrospective cohort study (international adrenal CS database) that included a total of 433 patients with adrenal CS (251 with unilateral adrenal disease, 87 with bilateral disease, and 95 with ACC) from multiple centers (23 centers in Spain, 1 in Croatia, 2 in Germany, 10 in Colombia, 1 in the United States, and 1 in Italy). Patients treated with osilodrostat were managed in 10 centers: 7 in Spain, 2 in Germany, and 1 in the United States.
Patients were followed by endocrinologists working in special- ized endocrinology departments at the participating hospitals. The protocol for the use of osilodrostat (including the initial dose, dose titration, and the use of block-and-replace therapy [B&R], among other strategies) was determined according to the clinical experience of the treating physicians.
The diagnosis of CS was based on current clinical practice guidelines (18). The inclusion criteria to enter in the study were as follows: (1) a biochemically confirmed diagnosis of CS of ad- renal origin, (2) treatment with osilodrostat at any time (at least one dose), and (3) availability of data on efficacy or safety. We have also included those patients who developed adverse events (AEs) after osilodrostat initiation with no available UFC after treatment, with a goal to avoid biases on the analysis of safety. For the efficacy assessment, we only included patients treated with osilodrostat for longer than 4 weeks.
Severe CS was defined by urinary free cortisol (UFC) levels above 5 times the upper limit of normal (ULN) or associated with severe and life-threatening complications of hypercortiso- lism (6). The clinical classification of ACC was based on the TNM-ENSAT staging system (I-IV) (19). For benign and malignant adrenal tumors, we also reported previous treatments used for tumor and hypercortisolism control (Table S1) (20).
The diagnosis of hypertension was based on a previous history of hypertension or treatment with antihypertensive medication, and type 2 diabetes mellitus diagnosis was established for those with previous history of diabetes or who were treated with anti- hyperglycemic medication.
The study was approved by the Ethics Committee of the Hospital Universitario Ramón y Cajal, Madrid, Spain (approval date: November 26, 2024, code: ACTA 472) and in each collabor- ating center. The waiver of informed consent was approved by the Ethics Committee due to the retrospective nature of the study. Informed consent was requested only for patients who continued follow-up.
Outcomes: efficacy and safety
Urinary free cortisol was measured by chemiluminescent immuno- assay or mass spectrometry and radioimmunoassay. As the normal range of UFC differed across centers, we calculated the deviations above the ULN for each UFC value (UFC x ULN).
The main efficacy endpoint was the proportion of responders
after treatment with osilodrostat for longer than 4 weeks: complete
or partial response. Complete response was defined by UFC
UFC values were recorded after 2, 4, and 12 weeks of treatment and at the last available follow-up visit. However, due to the retrospective nature of the information, UFC was not available for all patients at all these different time points. In addition, we have evaluated the time necessary to achieve hypercortiso- lism control. Data on morning serum cortisol, late-night salivary cortisol, and ACTH at different time points were available in few cases. Therefore, the analysis of these data was not included in the current study (>60% missing data).
Regarding clinical and biochemical variables, we collected infor- mation on systolic and diastolic blood pressure (BP), number of antihypertensive medications, serum potassium levels, body weight (kg), glucose levels (mg/dL), HbA1c (%), total cholesterol, low-density lipoprotein, and high-density lipoprotein at diagnosis of adrenal CS, before osilodrostat initiation and after treatment (after 4 and 12 weeks and at the last available follow-up visit).
In relation to osilodrostat treatment, we collected information on starting, maximum, and maintenance doses (mg/day). Information about the treatment strategy used was recorded: titration (when osilodrostat was used without glucocorticoid replacement ther- apy), B&R regimen upfront, or initial titration followed by B&R.
Safety evaluations included data on the development of AEs: hyperandrogenism, glucocorticoid withdrawal syndrome (GWS), adrenal insufficiency, hypertension, hypokalemia, QT interval prolongation, edema, or other AEs. We also described the proportion of patients who discontinued the drug due to the development of AEs.
Statistical analysis
The statistical analysis was performed with STATA 15. Categorical variables were expressed as percentages and abso- lute numbers and quantitative variables as mean (±standard de- viation) or median (range), depending on whether the assumption of normality was met. The Wilcoxon signed-rank test was used for comparison of variables of UFC, clinical score, systolic BP, diastolic BP, body weight, and the biological param- eters, such as potassium and glucose, glycemia, and HbA1c be- fore and during osilodrostat therapy. In all cases, a 2-tailed P-value <. 05 was considered statistically significant. Univariate and multivariate logistic regression analysis was used to identify predictors of response to osilodrostat therapy. Correlation be- tween continuous variables was tested by the estimation of the Pearson correlation coefficient (r). The Jonckheere- Terpstra trend test was used to analyze whether there were or- dered trends in the UFC groups and nonresponse to osilodrostat.
