Abarelix and other gonadotrophin-releasing hormone antagonists in prostate cancer

Authors


Roger Kirby, The Prostate Centre, 32 Wimpole St, London W1G 8GT, UK.
e-mail: rogerkirby@theprostatecentre.com

Abstract

Hormonal therapy is the main recommended treatment for locally advanced and metastatic prostate cancer. Luteinizing hormone-releasing hormone (LHRH) agonists, such as buserelin, goserelin, leuprorelin and triptorelin, stimulate the pituitary’s gonadotrophin-releasing hormone (GnRH) receptor, ultimately leading to its de-sensitization and subsequent reduction of LH and testosterone levels. However, this reduction is accompanied by a well described increase or ‘surge’ in LH and testosterone levels, necessitating the concomitant administration of an antiandrogen to combat the potential effects of transient acceleration in cancer activity. Two pure GnRH antagonists have been developed, abarelix and degarelix, that are devoid of any agonist effect on the GnRH receptor and consequently do not result in testosterone flare. Abarelix was the first GnRH antagonist to be developed and was approved by the USA Food and Drug Administration in 2004 for the initiation of hormonal castration in advanced or metastasizing hormone-dependent prostate carcinoma, when rapid androgen suppression is necessary. Clinical data on both abarelix and degarelix show that they can produce rapid and sustained decreases in testosterone to castrate levels without the need for co-administration of an antiandrogen, and with a very low complication rate in the short term.

Abbreviation
DHT

dihydrotestosterone.

INTRODUCTION

Prostate cancer is the second most common cause of male cancer-related deaths in the UK and the USA, being responsible for ≈12% of such deaths [1,2]. Prostate cancer is also the basis of ≈11% of all male cancers in Europe; ≈2.6 million new cases of cancer are diagnosed each year [3]. A total of 10 000 men die from the disease each year in the UK alone [1]. Hormonal therapy is the recommended treatment for advanced or metastatic disease and the principle of this therapy is to reduce testosterone levels medically or via surgical castration, or to block the peripheral action of testosterone using androgen blockade [4]. The control of testosterone secretion is via the hypothalamic-pituitary-gonadal axis (Fig. 1). The anterior pituitary gland is stimulated by hypothalamic GnRH (also termed LHRH) to release LH and FSH. Testosterone secretion is in response to stimulation by LH.

Figure 1.

Control of testosterone secretion via the hypothalamic-pituitary-gonadal axis.

THE ROLE OF HORMONAL THERAPY IN PROSTATE CANCER

Conventional hormonal therapy for prostate cancer has traditionally taken the form of surgical castration (bilateral orchidectomy), or medical therapy involving LHRH agonists or antiandrogens given alone or in combination. With orchidectomy, the removal of the testicular source of androgens achieves a hypogonadal status with a rapid decline in testosterone to castrate levels within 24 h [5]. The castrate levels of testosterone produced are lower overall than those seen with LHRH agonists in the long term [6], but the principal drawback of this approach is its negative psychological effect on patients. LHRH agonists (buserelin, goserelin, leuprorelin and triptorelin) stimulate the pituitary’s GnRH receptors, ultimately leading to their desensitization and subsequent reduction in LH and testosterone level. Analysis of clinical data shows that LHRH agonists are equivalent in terms of survival after therapy to orchidectomy [7]. However, the CIs reported with the different LHRH agonists were so wide that it is difficult to determine whether there are real differences between individual LHRH agonists. A significant issue relating to the use of LHRH agonists is testosterone ‘surge’ or ‘flare’ in advanced disease, i.e. increased bone pain, acute BOO, obstructive renal failure, spinal cord compression and fatal cardiovascular events due to hypercoagulation status [8]. A recent review addressing these issues concluded that clinical flare needs to be distinguished from the more common biochemical flare (i.e. increasing levels of PSA) and even from asymptomatic radiographic evidence of progression, and that patients at risk for clinical flare are overwhelmingly those with high-volume, symptomatic, bony disease, who account for only 4–10% of patients with M1 disease [9]. Thus, many men will not need flare protection. However, there are no clear thresholds or variables that will help clinicians to categorize specific patients into high or low risk for flare-related effects. Patients with a clinically heavy disease load should therefore be recognized as being at risk and flare protection should be considered.

