SUN-463 Tumor Shrinkage with Preoperative Relacorilant Therapy in Two Patients with Cushing Disease Due to Pituitary Macroadenomas

Abstract

Background: Relacorilant (RELA, Corcept Therapeutics) is a highly selective glucocorticoid receptor antagonist (GRA) that modulates the effects of excess cortisol, while showing no significant antagonism at the progesterone, mineralocorticoid, androgen, or estrogen receptors. It is currently being investigated for the treatment of patients with endogenous Cushing syndrome (CS) of any etiology. Results from the open-label Phase 2 study (NCT02804750) indicated that treatment with RELA was generally well tolerated and significantly improved glycemic and hypertension control in patients with endogenous hypercortisolism. In this Phase 2 study, two patients with Cushing disease (CD) showed evidence of tumor shrinkage on post-treatment MRIs performed after study completion. Cases: Two patients with de novo CD due to a macroadenoma were treated for 3 months with RELA prior to previously scheduled transsphenoidal pituitary surgeries. Pituitary imaging performed after treatment with RELA revealed significant shrinkage of the tumors. Patient 1 is a 50y/o woman with a pituitary macroadenoma measuring 10 x 6.3 mm on MRI. She presented with cushingoid features (moon face, dorsal & supraclavicular fat, plethora, central obesity, easy bruising, striae) and had confirmatory biochemical tests (ACTH 12.2 pmol/L (NR 1.3-11.1 pmol/L); UFC 177.7 nmol/d (NR 11.1-138 nmol/d); DST 156 ng/mL (15.6 mcg/dL). Patient 2 is a 43y/o man with a pituitary macroadenoma measuring 22 x 25 x 26 mm with suprasellar extension, right displacement of the pituitary stalk, and invasion of the left cavernous sinus on MRI. He also had cushingoid features and confirmatory biochemical tests (ACTH 20.9 pmol/L (NR 1.3-11.1 pmol/L); UFC 356.5 nmol/d (NR 11.1-138 nmol/d); DST 247 ng/mL (24.7 mcg/dL). After completing the 3-month study, pre-operative MRIs revealed reduction in the size of their tumors. The pituitary tumor for patient 1 decreased from 10 x 6.3 mm prior to treatment to 8.0 x 5.7 mm after treatment with RELA. The pituitary tumor for patient 2, decreased from 22 x 25 x 26 mm prior to treatment to 21 x 22 x 19 mm after treatment with RELA. Conclusion: Pituitary imaging performed as part of the pre-operative standard of care revealed tumor shrinkage in two patients with macroadenomas treated for 3 months with RELA. This unexpected finding will be formally investigated in an ongoing Phase 3 study with RELA (GRACE Study, NCT03697109). A potential explanation for this finding could be tumor sensitization to endogenous (hypothalamic) somatostatin via upregulation of somatostatin receptors type 2 (SSTR2) which are downregulated in patients with hypercortisolism. If confirmed, this finding may potentially support the role of RELA as pre-operative medical treatment in patients with CD with invasive macroadenomas.