Results
Baseline characteristics: at the time of the diagnosis of adrenal CS
Twenty-eight patients with adrenal CS were included in the study: 16 with ACC (13 stage IV and 3 nonmetastatic ACC) and 12 with benign adrenal disease (5 with unilateral adrenal aden- oma and 7 with bilateral adrenal disease). The median age of the cohort at the time of the CS diagnosis was 59.5 years (range 27-81), and 68% (n = 19) were women. Regarding ethnicity, 16 were Caucasian, 11 Native American, and 1 Asian. The median UFC at the time of CS diagnosis was 6.3 times above the ULN (range 1.3-53.3), and median ACTH levels were 5 pg/mL (range 1-15). There were 15 patients (53.6%) with severe CS. Patients with ACC were younger, had higher systolic and diastolic BP, had a higher prevalence of hypokalemia and unilateral adrenal tumors, and had more severe hypercortisolism than patients with benign adrenal CS (Table 1).
Osilodrostat: previous treatments
Previous and/or simultaneous treatments before or with osilo- drostat are described in Table S1 (20). In summary, in the group of patients with ACC, 9 patients underwent adrenalectomy, 13 re- ceived mitotane, 13 chemotherapy, 10 immunotherapy, and 4 radiotherapy. In the group of bilateral benign adrenal disease (n = 7), 2 underwent unilateral adrenalectomy (1 before starting osilodrostat and 1 after starting osilodrostat), and of the 6 pa- tients with unilateral disease, 4 patients underwent unilateral adrenalectomy after osilodrostat treatment. Of the 13 patients with ACC treated with mitotane, mitotane was used in combin- ation with osilodrostat in 4 patients.
In relation to the previous treatments used for hypercortisolism control before osilodrostat, 9 were treated with metyrapone, 4 with ketoconazole, and 4 with ketoconazole in combination with metyrapone. In summary, osilodrostat was used as the first- line therapy in 15 patients, as a second-line therapy in 9 (in 2 of them in combination with metyrapone), as a third-line therapy in 3, and as a fourth-line therapy in 1 case (Table S2) (20).
Efficacy of osilodrostat
Overall, the median duration of the therapy with osilodrostat was 7 months (range 1-64). Osilodrostat was used in monother- apy in 22 patients and in combination with metyrapone in 6 cases. The median starting dose was 4 mg/day (range 1-10), the maintenance dose was 9 mg/day (range 1-50), and the max- imum dose was 10 mg/day (range 1-50). No significant differen- ces were detected in the initial (P =. 910) or maximum doses (P = . 412) when osilodrostat was used in monotherapy or in com- bination. The initial, maintenance and maximum doses em- ployed in each patient according to the UFC level at diagnosis and before starting osilodrostat are described in Table S2 (20). In the group of combination therapy, the median dose of metyr- apone was 4 g/day (range 2-4.5). The median UFC (xULN) before starting osilodrostat was 4.2 (0.6-53.3). In this regard, 1 patient had normal UFC (0.6x ULN) at the time of osilodrostat initiation.
| Variable | ACC (n = 16) | Benign adrenal disease (n = 12) | P-value |
|---|---|---|---|
| Clinical and biochemical data | |||
| Age (years) | 50.7 ±13.83 | 65.7 ±13.12 | .008 |
| Female sex | 75% (n = 12) | 58.3% (n = 7) | .350 |
| Type 2 diabetes | 37.5% (n = 6) | 58.3% (n = 7) | .274 |
| Hypertension | 87.5% (n = 14) | 91.7% (n = 11) | .724 |
| Dyslipidemia | 50% (n = 8) | 91.7% (n = 11) | .019 |
| Hypokalemia | 81.3% (n = 13) | 8.3% (n = 1) | <. 001 |
| BMI (kg/m2) | 30.5 ±5.62 | 29.6 ± 6.04 | .693 |
| Systolic BP (mmHg) | 157.5 ±30.20 | 132.8 ±20.12 | .025 |
| Diastolic BP (mmHg) | 93.6 ±18.95 | 80.7 ±11.68 | .054 |
| Fasting plasma glucose levels (mg/dL) | 124.3 ±45.19 | 127.8 ±28.02 | .831 |
| HbA1c (%) | 6.5± 1.37 | 6.5 ±1.39 | .942 |
| Serum potassium levels (mEq/mL) | 3.4 ± 0.54 | 4.1 ± 0.36 | .002 |
| Cortisol after dexamethasone suppression test (µg/dL) | 26.6 ± 11.54 | 8.1 ±7.20 | .001 |
| UFC (values above the ULN) | 21.1 ± 19.59 | 3.7 ±2.72 | .016 |
| ACTH (pg/mL) | 8.1 ± 15.58 | 6.0 ± 3.83 | .666 |
| DHEAS (µg/dL) | 746.6 ±1022.28 | 44.7 ±47.78 | .055 |
| Radiological data | |||
| Unilateral disease | 93.8% (n = 15) | 41.7% (n = 5) | .003 |
| Tumor size of the largest nodule (mm) | 152 ±187.87 | 28.6 ± 19.21 | .082 |
Abbreviations: ACC, adrenocortical carcinoma; BMI, body mass index; BP, blood pressure; DHEAS, dehydroepiandrosterone sulfate; ULN, upper limit of normal; UFC, urinary free cortisol.