The flare phenomenon can be ameliorated by adding an antiandrogen, although some authors have suggested that even with this blocking therapy there is potentially an adverse effect in the long term [10]; however, there are no convincing long-term data to support this notion. Blockade of testosterone by antiandrogen monotherapy has also been shown to be an effective alternative to castration in certain patients. Two trials evaluating bicalutamide monotherapy in patients with non-metastatic locally advanced or metastatic prostate cancer showed that this antiandrogen had comparable effects to castration on survival in patients with locally advanced disease without metastases [11], but was less effective in patients with metastatic prostate cancer [12].

GnRH ANTAGONISTS

Pure GnRH antagonists have been developed that are devoid of any agonist activity on the GnRH receptor. Antagonistic analogues, peptides of native GnRH, cause rapidly sustained inhibition of LH and FSH, with an accompanying rapidly sustained decrease in testosterone [13–16]. These linear decapeptides occupy the GnRH receptor ligand-binding sites in the anterior pituitary and several of these have been studied, including abarelix, cetrorelix and degarelix. Cetrorelix has been studied in female hormonal control [14] and in symptom control in BPH [15]. Degarelix is administered subcutaneously and a pivotal, phase III, randomized controlled trial showed that degarelix was as effective as the GnRH agonist leuprolide in maintaining low testosterone levels (≤0.5 ng/mL) over a 1-year treatment period [16]. Median PSA levels at 14 and 28 days were lower in the degarelix group than in the leuprolide group. The most frequently reported side-effect associated with degarelix therapy is hot flushes, an expected androgen-withdrawal symptom. There was also a higher incidence of injection-site reactions with degarelix than with leuprolide (40% vs <1%; P < 0.001, respectively). Most of the longer term data are available on abarelix and a summary of the clinical trials conducted to date is shown in Table 1[17–22].

Table 1.  Published clinical trials on the GnRH antagonist abarelix
RefComparatorType of study
[17]Leuprolide and goserelin ± antiandrogenProspective, open label, multicentre comparison
[19]LeuprolideOpen label, randomized, multicentre
[21]Leuprolide + antiandrogenOpen label, randomized, multicentre
[18]Bilateral orchidectomy avoidanceOpen label multicentre, no active control
[22]Pharmacology/prostate volume reductionPharmacokinetics and pharmacodynamics
[20]Goserelin + antiandrogenOpen label, randomized, multicentre

EFFICACY

Tomera et al.[17] reported a phase II, open label study in 209 patients with prostate cancer who had increasing PSA levels after definitive local therapy, or who had had intermittent hormonal therapy for >6 months before study entry. Patients were given a 100-mg abarelix 1-month depot i.m. on days 1 and 15 followed thereafter by 50 mg i.m. at 28-day intervals. The dose was increased to 100 mg if castration levels (defined as testosterone <50 ng/dL) were not maintained. A further 33 patients received one of two LHRH agonists; leuprolide in 1-, 3- or 4-month depot formulations, or goserelin in a 1- or 3-month depot formulation. Both were given with or without the addition of nonsteroidal antiandrogen. The primary endpoint was castration levels of testosterone at 8 days, i.e. the measure of the rapidity of testosterone response; secondary endpoints included testosterone surge (defined as increased testosterone by ≥10% on any two of days 2, 4 or 8). Castration was achieved in 34.5% of patients treated with abarelix at day 2, increasing to 82.3% at day 13. None of the patients on LHRH agonist achieved castrate levels by day 13. At day 27, 98.1% and 100% of patients on abarelix and LHRH agonist had castrate levels of testosterone. None of the patients treated with abarelix reported testosterone flare, compared with 82% of those on LHRH agonist. Abarelix-related changes in dihydrotestosterone (DHT) levels paralleled those of testosterone, while the percentage decrease for LH and FSH was greater.

