Clinical Therapeutics/Volume xxx, Number xxx, xxxx A New Sustained-Release, 3-Month Leuprolide Acetate Formulation Achieves and Maintains Castrate Concentrations of Testosterone in Patients With Prostate Cancer Neal D. Shore, MD1; Sílvia Guerrero, PhD2; Rosa Ma Sanahuja, MS2; Gemma Gambús, MD, PhD2; and Antonio Parente, PhD2 1Carolina Urologic Research Center, Myrtle Beach, South Carolina, Spain; and 2GP-Pharm S.A., Pol. Industrial Els Vinyets-Els Fogars, St. Quintí de Mediona, Barcelona, Spain ABSTRACT having testosterone levels 20 ng/dL. At study end, mean luteinizing hormone and follicle-stimulating Purpose: This clinical trial investigated the hormone concentrations had decreased from baseline effectiveness, pharmacokinetic properties, and safety to below the lower limit of quantitation and below profile of leuprolide acetate 22.5-mg depot, a new 3- baseline levels, respectively, whereas mean serum month leuprolide depot formulation, as androgen prostate-specific antigen was reduced by 94.7% from deprivation therapy for patients with prostate cancer. baseline. Most patients (>96%) had no change in Methods: A Phase III, open-label, multicenter study their World Health Organization/Eastern Cooperative design for patients with prostate cancer, with patient Oncology Group score, whereby 84.0% of patients inclusion assessed by the investigative site as patient's had a baseline score of 0. Bone pain, urinary pain, appropriate for androgen deprivation therapy. and urinary symptoms were infrequent and remained Patients received 2 separate intramuscular injections so throughout the study. After administration, of leuprolide acetate 22.5-mg depot for a 3-month leuprolide concentrations increased rapidly. The peak depot interval of therapeutic effect. Plasma was followed by a decline up to day 28, maintaining testosterone concentrations were determined sustained drug levels until the following dose on day throughout the study. The primary efficacy analysis 84. The most common related treatment-emergent was the percentage of patients who achieve and adverse events, detected in >5% of patients, were hot maintain castrate testosterone levels (50 ng/mL) flushes, fatigue, and injection site pain reported by from days 28e168. Secondary end points included 77.3%, 9.8%, and 9.2% of patients, respectively. luteinizing hormone, follicle-stimulating hormone, Implications: Leuprolide acetate 22.5-mg depot was prostate-specific antigen, and safety assessments. A effective in achieving and maintaining testosterone pharmacokinetic study was also conducted in a suppression. Safety and tolerability profiles were subset of 30 patients. consistent with established profiles of androgen Findings: All 163 patients enrolled in the study deprivation therapy. Clinical Trials.gov identifier: received at least 1 dose of study drug; 162 of them NCT01415960. (Clin Ther. xxxx;xxx:xxx) 2019 were fully evaluable and 151 completed the study. © Published by Elsevier Inc. Castrate levels of testosterone were achieved and Keywords: Androgen deprivation therapy, Efficacy, maintained from days 28e168 in 96.8% (95% CI, Leuprolide depot, Prostate cancer, Testosterone. 92.5%e98.7%) 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, Accepted for publication January 9, 2019 149 of 151 patients (98.7%) patients achieved https://doi.org/10.1016/j.clinthera.2019.01.004 castrate testosterone levels, with 142 of 151 (94.0%) 0149-2918/$ - see front matter © 2019 Published by Elsevier Inc. ▪▪▪ xxxx 1 Clinical Therapeutics INTRODUCTION Leuprolide acetate 22.5-mg depot is a unique 3- Prostate cancer has a worldwide incidence of 1.1 month, sustained-release formulation of million cases and represents a leading cause of cancer microencapsulated leuprolide acetate. Leuprolide specific mortality globally.1 Androgen deprivation acetate 22.5-mg depot presents a double control therapy (ADT) has been the mainstay treatment for sustained-release delivery system. This innovative advanced prostate cancer. Current options for approach consists of microspheres formed by a androgen deprivation are surgical castration (bilateral biodegradable polymer of polylactic acid and small orchiectomy) or administration of luteinizing quantities of triethyl citrate (TEC), obtained by a hormone (LH)ereleasing hormone (LHRH) agonists2 coacervation process. TEC, acting as a hydrophobic or antagonists.3 second barrier, controls the diffusion rate of LHRH analogues, which are synthetic analogues of leuprolide acetate entrapped inside a polymeric LHRH, have become the standard of care in the matrix throughout the microsphere. This formulation achievement of androgen suppressive therapy, differs from the 1-month formulation