Efficacy and tolerance of osilodrostat in patients with Cushing’s syndrome due to adrenocortical carcinomas
Antoine Tabarin1, Magalie Haissaguerre1, Hélène Lassole2, Arnaud Jannin3, Anne-Cecile Paepegaey4, Olivier Chabre5 and Jacques Young6
1Department of Endocrinology, Diabetes and Nutrition, Hôpital Haut Lévêque, CHU and University of Bordeaux, Pessac, France, 2Fédération d’Endocrinologie, Hospices Civils de Lyon, Groupement Hospitalier Est, Bron, France, 3Department of Endocrinology, Diabetology and Metabolism, Lille University Hospital and University of Lille, Lille, France, 4Department of Endocrinology, Diabetes and Nutrition, Médipole Lyon Villeurbanne, Villeurbanne, France, 5University Grenoble Alpes, Service d’Endocrinologie CHU Grenoble Alpes, Unité Mixte de Recherche INSERM-CEA-UGA UMR1036, Grenoble Alpes, France, and 6Department of Reproductive Endocrinology, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin-Bicêtre and University Paris-Saclay, Paris, France
Correspondence should be addressed to A Tabarin Email antoine.tabarin@chu- bordeaux.fr
Cushing’s syndrome (CS) is frequently associated with adrenocortical carcinoma (ACC) and has a negative impact on the prognosis of this lethal disease as well as on the quality of life of patients (1, 2). In this setting, and in addition to anti-neoplastic therapy, steroidogenesis inhibitors such as ketoconazole and metyrapone are usually recommended, either alone or in association (1, 2, 3). Osilodrostat is a recently developed inhibitor of adrenal 11B-hydroxylase which has been shown to be effective in the treatment of Cushing’s disease (4). Only one case on the use of osilodrostat to treat CS induced by ACC has been previously reported (5). Following the shortage of metyrapone in 2019, temporary authorization to use osilodrostat was given by French authorities. We report herein the experience of six French centers in the treatment of CS due to ACCs with this drug.
Case reports
Seven cases (three males and four females, age: 29-86 years) with cortisol-secreting ACC are reported here (Table 1). Four patients had a recurrence or tumoral progression of a previously treated ACC. ACC was diagnosed during the workup of CS in three patients. Tumors were graded as ENSAT stage IV (n = 5), stage III (n = 1) and stage II (n = 1). All patients had clinical features of CS associated with an
increase in urinary-free cortisol (UFC), ranging from 1.8 to 34.8x the upper limit of normal range (ULN). Increased secretion of other steroids and IGF2 was observed in five and one patient, respectively. Plasma ACTH was suppressed in all patients. Five out of seven patients had intense hypercortisolism defined by an increase in UFC ≥5.0x ULN and/or the mean of several daily serum cortisol concentrations ≥1000 nmol/L.
Mitotane was already prescribed for at least 5 months at doses of 5000 mg/day, 7000 mg/day and 1500 mg/day in patients no. 4, 5 and 6, respectively, when CS was diagnosed (Table 1). As CS was associated with tumoral progression, mitotane was subsequently discontinued in patients no. 5 and 6. Mitotane was introduced but stopped after 4-6 days for cytolytic hepatitis and digestive intolerance in patients no. 1 and 2. Mitotane treatment was not considered in patient no. 7 due to his age and cognitive status. After 5 weeks of osilodrostat treatment, 1500 mg/day of mitotane was introduced in patient no. 3 and increased up to 6000 mg/day thereafter (Fig. 1). Metyrapone (750-1000 mg/day) was administered prior to osilodrostat in patients no. 1 and 2 but stopped due to lack of control of hypercortisolism or intolerance. Patient no. 4 simultaneously received osilodrostat and 2000 mg/day of metyrapone, the latter being discontinued after 4.5 weeks of concomitant treatment (Fig. 1).
