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Objectives This study will compare the incidence of major adverse cardiovascular events (MACEs) with androgen deprivation therapy (ADT) among men with advanced prostate cancer who are being treated with a gonadotropin-releasing hormone (GnRH) antagonist versus a GnRH agonist. Background Treatment of advanced prostate cancer with ADT might increase the risk of subsequent cardiovascular events among men with known atherosclerotic cardiovascular disease (ASCVD), but a recent meta-analysis suggested that this risk might be lower with ADT using a GnRH antagonist versus a GnRH agonist. Methods PRONOUNCE is a multicenter, prospective, randomized, open, blinded endpoint trial that will enroll approximately 900 patients with advanced prostate cancer and pre-existing ASCVD who will be treated with ADT. Participants will be randomized to receive the GnRH antagonist degarelix or the GnRH agonist leuprolide as ADT for 12 months. The primary endpoint is time from randomization to first confirmed, adjudicated occurrence of a MACE, which is defined as a composite of all-cause death, nonfatal myocardial infarction, or nonfatal stroke through 12 months of ADT treatment. Baseline cardiovascular biomarkers (high-sensitivity C-reactive protein, high-sensitivity troponin T, and N-terminal pro-brain natriuretic peptide), as well as serial inflammatory and immune biomarkers, will be evaluated in exploratory analyses. Results As of October 1, 2019, a total of 364 patients have been enrolled. The mean age is 74 years, 90% are white, 80% have hypertension or dyslipidemia, 30% diabetes mellitus, 40% have had a previous myocardial infarction, and 65% have had previous revascularization. Regarding prostate cancer features at randomization, 48% of the patients had localized disease, 23% had locally advanced disease, and 18% had metastatic disease. Conclusions PRONOUNCE is the first prospective cardiovascular outcomes trial in advanced prostate cancer that will delineate whether the risk of subsequent cardiovascular events associated with ADT is lower with a GnRH antagonist versus a GnRH agonist for men with pre-existing ASCVD. (A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease [PRONOUNCE]; NCT02663908), Central Illustration

Background: The utility of conventional prostate-specific 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®), 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 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.

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.

Study Type - Therapy (RCT) Level of Evidence 1b OBJECTIVE To compare the activity of degarelix, a new gonadotrophin-releasing hormone (GnRH) blocker, with leuprolide depot 7.5 mg in the control of total serum alkaline phosphatase (S-ALP) levels in patients with prostate cancer. PATIENTS AND METHODS In the randomized, phase III trial (CS21), patients with histologically confirmed prostate cancer (all stages), were randomized to one of three regimens: degarelix subcutaneous 240 mg for 1 month followed by monthly maintenance doses of 80 mg or 160 mg, or intramuscular leuprolide 7.5 mg/month. Patients receiving leuprolide could also receive antiandrogens for flare protection. We report exploratory S-ALP analyses from CS21, focusing on the comparison of degarelix 240/80 mg with leuprolide 7.5 mg, in line with the recent approvals of this dose by the USA Food and Drug Administration and the European Medicines Agency. RESULTS Overall, 610 patients were included, with a median age of 73 years and median prostate-specific antigen (PSA) level of 19.0 ng/mL. Baseline S-ALP levels were high in metastatic patients and highest in patients with metastatic disease and a haemoglobin level of or =50 ng/mL. Between-treatment differences in patients with metastatic disease and those with a PSA level of > or =50 ng/mL were significant at day 364 (P = 0.014 and 0.007, respectively). CONCLUSION Patients with metastatic disease or those with PSA levels of > or =50 ng/mL at baseline had greater reductions in S-ALP levels with degarelix than with leuprolide. Patients in the degarelix group maintained S-ALP suppression throughout the study, in contrast to those in the leuprolide group. This suggests that degarelix might offer better S-ALP control than leuprolide and might prolong control of skeletal metastases, compared with GnRH agonists, over a 1-year treatment period.

