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Glucocorticoid Receptor Antagonism Upregulates Somatostatin Receptor Subtype 2 Expression in ACTH-Producing Neuroendocrine Tumors: New Insight Based on the Selective Glucocorticoid Receptor Modulator Relacorilant.

ABSTRACT: Somatostatin exhibits an inhibitory effect on pituitary hormone secretion, including inhibition of growth hormone and adrenocorticotropic hormone (ACTH), and it can have antisecretory and antitumor effects on neuroendocrine tumors (NETs) that express somatostatin receptors. Although the precise mechanism remains unclear, the finding that glucocorticoids downregulate somatostatin receptor subtype 2 (SSTR2) expression has been used to explain the lack of efficacy of traditional SSTR2-targeting analogs in patients with ACTH-secreting NETs. Glucocorticoid receptor (GR) antagonism with mifepristone has been shown to reverse the glucocorticoid-induced downregulation of SSTR2; however, the effects of GR modulation on SSTR2 expression in ACTH-secreting NETs, particularly corticotroph pituitary tumors, are not well known. The current study presents new insight from in vitro data using the highly selective GR modulator relacorilant, showing that GR modulation can overcome dexamethasone-induced suppression of SSTR2 in the murine At-T20 cell line. Additional data presented from clinical case observations in patients with ACTH-secreting NETs suggest that upregulation of SSTR2 via GR modulation may re-sensitize tumors to endogenous somatostatin and/or somatostatin analogs. Clinical, laboratory, and imaging findings from 4 patients [2 ACTH-secreting bronchial tumors and 2 ACTH-secreting pituitary tumors (Cushing disease)] who were treated with relacorilant as part of two clinical studies (NCT02804750 and NCT02762981) are described. In the patients with ectopic ACTH secretion, SSTR2-based imaging (Octreoscan and ⁶⁸Ga-DOTATATE positron emission tomography) performed before and after treatment with relacorilant showed increased radiotracer uptake by the tumor following treatment with relacorilant without change in tumor size at computed tomography. In the patients with Cushing disease who received relacorilant prior to scheduled pituitary surgery, magnetic resonance imaging after a 3-month course of relacorilant showed a reduction in tumor size. Based on these findings, we propose that GR modulation in patients with ACTH-secreting NETs upregulates previously suppressed SSTR2s, resulting in tumor-specific antisecretory and anti-proliferative effects. The effect of relacorilant on pituitary corticotroph tumors is being investigated in an ongoing phase 3 study (NCT03697109; EudraCT 2018-003096-35).

SUBMITTER: Pivonello R

PROVIDER: S-EPMC8764187 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Introduction/purposeRelacorilant is a selective glucocorticoid receptor modulator (SGRM) with no progesterone receptor activity. We evaluated the efficacy and safety of relacorilant in patients with endogenous Cushing syndrome (CS).Materials and methodsA single-arm, open-label, phase 2, dose-finding study with 2 dose groups (NCT02804750, https://clinicaltrials.gov/ct2/show/NCT02804750) was conducted at 19 sites in the U.S. and Europe. Low-dose relacorilant (100-200 mg/d; n = 17) was administered for 12 weeks or high-dose relacorilant (250-400 mg/d; n = 18) for 16 weeks; doses were up-titrated by 50 mg every 4 weeks. Outcome measures included proportion of patients with clinically meaningful changes in hypertension and/or hyperglycemia from baseline to last observed visit. For patients with hypertension, clinical response was defined as a ≥5-mmHg decrease in mean systolic or diastolic blood pressure, measured by a standardized and validated 24-h ABPM. For patients with hyperglycemia, clinical response was defined ad-hoc as ≥0.5% decrease in HbA1c, normalization or ≥50-mg/dL decrease in 2-h plasma glucose value on oral glucose tolerance test, or decrease in daily insulin (≥25%) or sulfonylurea dose (≥50%).Results35 adults with CS and hypertension and/or hyperglycemia (impaired glucose tolerance or type 2 diabetes mellitus) were enrolled, of which 34 (24 women/10 men) received treatment and had postbaseline data. In the low-dose group, 5/12 patients (41.7%) with hypertension and 2/13 patients (15.4%) with hyperglycemia achieved response. In the high-dose group, 7/11 patients (63.6%) with hypertension and 6/12 patients (50%) with hyperglycemia achieved response. Common (≥20%) adverse events included back pain, headache, peripheral edema, nausea, pain at extremities, diarrhea, and dizziness. No drug-induced vaginal bleeding or hypokalemia occurred.ConclusionsThe SGRM relacorilant provided clinical benefit to patients with CS without undesirable antiprogesterone effects or drug-induced hypokalemia.

Project description:Abstract Background Relacorilant is a highly selective glucocorticoid receptor (GR) modulator in development for the treatment of endogenous Cushing syndrome (CS). Unlike the FDA-approved GR antagonist mifepristone, relacorilant lacks affinity for the progesterone and other receptors. In a phase 2 study in patients with CS (NCT02804750, Pivonello et al, 2021), relacorilant provided clinically meaningful changes in a number of cortisol-excess-related comorbidities, including hypertension and hyperglycemia, without undesirable antiprogesterone effects or drug-induced hypokalemia. Currently, 4 clinical studies of relacorilant in patients with CS are ongoing: GRACE (NCT03697109), a phase 3 trial enrolling patients with endogenous CS of all etiologies; GRADIENT (NCT04308590), a phase 3 trial focusing on hypercortisolism due to adrenal adenomas or hyperplasia; a phase 2/3 long-term extension study (NCT03604198); and a phase 1b study in patients with adrenocortical carcinoma associated with glucocorticoid excess (NCT04373265). Here, we report safety results and liver function test (LFT) changes from open-label phase 1 and 2 studies of relacorilant in healthy and hepatically impaired adults and in adult patients with CS. Methods In a special population study, 9 subjects with moderate hepatic impairment (Child-Pugh Class B) and 9 matched controls with normal hepatic function received relacorilant (300 mg QD) for 10 days. In a phase 1 fixed-sequence drug-drug interaction study (NCT03512548), 28 healthy subjects received relacorilant (300 mg QD) for 10 days followed by 10 days of relacorilant (300 mg QD) combined with itraconazole (200 mg QD). Thirty-five patients with CS received relacorilant (100–400 mg QD) for up to 16 weeks in the phase 2 study. Results While relacorilant is eliminated primarily through the hepatic route, no apparent difference in relacorilant pharmacokinetics in subjects with moderate hepatic impairment vs matched controls was observed, with relacorilant exposures (as measured by area under the concentration-time curve [AUC] and maximum concentration [Cmax]) largely overlapping across both groups. In addition, reductions in LFTs were observed in this study. In healthy adults treated with relacorilant followed by relacorilant + itraconazole (an agent with reported liver toxicity), a similar trend toward reduced LFTs was seen throughout the study. In the phase 2 study in patients with CS, reductions in LFTs were also observed, including normalization of LFTs in some patients with abnormal values at baseline. Conclusions These results suggest that relacorilant has a favorable liver safety profile that includes a trend toward improved LFTs in volunteers and patients with normal and abnormal liver function. The findings of the hepatic impairment study support the use of relacorilant without dose adjustment in patients with moderate hepatic impairment. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

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Glucocorticoid Receptor Antagonism Upregulates Somatostatin Receptor Subtype 2 Expression in ACTH-Producing Neuroendocrine Tumors: New Insight Based on the Selective Glucocorticoid Receptor Modulator Relacorilant.

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