Hein Van Poppel M.D., Ph.D., Department of Urology, UZ Leuven, Campus Gasthuisberg, Herestraat 49, Leuven 3000, Belgium. Email: email@example.com
Gonadotropin-releasing hormone agonists and antagonists provide androgen-deprivation therapy for prostate cancer. Unlike agonists, gonadotropin-releasing hormone antagonists have a direct mode of action to block pituitary gonadotropin-releasing hormone receptors. There are two licensed gonadotropin-releasing hormone antagonists, degarelix and abarelix. Of these, degarelix is the more extensively studied and has been documented to be more effective than the well-established, first-line agonist, leuprolide, in terms of substantially faster onset of castration, faster suppression of prostate-specific antigen, no risk for testosterone surge or clinical flare, and improved prostate-specific antigen progression-free survival, suggesting a delay in castration resistance. Other than minor injection-site reactions, degarelix is generally well tolerated, without systemic allergic reactions and with most adverse events consistent with androgen suppression or the underlying condition. In conclusion, degarelix provides a rational, first-line androgen-deprivation therapy suitable for the treatment of prostate cancer, with faster onset of castration than with agonists, and no testosterone surge. Furthermore, data suggest that degarelix improves disease control compared with leuprolide, and might delay the onset of castration-resistant disease. In view of these clinical benefits and the lack of need for concomitant anti-androgen treatment, gonadotropin-releasing hormone antagonists might replace gonadotropin-releasing hormone agonists as first-line androgen-deprivation therapy in the future.
ADT is the mainstay of treatment for advanced prostate cancer, and is increasingly used in combination with radiotherapy in patients with earlier stages of disease. For many years, GnRH agonists have been the ADT standard of care. There are, however, several drawbacks related to the mechanism of action of GnRH agonists. In particular, the initial testosterone surge associated with these agents delays the achievement of castration levels of testosterone and can produce a flare in clinical symptoms in patients with advanced disease.1,2 Furthermore, microsurges in testosterone levels occur with repeated agonist administration.3 In this context, it is interesting to note that increases in testosterone above 1.1 nmol/L (32 ng/dL) during agonist treatment were associated with a significantly shorter survival free of androgen-independent progression than patients who had increases <32 ng/dL.4
Despite the proven success of hormonal therapy, most patients showing an initial response will eventually experience disease progression.5 Cancer that relapses after initial ADT is termed androgen-independent or CRPC.6 The precise definition of CPRC is, however, controversial. Recent European Association of Urology guidelines define CRPC as castration levels of testosterone (<1.7 nmol/L [50 ng/dL]) and three consecutive rises of PSA, 1 week apart, resulting in two 50% increases over the nadir, with a PSA > 2 ng/mL, despite consecutive hormonal manipulations.7 However, other definitions of progression have been used. Sharifi et al., for example, defined androgen independence as the first sustained increase in PSA level from the PSA nadir after starting ADT.8 Based on this definition, they found that the median time to androgen independence was 13–19 months after starting ADT, depending on the disease stage at initiation. In patients with metastatic disease, it is estimated that >90% will progress to androgen independence within 18–24 months.9 As CRPC carries a much poorer prognosis10 and might signal the need for chemotherapy,11 any delay in the onset of castration resistance is clearly desirable.
GnRH antagonists represent an alternative form of ADT, with a direct and immediate action that allows castration without an initial testosterone surge or subsequent microsurges. Two GnRH antagonists are currently available: abarelix and degarelix. The present review will evaluate the comparative efficacy and safety of GnRH agonists and antagonists for prostate cancer, particularly their effects on disease progression.
