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  • br ABSTRACT br Purpose This clinical

    2019-10-15


    ABSTRACT
    Purpose: 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. Methods: 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 Imipenem 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 28e168. 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.
    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 pain reported by 77.3%, 9.8%, and 9.2% of patients, respectively.
    Implications: Leuprolide acetate 22.5-mg depot was effective in achieving and maintaining testosterone suppression. Safety and tolerability profiles were consistent with established profiles of androgen deprivation therapy. Clinical Trials.gov identifier: NCT01415960. (Clin Ther. 2019;41:412e425) © 2019 Elsevier Inc. All rights reserved.
    Keywords: Androgen deprivation therapy, Efficacy, Leuprolide depot, Prostate cancer, Testosterone.
    INTRODUCTION
    Prostate cancer has a worldwide incidence of 1.1 million cases and represents a leading cause of cancer specific mortality globally.1 Androgen deprivation therapy (ADT) has been the mainstay treatment for advanced prostate cancer. Current options for androgen deprivation are surgical castration (bilateral orchiectomy) or administration of luteinizing hormone (LH)ereleasing hormone (LHRH) agonists2 or antagonists.3
    LHRH analogues, which are synthetic analogues of LHRH, have become the standard of care in the achievement of androgen suppressive therapy, including the potential use for intermittent ADT application, with the consideration for testosterone recovery, as well as the avoidance of the physical and psychological morbidity associated with surgical castration.4,5 On initiation of LHRH ADT, anterior pituitary LHRH receptors are stimulated (agonized), thereby inducing a transient supraphysiologic increase in LH and follicle-stimulating hormone (FSH), leading to the testosterone surge, which may last from 3 to 7 days.6 However, on long-term LHRH agonist administration, there is resultant desensitization of these receptors, resulting in down-regulation and a subsequent suppression of serum LH, FSH, and testosterone.7,8
    In addition to LHRH agonists providing the mainstay of treatment for advanced prostate cancer, they may also serve an adjuvant role in patients with newly diagnosed prostate cancer. Indeed, in patients with locally advanced or high-risk localized disease, the addition of neoadjuvant and adjuvant hormone therapy is now considered the standard of care for these men treated with radiation therapy.9,10