Efficacy and Tolerance of Osilodrostat in Patients with Severe Cushing's

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M Haissaguerre and others Osilodrostat in severe Cushing 183:4 L7–L9 Letter

Efficacy and tolerance of osilodrostat in patients with severe Cushing’s syndrome due to non-pituitary cancers

Magalie Haissaguerre, Marie Puerto, Marie-Laure Nunes and Antoine Tabarin

Department of Endocrinology, Diabetes and Nutrition, Hôpital Haut Lévêque, CHU and University of Bordeaux, Pessac, France Correspondence should be addressed to A Tabarin Email antoine.tabarin@chu- bordeaux.fr

To the editor cortisol to 1200 nmol/L. Osilodrostat dose was immediately increased to 5 mg/day for 4 days, and based on repeated Severe hypercortisolism (SH) is a rare life-threatening plasma cortisol measurements, it was increased every 2–4 endocrine emergency, mainly caused by ectopic ACTH days in 5 mg/day steps. A maximal dose of 25 mg/day syndrome (EAS), which requires a rapid normalization was reached after 2 weeks which allowed the mean of cortisol concentrations (1, 2). Due to their rapidity of plasma cortisol concentrations (determined from 3-day action, steroidogenesis inhibitors, such as ketoconazole time samples) to be in the target range (200–500 nmol/L). and metyrapone, given in monotherapy or in association, Control of SH was sustained for 3 months until the death are recommended in this situation (1, 3, 4). Osilodrostat is of the patient due to tumoral burden (Fig. 1A). a recently developed inhibitor of adrenal 11B-hydroxylase (5) which has been shown to be effective, using a progressive titration of the drug dosage, in the treatment

European Journal of Endocrinology of Cushing’s disease (5, 6, 7). Limited data are available on Patient 2 the use of osilodrostat in SH induced by EAS (8). Following A 39-year-old man presented with an ACC responsible the shortage of metyrapone in 2019, a temporary for SH (plasma cortisol 1495 nmol/L). Liver intolerance authorization for the use of osilodrostat was given by = occurred after 10 days of ketoconazole treatment at French authorities. We report herein our experience 1200 mg/day. Osilodrostat was introduced at 5 mg/day with osilodrostat in the treatment of three patients together with mitotane 1500 mg/day. Based on repeated with severe Cushing’s syndrome due to EAS and adrenal plasma cortisol measurements, osilodrostat was increased carcinoma (ACC). every 4–5 days by 4–5 mg/day steps. The maximal dosage of 44 mg/day was reached after 2 weeks and achieved normalization of plasma cortisol. To simplify anticortisolic Patient 1 treatment during neoadjuvant anticancer chemotherapy, a block-and-replace (BAR) regimen was employed with A 51-year-old woman presented with a small cell lung osilodrostat 30 mg/day associated with hydrocortisone carcinoma (SCLC) responsible for SH. She was effectively that was introduced when 08:00 h plasma cortisol started treated for 2 years by chemotherapy and 500 mg/day to decrease below normal (173 nmol/L). A high dosage metyrapone after developing liver intolerance to (60 mg/day) of hydrocortisone was prescribed as required ketoconazole. Following metyrapone shortage, 2 mg/day in patients treated with mitotane (9). Hypercortisolism osilodrostat allowed control of cortisol levels. Recurrence was controlled for 4 months until surgical resection of the of the SCLC was associated with an increase in plasma ACC (Fig. 1B).

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-20-0557 European Journal of Endocrinology https://eje.bioscientifica.com ketoconazole treatmentwas continued,osilodrostatwas an increaseinplasmacortisol to900nmol/L.While mg/day). Recurrenceofthe SCLCwasassociatedwith hypercortisolism, inassociationwithketoconazole (1200 1 mg/day, adosethatmaintainedthe controlof metyrapone shortage, osilodrostat was introduced at (750 mg/day)andketoconazole(1200mg/day).Following with chemotherapyassociatedmetyrapone SH (plasma cortisol A 70-year-oldmanpresentedwithaSCLCresponsiblefor Patient 3 of liverintolerancetoketoconazole. line antineoplasticchemotherapy.Arrowhepatitis:occurrence osilodrostat inmg/day.Arrowchemo:beginningofthesecond background stepsrepresentthetitrationregimenof range inourlaboratory(200–500nmol/L).Thegray measurements. Theshadedareacorrespondstothenormal patient 3).Cortisolvaluesarethemeanof3-daytime patients treatedwithosilodrostat(A:patient1;B:2;C: Evolution ofmeanplasmacortisolconcentrationsinthree Figure 1 Letter =