| Patient | Sex/ age | Delay after diagnosis (years) | Size (mm) | Weiss score/ Ki 67 | Previous treatments (received prior to osilodrostat treatment) | Ensat stage/ metastasis (at the start of osilodrostat treatment) | Associated secretion ( by ACC) | Anti-neoplastic treatments associated with osilodrostat | Cushing clinical score | Systolic blood pressure | Kalemia | Fasting glycemia | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Before | After | Before | After | Before | After | Before | After | |||||||||
| 1 | M/71 | 0 | 92 | NA | None | II | D4A, DHEAS, 17OHP | None | 2 | NA | 160 | 120 | 2.7 | 4.5 | 6.4 | 4.4 |
| 2 | F/56 | 14 | 90 | 9/UK | Surgery, RXT, mitotane | IV/liver, lungs, pleura | Testosterone | None | 2 | NA | 150 | 111 | 2.7 | 4.1 | 7.8 | 5.0 |
| 3 | M/43 | 0 | 110 | NA | None | IV/liver, lungs | D4A | Mitotane (1.5-4.5 g/day), C+E | 2 | 1 | 150 | 106 | 2.8 | UK | 9.4 | 5.0 |
| 4 | M/55 | 0.5 | 150 | 8/30% | Surgery, mitotane, chemotherapy (2) | IV/liver, lungs, LN | None | Mitotane (5 g/day) | 2 | 1 | 172 | 132 | 2.9 | 4.3 | 10.3 | 4.8 |
| 5 | F/29 | 9 | 120 | 7/20% | Surgery, mitotane, chemotherapy (1) | IV/peritoneum | DHEAS, D4A | Cabozantinib | 1 | 0 | UK | UK | 3.2 | 4.0 | 5.0 | 5.1 |
| 6 | F/31 | 3.5 | 75 | 8/40% | Surgery, mitotane, chemotherapy (1) | IV/liver, peritoneum | 11DOC, IGF-2 | Cabozantinib | 2 | 0 | 170 | 100 | 3.2 | 4.2 | 4.1 | 4.3 |
| 7 | F/86 | 0 | 86 | NA | None | III/LN | D4A, 17OHP | None | 2 | 1 | 203 | 150 | 2.7 | 4.1 | 6.6 | 4.4 |
ACC, adrenal carcinomas; C+E, cysplatin + etoposide chemotherapy; DHEAS, dehydroepiandrosterone sulfate; D4A, delta4-androstenedione; LN, lymph nodes; NA, not applicable; RXT, radiotherapy; UK, unknown; 11DOC, 11 deoxycorticosterone; 17OHP, 17 hydroxyprogesterone.
Anti-neoplastic chemotherapy, the numbers in brackets correspond to the number of lines of chemotherapy; Cushing clinical score, the score for clinical appearance is expressed from 0 (lack of symptoms) to 2 (florid Cushing), which was assessed by experienced endocrinologists; before, parameters evaluated immediately prior the start of osilodrostat treatment; after, parameters evaluated after normalization of serum cortisol concentration and/or UFC following osilodrostat treatment.
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Figure 1 Evolution of UFC (shown as ULN) and mean serum cortisol concentrations in seven patients with Cushing’s syndrome and adrenocortical carcinomas treated with osilodrostat. The broken line corresponds to the ULN for serum cortisol and UFC concentrations. The shaded area with a number above corresponds to the osilodrostat dosage administered during this period. Mtp, metyrapone; Mtt, mitotane, UFC, urinary-free cortisol; ULN, upper limit of normal range.
The osilodrostat regimen was highly variable between patients in terms of starting dose, dose increases and duration of titration steps (Fig. 1). A significant decrease in UFC and/or serum cortisol was observed in 6/7 patients within 2 weeks. Osilodrostat induced a maximal decrease in UFC from 10.5 ± 5.0 to 0.6 + 0.1x ULN (P =0.03) and a decrease of mean serum cortisol from 989 ± 159 to 330 ± 47 nmol/L (P =0.02). Overall, osilodrostat was able to fully control hypercortisolism in all seven patients at daily doses of 4 mg (n=1), 8 mg (n=1), 10 mg (N= 1), 20 mg (n= 1) and 40 mg (n = 3). Control of hypercortisolism was obtained at variable intervals: within 1 week in two patients, within 1
month in one patient, around 2 months in two patients and 3 months in two patients. In patients observed for a sufficient period of time, control of hypercortisolism was associated with a significant improvement in Cushing’s symptoms as illustrated by the decrease in a Cushing score for clinical appearance expressed from 0 (lack of symptoms) to 2 (florid Cushing) and assessed by experienced endocrinologists (Table 1). Of note, patient no. 7 presented with steroid psychosis that disappeared within 10 days following osilodrostat treatment. Systolic blood pressure decreased from 168 ± 8 to 120 ± 7 mm Hg (P=0.03) together with reduction in daily anti-hypertensive drug dosage (from 4.0 ± 1.4 to 1.9 ± 1.1; P =0.03). An increase in serum potassium (from 2.9 ± 0.1 to 4.2 ± 0.1 mmol/L, P=0.03) associated with a reduction in potassium supplementation (from 2.5 ± 0.7 to 1.4 ± 0.7 g/day) and/ or spironolactone dosage was obtained in six out of seven patients. Three patients had diabetes mellitus and two had glucose intolerance that disappeared following the control of hypercortisolism. Osilodrostat treatment was well- tolerated and in no case stopped due to side effects. Mild and transient adrenal insufficiency was observed in three out of seven patients, especially during a period of sepsis in two patients, and required a dose reduction or the addition of hydrocortisone supplementation. Patient no. 6 had a worsening of hypokalemia (from 3.2 to 2.8 mmol/L) during concomitant osilodrostat (60 mg/day) and cabozantinib treatment. No treatment escape was observed; however, its duration was limited to 13.7 ± 4.2 weeks (range: 1-29) due to death following progression of ACC (patients 3, 4, 6 and 7), COVID-19 infection (patient no. 1), being lost to follow-up (patient no. 2) or the resolution of CS after surgical removal of peritoneal metastasis (patient no. 5).