The diagnosis of hypercortisolism in this case was based on clin- ical data (CS phenotype and hypokalemia) and high levels of baseline and night serum cortisol (23.4 and 24.6 µg/dL, respect- ively). This patient was not included in the efficacy evaluation as UFC was normal at the time of osilodrostat initiation.
A positive correlation was observed between UFC before osilo- drostat initiation and the initial (r = 0.41, P = . 032) and maximum doses (r = 0.53, P = . 005) of osilodrostat. The maintenance doses (at last visit) were significantly higher than the starting doses (12 ± 11.87 vs 4.3 ± 2.84 mg/day, P =. 002), but no significant dif- ferences were detected between the maintenance and maximum doses (P =. 622). No correlation was detected between the initial (r = - 0.18, P = . 411) or maximum doses (r = - 0.04, P = . 864) and the percentage decrease in UFC with osilodrostat.
There were 10 patients treated with osilodrostat using the ti- tration approach followed by B&R, and 1 patient in the combin- ation therapy who started B&R from the beginning. Overall, B&R was used in 4 of the 6 patients treated in combination with me- tyrapone and in 6 of the 22 patients treated with monotherapy. Hydrocortisone was the glucocorticoid of choice in 9 patients (median dose 20 mg/day), while 1 patient was treated with dexa- methasone (2 mg/day). The maximum doses of osilodrostat were higher in the B&R group than in the titration group (19.2 + 13.24 vs 10.3 ± 9.25 mg/day, P =. 050).
Of the 28 patients treated with osilodrostat, 2 patients with- drew treatment before hormonal assessment due to poor toler- ability, 1 died after only 1 month of therapy precluding UFC assessment, 3 patients were treated for less than 4 weeks, and 1 patient had normal UFC levels at the time of osilodrostat initi- ation (UFC 0.6x ULN). Thus, only 21 patients were included in the efficacy assessment (treatment with osilodrostat for longer than 4 weeks). The response to osilodrostat was 66.7% (n = 14): 6 with
complete response and 8 with partial response. The rate of re- sponse was 80% in the combination therapy group and 62.5% in the monotherapy group (Fig. 1). In the group of complete res- ponders, the median time to normalize UFC was 10 weeks (range 5-17). Response tended to be higher in patients with benign dis- ease than in those with ACC (87.5% vs 53.9%, P = . 112).
The rate of response increased to 87.5% (62.5% with complete response and 25% with partial response) when we assessed those cases treated with osilodrostat for longer than 12 weeks (n = 7/8).
The evolution of UFC in the different times for those patients treated for longer than 1 month (before, after 2 weeks, 1 month, 3 months, and at the last visit) is described in Fig. 2. Three pa- tients had a small increase in UFC from baseline to >ULN at last visit, and all of these cases had tumoral progression associ- ated with the UFC increase.
Predictors of osilodrostat response
When we compared the group of responders (n = 14) and nonres- ponders (n = 7), we found that the probability of response was higher when osilodrostat was used as a second-/third- or fourth- line therapy (odds ratio [OR] 15, 95% confidence interval [CI] 1.34-167.64, P = . 010) (Table 2). The use of osilodrostat as a first- line therapy tended to be more common in patients with ACC than benign adrenal CS (68.8% vs 33.3%, P = . 063). In this regard, the association between response to osilodrostat and the nonfirst-line therapy use disappeared after adjusting by the vari- able ACC (adjusted OR 11.53, 95% CI 0.97-136.75, P =. 053).
Those cases with UFC below 5x ULN before osilodrostat initi- ation tended to have a higher rate of response (OR 6.25, 95% CI 0.84-46.57, P = . 059). All patients with ACC treated with osilodro- stat in combination with mitotane had response, while only
Response to osilodrostat
Non-response 33%
Complete 29%
Partial 38%
Complete
Partial
Non-response
UFC (xULN) before osilodrostat and at the last visit
10
9
9,1
8
7
6
6,4
5
8
5
5
4
#
€
3
A
4
3
-
A
3
A
2
2
28
1
3
7
0
UFC before
UFC last
37.5% of the cases treated with osilodrostat without concomi- tant mitotane (P = . 064). In addition, it was found that patients with type 2 diabetes tended to have a higher response to osilo- drostat than those with no diabetes (81.8% vs 50%, P = . 122).
In the tendency analysis, patients were stratified into 3 groups based on UFC levels prior to the initiation of osilodrostat (UFC <2x ULN, UFC 2-5x ULN, and UFC >5x ULN). The proportion of nonresponders tended to increase as the category increased (UFC <2x ULN, UFC 2-5x ULN, and UFC >5x ULN) (14.3%, 20%, and 55.6%, respectively, MH test for linear Trend: x2(1) = 3.01 [P = . 083]) (Fig. 3).