in the polymer including the potential use for intermittent ADT composition, which permits a prolonged leuprolide application, with the consideration for testosterone release. Leuprolide acetate 22.5-mg depot has been recovery, as well as the avoidance of the physical and approved in 26 European countries and more psychological morbidity associated with surgical recently in the United States. castration.4,5 On initiation of LHRH ADT, anterior This Phase III, open-label, multicenter clinical study pituitary LHRH receptors are stimulated (agonized), was performed to investigate the efficacy, thereby inducing a transient supraphysiologic pharmacokinetic properties, and safety profile of increase in LH and follicle-stimulating hormone leuprolide acetate 22.5-mg depot in suppressing (FSH), leading to the testosterone surge, which may testosterone levels in patients with prostate cancer. last from 3 to 7 days.6 However, on long-term The primary efficacy end point of the study was the LHRH agonist administration, there is resultant proportion of castrated patients (ie, testosterone desensitization of these receptors, resulting in down- levels 50 ng/dL) over the total number of the regulation and a subsequent suppression of serum intent-to-treat (ITT) patients at specific time points. LH, FSH, and testosterone.7,8 During US Food and Drug Administration (FDA) In addition to LHRH agonists providing the evaluation, reviewers requested efficacy results to be mainstay of treatment for advanced prostate cancer, presented according to their current standards for they may also serve an adjuvant role in patients with LHRH analogues approval (KaplaneMeier analysis), newly diagnosed prostate cancer. Indeed, in patients which ensure not only achievement but also with locally advanced or high-risk localized disease, maintenance of testosterone suppression throughout the addition of neoadjuvant and adjuvant hormone the study. Therefore, efficacy study results are therapy is now considered the standard of care for presented based on KaplaneMeier analysis. these men treated with radiation therapy.9,10 Leuprolide acetate is a synthetic nonapeptide LHRH PATIENTS AND METHODS analogue with increased duration of action and Study Design increased affinity for the pituitary receptor, the The efficacy of leuprolide acetate 22.5-mg depot targeted receptor for endocrine suppression of was evaluated in an open-label, multicenter, multiple- e androgen production.11 14 Various depot dose clinical trial. Patients with prostate cancer were formulations of leuprolide have been developed to administered leuprolide acetate 22.5-mg depot in 2 avoid issues associated with patient convenience and discrete doses separated during a 3-month interval. e to enhance patient adherence.15 20 A leuprolide The patients received the first intramuscular injection acetate 3.75-mg depot was previously developed as a of study drug initially at baseline (day 0) and the monthly sustained-release formulation of leuprolide. second dose at day 84. The duration of the study Its tolerability and efficacy were proven during a was 6 months. Plasma testosterone determinations Phase III clinical trial in patients with prostate were obtained in all patients at specific time points cancer.21 throughout the study as listed below. The 2 Volume xxx Number xxx N.D. Shore et al. pharmacokinetic profile of leuprolide was investigated reconstitution and administration of the study during the six 6 in a subset of 30 patients, involving product, a device (Mixject, Medimop Medical different US investigative sites. Projects Ltd, West Pharmaceutical Services, Exton, Pennsylvania), was used to connect the prefilled Patients syringe that contained the diluent (ie, 2 mL of 0.8% Patients with biopsy-proven carcinoma of the mannitol) with the vial that contained the study prostate, who in the judgment of the trial product, allowing a direct drug reconstitution and investigators could benefit from ADT, were enrolled subsequent intramuscular injection into the gluteal in the study at 25 US investigational sites. Study area, anterior thigh, or deltoid. eligible patients were >18 years old, had a World Health Organization (WHO)/Eastern Cooperative Study Procedures Oncology group (ECOG) score of 0, 1, or 2; had The screening visit was performed within 14 days of eugonadal testosterone levels at screening >150 ng/ the first study drug administration. Patients who dL; had adequate renal and hepatic function, a life met all eligibility criteria were offered study expectancy of at least 1 year, and no known enrollment. hypersensitivity to the active ingredient or excipients Blood samples for testosterone, LH, and FSH were of