Treatment with pasireotide LAR normalizes prolactin levels in patients with acromegaly and hyperprolactinemia: randomized, double-blind, 12-month, phase III study

Abstract

Introduction: Around 20-30% of patients with acromegaly also have hyperprolactinemia, which is associated with infertility and gonadal/sexual dysfunction. Current therapy for these patients involves somatostatin analogues to treat GH/IGF-1 excess and a dopamine agonist to decrease prolactin levels. The objective of this analysis was to assess treatment with pasireotide LAR or octreotide LAR in patients with acromegaly and hyperprolactinemia. Methods: Patients with active acromegaly (GH >5 mug/L or GH nadir >1 mug/L post-OGTT, and IGF-1 >ULN) who were de novowith a visible adenoma on MRI or medically naive (no previous medical therapy but prior pituitary surgery) received pasireotide LAR 40 mg/28 days (n=176) or octreotide LAR 20 mg/28 days (n=182) for 12 months; dose titration (to pasireotide LAR 20 or 60 mg or to octreotide LAR 10 or 30 mg) was permitted. This analysis focuses on the efficacy and safety of pasireotide LAR and octreotide LAR in those patients with baseline hyperprolactinemia (prolactin above age- and sex-matched ULN). Results: Twenty-nine (16.5%) pasireotide LAR and 30 (16.5%) octreotide LAR patients had baseline hyperprolactinemia (mean prolactin levels 83.5 and 55.9 mug/L, respectively). After 12 months, 21/29 (72.4%; 95% CI 52.8, 87.3) pasireotide LAR and 17/30 (56.7%; 95% CI 37.4, 74.5) octreotide LAR patients had normalized prolactin levels; 3/29 (10.3%; 95% CI 2.2, 27.4) and 5/30 (16.7%; 95% CI 5.6, 34.7) had normal IGF-1 and GH <2.5 mug/L; 10/29 (34.5%) and 13/30 (43.3%) had GH <2.5 mug/L; while 7/29 (24.1%) and 8/30 (26.7%) had normal IGF-1, respectively. After 12 months, mean prolactin levels decreased by 60.4% and 39.6%, mean GH decreased by 71.1% and 67.6%, and mean standardized IGF-1 (x ULN) decreased by 41.1% and 39.6%, respectively, in the pasireotide LAR and octreotide LAR patients. Tumor volume decreased by ~40% in both treatment groups. Pasireotide LAR was well tolerated and most adverse events were mild or moderate in nature; hyperglycemia-related adverse events were more common with pasireotide LAR than octreotide LAR. Conclusions: In this subset of patients with baseline hyperprolactinemia, pasireotide LAR and octreotide LAR normalized prolactin levels in >70% and ~55% of patients, respectively, normalizing IGF-1 in ~25% and reducing GH levels to <2.5 mug/L in ~35% and ~44% of patients. The observed decrease in tumor volume may be particularly important in patients with hyperprolactinemia caused by compression of the pituitary stalk. Pasireotide LAR and octreotide LAR may be effective treatments for patients with a GH- and prolactin-secreting pituitary adenoma.