Impact of osilodrostat on comorbidities
At the time of diagnosis of CS, hypertension was present in 89.3% (n = 25) of patients, dyslipidemia in 67.9% (n = 19), obesity in 50%
(n =14), hypokalemia in 50% (n =14), and diabetes mellitus in 46.4% (n = 13) (Table 1). The mean levels before the initiation of osilodrostat and at the last available visit are described in Table 3. Overall, most cardiovascular and metabolic-related pa- rameters remained stable during treatment, while a significant de- crease of systolic BP and body weight was observed after osilodrostat initiation. In patients with systolic BP >140 mmHg at baseline (39.1%, n = 9/23), 62.5% had systolic BP ≤130 mmHg at the last visit. Among those with diastolic BP >90 mmHg at baseline (34.8%, n = 8/23), 57.1% had diastolic BP ≤90 mmHg at the last visit.
Safety of osilodrostat and follow-up
There were 9 patients (32.1%) who developed one or more AEs potentially related to osilodrostat therapy and in 56% (n = 5)
| Variable | Responders (n = 14) | No responders (n = 7) | OR (95% CI), P-value |
|---|---|---|---|
| Age (years) | 61 ± 13.92 | 52.9 ± 15.51 | 1.04 (0.97-1.12), .214 |
| Female sex | 71.4% (n = 10) | 57.1% (n = 4) | 0.53 (0.08-3.54), .516 |
| Type 2 diabetes | 64.3% (n = 9) | 28.6% (n = 2) | 4.50 (0.63-32.29), .118 |
| Hypertension | 92.9% (n = 13) | 85.7% (n = 6) | 2.17 (0.12-40.81), .609 |
| Dyslipidemia | 64.3% (n = 9) | 71.4% (n = 5) | 0.72 (0.10-5.17), .742 |
| Hypokalemia | 57.1% (n = 8) | 57.1% (n = 4) | 1.00 (0.16-6.25), 1.000 |
| Obesity | 57.1% (n = 8) | 28.6% (n = 2) | 3.33 (0.47-23.47), .210 |
| Ethnicity (Caucasian vs others) | 57.1% (n = 8) | 71.4% (n = 5) | 0.53 (0.08-3.76), .521 |
| ACC diagnosis | 50% (n = 7) | 85.7% (n = 6) | 0.16 (0.02-1.77), .096 |
| UFC (xULN) at diagnosis | 11.3 ±15.90 | 23.8 ±18.67 | 0.96 (0.90-1.02), .164 |
| UFC (xULN) before osilodrostat | 9.3 ±15.93 | 21.1 ±17.23 | 0.96 (0.91-1.01), .132 |
| UFC <2x ULN before osilodrostat | 42.9% (n = 6) | 14.3% (n = 1) | 4.50 (0.42-47.99), .171 |
| UFC <5x ULN before osilodrostat | 71.4% (n = 10) | 28.6% (n = 2) | 6.25 (0.84-45.57), .059 |
| ACTH (pg/mL) | 9.0 ±16.33 | 5.0 ± 3.26 | 1.04 (0.90-1.20), .484 |
| Duration of treatment (months) | 15.9 ±19.95 | 7.3 ±8.26 | 1.06 (0.93-1.20), .230 |
| Initial doses (mg/day) | 4.1 ±2.37 | 5.4 ± 3.55 | 0.84 (0.60-1.17), .289 |
| Maximum doses (mg/day) | 14.9 ±13.12 | 15.5 ±10.19 | 1.00 (0.92-1.08), .921 |
| Combination therapy (different than mitotane) | 28.6% (n = 4) | 14.3% (n = 1) | 2.40 (0.21-24.82), .454 |
| Concomitant therapy with mitotane | 50% (N = 3) | 0% | OR not calculable, .064 |
| Use as nonfirst-line | 71.4% (n = 10) | 14.3% (n = 1) | 15.0 (1.34-167.64), .010 |
Abbreviations: ACC, adrenocortical carcinoma; UFC, urinary free cortisol; ULN, upper limit of normal.
Non-responders
55,6%
20%
14,3%
UFC 2 X ULN
UFC 2-5 ULN
UFC >5 ULN
of them osilodrostat was discontinued for this reason (1 with ad- renal insufficiency, 3 with gastrointestinal discomfort, and 1 gastrointestinal symptoms, brain fog, memory issues, slurred speech, blurry vision, and weakness) (Table 4). None of the AEs were classified as severe. No cases of hyperandrogenism worsen- ing or QT interval prolongation were reported. No significant dif- ferences in the initial or maximum doses were observed between patients who developed AEs and those who did not (P > .05). The rate of AEs tended to be higher in patients treated for a period shorter than 4 weeks (50%) vs those treated for a longer period
(27.3%, P = . 291) since some of the patients of the first group dis- continued the drug due to the development of AEs.