Mechanisms of action of GnRH agonists and antagonists
GnRH agonists and antagonists ultimately act by suppressing testosterone to castration levels,7 although the mechanisms by which this is achieved differ. LH, secreted by the pituitary gland, acts on Leydig cells in the testes to stimulate testosterone production. Release of LH is in turn controlled by GnRH secretion from the hypothalamus, which normally occurs in a regular, pulsatile manner.12 GnRH agonists override this pulsatile control of the pituitary by providing continuous stimulation, which eventually leads to downregulation of pituitary GnRH receptors, a reduction in LH (and FSH) production, and therefore a suppression of testosterone levels. Before this occurs, however, there is a transient increase in levels of LH and FSH, accompanied by a surge in testosterone.
In contrast, GnRH antagonists bind directly to GnRH receptors and block the effect of GnRH on the pituitary, producing immediate suppression of LH, FSH and testosterone. Furthermore, studies in animals have shown that testosterone surge occurs even when administering an agonist after an antagonist. Pre-administration of GnRH antagonists has been shown to blunt the typical agonist-induced surge in LH and testosterone levels, but when the antagonist was withdrawn, LH levels increased, leading to a rise in testosterone above castration level.13
GnRH antagonists: Improved testosterone control compared with GnRH agonists
Consistent with their mechanism of action, comparative preclinical and clinical studies clearly and consistently show that unlike GnRH agonists, GnRH antagonists are associated with a rapid and immediate testosterone reduction; that is, they are not associated with an initial testosterone surge. Furthermore, antagonists also do not induce microsurges on repeated administration.
The comparative effects of degarelix and GnRH agonists were assessed in two studies in a rat model of prostate cancer.14 In a 2-month study, rats receiving the GnRH agonist, triptorelin (0.5 mg/kg daily), experienced an initial testosterone surge, followed by suppression to castration levels by day 28, which was maintained for the remainder of the study. In rats receiving degarelix (1 mg/kg monthly), castration levels of testosterone were reached at day 3, with no initial surge, and maintained until the end of the study. Testes weight – a measure of pituitary–gonadal axis activity over time – and tumor weight after 2 months were significantly lower in rats treated with degarelix compared with those treated with triptorelin. In a 1-year study, degarelix (1 mg/kg monthly) was compared with leuprolide depot (1.5 mg/kg 3-weekly); control groups consisting of surgically castrated rats and vehicle-treated rats were also included.14 Again, the GnRH agonist was associated with an initial testosterone surge that was absent in degarelix-treated rats. Castration levels of testosterone were achieved by day 2 with degarelix and within 1 month with leuprolide depot. Tumor volume in rats receiving degarelix was suppressed to a level similar to that seen in surgically castrated animals. Degarelix sustained inhibition of tumor growth over the whole study period. In contrast, tumor growth started to escape androgen deprivation after approximately 5 months of treatment with leuprolide depot.
Abarelix has been shown to suppress testosterone levels in rats, dogs and monkeys,15 but comparative preclinical data with GnRH agonists do not appear to be published.
Importantly, the effects of degarelix on testosterone levels in preclinical studies have been reproduced clinically. In two randomized, 1-year dose-finding trials in patients with prostate cancer in Europe/South Africa16 and North America,17 degarelix produced rapid, profound, and sustained testosterone and PSA suppression, without a testosterone surge. These trials identified 240 mg as the most effective starting dose, and 80 mg and 160 mg as the most suitable maintenance doses.
The efficacy of degarelix was compared with that of leuprolide depot in a 12-month randomized, open-label study (CS21; n = 610).18 Men with prostate cancer suitable for hormonal treatment were randomly allocated to monthly leuprolide 7.5 mg or to one of two degarelix regimens (a starting dose of 240 mg followed by monthly doses of 80 or 160 mg); patients in the leuprolide group could receive bicalutamide flare protection at the discretion of the investigator. In the degarelix group, suppression of testosterone to below castration levels was achieved by >95% of patients by day 3. In those receiving leuprolide, there was an initial testosterone surge, as expected; median testosterone levels increased by 65% by day 3 (P < 0.0001 compared with degarelix) and remained above castration level until day 28 (Fig. 1). Beyond 28 days, suppression of testosterone was sustained for 1 year in all treatment groups, although leuprolide treatment was associated with microsurges (testosterone increases >25 ng/dL and >50 ng/dL) in eight (4%) and four (2%) patients, respectively. No patient receiving degarelix experienced testosterone microsurges.