OBJECTIVE 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. PATIENTS AND METHODS In all, 610 patients with adenocarcinoma of the prostate (any stage; median age 72 years; median testosterone 3.93 ng/mL, median prostate-specific antigen, PSA, level 19.0 ng/mL) were randomized and received study treatment. Androgen-deprivation therapy was indicated (neoadjuvant hormonal treatment was excluded) according to the investigator’s assessment. Three dosing regimens were evaluated: a starting dose of 240 mg of degarelix subcutaneous (s.c.) for 1 month, followed by s.c. maintenance doses of 80 mg or 160 mg monthly, or intramuscular (i.m.) leuprolide doses of 7.5 mg monthly. Therapy was maintained for the 12-month study. Both the intent-to-treat (ITT) and per protocol populations were analysed. RESULTS The primary endpoint of the trial was suppression of testosterone to ≤0.5 ng/mL at all monthly measurements from day 28 to day 364, thus defining the treatment response. This was achieved by 97.2%, 98.3% and 96.4% of patients in the degarelix 240/80 mg, degarelix 240/160 mg and leuprolide groups, respectively (ITT population). At 3 days after starting treatment, testosterone levels were ≤0.5 ng/mL in 96.1% and 95.5% of patients in the degarelix 240/80 mg and 240/160 mg groups, respectively, and in none in the leuprolide group. The median PSA levels at 14 and 28 days were significantly lower in the degarelix groups than in the leuprolide group (P

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/mI (range: P2S-P75,3.37-5.19 ng/ml) and PSA was 27.6 ng/ml (range: P25-P75,11.9-S5.0 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

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.

Androgen deprivation therapy remains the mainstay of medical treatment for prostate cancer. Generally, this is achieved with medical androgen deprivation rather than orchidectomy, as most patients find the permanency and psychological effects of the latter unacceptable. Gonadotrophin-releasing hormone (GnRH) agonists are the most widely used androgen deprivation therapy, but do have some drawbacks. The most apparent is the induction of a transient surge in serum testosterone that may stimulate tumor growth, causing patients to experience new or worsening cancer symptoms. These may include increased bone pain and urinary retention, and consequently delay the therapeutic benefit of these agents. These shortcomings led to the development of the GnRH antagonists/receptor blockers. Degarelix is a novel GnRH receptor blocker that has an immediate onset of action, producing a rapid decrease in luteinizing hormone and follicle-stimulating hormone leading to fast testosterone suppression without the initial surge associated with the GnRH agonists. Administration of subcutaneous degarelix depot has been investigated in multicenter, open-label, randomized, phase II trials of up to 1 year’s duration in patients with prostate cancer. Degarelix induced rapid luteinizing hormone suppression and fast, profound and sustained suppression of serum testosterone (≤0.5 ng/ml), with additional rapid and sustained reductions in dihydrotestosterone and prostate-specific antigen. Dose-finding trials indicate that a 240 mg starting dose and an 80 or 160 mg maintenance dose is most effective for long-term testosterone suppression. In a phase III, 1-year comparator trial, degarelix produced fast testosterone suppression and prostate-specific antigen reduction ≥2 weeks before clinically relevant changes were induced by the GnRH agonist leuprolide. Degarelix was as effective as leuprolide at reducing testosterone ≤0.5 ng/ml from 1 month to study end. Degarelix was well tolerated, with uneventful toxicology and no evidence of systemic allergic reactions. This new agent represents an important pharmacological development in the hormonal treatment of prostate cancer.

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.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.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.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.

42 Background: LHRH agonists are used to treat patients (pts) with advanced prostate cancer and have been associated with an increased risk of cardiovascular (CV) events and related deaths. Degarelix is a GnRH antagonist that appears to mitigate this risk. Methods: Results were pooled from 2328 pts participating in 6 prospective randomised trials. Most pts (n=1,686) received 1 year of GnRH antagonist or LHRH agonist treatment; the remainder (n=642) had 3–7 months’ treatment. Data were classified based on the MedDRA system and analysed using Kaplan Meier plots and a Cox proportional hazard model. Event analysis was based on death from any cause or CV event defined as arterial embolic/thrombotic; haemorrhagic or ischemic cerebrovascular; myocardial infarction or other ischemic heart disease. High risk pts were defined as men with a baseline CV disease (CVD) history. Results: Treatment groups (GnRH antagonist, n=1,491 [degarelix]; LHRH agonist, n=837 [goserelin, n=458; leuprolide, n=379]) were balanced for baseline characteristics and CVD history (31% vs. 29%). Characteristics associated with CVD (e.g. statin medication, elevated blood pressure, diabetes, cholesterol >6.2 mmol/L) were similar between groups. The risk of a CV event or death was significantly lower in pts receiving degarelix during the first year of treatment (see Table). In pts with baseline CVD the findings remained significant. In pts with no baseline CVD, there was no difference in subsequent CVD events or death in either group. In analysis by time to CV event only in all pts and pts with baseline CVD (see Table), men receiving GnRH antagonist had a significantly lower risk of CV events. Conclusions: In all pts treated with a GnRH antagonist (degarelix) risk of a CV event or death was significantly lower than in pts receiving an LHRH agonist over a treatment period of up to 1 year. In pts with baseline CVD, risk reduction remained significant at ~50%. [Table: see text]

