Isturisa Quickly, Safely Lowers Cortisol Levels in 3 Severe Cushing’s Cases

Isturisa (osilodrostat) rapidly and safely controlled high cortisol levels associated with severe Cushing’s syndrome in three cancer patients who could not take standard medications, a case series study reported.

The study, “Efficacy and tolerance of osilodrostat in patients with severe Cushing’s syndrome due to non-pituitary cancers,” was published in the European Journal of Endocrinology.

All three patients could not be prescribed the cortisol-lowering medications metyrapone (marketed as Metopirone) or ketoconazole (marketed as Nizoral, among other brand names); they were treated by physicians at l’Hôpital Haut Lévêque in Pessac, France.

Isturisa, marketed by Recordati, became commercially available in France this year. The medication blocks the activity of an enzyme, called 11-beta-hydroxylase, that controls cortisol production. The patients described in the report received treatment in 2019, following a national shortage of Metopirone, during which French authorities temporarily authorized the use of Isturisa.

The first patient was a 51-year-old woman with Cushing’s syndrome caused by small cell lung carcinoma (SCLC), an aggressive form of lung cancer that often occurs in smokers. Although  outside the pituitary gland, which produces the adrenocorticotropic hormone (ACTH) that stimulates cortisol production, SCLC is also able to trigger ACTH production and cause ectopic Cushing’s syndrome.

This woman had been taking Metopirone after becoming intolerant to ketoconazole. Following the Metopirone shortage, a daily regimen of 2 mg of Isturisa was used to control her cortisol levels.

A recurrence of her cancer, which was previously controlled by chemotherapy, led to a surge in her cortisol levels up to 1,200 nanomole per liter (nmol/L). At this point, physicians upped her daily dose of Isturisa to 5 mg for four days, with 5 mg increments every two to four days thereafter, based on blood cortisol measurements.

Her cortisol levels stabilized within the target range of 200–500 nmol/L after she reached the maximum daily dose of 25 mg two weeks later. This dose effectively controlled her cortisol levels for three months, until she died from her cancer.

The second patient was a 39-year-old man with Cushing’s syndrome caused by adrenocortical carcinoma. He, too, had developed liver intolerance to ketoconazole.

He began taking 5 mg of Isturisa per day, alongside the anti-cancer therapy mitotane (1,500 mg/day). Based on blood cortisol measures, physicians decided to increase his Isturisa dose by 4–5 mg/day, every four to five days, for two weeks, up to a maximum dose of 44 mg/day.

This changed to a “block-and-replace” (BAR) strategy, in which a high-dose of hydrocortisone (60 mg/day) was administered every time cortisol levels dropped below 173 nmol/L, following treatment with Isturisa at a daily dose of 30 mg.

This strategy controlled the man’s previously high cortisol levels for four months, until doctors surgically removed his tumor.

The third patient was a 70-year-old man with severe Cushing’s syndrome also due to SCLC. His condition had been controlled with a combination of chemotherapy, Metopirone, and ketoconazole. He changed from Metopirone to Isturisa at a daily dose of 1 mg during the shortage.

Cancer recurrence increased his cortisol levels to 900 nmol/L, and doctors upped his Isturisa dose to 4 mg a day for 14 days, while keeping the patient on a stable dose of ketoconazole. This treatment regimen halved his cortisol levels, until a reaction between ketoconazole and his chemotherapy caused liver intolerance and all medications had to be stopped.

After remaining off the medications for one week, the patient saw his cortisol levels reach 1,200 nmol/L, at which point he was started on Isturisa (7 mg/day) alone. This single therapy regimen brought his cortisol levels under control within seven days.

His cortisol levels then fell below the normal range of 200-500 nmol/L to 150 nmol/L. At this point, he too was placed on a BAR regimen of 6 mg of Isturisa and 10 mg hydrocortisone, both given daily.

He returned to chemotherapy and controlled his cortisol levels for two months until he also died of his cancer.

The investigators noted that using Isturisa in a BAR regimen had not been described before, and that this strategy may be useful in complex situations. They found it particularly helpful that Isturisa comes in a variety of doses.

“In our opinion,” they wrote, “the BAR regimen with an effective drug that is associated with a low prevalence of drug-to-drug interactions represents a valid therapeutic approach in these patients.”