Discussion
Although limited, this small series together with a previously published case (5) shows that osilodrostat treatment allowed the control of hypercortisolism in eight patients with ACC. It was associated with clinical improvement, a characteristic which is particularly important in these fragile patients with limited life expectancy who often require multiple medical treatments for co-morbidities. The control of hypercortisolism during osilodrostat treatment could not be attributed to the effectiveness of concomitant anti- neoplastic therapy in patients no. 3, 5 and 6 since tumor progression was observed during this period (Table 1). Mitotane is characterized by a slow onset of action (6).
It is therefore unlikely that steroidogenesis inhibition by mitotane could be entirely responsible for the control of hypercortisolism in patient no. 3 given the short delay (4 weeks) between the introduction of mitotane and the control of serum cortisol concentrations (1, 2, 6). Control of hypercortisolism was obtained, regardless of its intensity, as illustrated by the normalization of UFC with 40 mg/day of osilodrostat in patient no. 3 with a baseline value of 34.8x ULN. However, there was wide variability in the sensitivity to the drug among tumors as illustrated by the contrast between patient no. 2 with 3.0x ULN UFC in whom a dosage of 10 mg/day induced adrenal insufficiency within 4 days and patient no. 5 in whom a dosage of 40 mg/day was necessary to control a 1.8x ULN UFC (Fig. 1). As noted in Cushing’s disease trials (4), the overall tolerance of treatment was good except for one case with worsening hypokalemia and three cases of mild adrenal insufficiency, an easily manageable event. This reflects the efficacy of the drug which should however be carefully monitored during titration or during intercurrent episodes such as infection.
The rapidity of action, efficacy and safety of osilodrostat treatment combined with a reduced number of tablets per day and limited drug interactions make it suitable for the treatment of CS associated with ACC. The starting dose of the treatment and the rate of progression of dose titration to be used in this situation remain debatable (5, 7). Although the data obtained in Cushing’s disease studies suggests that the steady state of the anticortisolic effect is obtained after several weeks for a given dose (4), the severity of CS and limited life expectancy of ACC patients suggests the use of regimens different from those recommended in Cushing’s disease, at least in patients with intense hypercortisolism. We therefore suggest using a relatively high starting dose (≥10 mg/day) associated with close monitoring of serum cortisol (using specific assays to avoid cross-reactivity with 11-deoxycortisol) and a rapid titration rate adapted to the urgency of the situation and/or the need to initiate anti- neoplastic therapy. Further data is now needed to clarify this point and the use of a ‘block and replace’ regimen. Indeed, in patients responding to anti-neoplastic therapy, a rapid decrease in cortisol production leading to adrenal insufficiency may be observed which complicates the monitoring of drug dosage and requires repeated serum cortisol or UFC measurements. A ‘block and replace’
regimen should therefore be considered especially when concomitant anti-neoplastic therapy is initiated.
Declaration of interest
A Tabarin, O Chabre and J Young have been investigators on studies, received honoraria as board members and attended ymposia for Recordati rare diseases, Novartis and HRA Pharma.
Funding
This work did not receive any specific grant from any funding agency in the public commercial; not for profit sector or industry.
Patient consent
Informed consent has been obtained from the only patient alive on the date of submission of the article for publication of the case report and accompanying images. Consent has not been obtained for the six remaining patients who are deceased.
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