Patients who completed the CS21 study were eligible to enter an open-label extension study (CS21A) in which those who received degarelix continued on the same dose, whereas those who received leuprolide were randomized to one of the two degarelix doses.19 It is important to note that the crossover from leuprolide to degarelix was preplanned, and that patients in the leuprolide group had not failed on treatment. For patients continuing on degarelix, data were reported for the approved dose (240/80 mg), whereas for patients in the leuprolide/degarelix group, data for both degarelix doses were pooled. At a median follow up of 27.5 months, castration testosterone levels were maintained in both treatment groups.19
Phase II/III trials with abarelix also show that castration testosterone levels are reached rapidly, with no surge.20–23 For example, in a randomized comparison of abarelix with leuprolide (n = 269), 78% of men receiving abarelix achieved castration levels of testosterone after 7 days compared with 0% of leuprolide-treated patients.20 However, with long-term abarelix use, the percentage of patients maintaining castration levels of testosterone appeared to decrease with time.24
Implications of improved testosterone control
Improved testosterone control with GnRH antagonists can have immediate implications – at the onset of therapy – as well as during long-term disease control. First, they are not associated with the surge-induced clinical flare that might occur with GnRH agonists. Symptoms of the stimulation of the cancer can be serious, and include bone pain and bladder outlet/ureteral obstruction, but also potentially fatal complications, such as cardiovascular events and spinal cord compression.1,2 GnRH antagonists do not require AA flare protection, and patients can be treated with monotherapy, thus avoiding the potential side effects of AA treatment and potentially improving compliance. The improved testosterone control might also be a reason for the improved disease control as compared with that of the agonists as discussed later.
GnRH antagonists and agonists: Differential effects on PSA control
PSA levels are routinely measured to assess the efficacy of prostate cancer treatment and provide an indication of disease control; indeed, PSA recurrence can precede clinically-detectable recurrence by years. Furthermore, the achievement of effective PSA control is associated with improved overall survival.25–27 Clinical data have shown that the GnRH antagonist, degarelix, is associated with more rapid PSA suppression and improved PSA PFS compared with the GnRH agonist, leuprolide.
As well as faster testosterone suppression, degarelix was associated with significantly faster PSA reduction versus leuprolide in the pivotal phase III study (CS21).18 At days 14 and 28, the decrease in PSA from baseline was significantly greater with degarelix (P < 0.001). Beyond 28 days, PSA levels were suppressed to a similar extent in the degarelix and leuprolide groups until the end of the 1-year study. In the long-term extension (CS21A), PSA suppression was maintained in the continuous degarelix group and in those crossed over from leuprolide to degarelix.19
PSA failure (defined as two consecutive increases in PSA >50% compared with nadir and PSA ≥ 5 ng/mL on two consecutive measurements at least 2 weeks apart) was also measured in CS21. PSA failure occurred exclusively in the subgroup of patients with baseline PSA levels > 20 ng/mL. In this subgroup of patients, PSA failure was significantly lower for degarelix 240/80 mg than with leuprolide (P = 0.04).28
As well as the differences in speed of PSA reduction and PSA failure, degarelix 240/80 mg was associated with significantly improved PSA PFS compared with leuprolide during the first year (P = 0.05; log–rank); the hazard ratio adjusted for baseline disease stage and PSA was 0.664 (95% confidence interval: 0.385, 1.146),28 showing a 34% lower risk of PSA failure or death with degarelix. Furthermore, in the long-term extension (CS21A), the risk of PSA failure or death decreased in patients crossed over from leuprolide to degarelix.19 At a median follow up of 27.5 months, PSA PFS hazard rates decreased from 0.20 to 0.08 events annually after crossover (P = 0.003). Corresponding hazard rates for the continuous degarelix arm were unchanged (0.11 and 0.14; P = 0.464), showing a consistent effect of degarelix over time (Fig. 2). These data highlight that degarelix should be used as first-line ADT for prostate cancer. This is further supported by studies in which antagonists were used as the second-line, after failure on GnRH agonists; response rates were low in these studies.29–31
Implications of differential effects on PSA
As aforementioned, degarelix was associated with a significantly longer PSA PFS than leuprolide,28 and this effect was confirmed by the significant improvement in PSA PFS when patients were crossed over from degarelix.19 As PSA PFS is indicative of time to castration resistance in these patients, these data suggest that degarelix delays progression to castration-resistant disease compared with the agonist. In a post-hoc analysis of patients with baseline PSA > 20 ng/mL (those at highest risk of PSA failure), time to PSA failure or death in 25% of patients was significantly longer with degarelix (514 vs 303 days; P = 0.01; Fig. 3).32 In other words, progression or death was delayed by approximately 7 months with degarelix compared with leuprolide. Any improvement in the time to progression (which can trigger the use of chemotherapy and its associated toxicity) or death is clearly desirable for patients.