12 Background: Comparative effectiveness of the gonadotropin-releasing hormone (GnRH) blocker, degarelix, vs the GnRH agonist, leuprolide, was evaluated during a 1-year phase III trial (CS21); data have been presented. We now report long-term data from an ongoing 5-year extension study (CS21A). Methods: In CS21, patients with prostate cancer (all stages) were randomized to degarelix (240 mg for 1 month, then monthly maintenance doses of 80 mg [n=207] or 160 mg [n=202]), or leuprolide 7.5 mg/month (n=201). Leuprolide patients could receive bicalutamide. Of the 504 patients who completed the 1-year trial, 384 chose to continue in an extension study; those on leuprolide were re-randomized to degarelix 240/80 mg or 240/160 mg. PSA PFS was defined as time to first PSA failure (two consecutive increases in PSA of 50% and ≥5 ng/mL above nadir) or death. Time for 25% of patients to experience PSA PFS (TTP25%) was analyzed using Weibull estimates. Results: Up to 1 year, the risk of PSA PFS was significantly lower with degarelix 240/80 mg vs leuprolide (p=0.05, log-rank). At 27.5 months' median follow-up, hazard rate of PSA PFS significantly decreased in leuprolide patients switched to degarelix compared with before the switch (0.20 vs 0.08; p=0.003). Similar improvements occurred in patients with baseline PSA >20 ng/mL. During the first year, TTP25% for patients with baseline PSA >20 ng/mL was numerically longer with degarelix vs leuprolide (407 vs 303 days; p=0.085); the difference was even greater when degarelix data were analyzed beyond 1 year (514 vs 303 days; p=0.01). Conclusions: Patients receiving degarelix had a significantly lower risk of PSA failure or death vs leuprolide during the first year of treatment. After switching to degarelix, patients who initially received leuprolide experienced a significantly lower rate of PSA failure or death. In patients with baseline PSA >20 ng/mL, TTP25% was significantly longer for degarelix patients. These data support the durability of the significant PSA PFS benefit of degarelix vs monthly leuprolide observed during the first year and the use of degarelix as first-line androgen deprivation therapy. [Table: see text]

4673 Background: Gonadotropin releasing-hormone (GnRH) blockers are a new type of fast-acting hormonal therapy for prostate cancer, which are devoid of agonist-associated surge/microsurges. Degarel...

14516 Background: The GnRH receptor blocker degarelix has immediate onset of action in suppressing gonadotropins (LH and FSH), testosterone (T) and prostate specific antigen (PSA) and does not cause T surge. Its long-term efficacy and safety in different maintenance dosing regimens were evaluated in prostate cancer (CaP) patients. Methods: Degarelix was investigated in two multicenter, one-year studies in North America and Europe/South Africa. Degarelix initiation doses of 200 and 240 mg administered subcutaneously, followed by three maintenance doses (80, 120 and 160 mg). Therapeutic effect was assessed by measuring T and PSA levels. 314 patients (age 47–93, median 73 years) with histologically confirmed CaP, PSA ≥2 ng/mL received degarelix subcutaneously every 28 days. Median baseline T was 4.1 ng/mL and PSA was 20 ng/mL. 19% of patients had metastatic, 24% had locally advanced and 30% had localized CaP. 27% were M0/MX and not T-staged. Tumour grade was well differentiated (Gleason 2–4) in 13%, moderately differentiated (5–6) in 38%, and poorly differentiated (7–10) in 49% of the patients. Results: T levels ≤0.5 ng/mL were achieved in 92% of patients at Day 3 and 95% of patients at Day 28 among those treated with 240 mg (40 mg/mL) degarelix. From Day 28 until Day 364, 100% of patients receiving maintenance doses of 160 mg had T levels consistently ≤0.5 ng/mL. No evidence of T surge was detected. PSA decreased by 90% at 8 weeks after starting therapy, 94% at 12 weeks and 96% at 24 weeks. Twelve patients (6%) withdrew from the study due to adverse events, largely related to androgen deprivation. There were no cases of systemic allergic reactions. Conclusion: Degarelix treatment for one year resulted in fast, profound and sustained suppression of T (≤0.5 ng/mL) and fast, profound and sustained reduction of PSA levels. Degarelix was well tolerated without evidence of T surge or systemic allergic reactions. [Table: see text] [Table: see text]