1970 nmol/L) that was controlled M Haissaguerreandothers

osilodrostat rapidlyandsafelycontrolledSHinthree showthat,usingvariableregimens, These observations Discussion 2 monthslaterduetotumoralburden( control ofhypercortisolism untilthedeathofpatient reintroduction ofanticancerchemotherapyandsustained with osilodrostatat6mg/day. ThisBARregimenallowed dose ofhydrocortisonewasprescribedinassociation (150 nmol/L,normal:200–500nmol/L),a10mgmorning days. Threeweekslater, duetolowcortisolconcentrations as monotherapyat7mg/dayleadingtocontrolofSHin increased to1200nmol/L.Osilodrostatwasreintroduced stopped. After1weekofdrugwithdrawal,plasmacortisol induced liverintoleranceandallmedicationswere between chemotherapy(paclitaxel)andketoconazole in cortisolconcentration.Apharmacologicalinteraction increased to4mg/dayover14days,allowinga50%decrease measurements. 2–5 daystitrationstepsbased onserialplasmacortisol following asingledose( dramatic decreaseinplasma cortisolafteratmost8h with thosederivedfromanimalstudies,suggesting a steady statereachedin2days( rapid absorption(Tmax≈1h),ahalf-life4h,and a on thepharmacokineticsofosilodrostat,including a study ( used intheLincStudies( using a rapid increase in dosage that differs from that ethnicities ( 20% higherinAsianpatientsascomparedtoother the relativebioavailabilityofdrugisapproximately any casecannotbeextrapolatedtoCaucasians,since dosage ofosilodrostatwasnotspecificallygiven,butin inourpatients.Theprecise period thanthatobserved approximately 5–9weeks,thatis,asignificantlylonger that osilodrostatnormalizedUFCintheshort-term not provided,analysisoffiguresfromthispapershows titration protocol. Although theindividual data were who weretreatedinaphase2studyusingfixeddose- study ( Towere observed. date,weareonlyawareofoneJapanese excellent: neithernauseanorchangesinQTc orkalemia 44 mg/day was used. Thetoleranceof osilodrostat was concentrations was not beprescribed patients inwhommetyraponeandketoconazolecould Osilodrostat insevereCushing In ourseries,osilodrostatcontrolledrapidlySH 8 8 ). Ourtitrationprotocolwasestablishedbased ) involvingthreepatientswithSHandEAS, 5 , 8 ). . Thetimetocontrolofplasmacortisol ≤ 2 weeks,andamaximaldoseof Downloaded fromBioscientifica.com at10/06/202111:38:51AM 10 ), whichpromptedustouse 5 , 5 6 ). Thesedataassociated , 7 ) andtheJapanese 183 Fig. 1C :4 ). L8 via freeaccess

European Journal of Endocrinology References public, commercial,ornot-for-profitsectorindustry. This work did not receive any specific grant from any funding agency in the Funding be could that interest of conflict perceived asprejudicingtheimpartialityofthisletter. no is there that declare authors The Declaration ofinterest titration steps. optimal startingdosesofosilodrostatandduration complex therapeuticsituationsareneededtodetermine inthese observations replacement. Complementary adjustments andconsiderprescriptionofglucocorticoid (ideally associatedwithUFC)after2–5daysforfurther cortisol levelsare a relativelyhighdosage,ofatleast6mg/day, whenbaseline we suggest to start osilodrostat at number of observations, at controllingSHrapidly( a validtherapeuticapproachinthesepatients. low prevalence of drug-to-drug interactions ( regimen withaneffectivedrugthatisassociateda repeated cortisolmeasurements.Inouropinion,theBAR complicates themonitoringofdrugdosageandrequires induce arapidconcomitantdecreaseincortisolwhich by imagingafterseveralweeksofdelay, itmayalso on tumorburden,aconditionthatisusuallyevaluated cancers. Indeed, when antineoplastic therapy is effective situation, suchasSHinpatientswithnon-pituitary The BARregimenmaypeculiarlybeusefulinacomplex compliance andberelevantintermsofqualitylife. be taken( reduced thenumberofsteroidogenesisinhibitorpillsto availability ofvariousdosagesforosilodrostatsignificantly previously describedwiththisdrug.TheTIDregimenand patients, a therapeutic scenario which has not been 1 Letter Young J, Haissaguerre M,Viera-Pinto O, Chabre O,Baudin E& (https://doi.org/10.1530/EJE-19-0877) opinion. syndrome duetoectopicACTHsecretion:anexpertoperational Tabarin A. MANAGEMENT OFENDOCRINEDISEASE:Cushing’s In conclusion,inablock-and-replacestrategyaiming Osilodrostat wasusedusingaBARregimenintwo 3 European Journal ofEndocrinology European Journal , 4 , 11 > , 1000 nmol/L;re-assessplasmacortisol 12 ), apointthat may favorpatient 13 ), andbasedonalimited M Haissaguerreandothers 2020 182 R29–R58. 5 ) represents Accepted 17July2020 Revised versionreceived24June2020 Received 29May2020

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