The mechanism by which degarelix improves PSA PFS relative to leuprolide is not fully established, but is likely to reflect a combination of its differential hormonal effects. As aforementioned, in addition to the differences at the start of therapy, GnRH agonists are also associated with testosterone microsurges, and small increases in testosterone levels might be associated with faster progression.4 It is therefore possible that the lack of microsurges with degarelix contributes to the improvement in progression observed. However, other hormonal mechanisms could also be involved.
Interestingly, it has recently been suggested that the speed of PSA decline – the PSA half-life – might be of prognostic significance, perhaps not only related to disease characteristics, but also to treatment effects. Although conflicting results have been obtained, some studies show that a shorter half-life (faster PSA reduction) is associated with improved progression and survival.33,34 In the study by Lin et al., in which 153 patients received ADT, a shorter PSA half-life (≤0.5 months) was associated with significantly longer PFS (median 24.6 and 17.2 months, respectively) and overall survival (48 and 43 months) than a longer (>0.5 months) PSA half-life (multivariate analysis).34 In the phase III comparative study (CS21),18 the PSA half-lives for degarelix and leuprolide were <0.5 months (9–10 days) and >0.5 months (22–23 days), respectively.
GnRH agonists and antagonists: Comparative safety and tolerability data
In the CS21 study, the overall incidence of adverse events was similar in the three arms (degarelix 240/80 mg, 79%; degarelix 240/160 mg, 83%; leuprolide, 78%).18 The most frequently occurring adverse events in each arm were generally related to androgen suppression (i.e. hot flushes, weight increase), and most were mild or moderate in severity. Patients receiving degarelix experienced a higher incidence of injection-site reactions (40% vs <1%; P < 0.001) and chills (4% vs 0%; P < 0.01) compared with leuprolide, but a lower incidence of urinary tract infection (3% vs 9%; P < 0.01) and musculoskeletal and connective tissue events (17% vs 26%; P < 0.05). No immediate-onset systemic allergic reactions were reported in patients receiving degarelix.
Recently, the USA FDA requirements for GnRH agonists have been altered to include new safety warnings on their labels regarding an increased risk of diabetes and certain cardiovascular diseases (myocardial infarction, sudden cardiac death and stroke).35 In CS21, death rates were 2% and 4% with degarelix and leuprolide, respectively.18 The most frequently reported cardiac disorder was ischemic heart disease, which occurred in 4% of all patients receiving degarelix compared with 10% of those receiving leuprolide. The most common type of arrhythmia was supraventricular arrhythmia, which occurred in 2% and 4% of patients receiving degarelix or leuprolide, respectively. Additional analyses with degarelix suggest that the rate of cardiovascular events mirrors that associated with normal aging.36,37 A greater risk of cardiovascular events was observed in older patients and those with established cardiovascular disease, and risk was also influenced by modifiable risk factors (e.g. obesity and alcohol consumption), but not by variation in degarelix doses or testosterone values.
