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Boeric Persson - One of the best experts on this subject based on the ideXlab platform.

  • overall survival of patients with metastatic prostate cancer starting androgen deprivation therapy with Degarelix a gonadotropin releasing hormone antagonist
    Journal of Clinical Oncology, 2018
    Co-Authors: Stephen J Freedland, P Sorensen, Boeric Persson
    Abstract:

    198Background: Morbidity and mortality amongst patients diagnosed with metastatic prostate cancer remains high and androgen deprivation therapy is the mainstay of hormonal treatments for these patients. The gonadotropin-releasing hormone (GnRH) antagonist, Degarelix, has a fast and profound onset of action and compares favorably with GnRH agonists in terms of progression-free survival (PFS) and overall survival during the first year of treatment. It is of interest to assess longer term survival data in patients with very advanced disease. Methods: Data from several studies of patients treated with Degarelix are available for descriptive analysis from a study repository. We analyzed data from patients with metastatic disease and prostate-specific antigen (PSA) > 50 ng/mL treated with Degarelix from 17 controlled and uncontrolled trials for overall survival and PFS. Possible selection bias over time was also estimated. Results: Overall, 519 patients with metastatic disease and PSA > 50 ng/mL were included; ...

  • Degarelix monotherapy compared with luteinizing hormone releasing hormone lhrh agonists plus anti androgen flare protection in advanced prostate cancer an analysis of two randomized controlled trials
    Therapeutic Advances in Urology, 2016
    Co-Authors: Peter Iversen, Anders Malmberg, Jan-erik Damber, Boeric Persson, Laurence Klotz
    Abstract:

    Objectives:The objective of this study was to assess differences in efficacy outcomes between luteinizing hormone-releasing hormone (LHRH) agonist plus antiandrogen (AA) flare protection and monotherapy with the gonadotrophin-releasing hormone antagonist Degarelix in patients with prostate cancer.Methods:Data from 1455 patients were pooled from two prospective, phase III randomized 1-year clinical trials of Degarelix versus LHRH agonist with or without AA. The AA bicalutamide was administered at the investigator’s discretion. Adjusted hazard ratios (HRs) were calculated using a Cox proportional hazards regression model and a conditional logistic regression model was used for a case-control analysis of odds ratios (ORs).Results:Patients received Degarelix monotherapy (n = 972) or LHRH agonist (n = 483) of whom 57 also received AA. Overall, prostate-specific antigen progression-free survival (PSA PFS) was improved with Degarelix versus LHRH agonist + AA (Cox proportional hazards regression model-adjusted HR...

  • efficacy of Degarelix in prostate cancer patients following failure on luteinizing hormone releasing hormone agonist treatment results from an open label multicentre uncontrolled phase ii trial cs27
    Therapeutic Advances in Urology, 2015
    Co-Authors: Kurt Miller, Gabriele Simson, Sandra Goble, Boeric Persson
    Abstract:

    Objective:To evaluate the efficacy of second-line Degarelix in patients with prostate cancer (PCa) after treatment failure with a luteinizing hormone-releasing hormone (LHRH) agonist.Methods:This 1-year exploratory, multicentre, open-label phase II trial was performed in 2 patient cohorts (Cohort 1, n = 25; Cohort 2, n = 12) in Germany. Patients with castrate-resistant PCa after primary hormonal treatment received Degarelix 240 mg, followed by 11 monthly maintenance doses of 80 mg. The primary endpoint was the proportion of patients with decreasing/stable prostate-specific antigen (PSA) (relative change ⩽+10% of baseline PSA) after 3 months.Results:At Month 3, the response rate (intention-to-treat, last observation carried forward analysis) was 16.7% [95% confidence interval (CI): 4.74–37.38] in Cohort 1 and 33.3% (95% CI: 9.92–65.11) in Cohort 2. The probability of completing 12 months without PSA progression was 8.8% (95% CI: 1.51–24.3) in Cohort 1 and 8.3% (95% CI: 0.5–31.1) in Cohort 2. Degarelix was ...

  • Efficacy of Degarelix in prostate cancer patients following failure on luteinizing hormone-releasing hormone agonist treatment: results from an open-label, multicentre, uncontrolled, phase II trial (CS27)
    'SAGE Publications', 2015
    Co-Authors: Kurt Miller, Gabriele Simson, Sandra Goble, Boeric Persson
    Abstract:

    Objective: To evaluate the efficacy of second-line Degarelix in patients with prostate cancer (PCa) after treatment failure with a luteinizing hormone-releasing hormone (LHRH) agonist. Methods: This 1-year exploratory, multicentre, open-label phase II trial was performed in 2 patient cohorts (Cohort 1, n = 25; Cohort 2, n = 12) in Germany. Patients with castrate-resistant PCa after primary hormonal treatment received Degarelix 240 mg, followed by 11 monthly maintenance doses of 80 mg. The primary endpoint was the proportion of patients with decreasing/stable prostate-specific antigen (PSA) (relative change ⩽+10% of baseline PSA) after 3 months. Results: At Month 3, the response rate (intention-to-treat, last observation carried forward analysis) was 16.7% [95% confidence interval (CI): 4.74–37.38] in Cohort 1 and 33.3% (95% CI: 9.92–65.11) in Cohort 2. The probability of completing 12 months without PSA progression was 8.8% (95% CI: 1.51–24.3) in Cohort 1 and 8.3% (95% CI: 0.5–31.1) in Cohort 2. Degarelix was well tolerated; the most frequently reported adverse events were local injection-site reactions. Conclusions: In PCa patients who failed LHRH therapy, Degarelix was well tolerated and achieved a limited PSA response. Phase III trials show that disease control benefits with Degarelix versus agonists are more clearly demonstrated as first-line therapy