The median follow-up time (from diagnosis of CS to last visit) was 1.5 years (0.2-10.9), being significantly higher in patients with benign disease than in those with ACC (4.4 ± 3.5 vs 1.4 ± 1.32 years, P = . 004). At the last follow-up, 16 patients had died (9 due to tumor progression, 3 due to hypercortisolism complica- tions, and 4 due to other medical or unknown causes). All the pa- tients who died had ACC except 1 patient with benign adrenal disease who died due to progression of other nonadrenal tumor.
| Variable | Before osilodrostat | After osilodrostat (last available) | P-value |
|---|---|---|---|
| FPG (mg/dL) | 128.3 ± 46.27 (n=25) | 114.6 ± 45.68 (n =20) | .286 |
| HbA1c (%) | 6.4 ±1.36 (n=25) | 6.4 ± 1.61 (n=12) | .844 |
| Total cholesterol (mg/dL) | 176.3 ±42.04 (n=26) | 179.6 ± 56.26 (n=14) | .346 |
| LDL (mg/dL) | 99.6 ± 38.78 (n = 25) | 95.6 ± 41.27 (n=14) | .346 |
| HDL (mg/dL) | 53.4 ± 14.50 (n=22) | 48.2 ± 16.62 (n=11) | .721 |
| Weight (kg) | 81.2 ± 18.57 (n=27) | 77.8 ± 20.77 (n=22) | .009 |
| SBP (mmHg) | 137.5 ± 17.55 (n=28) | 123.7 ± 22.33 (n=32) | .047 |
| DBP (mmHg) | 83.2 ± 13.71 (n=23) | 78.9 ± 23.50 (n=22) | .821 |
| Antihypertensive drugs (n) | 2 (0-4) (n = 34) | 2 (0-4) (n = 33) | .622 |
| Potassium (mmol/L) | 4.1 ± 0.65 (n=27) | 3.9 ± 0.56 (n =25) | .100 |
Comparison of cardiometabolic parameters before and after the initiation of osilodrostat, considering the minimum values achieved during the follow-up period. The Wilcoxon signed-rank test was used for comparison of variables.
Abbreviations: DBP, diastolic blood pressure; HDL, high-density lipoprotein; FPG, fasting plasma glucose; HbA1c, glycated hemoglobin Alc; LDL, low-density lipoprotein; SBP, systolic blood pressure.
| Adverse event | Proportion (n) |
|---|---|
| Gastrointestinal intolerance | 14.3% (4) |
| GWS | 7.1% (2) |
| Edema | 7.1% (2) |
| Hypertension | 7.1% (2) |
| Hypokalemia | 3.6% (1) |
| Liver function alteration | 3.6% (1) |
| Hypocortisolism | 7.1% (2) |
| Others | 10.7% (3)ª |
Abbreviation: GWS, glucocorticoid withdrawal syndrome.
“One patient reported brain fog, memory issues, slurred speech, blurry vision, and weakness, another tachycardia, and another hyporexia.
Overall, at the last visit, only 2 of the 6 patients in combination with metyrapone remained on osilodrostat, while 3 died due to tumor progression and 1 developed adrenal insufficiency. In the group of monotherapy, only 6 continued on osilodrostat, while 72.7% (n = 16) discontinued. The reasons for discontinu- ation were cure after surgery (n = 3), death (n = 8), and develop- ment of AEs (n = 5).
Discussion
Our study is the first international study specifically focused on evaluating the efficacy and safety of osilodrostat in patients with adrenal CS, including benign and malignant tumors. The main findings of our study were that osilodrostat led to a normal- ization of UFC or a decrease >50% in 67% of these patients and had a positive impact on BP control and body weight. In add- ition, the incidence of AEs was relatively low, with adrenal insuf- ficiency occurring only in 7% of the patients, which is much lower than the reported incidence when osilodrostat is used for the treatment of CS of other etiologies (9, 21). As a novelty of our study, we found that the use of osilodrostat as a nonfirst-line medical option for hypercortisolism control might be a potential
predictor of response to osilodrostat. However, this association seemed to be influenced by the more frequent use of osilodrostat as a nonfirst-line therapy in patients with benign adrenal disease than in cases with ACC, as the association disappeared after ad- justing for the presence of ACC.
In relation to the efficacy of osilodrostat, we observed some differences when we compared our results with those described in patients with ACTH-dependent CS. In our study, 67% of the cases were classified as responders and only 28.6% as complete responders. Nevertheless, the rate of control increased to 87.5% when we analyzed those patients treated with osilodrostat for longer than 12 weeks. In this regard, it should be highlighted that the duration of the treatment is an important factor to con- sider as for cases with moderate-severe CS, several titrations of the doses are frequently needed to get the correct dose that con- trols hypercortisolism. Although the rate of control is similar to that described with other steroidogenesis inhibitors such as ketoconazole (22) and metyrapone (23), the response to osilo- drostat in adrenal CS in our series was lower than that previously reported in patients with CD (13, 16, 24) and ectopic CS (ECS) (7, 25) in a similar scenario of real-world practice. For example, in our recent Spanish studies, we reported UFC normalization in 88% (n = 14/16) of ECS patients (25) and in 89.2% of patients with CD (13), while no cases of nonresponse were identified. However, in the recent LINC 7 study evaluating the effectiveness of osilodrostat in nonpituitary CS in real-world practice, the re- sults were in accordance with ours (17). The rate of complete re- sponse in the LINC7 was 44.2% (95% CI 30.5-58.7), with 41% in ECS (n =12/29), 66.6% in ACC (n =4/6), 33.3% in adrenal adenomas (n =1/3), and 85.7% in bilateral adrenal disease (n = 6/7). It should be noted that in the LINC7 study, only 6 pa- tients with ACC and 10 patients with benign disease were in- cluded in the effectiveness evaluation, so the results should be interpreted with caution. On the other hand, in the Tabarin et al’s series with 7 patients with ACC included, osilodrostat nor- malized UFC in all patients (12). The explanation for the differen- ces across studies is not fully understood, as neither the severity of CS nor other factors that differ across series have been de- scribed as predictors of response to osilodrostat in previous studies. Nonetheless, considering all the data together, it seems
that osilodrostat is a less effective treatment for patients with ad- renal CS than for ACTH-dependent CS, and the real explanation for this finding is unknown.
