Effectiveness, Pharmacokinetics, and Safety of a New Sustained-Release Leuprolide Acetate 3.75-mg Depot Formulation for Testosterone Suppression in Patients With Prostate Cancer: A Phase III, Open-Label, International Multicenter Study

Background: A microencapsulated, sustained-release formulation of leuprolide acetate 3.75 mg has been developed. Objective: This study investigated the effectiveness, pharmacokinetics, and safety profile of a 1-month leuprolide acetate 3.75-mg depot formulation for suppressing testosterone concentrations in patients with prostate cancer. Methods: This was a Phase HI, open-label, international multicenter clinical trial. Patients with prostate dancer who, in the judgment of the investigators, could benefit from androgen deprivation therapy received 6 monthly intramuscular injections of leuprolide acetate 3.75-mg depot. Plasma testosterone concentrations were determined at specific times throughout the study. The primary end point was the proportion of successful patients over the total number of evaluable patients (ie, patients with evaluable testosterone concentrations at all monthly assessments and no missing values due to treatment-related adverse events). Treatment success was defined as testosterone suppression below the clinical castration level (ie, <= 0.5 ng/mL) at day 28 and maintenance of clinical castration until study completion (day 168). The frequency of patients with testosterone concentrations <= 0.2 ng/mL was also studied. Results: The study included 160 patients with a mean (SD) age of 71.6 (9.2) years, weight of 83.7 (15.5) kg, and predominantly white race (87.5% [140/160]). All 160 patients received at least one dose of study drug; 157 of them were fully evaluable, and 152 completed the study. The proportion of successful patients over the total number of evaluable patients was 96.8% (152/157; 95% CI, 92.7%-99.0%). Five of the 157 evaluable patients (3.2%) did not achieve the primary end point of testosterone concentration 0.5 ng/mL by day 28. Of the evaluable patients, 78.7% (122/155) achieved testosterone suppression by day 21. By day 28, 96.8% (151/156) of the evaluable patients had achieved castrate levels, and 73.1% (114/156) achieved testosterone concentrations <= 0.2 ng/mL. At study end, 100% (152/152) of the patients completing the study maintained castrate levels, and 92.8% (141/152) had testosterone concentrations <= 0.2 ng/mL. The pharmacokinetic profile of leuprolide during the first 3 months of treatment, evaluated in a subset of the study population (n = 12), showed sustained release of leuprolide from the formulation. Values for AUC(0-t), calculated from day 0 to day 28, days 28 to 56, and days 56 to 84 were 25,976.5 (7892.0), 30,685.5 (9348.4), and 31,030.9 (10,745.0) pg/mL per day, respectively. The most common treatment-related adverse event was hot flashes (45.0% [72/160]). Fatigue, hyperhidrosis, night sweats, and headache each occurred in <= 6.3% (10/160) of the patients. The most frequently reported local adverse reaction was pain at the injection site, experienced by 8.1% (13/160) of the patients. Conclusions: Leuprolide acetate 3.75-mg depot was effective in achieving and maintaining testosterone suppression and was well tolerated throughout the study in this cohort of patients with prostate cancer. ClinicalTrials.gov identifier: NCT00128531. (Clin Ther. 2010;32:744-757) (C) 2010 Excerpta Medica Inc.