  • disease control outcomes from analysis of pooled individual patient data from five comparative randomised clinical trials of Degarelix versus luteinising hormone releasing hormone agonists
    European Urology, 2014
    Co-Authors: Laurence Klotz, Anders Malmberg, Neal D Shore, Bertrand Tombal, Kurt Miller, David E Crawford, Cathrina Karup, Boeric Persson
    Abstract:

    BACKGROUND: Studies comparing the gonadotropin-releasing hormone antagonist, Degarelix, with luteinising hormone-releasing hormone (LHRH) agonists indicate differences in outcomes. OBJECTIVE: To assess differences in efficacy and safety outcomes in a pooled analysis of trials comparing Degarelix with LHRH agonists. DESIGN, SETTING, AND PARTICIPANTS: Data were pooled from five prospective, phase 3 or 3b randomised trials (n=1925) of Degarelix and leuprolide or goserelin in men requiring androgen deprivation therapy for the treatment of prostate cancer. Patients received either 3 mo (n=467) or 12 mo (n=1458) of treatment. INTERVENTION: Men were randomised to receive Degarelix (n=1266), leuprolide (n=201), or goserelin (n=458). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Unadjusted Kaplan-Meier analyses were supported by the Cox proportional hazards model, adjusted for disease-related baseline factors, to estimate hazard ratios (HRs) of efficacy and safety outcomes. The Fisher exact test compared crude incidences of adverse events. RESULTS AND LIMITATIONS: Prostate-specific antigen (PSA) progression-free survival (PFS) was improved in the Degarelix group (HR: 0.71; p=0.017). For patients with baseline PSA levels >20 ng/ml, the HR for PSA PFS was 0.74 (p=0.052). Overall survival (OS) was higher in the Degarelix group (HR: 0.47; p=0.023). OS was particularly improved with Degarelix in patients with baseline testosterone levels >2 ng/ml (HR: 0.36; p=0.006). In terms of disease-related adverse events, there were, overall, fewer joint-related signs and symptoms, musculoskeletal events, and urinary tract events in the Degarelix group. CONCLUSIONS: These data indicate clinical benefits with Degarelix, including a significant improvement in PSA PFS and OS, as well as reduced incidence of joint, musculoskeletal, and urinary tract adverse events, compared with LHRH agonists.

Laurence Klotz - One of the best experts on this subject based on the ideXlab platform.

  • Degarelix monotherapy compared with luteinizing hormone releasing hormone lhrh agonists plus anti androgen flare protection in advanced prostate cancer an analysis of two randomized controlled trials
    Therapeutic Advances in Urology, 2016
    Co-Authors: Peter Iversen, Anders Malmberg, Jan-erik Damber, Boeric Persson, Laurence Klotz
    Abstract:

    Objectives:The objective of this study was to assess differences in efficacy outcomes between luteinizing hormone-releasing hormone (LHRH) agonist plus antiandrogen (AA) flare protection and monotherapy with the gonadotrophin-releasing hormone antagonist Degarelix in patients with prostate cancer.Methods:Data from 1455 patients were pooled from two prospective, phase III randomized 1-year clinical trials of Degarelix versus LHRH agonist with or without AA. The AA bicalutamide was administered at the investigator’s discretion. Adjusted hazard ratios (HRs) were calculated using a Cox proportional hazards regression model and a conditional logistic regression model was used for a case-control analysis of odds ratios (ORs).Results:Patients received Degarelix monotherapy (n = 972) or LHRH agonist (n = 483) of whom 57 also received AA. Overall, prostate-specific antigen progression-free survival (PSA PFS) was improved with Degarelix versus LHRH agonist + AA (Cox proportional hazards regression model-adjusted HR...

  • pharmacokinetic and pharmacodynamic profile of Degarelix for prostate cancer
    Expert Opinion on Drug Metabolism & Toxicology, 2015
    Co-Authors: Laurence Klotz
    Abstract:

    Introduction: Luteinizing hormone-releasing hormone (LHRH) agonists have been the mainstay of androgen deprivation therapy (ADT) for advanced prostate cancer for over two decades. However, their limitations include a transient initial rise in testosterone, failure to reduce testosterone to castrate levels in some patients, incomplete suppression of follicle-stimulating hormone (FSH), and an increased risk of cardiovascular (CV) events in those with pre-existing CV disease. This article considers whether the LHRH antagonist Degarelix offers significant advantages over LHRH agonists.Areas covered: This review covers the development and introduction of Degarelix, its pharmacodynamic and pharmacokinetic properties, and the efficacy and safety results of Phase II and III clinical studies.Expert opinion: Degarelix has clear pharmacodynamic advantages over the LHRH agonist leuprolide in terms of almost immediate suppression of testosterone to castrate levels and sustained suppression of FSH levels. It reduces th...

  • risk of cardiovascular events with Degarelix versus leuprolide after biochemical relapse of prostate cancer exploratory analysis of a randomized controlled trial
    Journal of Clinical Oncology, 2015
    Co-Authors: Celestia S Higano, Zsolt Bosnyak, Anders Malmberg, Anders Neijber, Neal D Shore, David E Crawford, Laurence Klotz
    Abstract:

    151 Background: Androgen deprivation therapy (ADT) has been associated with increased cardiovascular (CV) risk in men. A pooled analysis of phase 3 trials comparing LHRH agonists with Degarelix in PCa patients indicated a lower risk of CV events or death in those treated with Degarelix. We now report the incidence of non-fatal CV events in men with PCa and pre-existing CV disease (CVD) treated with Degarelix or leuprolide in the CS37 trial. Methods: CS37 was a prospective, randomized trial comparing intermittent (n=175) and continuous (n=50) Degarelix with continuous leuprolide (n=178) in patients with biochemical relapse of PCa in the United States. CV events were retrospectively analyzed up to Month 12 (intermittent arm events censored at Month 7). Cox regression models were used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI). Results: 143 men (35%) had pre-existing CVD at baseline; 88 treated with Degarelix and 55 treated with leuprolide. For Degarelix and leuprolide treatmen...