In the long-term, open-label extension to CS21, the incidence of adverse events, and of musculoskeletal events in particular, was measured.19 The overall incidence of adverse events was similar in those who had received continuous degarelix and those who switched from leuprolide after 1 year, and decreased throughout the 4 years of follow up. After a median follow up of 27.5 months, the lower probability of occurrence of musculoskeletal or connective tissue adverse events that was observed with degarelix 240/80 mg after 1 year persisted during subsequent treatment. Patients who switched from leuprolide to degarelix after 1 year experienced an increase in injection-site reactions in year 2, although the incidence decreased in years 3 and 4 to a similar level to that in patients who had received degarelix continuously.
For abarelix, phase III studies showed a broadly similar safety profile to GnRH agonists, with most adverse events resulting from androgen suppression or comorbid disorders.15,20,21,23 However, as aforementioned, abarelix is associated with potentially serious systemic allergic reactions.38
How do abarelix and degarelix compare?
Abarelix was approved by the FDA in 2004, as a “last-line” hormonal therapy for men with advanced symptomatic prostate cancer who were not suitable for GnRH agonists and had refused surgical castration. Furthermore, in view of the risk of potentially serious, immediate-onset systemic allergic reactions, the FDA imposed an extensive risk management program for abarelix.39 In 2005, abarelix was voluntarily withdrawn from the USA market. In the same year, abarelix was approved in Germany for advanced prostate cancer. However, as its efficacy was found to decline between 3 and 12 months after the start of therapy, it was recommended that patients are monitored if they are treated for longer than 3 months.24,40 Abarelix has now been approved in other EU countries and is expected to become more widely available in Europe in the future.41
Degarelix was licensed in the USA and Europe in 2008. Like the GnRH agonists (and abarelix in Germany), it is licensed as a first-line hormonal therapy for advanced prostate cancer. However, it is more widely available and more extensively studied than abarelix. Furthermore, in a large, phase III study in which 409 patients were treated with degarelix, there were no reports of systemic allergic reactions.18 This is consistent with comparative data from preclinical studies. In an in vitro study using rat peritoneal mast cells, degarelix showed a lower propensity than abarelix for histamine release.42 In a study using an ex vivo human skin model, degarelix had no significant effect on basal histamine release, in contrast to abarelix.43 Furthermore, data from a pivotal phase III study and its long-term extension show the efficacy of degarelix is maintained for 1 year and beyond.18,19
Which patients are most suitable for degarelix treatment?
As CS21 included patients with a broad range of cancer stages (31% localized, 29% locally advanced, 20% metastatic, 15% unclassified), subgroup analyses were carried out to establish whether disease stage has an impact on the relative efficacy of degarelix 240/80 mg (the licensed dose) compared with leuprolide. In later stage disease, treatment differences might be more evident, as event rates are likely to be higher over shorter time periods.
Baseline PSA > 20 ng/mL
As aforementioned, PSA failure occurred exclusively in patients with baseline PSA > 20 ng/mL.28 In this subgroup of patients, PSA failure rates were significantly lower with degarelix 240/80 mg than with leuprolide (P = 0.04).28 Furthermore, the results obtained for PSA PFS in the overall population in CS21A were also observed in those with a baseline PSA > 20 ng/mL; that is, at a median of 27.5 months of follow up, there was a significant reduction in PSA PFS after crossover from leuprolide to degarelix 240/80 mg, from 0.38 events annually to 0.19 events annually (P = 0.031). Finally, in the PSA > 20 ng/mL subgroup, the time for 25% of patients to experience PSA failure or death was 514 days for degarelix compared with 303 days for leuprolide (P = 0.01).