One of the most important findings of our study is that the use of osilodrostat after the use of other previous adrenal steroido- genesis inhibitors (ie, as a second-/third- or fourth-line therapy vs first line) might be a potential predictor of response to osilo- drostat. The higher efficacy of osilodrostat when it was used in a nonfirst-line therapy may be related to the more frequent use of osilodrostat as first-line therapy in patients with ACC than with benign adrenal CS and a tendency to a higher proportion of pa- tients treated with concomitant mitotane in the group of nonfirst-line therapy in comparison with the first-line therapy group. In this regard, although the differences were not statistic- ally significant, our results suggest that ACC patients showed a worse control of hypercortisolism than benign adrenal CS, and patients with ACC treated with concomitant mitotane had a high- er rate of response than those treated without mitotane. The lack of statistically significant differences may be due to a type II error or a small sample size among the comparators, especially con- sidering the relationship that we found between ACC and severe hypercortisolism, a predictor of lower response found in the stat- istical analysis. In addition, we identified 3 patients with ACC who experienced UFC increase during osilodrostat therapy in the con- text of tumoral progression. It is known that cortisol hypersecre- tion is an independent poor prognostic parameter of ACC, and the normalization of hormonal excess represents a priority in the management of patients with hormone-secreting ACC (26). Regarding the severity of hypercortisolism as a predictor of re- sponse, the rate of hypercortisolism control tended to be higher in patients with UFC before starting osilodrostat <5x ULN than in those with higher levels. In line with these results, the pooled analysis of LINC 2, 3, and 4 showed that patients with baseline UFC <2x ULN generally achieved UFC control faster than those with UFC 2-5 or >5x ULN, requiring a lower median osilodrostat dose for hypercortisolism control (27).
Hypertension and obesity are common comorbidities in pa- tients with CS and are present in 70-90% of patients at diagnosis, which contributes to the increased morbidity and mortality risk. One of the main outcomes of medical therapy (together with UFC normalization/reduction) is the improvement of comorbidities and quality of life. The most common evolution of the control of the comorbidities in patients with ACC and in CS in general is to worsen over time, especially if hypercortisolism remains uncon- trolled. In our cohort, osilodrostat avoided this deterioration and even led to an improvement in the control of systolic BP and body weight. These results are in line with those described in other real- world studies and clinical trials (13, 16, 25, 28). For example, in the pooled analysis of LINC 2, 3, and 4, antihypertensive medication dose was reduced or stopped in 26.8% of patients, and in patients with diabetes, mean fasting plasma glucose levels and HbA1c de- creased after osilodrostat therapy initiation (28). We have to high- light that given the life-threatening clinical impact of comorbidities associated with severe hypercortisolism in these patients, the rapid systemic evaluation and multidisciplinary treatment in association with targeted cortisol-lowering therapies are critical for optimizing clinical outcomes (6).
AEs were reported in 32% of the patients in our series, leading to osilodrostat discontinuation in 5 of them, but none of these AEs were classified as severe. In accordance with previous
studies, gastrointestinal AEs, including nausea and vomiting, were the most commonly noted (29). Adrenal insufficiency merits a special mention. We observed a lower prevalence of hypocortisolism (7%) than that reported in patients with ACTH-dependent CS (7, 9, 12). For example, in the LINC 3 (patients with CD), adrenal insufficiency occurred in 28% of the patients (9); in the Dormoy et al’s study with 33 patients with ECS included (7), hypocortisolism occurred in 8 (24%) patients; and in the Tabarin et al’s series (12) with 7 patients with ACC in- cluded, mild and transient adrenal insufficiency was observed in 43% of the cases (n = 3/7). These differences may be related to the differences in the doses used across studies and/or the base- line characteristics of the cases included. For example, the max- imum doses in our study were 10 mg/day (range 1-50), while it was 20 mg/day (range 4-40) in the Tabarin et al’s series (12) and 20 mg/day (10-100/mg/d) in the Dormoy et al’s study (7). However, it was lower in the LINC3 with patients with CD (9), but the population study was very different, as the proportion of cases with severe CS was 71% in Tabarin et al’s study (12) and 91% in the Dormoy et al’s study (7). In this regard, it is im- portant to emphasize that the initial doses of osilodrostat should be tailored based on the severity of hypercortisolism. As we recently proposed in our Spanish Consensus for the man- agement of severe CS, in general for severe hypercortisolism (UFC >5 but <10x ULN), osilodrostat should be employed using higher starting doses (10-30 mg/day), and in patients with life- threatening hypercortisolism (UFC >10x ULN), very high initial doses (30-60 mg/day) are necessary for rapid cortisol control (6). However, in the recent pooled analysis of the LINC 2, 3, and 4, the doses of osilodrostat did not predict the develop- ment of adrenal insufficiency, while patients with less severe hypercortisolism at baseline (UFC <2 or 2-5x ULN) and no prior medical therapy had a significantly lower risk of experiencing hypocortisolism-related AE than those with baseline UFC >5x ULN and prior medical therapy (27).