  • disease control outcomes from analysis of pooled individual patient data from five comparative randomised clinical trials of Degarelix versus luteinising hormone releasing hormone agonists
    European Urology, 2014
    Co-Authors: Laurence Klotz, Anders Malmberg, Neal D Shore, Bertrand Tombal, Kurt Miller, David E Crawford, Cathrina Karup, Boeric Persson
    Abstract:

    BACKGROUND: Studies comparing the gonadotropin-releasing hormone antagonist, Degarelix, with luteinising hormone-releasing hormone (LHRH) agonists indicate differences in outcomes. OBJECTIVE: To assess differences in efficacy and safety outcomes in a pooled analysis of trials comparing Degarelix with LHRH agonists. DESIGN, SETTING, AND PARTICIPANTS: Data were pooled from five prospective, phase 3 or 3b randomised trials (n=1925) of Degarelix and leuprolide or goserelin in men requiring androgen deprivation therapy for the treatment of prostate cancer. Patients received either 3 mo (n=467) or 12 mo (n=1458) of treatment. INTERVENTION: Men were randomised to receive Degarelix (n=1266), leuprolide (n=201), or goserelin (n=458). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Unadjusted Kaplan-Meier analyses were supported by the Cox proportional hazards model, adjusted for disease-related baseline factors, to estimate hazard ratios (HRs) of efficacy and safety outcomes. The Fisher exact test compared crude incidences of adverse events. RESULTS AND LIMITATIONS: Prostate-specific antigen (PSA) progression-free survival (PFS) was improved in the Degarelix group (HR: 0.71; p=0.017). For patients with baseline PSA levels >20 ng/ml, the HR for PSA PFS was 0.74 (p=0.052). Overall survival (OS) was higher in the Degarelix group (HR: 0.47; p=0.023). OS was particularly improved with Degarelix in patients with baseline testosterone levels >2 ng/ml (HR: 0.36; p=0.006). In terms of disease-related adverse events, there were, overall, fewer joint-related signs and symptoms, musculoskeletal events, and urinary tract events in the Degarelix group. CONCLUSIONS: These data indicate clinical benefits with Degarelix, including a significant improvement in PSA PFS and OS, as well as reduced incidence of joint, musculoskeletal, and urinary tract adverse events, compared with LHRH agonists.

  • gnrh antagonist associates with less adiposity and reduced characteristics of metabolic syndrome and atherosclerosis compared with orchiectomy and gnrh agonist in a preclinical mouse model
    Urologic Oncology-seminars and Original Investigations, 2014
    Co-Authors: Sarah N. Hopmans, Geoff H. Werstuck, Wilhelmina C. M. Duivenvoorden, Laurence Klotz, Jehonathan H. Pinthus
    Abstract:

    Abstract Objectives Observational studies relate androgen deprivation therapy (ADT) to metabolic syndrome (MS) and cardiovascular disease, an association potentially subject to uncontrollable confounding factors, especially diet and genetic/metabolic risk factors. In the absence of prospective randomized clinical trials, causality remains unproven. We comparatively investigated the effects of different ADT modalities on the development of MS and atherosclerosis in a mouse model. Materials and methods Low-density lipoprotein receptor knockout mice underwent orchiectomy plus vehicle (2.5% mannitol), sham surgery plus vehicle (control), sham surgery plus gonadotropin-releasing hormone (GnRH) antagonist (Degarelix), or sham surgery plus GnRH agonist (leuprolide) (n = 9–13/group) and were followed for 4 months. Visceral fat accumulation, lean body mass, adipocyte size, fasting blood glucose, glucose tolerance, serum levels of leptin, follicle-stimulating hormone, luteinizing hormone, and testosterone, along with atherosclerotic plaque size and characteristics were measured. Results All 3 modes of ADT decreased circulating testosterone levels in mice, although leuprolide treatment reached nadir levels of testosterone later. Orchiectomized and leuprolide-treated mice gained significantly more visceral fat compared with Degarelix-treated mice. Improved glucose tolerance tests were recorded in Degarelix-treated mice. The aortic atherosclerotic plaque area in leuprolide-treated and orchiectomized mice was larger than in control mice (P Conclusions Our results suggest that ADT induced MS and atherosclerosis in a preclinical mouse model to a mode-specific extent. GnRH antagonist generated the least atherosclerosis and characteristics of MS compared with orchiectomy and GnRH agonist.

Anders Malmberg - One of the best experts on this subject based on the ideXlab platform.

  • effect of Degarelix a gonadotropin releasing hormone receptor antagonist for the treatment of prostate cancer on cardiac repolarisation in a randomised placebo and active comparator controlled thorough qt qtc trial in healthy men
    Clinical Drug Investigation, 2017
    Co-Authors: Hakan Olsson, Anders Malmberg, Niclas Petri, Lars Erichsen, Lars Grundemar
    Abstract:

