Tine Kold Olesen

The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer

To evaluate the efficacy and safety of degarelix, a new gonadotrophin‐releasing hormone (GnRH) antagonist (blocker), vs leuprolide for achieving and maintaining testosterone suppression in a 1‐year phase III trial involving patients with prostate cancer.

Cardiovascular Morbidity Associated with Gonadotropin Releasing Hormone Agonists and an Antagonist

BACKGROUND Androgen deprivation therapy (ADT) is associated with increased cardiovascular morbidity. OBJECTIVE To determine whether cardiovascular morbidity differs following initiation of gonadotropin-releasing hormone (GnRH) agonists compared with an antagonist. DESIGN, SETTING, AND PARTICIPANTS Pooled data from six phase 3 prospective randomized trials that recruited 2328 men between 2005 and 2012 to compare the efficacy of GnRH agonists against an antagonist. Men recruited had pathologically confirmed prostate cancer, an Eastern Cooperative Oncology Group score <2, a minimum life expectancy of 12 mo, and were naïve to ADT. Men were excluded if they had a prolonged baseline QT/corrected QT interval, other risk factors for heart failure, hypokalemia or a family history of long QT syndrome, or had another cancer diagnosed within 5 yr. INTERVENTION Men were randomized to receive a GnRH agonist or an antagonist for either 3-7 mo (n=642) or 12 mo (n=1686). Treatment groups were balanced for common baseline characteristics. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Event analysis was based on death from any cause or cardiac events. Data documenting adverse experiences were classified based on the Medical Dictionary for Regulatory Activities. The following conditions defined a cardiac event: arterial embolic or thrombotic events, hemorrhagic or ischemic cerebrovascular conditions, myocardial infarction, and other ischemic heart disease. Kaplan-Meier curves and log-rank tests were used to compare time to a cardiovascular event or death. RESULTS AND LIMITATIONS Among men with preexisting cardiovascular disease, the risk of cardiac events within 1 yr of initiating therapy was significantly lower among men treated with a GnRH antagonist compared with GnRH agonists (hazard ratio: 0.44; 95% confidence interval, 0.26-0.74; p=0.002). Since our analysis is post hoc, our findings should only be interpreted as hypothesis generating. CONCLUSIONS GnRH antagonists appear to halve the number of cardiac events experienced by men with preexisting cardiovascular disease during the first year of ADT when compared to GnRH agonists.

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

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 (<10, 10-20, >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.

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.

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.

Degarelix: a novel gonadotropin-releasing hormone (GnRH) receptor blocker--results from a 1-yr, multicentre, randomised, phase 2 dosage-finding study in the treatment of prostate cancer.

BACKGROUND Degarelix is a gonadotropin-releasing hormone antagonist (GnRH receptor blocker) with immediate onset of action, suppressing gonadotropins, testosterone, and prostate-specific antigen (PSA) in prostate cancer. OBJECTIVE To determine the efficacy and safety of initial doses of 200 mg or 240 mg of degarelix and thereafter monthly subcutaneous maintenance doses of 80 mg, 120 mg, or 160 mg of degarelix for the treatment of prostate cancer. DESIGN, SETTING, AND PARTICIPANTS The 1-yr study was of open-label, randomised design and involved 187 patients (range: 52-93 yr, median: 72 yr) with histologically confirmed adenocarcinoma of the prostate and a baseline PSA >2 ng/ml. RESULTS AND LIMITATIONS At baseline, median serum testosterone was 4.13 ng/ml (range: P25-P75, 3.37-5.19 ng/ml) and PSA was 27.6 ng/ml (range: P25-P75, 11.9-55.0 ng/ml). On day 3, 88% and 92% of patients in the groups to whom 200-mg and 240-mg initial doses of degarelix were administered, respectively, had testosterone levels < or =0.5 ng/ml. For patients with testosterone levels < or =0.5 ng/ml at 1 mo, the testosterone levels remained < or =0.5 ng/ml until the end of the study in 100% of the patients treated with a monthly maintenance dosage of 160 mg of degarelix. No evidence of testosterone surge was detected. PSA decreased by 97-98% after 1 yr and the median time to 90% reduction in PSA was 8 wk in all but one patient (from the 80-mg dosage treatment group at the initial 200-mg dose of degarelix). Thirteen patients (6%) withdrew from the study due to adverse events, largely related to androgen deprivation. CONCLUSIONS Degarelix treatment for 1 yr resulted in a fast, profound, and sustained suppression of testosterone and PSA, with no evidence of testosterone surge. Degarelix was well tolerated.

A 1-Year, Open Label, Randomized Phase II Dose Finding Study of Degarelix for the Treatment of Prostate Cancer in North America

PURPOSE Degarelix is a gonadotropin-releasing hormone receptor antagonist (blocker) with rapid onset of action suppressing gonadotropins, testosterone and prostate specific antigen in prostate cancer. In the present open label, randomized study in North America we evaluated the efficacy and safety of a starting dose of 200 mg degarelix followed by monthly injections of 60 or 80 mg during 1 year of prostate cancer treatment. MATERIALS AND METHODS A total of 127 patients (median age 76 years, range 47 to 93) with histologically confirmed prostate cancer were enrolled in the study. Efficacy was assessed by measuring serum testosterone and prostate specific antigen. RESULTS Median baseline testosterone and prostate specific antigen levels were 4.13 ng/ml (P25-P75 3.03-5.11) and 13.4 ng/ml (P25-P75 6.80-25.7), respectively. The starting dose induced a rapid suppression of testosterone in that 88% of the patients had testosterone levels of 0.5 ng/ml or less 1 month after the injection. For patients who had testosterone levels of 0.5 ng/ml or less after 1 month, 93% and 98% of those receiving maintenance doses of 60 and 80 mg, respectively, had testosterone levels that were consistently 0.5 ng/ml or less at all monthly measurements from 1 month to 1 year. No evidence of testosterone surge was detected. In both groups prostate specific antigen decreased by 96% after 1 year and median time to 90% reduction in prostate specific antigen was 56 days. Six patients (5%) withdrew from the study due to adverse events. CONCLUSIONS Degarelix treatment for 1 year resulted in a fast, profound and sustained suppression of testosterone and prostate specific antigen with no evidence of testosterone surge. Degarelix was well tolerated.

Changes in alkaline phosphatase levels in patients with prostate cancer receiving degarelix or leuprolide: results from a 12-month, comparative, phase III study

Study Type – Therapy (RCT)
Level of Evidence 1b

Cardiovascular Safety of Degarelix: Results From a 12-Month, Comparative, Randomized, Open Label, Parallel Group Phase III Trial in Patients With Prostate Cancer

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 Fridericias correction of QT during the trial. Markedly abnormal Fridericias 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.

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

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.

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: <3.5, 3.5-5.0, and >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.