A New Sustained-release, 3-Month Leuprolide Acetate Formulation Achieves and Maintains Castrate Concentrations of Testosterone in Patients With Prostate Cancer

• Published in: Clinical therapeutics 2019-03, Vol.41 (3), p.412-425
• Main Authors: Shore, Neal D., Guerrero, Sílvia, Sanahuja, Rosa Ma, Gambús, Gemma, Parente, Antonio
• Format: Article
• Language: English
• Subjects: Acetic acid; Aged; Aged, 80 and over; Androgen deprivation therapy; Androgens; Antineoplastic Agents, Hormonal - administration & dosage; Antineoplastic Agents, Hormonal - adverse effects; Antineoplastic Agents, Hormonal - pharmacokinetics; Cancer; Cancer therapies; Clinical trials; Controlled release; Delayed-Action Preparations - administration & dosage; Delayed-Action Preparations - adverse effects; Delayed-Action Preparations - pharmacokinetics; Deprivation; Dictionaries; Drug dosages; Efficacy; FDA approval; Follicle Stimulating Hormone - blood; Follicle-stimulating hormone; Humans; Kallikreins - blood; Leuprolide - administration & dosage; Leuprolide - adverse effects; Leuprolide - pharmacokinetics; Leuprolide depot; Luteinizing hormone; Luteinizing Hormone - blood; Male; Medical research; Middle Aged; Oncology; Pain; Patients; Pharmacology; Polymers; Population; Prostate cancer; Prostate-specific antigen; Prostate-Specific Antigen - blood; Prostatic Neoplasms - blood; Prostatic Neoplasms - drug therapy; Quantitation; Safety; Signs and symptoms; Substance abuse treatment; Testosterone; Testosterone - blood; Therapy; Urology
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2019.01.004

This clinical trial investigated the effectiveness, pharmacokinetic properties, and safety profile of leuprolide acetate 22.5-mg depot, a new 3-month leuprolide depot formulation, as androgen deprivation therapy for patients with prostate cancer. A Phase III, open-label, multicenter study design for patients with prostate cancer, with patient inclusion assessed by the investigative site as patient's appropriate for androgen deprivation therapy. Patients received 2 separate intramuscular injections of leuprolide acetate 22.5-mg depot for a 3-month depot interval of therapeutic effect. Plasma testosterone concentrations were determined throughout the study. The primary efficacy analysis was the percentage of patients who achieve and maintain castrate testosterone levels (≤50 ng/mL) from days 28–168. Secondary end points included luteinizing hormone, follicle-stimulating hormone, prostate-specific antigen, and safety assessments. A pharmacokinetic study was also conducted in a subset of 30 patients. All 163 patients enrolled in the study received at least 1 dose of study drug; 162 of them were fully evaluable and 151 completed the study. Castrate levels of testosterone were achieved and maintained from days 28–168 in 96.8% (95% CI, 92.5%–98.7%) of patients. Five patients presented with sporadic testosterone levels >50 ng/dL. By day 28, of the 161 patients, 150 (99.4%) had achieved castrate levels, and 127 (78.9%) had achieved testosterone concentrations ≤20 ng/dL. At study end, 149 of 151 patients (98.7%) patients achieved castrate testosterone levels, with 142 of 151 (94.0%) having testosterone levels ≤20 ng/dL. At study end, mean luteinizing hormone and follicle-stimulating hormone concentrations had decreased from baseline to below the lower limit of quantitation and below baseline levels, respectively, whereas mean serum prostate-specific antigen was reduced by 94.7% from baseline. Most patients (>96%) had no change in their World Health Organization/Eastern Cooperative Oncology Group score, whereby 84.0% of patients had a baseline score of 0. Bone pain, urinary pain, and urinary symptoms were infrequent and remained so throughout the study. After administration, leuprolide concentrations increased rapidly. The peak was followed by a decline up to day 28, maintaining sustained drug levels until the following dose on day 84. The most common related treatment-emergent adverse events, detected in >5% of patients, were hot flushes, fatigue, and injection site