Our study is the first and largest study focused on evaluating the efficacy and safety of osilodrostat and the first study that identified potential predictors of response to osilodrostat in patients with ad- renal CS. However, we are aware of some of the limitations of the study. One of the biggest limitations is the retrospective nature of the study with its intrinsic limitations and the variability of the pro- tocols used across participating centers, including different starting doses and the fact that information on UFC and cardiometabolic parameters was not available in all the patients at the different evaluation times. Furthermore, although it is the reported largest study, the sample size is relatively small, so differences between groups may be difficult to detect due to the low power in the stat- istical analysis. In addition, we also know that chronotherapy is an- other important aspect that should be considered in the treatment of CS as the administration in the afternoon-evening may be useful to restore the circadian rhythm and improve circadian cortisol pro- files, quality of life, and sleep (30). However, in our study, patients were treated according to traditional recommendations for osilo- drostat use, without considering higher doses in the evening.
Conclusions
Osilodrostat effectively controls hypercortisolism in up to 67% of the patients with adrenal CS treated for longer than 4 weeks and
in 87.5% of cases treated for longer than 12 weeks, with a posi- tive impact on BP and body weight. Patients who received osilo- drostat after previous steroidogenesis inhibitors had a higher probability of response to osilodrostat.
Funding
No funding support was received for the publication of this study.
Disclosures
M.A.C. received speakers’ honoraria, consulting fees and re- search grants from Esteve and Recordati, she is involved in clin- ical research with Lundbeck and Allucent, Recordati and Esteve. The other authors declare no conflict of interest. The industry was not involved in any part of the study, including the design, data collection, analysis, or interpretation of the results.
Data availability
The data are not publicly available but is available from the au- thors upon reasonable request.
Institutional review board
The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of the Hospital Universitario Ramón y Cajal, Madrid, Spain (ap- proval date: November 26, 2024, code: ACTA 472) and in each col- laborating center.
Informed consent
Patient consent was waived due to the retrospective nature of the study. Informed consent was requested only for patients who continued follow-up or who were prospectively included.
References
1. Pivonello R, Isidori AM, De Martino MC, Newell-Price J, Biller BMK, Colao A. Complications of Cushing’s syndrome: state of the art. Lancet Diabetes Endocrinol. 2016;4(7):611-629.
2. Nieman LK, Castinetti F, Newell-Price J, et al. Cushing syn- drome. Nat Rev Dis Primers. 2025;11(1):4.
3. Fassnacht M, Tsagarakis S, Terzolo M, et al. European Society of Endocrinology clinical practice guidelines on the manage- ment of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2023;189(1):G1-G42.
4. Puglisi S, Perotti P, Pia A, Reimondo G, Terzolo M. Adrenocortical carcinoma with hypercortisolism. Endocrinol Metab Clin North Am. 2018;47(2):395-407.
5. Guarnotta V, Stigliano A, Terzolo M, Arnaldi G. Management of Cushing’s syndrome in patients with adrenocortical can- cer: state of the art and future perspectives. Rev Endocr Metab Disord. 2025;26(6):1023-1035.
6. Araujo-Castro M, García-Centeno R, Aller J, et al. Executive summary of the consensus document for the management of severe Cushing’s syndrome: consensus document of the Neuroendocrinology Focus Group of the Spanish Society of Endocrinology and Nutrition (SEEN). Endocrinol Diabetes y Nutr. 2025;72(10):501654.
7. Dormoy A, Haissaguerre M, Vitellius G, et al. Efficacy and safety of osilodrostat in paraneoplastic Cushing syndrome: a real-world multicenter study in France. J Clin Endocrinol Metab. 2023;108(6):1475-1487.
8. Fleseriu M, Pivonello R, Young J, et al. Osilodrostat, a potent oral 116-hydroxylase inhibitor: 22-week, prospective, phase II study in Cushing’s disease. Pituitary. 2016;19(2): 138-148.
9. Pivonello R, Fleseriu M, Newell-Price J, et al. Efficacy and safety of osilodrostat in patients with Cushing’s disease (LINC 3): a multicentre phase III study with a double-blind, randomised withdrawal phase. Lancet Diabetes Endocrinol. 2020;8(9):748-761.
10. Gadelha M, Bex M, Feelders RA, et al. Randomized trial of osi- lodrostat for the treatment of Cushing disease. J Clin Endocrinol Metab. 2022;107(7):E2882-E2895.
11. Fleseriu M, Newell-Price J, Pivonello R, et al. Long-term out- comes of osilodrostat in Cushing’s disease: LINC 3 study ex- tension. Eur J Endocrinol. 2022;187(4):531-541.