    Degarelix is a gonadotropin-releasing hormone antagonist registered for the treatment of advanced hormone-dependent prostate cancer. Treatment causing androgen deprivation is associated with QT prolongation and this study investigated whether Degarelix at supratherapeutic concentrations has an intrinsic effect per se on cardiac repolarisation and the QT interval. This was a single-centre, randomised, crossover study comparing the effect of Degarelix, placebo, and the positive control moxifloxacin on the QT interval. Degarelix and placebo treatments were double-blind, whereas moxifloxacin treatment was open-label. Eighty healthy men, aged 18–45 years, received single intravenous doses of Degarelix 2.8 mg, and placebo, as well as a single oral dose of moxifloxacin 400 mg. Electrocardiograms were collected up to 24 h after the start of administration, with the QT interval assessed and plasma concentrations of Degarelix concomitantly analysed. Time-matched, one-sided 95% upper confidence boundaries for baseline-corrected average changes from placebo for the QT interval, corrected using the Fridericia method (ΔΔQTcF), did not exceed 10 ms at any timepoint, with maximum Degarelix concentrations reaching approximately threefold the concentrations seen in the treatment of prostate cancer. Furthermore, concentration-exposure analysis indicated absence of any QT prolongation effects of Degarelix. No significant effect on any other cardiac parameter was observed. The lower bound of the 98.3% confidence interval for moxifloxacin ΔΔQTcF exceeded 5 ms, thus verifying assay sensitivity. The results showed that the study was validated to detect a significant effect on the QT interval, and that Degarelix by itself does not have any effect on the QT interval and cardiac repolarisation at supratherapeutic concentrations.

  • Degarelix versus goserelin plus bicalutamide in the short term relief of lower urinary tract symptoms in prostate cancer patients results of a pooled analysis
    Luts: Lower Urinary Tract Symptoms, 2017
    Co-Authors: Malcolm David Mason, Zsolt Bosnyak, Anders Malmberg, Pierre Richaud, Anders Neijber
    Abstract:

    Objective In patients with prostate cancer (PCa), prostate enlargement may give rise to lower urinary tract symptoms (LUTS); many patients suffer from moderate-to-severe symptoms. We compare the efficacy of Degarelix and goserelin plus bicalutamide in improving LUTS in PCa patients. Methods Data were pooled from three Phase 3, randomized clinical trials of once-monthly treatment for 12 weeks with Degarelix (240/80 mg; n = 289) or goserelin (3.6 mg) plus bicalutamide (50 mg; n = 174) for initial flare protection. LUTS at weeks 4, 8, and 12 were compared to baseline. Clinically relevant LUTS relief was a ≥3-point International Prostate Symptom Score (IPSS) decrease. Adverse events were assessed throughout the trials. Results Patients receiving Degarelix had significantly greater decreases in IPSS vs. goserelin at week 12 (adjusted difference: −1.24; 95% CI −2.33 to −0.14, P = 0.03). Clinically relevant LUTS relief with Degarelix was especially pronounced in patients with moderate-to-severe LUTS (baseline IPSS ≥13) (odds ratio; OR 2.31; 95% CI 1.19–4.47, P = 0.01) and advanced PCa (OR 2.36; 95% CI 1.10–5.04, P = 0.03). A twofold higher OR for early (week 4) LUTS relief was seen with Degarelix vs. goserelin (OR 2.03; 95% CI 1.14–3.60, P = 0.02). No difference in total prostate volume or urinary tract infection-related adverse events (2%) was seen between treatment groups. Conclusion An early, significant and clinically more pronounced improvement of LUTS, especially in patients with moderate-to-severe LUTS or advanced PCa, was seen with Degarelix vs. goserelin plus bicalutamide.

  • Degarelix monotherapy compared with luteinizing hormone releasing hormone lhrh agonists plus anti androgen flare protection in advanced prostate cancer an analysis of two randomized controlled trials
    Therapeutic Advances in Urology, 2016
    Co-Authors: Peter Iversen, Anders Malmberg, Jan-erik Damber, Boeric Persson, Laurence Klotz
    Abstract:

    Objectives:The objective of this study was to assess differences in efficacy outcomes between luteinizing hormone-releasing hormone (LHRH) agonist plus antiandrogen (AA) flare protection and monotherapy with the gonadotrophin-releasing hormone antagonist Degarelix in patients with prostate cancer.Methods:Data from 1455 patients were pooled from two prospective, phase III randomized 1-year clinical trials of Degarelix versus LHRH agonist with or without AA. The AA bicalutamide was administered at the investigator’s discretion. Adjusted hazard ratios (HRs) were calculated using a Cox proportional hazards regression model and a conditional logistic regression model was used for a case-control analysis of odds ratios (ORs).Results:Patients received Degarelix monotherapy (n = 972) or LHRH agonist (n = 483) of whom 57 also received AA. Overall, prostate-specific antigen progression-free survival (PSA PFS) was improved with Degarelix versus LHRH agonist + AA (Cox proportional hazards regression model-adjusted HR...

  • risk of cardiovascular events with Degarelix versus leuprolide after biochemical relapse of prostate cancer exploratory analysis of a randomized controlled trial
    Journal of Clinical Oncology, 2015
    Co-Authors: Celestia S Higano, Zsolt Bosnyak, Anders Malmberg, Anders Neijber, Neal D Shore, David E Crawford, Laurence Klotz
    Abstract:

    151 Background: Androgen deprivation therapy (ADT) has been associated with increased cardiovascular (CV) risk in men. A pooled analysis of phase 3 trials comparing LHRH agonists with Degarelix in PCa patients indicated a lower risk of CV events or death in those treated with Degarelix. We now report the incidence of non-fatal CV events in men with PCa and pre-existing CV disease (CVD) treated with Degarelix or leuprolide in the CS37 trial. Methods: CS37 was a prospective, randomized trial comparing intermittent (n=175) and continuous (n=50) Degarelix with continuous leuprolide (n=178) in patients with biochemical relapse of PCa in the United States. CV events were retrospectively analyzed up to Month 12 (intermittent arm events censored at Month 7). Cox regression models were used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI). Results: 143 men (35%) had pre-existing CVD at baseline; 88 treated with Degarelix and 55 treated with leuprolide. For Degarelix and leuprolide treatmen...

