Osilodrostat Therapy and 11C-methionine PET to IMprove Corticotroph Pituitary Adenoma Detection and Localisation in Patients With Cushing's Disease

BACKGROUND Cushing's disease is a rare endocrine disorder caused by the overproduction of adrenocorticotropic hormone (ACTH) from a corticotroph pituitary adenoma. It accounts for approximately 15% of all pituitary adenomas and has a female predominance (4:1). Cushing's disease is associated with increased mortality, substantial morbidity, and a notable impact on health-related quality of life. Diagnosis involves a variety of assessments, including demonstration of autonomous ACTH-driven hypercortisolaemia, inferior petrosal sinus sampling to exclude an ectopic source of ACTH production and MRI of the pituitary gland to identify a pathological pituitary adenoma.

Trans-sphenoidal surgical (TSS) resection of a pituitary adenoma remains the primary treatment. However, the surgical cure rate only ranges between 60% and 80% and therefore, repeated pituitary surgery, pituitary radiotherapy, or bilateral adrenalectomy are often required to achieve cure. Pre-operative medical (cortisol-lowering) therapy reduces both morbidity and perioperative complications. Both ketoconazole and metyrapone have been used as cortisol-lowering treatments, but effectiveness can be variable and adverse side effects are often significant necessitating dose reduction.

Osilodrostat, a potent inhibitor of the enzyme 11-beta-hydroxylase has been shown to be highly effective in normalising urinary free cortisol levels and achieving clinical remission in patients with Cushing's disease. The Phase III LINC-3 study investigated the efficacy and safety of osilodrostat in patients with Cushing's disease who were ineligible for pituitary surgery or had previously undergone unsuccessful pituitary surgery. The trial revealed that osilodrostat successfully normalised urinary free cortisol levels in a significant proportion of patients leading to improvements in clinical signs and symptoms of Cushing's disease. Importantly, the study reported a very favourable side effect and safety profile for Osilodrostat.

In Cushing's disease, dedicated pituitary MRI only identifies a suitable surgical target in 60% of cases. Recently, 11C-methionine PET/CT has emerged as a valuable additional tool for the localisation of pituitary lesions not clearly identified with conventional MRI. 11C-methionine is taken up by peptide-secreting cells via the L-type amino acid transporter 1 (LAT1), which is expressed in pituitary tissue, including pituitary adenomas. Functioning pituitary adenomas such as somatotroph adenomas, prolactinomas and, to a lesser extent, corticotroph adenomas, show increased uptake of 11C-methionine compared to normal pituitary tissue, and this can allow accurate localisation of small tumours that are not clearly visualised on anatomical imaging, as well as discriminate between post-surgical tissue re-modelling and residual tumour in patients who have undergone previous unsuccessful surgery.

Treatment with osilodrostat is associated with an increase in circulating ACTH levels, reflecting reduction in adrenal glucocorticoid biosynthesis by osilodrostat with consequent attenuation of negative feedback by cortisol at the level of the hypothalamus and pituitary, but also corticotroph pituitary adenomas, as corticotroph adenomas, albeit autonomously ACTH-producing, appear to retain a degree of feedback regulation. The investigators predict that the lack of negative feedback may lead to an increase in corticotroph tumour activity, thereby improving radiological detection of corticotroph tumours not seen on imaging prior to osilodrostat treatment.