12. Tabarin A, Haissaguerre M, Lassole H, et al. Efficacy and tol- erance of osilodrostat in patients with Cushing’s syndrome due to adrenocortical carcinomas. Eur J Endocrinol. 2022:186:K1-K4.
13. Araujo-Castro M, García-Centeno R, González L, et al. Real-world data on the efficacy and safety of osilodrostat in patients with Cushing’s disease in Spain. J Clin Med. 2025;14(21):7575.
14. Laskowski G, Dzialach L, Maksymiuk-Kłos A, Witek P. Successful non-surgical treatment of bilateral macronodular adrenocortical disease with osilodrostat. Endokrynol Pol. 2025;76(6):674-675.
15. Veloski C, Sturgeon A, Hallanger Johnson J. Prolonged ad- renal insufficiency after failed cryoablation and osilodrostat for Cushing syndrome in nodular adrenal disease. JCEM Case Rep. 2025;3(6):luaf091.
16. Fleseriu M, Auchus RJ, Huang W, et al. Osilodrostat treatment of Cushing syndrome in real-world clinical practice: findings from the ILLUSTRATE study. J Endocr Soc. 2025;9: bvaf046.
17. Tabarin A, Bertherat J, Decoudier B, et al. Real-world osilo- drostat effectiveness and safety in nonpituitary Cushing syn- drome. J Clin Endocrinol Metab. 2025;dgaf633. Doi: 10.1210/ clinem/dgaf633
18. Motohashi K, Osawa N, Yamaji T, Tanioka T, Ibayashi H. Cushing syndrome. Nat Rev Dis Primers. 2025;11:3141-3150.
19. Fassnacht M, Johanssen S, Quinkler M, et al. Limited prognostic value of the 2004 International Union Against Cancer staging classification for adrenocortical carcinoma: proposal for a Revised TNM Classification. Cancer. 2009; 115(2):243-250.
20. Araujo-Castro M, Bancos I, Detomas M, et al. Supplementary material for “International Real-world Study on Osilodrostat Efficacy and Safety in Adrenal Cushing Syndrome”. Zenodo. 2026. https://zenodo.org/records/18244071
Downloaded from https://academic.oup.com/jcem/advance-article/doi/10.1210/clinem/dgag115/8519556 by WT Cox Information Services user on 03 April 2026
21. Gadelha M, Snyder PJ, Witek P, et al. Long-term efficacy and safety of osilodrostat in patients with Cushing’s disease: re- sults from the LINC 4 study extension. Front Endocrinol (Lausanne). 2023;14:1236465.
22. Castinetti F, Guignat L, Giraud P, et al. Ketoconazole in Cushing’s disease: is it worth a try. J Clin Endocrinol Metab. 2014;99(5):1623-1630.
23. Broersen LHA, Jha M, Biermasz NR, Pereira AM, Dekkers OM. Effectiveness of medical treatment for Cushing’s syndrome: a systematic review and meta-analysis. Pituitary. 2018;21(6): 631-641.
24. Dzialach L, Sobolewska J, Respondek W, Szamotulska K, Witek P. Cushing’s disease: long-term effectiveness and safety of osilodrostat in a polish group of patients with per- sistent hypercortisolemia in the experience of a single center. Biomedicines. 2023;11(12):3227.
25. Araujo-Castro M, Garcia-Centeno R, González Fernández L, et al. Efficacy and safety of osilodrostat in patients with ectopic Cushing’s syndrome. a real-world study in Spain. J Endocrinol Invest. 2025. Doi: 10.1007/s40618-025-02769-0
26. Ayala-Ramirez M, Jasim S, Feng L, et al. Adrenocortical carcinoma: clinical outcomes and prognosis of 330 patients at a tertiary care center. Eur J Endocrinol. 2013;169(6): 891-899.
27. Fleseriu M, Pivonello R, Lacroix A, et al. Osilodrostat dose im- pact on efficacy/safety in Cushing’s disease: large, pooled analysis of LINC 2, 3, and 4. Eur J Endocrinol. 2025;193(5): 506-5017.
28. Fleseriu M, Pivonello R, Newell-Price J, et al. Osilodrostat im- proves blood pressure and glycemic control in patients with Cushing’s disease: a pooled analysis of LINC 3 and LINC 4 studies. Pituitary. 2025;28(1):22.
29. Nagendra L, Dutta D, Raizada N, Surana V, Selvan C, Bhattacharya S. Efficacy and safety of osilodrostat in man- aging Cushing’s syndrome: a systematic review and meta- analysis. Indian J Endocrinol Metab. 2024;28(3):232-238.
30. Ferrari D, Bonaventura I, Simeoli C, et al. Chronotherapy with once-daily osilodrostat improves cortisol rhythm, quality of life, and sleep in Cushing’s syndrome. J Clin Endocrinol Metab. 2025;110(12):3525-3537.
Downloaded from https://academic.oup.com/jcem/advance-article/doi/10.1210/clinem/dgag115/8519556 by WT Cox Information Services user on 03 April 2026