  • disease control outcomes from analysis of pooled individual patient data from five comparative randomised clinical trials of Degarelix versus luteinising hormone releasing hormone agonists
    European Urology, 2014
    Co-Authors: Laurence Klotz, Anders Malmberg, Neal D Shore, Bertrand Tombal, Kurt Miller, David E Crawford, Cathrina Karup, Boeric Persson
    Abstract:

    BACKGROUND: Studies comparing the gonadotropin-releasing hormone antagonist, Degarelix, with luteinising hormone-releasing hormone (LHRH) agonists indicate differences in outcomes. OBJECTIVE: To assess differences in efficacy and safety outcomes in a pooled analysis of trials comparing Degarelix with LHRH agonists. DESIGN, SETTING, AND PARTICIPANTS: Data were pooled from five prospective, phase 3 or 3b randomised trials (n=1925) of Degarelix and leuprolide or goserelin in men requiring androgen deprivation therapy for the treatment of prostate cancer. Patients received either 3 mo (n=467) or 12 mo (n=1458) of treatment. INTERVENTION: Men were randomised to receive Degarelix (n=1266), leuprolide (n=201), or goserelin (n=458). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Unadjusted Kaplan-Meier analyses were supported by the Cox proportional hazards model, adjusted for disease-related baseline factors, to estimate hazard ratios (HRs) of efficacy and safety outcomes. The Fisher exact test compared crude incidences of adverse events. RESULTS AND LIMITATIONS: Prostate-specific antigen (PSA) progression-free survival (PFS) was improved in the Degarelix group (HR: 0.71; p=0.017). For patients with baseline PSA levels >20 ng/ml, the HR for PSA PFS was 0.74 (p=0.052). Overall survival (OS) was higher in the Degarelix group (HR: 0.47; p=0.023). OS was particularly improved with Degarelix in patients with baseline testosterone levels >2 ng/ml (HR: 0.36; p=0.006). In terms of disease-related adverse events, there were, overall, fewer joint-related signs and symptoms, musculoskeletal events, and urinary tract events in the Degarelix group. CONCLUSIONS: These data indicate clinical benefits with Degarelix, including a significant improvement in PSA PFS and OS, as well as reduced incidence of joint, musculoskeletal, and urinary tract adverse events, compared with LHRH agonists.

Laurent Boccongibod - One of the best experts on this subject based on the ideXlab platform.

  • Degarelix as an intermittent androgen deprivation therapy for one or more treatment cycles in patients with prostate cancer
    European Urology, 2014
    Co-Authors: Laurent Boccongibod, Anders Malmberg, Anders Neijber, Hendrik Van Poppel, Jean J M C H De La Rosette, Peter Albers, Juan Morote, Arnauld Villers, Francesco Montorsi
    Abstract:

    Abstract Background Guidelines for prostate cancer treatment suggest that intermittent androgen deprivation (IAD) can be considered for certain patients. Objective To evaluate the efficacy and safety of Degarelix as IAD for one or more treatment cycle(s) in prostate cancer patients requiring androgen deprivation. Design, setting, and participants This open-label uncontrolled multicenter study included patients with prostate-specific antigen (PSA) >4 to 50 ng/ml or PSA doubling time 4 ng/ml. Intervention Each induction period included a starting dose of Degarelix 240mg, and thereafter 80mg once a month for 6 mo, followed by off-treatment periods. Outcome measurements and statistical analysis The primary end point was time to PSA >4 ng/ml. Secondary end points were subgroup analysis of the primary end point, time to testosterone >0.5 and >2.2 ng/ml, quality of life (QoL), and sexual function during the first off-treatment period. Results and limitations Of 213 patients in the first induction period, 191 entered the first off-treatment period, 35 patients entered the second induction, and 30 entered the second off-treatment period. Only two patients entered the third cycle. Median time to PSA >4 ng/ml and duration of first off-treatment period was 392 d each. Significant differences in time to PSA >4 ng/ml were observed between subgroups stratified by prognostic factors (previous curative treatment, cancer stage, PSA levels, and Gleason scores). Time to testosterone >0.5 and >2.2 ng/ml was 112 and 168 d, respectively. Change in QoL remained nonsignificant, and sexual function gradually improved during the off-treatment period. Adverse events were fewer during the off-treatment period and subsequent treatment cycles. Conclusions IAD with Degarelix resulted in an improvement in sexual function commensurate with increased testosterone levels while PSA remained suppressed. The treatment for one treatment cycle or more was well tolerated. Patient summary Guidelines for prostate cancer treatment suggest that intermittent androgen deprivation (IAD) can be considered for certain patients. IAD with Degarelix resulted in improved sexual function commensurate with increased testosterone levels while prostate-specific antigen remained suppressed. The treatment for one treatment cycle or more was well tolerated. Trial registration Clinicaltrials.gov identifier NCT00801242.

  • long term tolerability and efficacy of Degarelix 5 year results from a phase iii extension trial with a 1 arm crossover from leuprolide to Degarelix
    Urology, 2014
    Co-Authors: David E Crawford, Anders Malmberg, Neal D Shore, Fritz H Schroder, Bertrand Tombal, Kurt Miller, Laurent Boccongibod, Judd W Moul, Tine Kold Olesen, Boeric Persson
    Abstract:

    OBJECTIVE: To demonstrate the safety and efficacy of up to 5 years of Degarelix treatment and the effects of crossing over from leuprolide to Degarelix in the extension phase of a phase III pivotal 1-year trial. METHODS: Patients receiving Degarelix who completed the 1-year trial continued on 80 mg (n = 125) or 160 mg (n = 126) maintenance doses. Patients who received leuprolide were rerandomized to Degarelix 240/80 mg (n = 69) or 240/160 mg (n = 65). Safety and tolerability were assessed (primary end point), as well as testosterone and prostate-specific antigen levels and prostate-specific antigen progression-free survival (secondary end points). RESULTS: Adverse event frequency was similar between both the groups. Adverse events included initial injection site reactions, hot flushes, and increased weight. Testosterone and prostate-specific antigen values during the extension study were similar to those seen during the 1-year trial in patients who continued on Degarelix or crossed over from leuprolide. The prostate-specific antigen progression-free survival hazard rate was decreased significantly after the crossover in the leuprolide to Degarelix group (from 0.20 to 0.09; P = .002), whereas in patients who continued on Degarelix, the rate did not change significantly. In patients with baseline prostate-specific antigen >20 ng/mL, the same hazard rate change pattern was observed on crossover (from 0.38 to 0.19; P = .019). CONCLUSION: Degarelix was well tolerated; no safety concerns were identified. The significant prostate-specific antigen progression-free survival benefit established for Degarelix over leuprolide during year 1 remained consistent at 5 years.