In patients with metastatic disease, there were differences between the PSA profiles for degarelix 240/80 mg and leuprolide. In leuprolide-treated patients, there was an initial PSA increase; this was not seen in the degarelix 240/80 mg group.28 In addition, the proportion of patients achieving PSA < 4 ng/mL over the study period was higher with degarelix 240/80 mg than with leuprolide.28
As well as PSA, there were also between-group differences in the levels of S-ALP, a marker of bone turnover. Patients with metastatic disease had significantly greater reductions in S-ALP with degarelix than with leuprolide; after initial peaks in both groups, patients receiving degarelix maintained S-ALP suppression throughout the study, without the late increases in S-ALP (which might suggest therapy failure) noted with leuprolide.44 Thus, degarelix might offer better S-ALP control than leuprolide, and might prolong control of skeletal metastases in metastatic disease compared with GnRH agonists.
The rapid reduction in testosterone and PSA levels with degarelix suggest that it might be particularly appropriate for patients requiring fast symptom relief or volume reduction. The efficacy of degarelix compared with a GnRH agonist (goserelin, plus flare protection with bicalutamide) was evaluated in a 12-week trial in men with lower urinary tract symptoms secondary to prostate cancer.45 The study was stopped early as a result of low recruitment and just 40 patients were treated; despite this, degarelix was non-inferior to goserelin/bicalutamide for the primary end-point (International Prostate Symptom Score at week 12) and superior in the per-protocol analysis (P = 0.04). Degarelix was also associated with numerically better improvements in prostate volume and peak urinary flow rate.
Several other studies are ongoing to evaluate the effect of degarelix in patients requiring fast symptom relief or volume reduction. These include another study evaluating its effect on prostate size, also in comparison to goserelin/bicalutamide (but with less stringent entry criteria; NCT00884273) and two studies of intermittent ADT: one an open-label, single-arm study (NCT00801242) and one comparing intermittent degarelix therapy with continuous ADT using degarelix or leuprolide (NCT00928434). Other degarelix studies underway include a comparison of degarelix and goserelin for prostate size reduction in men undergoing neoadjuvant hormonal therapy before radiotherapy with curative intent (NCT00833248).
GnRH antagonists offer an alternative to GnRH agonists as a pharmacological approach for castration in prostate cancer. Their direct mechanism of action results in an immediate suppression of testosterone, with no surge or microsurges. PSA suppression is also faster with GnRH antagonists than with agonists. For degarelix at least, these effects appear to translate into tangible clinical benefits, as shown by the significant improvement in PSA PFS compared with leuprolide; in these patients, PSA PFS is indicative of time to castration resistance. Indeed, in those at highest risk of PSA failure, degarelix delayed progression or death by 7 months compared with leuprolide. Also, in patients with metastatic disease, degarelix was associated with better control of the bone formation marker S-ALP than leuprolide, suggesting that it might offer prolonged control of skeletal metastases.
With the exception of injection-site reactions, which occurred more frequently with degarelix, the side-effect profile of GnRH antagonists was similar to that observed with GnRH agonists. In contrast to degarelix, the efficacy of abarelix declines over time, and a beneficial effect over agonists in terms of disease progression has not been shown; it also has the potential for rare, but serious, systemic allergic reactions. In conclusion, the overall benefit : risk profile of degarelix supports its first-line use as ADT in prostate cancer; indeed, GnRH agonists might become second-line treatment after antagonists in the future. A number of new agents, including the CYP17 antagonists, abiraterone and orteronel, and the novel AA, MDV3100, have been approved or are in development for CRPC in chemotherapy-treated and chemotherapy-naïve patients; it remains to be established how these will be sequenced (and possibly combined) with existing androgen deprivation therapies, including GnRH antagonists.
Medical writing assistance (funded by Ferring Pharmaceuticals) was provided by Dan Booth and Tom Lavelle of Bioscript Stirling Ltd.
Conflict of interest
H Van Poppel and L Klotz received from Ferring:
• Honoraria: for being a member of the Advisory Board
• Funding Research: for participating in a clinical trial