  • the effect of baseline testosterone on the efficacy of Degarelix and leuprolide further insights from a 12 month comparative phase iii study in prostate cancer patients
    Urology, 2012
    Co-Authors: Jan-erik Damber, Laurent Boccongibod, Tine Kold Olesen, Teuvo L J Tammela, Peter Iversen, Peranders Abrahamsson, Egbert Van Der Meulen, Boeric Persson
    Abstract:

    Objective To investigate the effects of baseline testosterone on testosterone control and prostate-specific antigen (PSA) suppression using data from a phase III trial (CS21) comparing Degarelix and leuprolide in prostate cancer. Methods In CS21, patients with histologically confirmed prostate cancer (all stages) were randomized to Degarelix 240 mg for 1 month followed by monthly maintenance doses of 80 or 160 mg, or leuprolide 7.5 mg/month. Patients receiving leuprolide could receive antiandrogens for flare protection. Treatment effects on testosterone and PSA reduction, testosterone surge, and microsurges were investigated in 3 baseline testosterone subgroups: 5.0 ng/mL. Data are presented for the groups receiving Degarelix 240/80 mg (the approved dose) and leuprolide 7.5 mg. Results Higher baseline testosterone delayed castration with both treatments. However, castrate testosterone levels and PSA suppression occurred more rapidly with Degarelix irrespective of baseline testosterone. With leuprolide, the magnitude of testosterone surge and microsurges increased with increasing baseline testosterone. There was no overall correlation between baseline testosterone and initial PSA decrease in either treatment group, although PSA suppression tended to be slowest with leuprolide and fastest with Degarelix in the high baseline testosterone subgroup. Conclusion Patients with high baseline testosterone may have greater risk of tumor stimulation (clinical flare) and mini-flares during gonadotrophin-releasing hormone agonist treatment and so the need for flare protection with antiandrogens in these patients is obvious, especially in metastatic disease. Although higher baseline testosterone delays castration, castrate testosterone and PSA suppression occur more rapidly with Degarelix, irrespective of baseline testosterone, without the need for flare protection.

  • a phase iii extension trial with a 1 arm crossover from leuprolide to Degarelix comparison of gonadotropin releasing hormone agonist and antagonist effect on prostate cancer
    The Journal of Urology, 2011
    Co-Authors: David E Crawford, Neal D Shore, Fritz H Schroder, Bertrand Tombal, Kurt Miller, Laurent Boccongibod, Judd W Moul, Tine Kold Olesen, Jenskristian Jensen, Boeric Persson
    Abstract:

    Purpose: We investigated the efficacy and safety of Degarelix treatment and the effects of switching from leuprolide to Degarelix in an ongoing extension study with a median 27.5-month followup of a pivotal 1-year prostate cancer trial. Materials and Methods: Patients who completed a 1-year pivotal phase III trial continued on the same monthly Degarelix maintenance dose (160 or 80 mg in 125 each), or were re-randomized from leuprolide 7.5 mg to Degarelix 240/80 mg (69) or 240/160 mg (65). Data are shown on the approved Degarelix 240/80 mg dose. The primary end point was safety/tolerability and the secondary end points were testosterone, prostate specific antigen, luteinizing hormone and follicle-stimulating hormone responses, and prostate specific antigen failure and progression-free survival. Results: During followup testosterone and prostate specific antigen suppression were similar to those in the 1-year trial in patients who continued on Degarelix or switched from leuprolide. The prostate specific antigen progression-free survival hazard rate was decreased significantly after the switch in the leuprolide/Degarelix group while the rate in those who continued on Degarelix was consistent with the rate in treatment year 1. The same hazard rate change pattern occurred in the group with baseline prostate specific antigen greater than 20 ng/ml. Adverse event frequency was similar between the groups and decreased with time. Conclusions: Data support the statistically significant prostate specific antigen progression-free survival benefit for Degarelix over leuprolide seen during year 1 and the use of Degarelix as first line androgen deprivation therapy as an alternative to a gonadotropin-releasing hormone agonist.

  • additional analysis of the secondary end point of biochemical recurrence rate in a phase 3 trial cs21 comparing Degarelix 80 mg versus leuprolide in prostate cancer patients segmented by baseline characteristics
    European Urology, 2010
    Co-Authors: Bertrand Tombal, Neal D Shore, Fritz H Schroder, Kurt Miller, Laurent Boccongibod, David E Crawford, Judd W Moul, Tine Kold Olesen, Jenskristian Jensen, Boeric Persson
    Abstract:

    Background: Recent data suggest prostate-specific antigen (PSA) progression may predict overall survival in prostate cancer patients. Objective: To compare the activity of Degarelix and leuprolide regarding PSA recurrence-free survival. Design, setting, and participants: Phase 3, 1-yr, multicentre, randomised, open-label trial comparing the efficacy and safety of Degarelix at 240 mg for 1 mo, and then 80 mg monthly (240/80 mg); Degarelix at 240 mg for 1 mo, and then 160 mg monthly; and leuprolide at 7.5 mg/mo. Overall, 610 patients with histologically confirmed prostate cancer (all stages), for whom androgen deprivation therapy was indicated, were included. The primary end point of this trial has been reported previously; the protocolled and exploratory subgroup analyses reported in this paper focus on Degarelix at 240/80 mg (dose approved by the US Food and Drug Administration and the European Medicine Evaluation Association for the treatment of patients with hormone-naive advanced prostate cancer). Measurements: PSA progression-free survival (two consecutive increases in PSA of 50% compared with nadir and >= 5 ng/ml on two consecutive measurements at least 2 wk apart or death) and change in PSA were reviewed. Effects of baseline disease stage (localised, locally advanced, and metastatic) and PSA level ( 20-50, and >50 ng/ml) were analysed. Results and limitations: Patients receiving Degarelix showed a significantly lower risk of PSA progression or death compared with leuprolide (p = 0.05). PSA recurrences occurred mainly in patients with advanced disease and exclusively in those with baseline PSA >20 ng/ml. Patients with PSA >20 ng/ml had a significantly longer time to PSA recurrence with Degarelix (p = 0.04). The relatively low number of patients in each subgroup is a limitation of this study. Conclusions: These results generate the hypothesis that Degarelix at 240/80 mg offers improved PSA control compared with leuprolide. PSA recurrences occurred almost exclusively in patients with metastatic prostate cancer or high baseline PSA during this 1-yr study. Further studies are warranted to confirm these findings. (C) 2009 European Association of Urology. Published by Elsevier B. V. All rights reserved.

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  • long term tolerability and efficacy of Degarelix 5 year results from a phase iii extension trial with a 1 arm crossover from leuprolide to Degarelix
    Urology, 2014
    Co-Authors: David E Crawford, Anders Malmberg, Neal D Shore, Fritz H Schroder, Bertrand Tombal, Kurt Miller, Laurent Boccongibod, Judd W Moul, Tine Kold Olesen, Boeric Persson
    Abstract:

    OBJECTIVE: To demonstrate the safety and efficacy of up to 5 years of Degarelix treatment and the effects of crossing over from leuprolide to Degarelix in the extension phase of a phase III pivotal 1-year trial. METHODS: Patients receiving Degarelix who completed the 1-year trial continued on 80 mg (n = 125) or 160 mg (n = 126) maintenance doses. Patients who received leuprolide were rerandomized to Degarelix 240/80 mg (n = 69) or 240/160 mg (n = 65). Safety and tolerability were assessed (primary end point), as well as testosterone and prostate-specific antigen levels and prostate-specific antigen progression-free survival (secondary end points). RESULTS: Adverse event frequency was similar between both the groups. Adverse events included initial injection site reactions, hot flushes, and increased weight. Testosterone and prostate-specific antigen values during the extension study were similar to those seen during the 1-year trial in patients who continued on Degarelix or crossed over from leuprolide. The prostate-specific antigen progression-free survival hazard rate was decreased significantly after the crossover in the leuprolide to Degarelix group (from 0.20 to 0.09; P = .002), whereas in patients who continued on Degarelix, the rate did not change significantly. In patients with baseline prostate-specific antigen >20 ng/mL, the same hazard rate change pattern was observed on crossover (from 0.38 to 0.19; P = .019). CONCLUSION: Degarelix was well tolerated; no safety concerns were identified. The significant prostate-specific antigen progression-free survival benefit established for Degarelix over leuprolide during year 1 remained consistent at 5 years.

  • rapid elimination kinetics of free psa or human kallikrein related peptidase 2 after initiation of gonadotropin releasing hormone antagonist treatment of prostate cancer potential for rapid monitoring of treatment responses
    Clinical Chemistry and Laboratory Medicine, 2012
    Co-Authors: David Ulmert, Tine Kold Olesen, Jenskristian Jensen, Peter Iversen, Andrew J Vickers, Howard I Scher, Charlotte Becker, David Frankel, Hans Lilja
    Abstract:

    Background: The utility of conventional prostate-specifi c antigen (PSA) measurements in blood for monitoring rapid responses to treatment for prostate cancer is limited because of its slow elimination rate. Prior studies have shown that free PSA (fPSA), intact PSA (iPSA) and human kallikrein-related peptidase 2 (hK2) are eliminated more rapidly after radical prostatectomy. In contrast, all three markers have similarly slow elimination rates after castration induced by gonadotropin-releasing hormone (GnRH) agonists, possibly due to the slow onset of castration. Therefore, we assessed elimination rates of tPSA, fPSA, iPSA and hK2 after rapid induction of castration with Degarelix (Firmagon (R)), a novel GnRH antagonist. Methods: This study included 24 patients treated with Degarelix. Blood was taken at 1, 3, 7, 14, 21 and 28 days after injection of Degarelix. Free and total PSA were measured with a commercial dual-label assay, and with inhouse research assays of intact PSA and hK2. Results: Median (interquartile range, IQR) tPSA at baseline was 23.4 (15.8, 59.8). Twenty-two patients (92%) reached castrate levels of testosterone within 24 h of Degarelix initiation, and all patients did so within 72 h. All kallikrein forms declined in an exponential fashion after Degarelix administration. The median time to 50% reduction in biomarker level was 8-9 days for tPSA or complexed PSA vs. 2-4 days for hK2, iPSA and fPSA. The percentage eliminated at day 3 and day 7 was significantly higher for hK2, iPSA and fPSA than for tPSA (all p<0.02), while tPSA and complexed PSA were similar. Conclusions: The rapid decline of fPSA, iPSA and hK2 after fast induction of castration with Degarelix is similar to that reported after prostatectomy and offers a novel, informative method to monitor rapid onset of therapeutic action targeting signaling of the androgen receptor.

  • the effect of baseline testosterone on the efficacy of Degarelix and leuprolide further insights from a 12 month comparative phase iii study in prostate cancer patients
    Urology, 2012
    Co-Authors: Jan-erik Damber, Laurent Boccongibod, Tine Kold Olesen, Teuvo L J Tammela, Peter Iversen, Peranders Abrahamsson, Egbert Van Der Meulen, Boeric Persson
    Abstract:

    Objective To investigate the effects of baseline testosterone on testosterone control and prostate-specific antigen (PSA) suppression using data from a phase III trial (CS21) comparing Degarelix and leuprolide in prostate cancer. Methods In CS21, patients with histologically confirmed prostate cancer (all stages) were randomized to Degarelix 240 mg for 1 month followed by monthly maintenance doses of 80 or 160 mg, or leuprolide 7.5 mg/month. Patients receiving leuprolide could receive antiandrogens for flare protection. Treatment effects on testosterone and PSA reduction, testosterone surge, and microsurges were investigated in 3 baseline testosterone subgroups: 5.0 ng/mL. Data are presented for the groups receiving Degarelix 240/80 mg (the approved dose) and leuprolide 7.5 mg. Results Higher baseline testosterone delayed castration with both treatments. However, castrate testosterone levels and PSA suppression occurred more rapidly with Degarelix irrespective of baseline testosterone. With leuprolide, the magnitude of testosterone surge and microsurges increased with increasing baseline testosterone. There was no overall correlation between baseline testosterone and initial PSA decrease in either treatment group, although PSA suppression tended to be slowest with leuprolide and fastest with Degarelix in the high baseline testosterone subgroup. Conclusion Patients with high baseline testosterone may have greater risk of tumor stimulation (clinical flare) and mini-flares during gonadotrophin-releasing hormone agonist treatment and so the need for flare protection with antiandrogens in these patients is obvious, especially in metastatic disease. Although higher baseline testosterone delays castration, castrate testosterone and PSA suppression occur more rapidly with Degarelix, irrespective of baseline testosterone, without the need for flare protection.

  • a phase iii extension trial with a 1 arm crossover from leuprolide to Degarelix comparison of gonadotropin releasing hormone agonist and antagonist effect on prostate cancer
    The Journal of Urology, 2011
    Co-Authors: David E Crawford, Neal D Shore, Fritz H Schroder, Bertrand Tombal, Kurt Miller, Laurent Boccongibod, Judd W Moul, Tine Kold Olesen, Jenskristian Jensen, Boeric Persson
    Abstract:

    Purpose: We investigated the efficacy and safety of Degarelix treatment and the effects of switching from leuprolide to Degarelix in an ongoing extension study with a median 27.5-month followup of a pivotal 1-year prostate cancer trial. Materials and Methods: Patients who completed a 1-year pivotal phase III trial continued on the same monthly Degarelix maintenance dose (160 or 80 mg in 125 each), or were re-randomized from leuprolide 7.5 mg to Degarelix 240/80 mg (69) or 240/160 mg (65). Data are shown on the approved Degarelix 240/80 mg dose. The primary end point was safety/tolerability and the secondary end points were testosterone, prostate specific antigen, luteinizing hormone and follicle-stimulating hormone responses, and prostate specific antigen failure and progression-free survival. Results: During followup testosterone and prostate specific antigen suppression were similar to those in the 1-year trial in patients who continued on Degarelix or switched from leuprolide. The prostate specific antigen progression-free survival hazard rate was decreased significantly after the switch in the leuprolide/Degarelix group while the rate in those who continued on Degarelix was consistent with the rate in treatment year 1. The same hazard rate change pattern occurred in the group with baseline prostate specific antigen greater than 20 ng/ml. Adverse event frequency was similar between the groups and decreased with time. Conclusions: Data support the statistically significant prostate specific antigen progression-free survival benefit for Degarelix over leuprolide seen during year 1 and the use of Degarelix as first line androgen deprivation therapy as an alternative to a gonadotropin-releasing hormone agonist.

  • cardiovascular safety of Degarelix results from a 12 month comparative randomized open label parallel group phase iii trial in patients with prostate cancer
    The Journal of Urology, 2010
    Co-Authors: Matthew R Smith, Laurence Klotz, Tine Kold Olesen, Boeric Persson, Arthur A M Wilde
    Abstract:

    Purpose We assessed the cardiovascular safety profile of Degarelix, a new gonadotropin-releasing hormone antagonist. Materials and Methods This is the first report to our knowledge on cardiovascular safety data from a completed 1-year randomized controlled trial of leuprolide acetate vs Degarelix. Outcomes considered in these analyses included the QT interval by central reading and analysis, and cardiovascular adverse events. On multivariate analyses relationships between selected baseline factors and cardiovascular events were evaluated. Results There were no significant differences between treatment groups for mean change in Fridericia's correction of QT during the trial. Markedly abnormal Fridericia's correction of QT values (500 milliseconds or greater) were observed in only a small number of subjects by treatment group, that is 2 (less than 1%) in the pooled Degarelix group and 2 (1%) in the leuprolide group. Supraventricular arrhythmias were the most common type of arrhythmias, affecting 2% of subjects in the pooled Degarelix group and 4% in the leuprolide group. Other arrhythmias occurred in 1% or less of subjects by treatment group. The most frequently reported cardiac disorder was ischemic heart disease, which occurred in 4% of subjects treated with Degarelix and 10% of those on leuprolide. Cox proportional hazard ratio estimates for selected baseline covariates showed a significantly increased risk of cardiovascular events by age (p = 0.0459) and systolic blood pressure (p = 0.0061). Conclusions In men with prostate cancer Degarelix and leuprolide have similar cardiovascular safety profiles. These observations suggest that the cardiovascular events associated with both agents result from hypogonadism rather than a direct drug effect.