Another open-label study of abarelix in patients with advanced symptomatic prostate cancer determined the possibility of avoiding bilateral orchidectomy; endocrine, PSA outcomes, pain scores and disease response were also assessed [18]. In all, 81 patients with primarily D1 or D2 disease received abarelix 100 mg per month for 6 months. All patients avoided the requirement for a bilateral orchidectomy, although two withdrew from the study and were therefore classed as failures. In the remainder, testosterone reduction was rapid, with 79% of patients achieving castrate levels at day 8, and 97% and 93% being at castrate levels at days 85 and 169, respectively. The PSA level decreased by 75% at day 15, again indicating a rapid onset of biochemical response, with PSA nadir at day 113 in most patients. Therapeutic responses were high, with 90% (65/72) men having an improvement in pain score and/or analgesic use. Of seven patients at risk of impending neurological compromise at study entry, none developed spinal cord compression. At day 85, 21 of 34 patients evaluated had improvements in bladder neck outlet obstruction, while 10 of 13 catheterized at baseline no longer required catheters at day 85.

A phase III open-label study of abarelix reported data from 269 men with locally advanced and metastatic disease; most cancers were Gleason grade ≥5 [19]. Patients were randomized (2 : 1) to treatment with abarelix 100 mg (180 men) or leuprolide acetate 7.5 mg (89 men) given monthly for 1 year. The abarelix group received an additional dose at day 15. Primary endpoints were the percentage of patients having a testosterone surge, the rapidity of testosterone reduction and the maintenance of castration (testosterone ≤50 ng/dL). There was a testosterone surge in 80% of patients receiving leuprolide but in none of the abarelix-treated patients (P < 0.001). Medical castration was achieved more rapidly with antagonist than with the agonist (abarelix, 24% by day 2, 72% by day 8; vs none of the patients in the leuprolide group; P < 0.001). Overall, similar numbers in both groups achieved castrate levels, i.e. 91.7% and 95.5% for abarelix and leuprolide, respectively. Reductions in LH, FSH, PSA and DHT followed those for testosterone.

A second comparative study (the ABACAS Study) involved 177 patients with advanced or metastatic cancer treated for 12 months with abarelix 100 mg 4-weekly or the LHRH agonist goserelin 3.6 mg 4-weekly plus bicalutamide 50 mg daily [20]. The primary endpoint was time to induction of medical castration during the first 12 weeks. Secondary endpoints included castration rates at day 1 and 3, maintenance of castration, PSA and endocrine levels, and rates of disease progression. The median time to castration was significantly shorter for abarelix than for goserelin plus bicalutamide (7 vs 21 days; P < 0.001). Castration rates on day 3 were also significantly higher for abarelix than for combined therapy (36% vs 0%; P < 0.001). Flare was not reported in any abarelix-treated patients, in comparison with 96% of men receiving goserelin plus bicalutamide (P < 0.001). PSA values were significantly lower on day 7 in abarelix-treated patients (P = 0.047) and were similar on days 14 and 21. There was a >90% reduction in PSA values in both groups from day 56 onwards. Testosterone fluctuations of >50 ng/dL occurred in 22% of abarelix-treated patients; on continued use of abarelix, patients had castrate levels. This was the case in only 8% of patients on goserelin plus bicalutamide, with most fluctuations occurring on or after day 168. Overall disease progression rates were 9% in both treatment groups.

A further study comparing GnRH antagonist vs LHRH agonist and antiandrogen randomized patients to abarelix 100 mg monthly or a combination of leuprolide 7.5 mg monthly and bicalutamide 50 mg daily over 24 weeks [21]. In all, 255 patients with D1 or D2 disease received abarelix (170) or combined therapy (85). Endpoints were as previously described and included the incidence of testosterone surge, efficacy of medical castration and rapidity of testosterone reduction. None of the patients receiving abarelix had flare, compared with 14% in the combined-therapy group (P < 0.001). On day 8, 68% and 0% of abarelix and leuprolide/bicalutamide patients achieved defined castrate levels. By day 29, 85% of patients in both groups had castrate levels and this was maintained to day 169 for most of these patients. DHT, LH and FSH followed the same pattern of reduction as testosterone and PSA reductions were similar in both groups, with >90% of patients with abnormal baseline PSA achieving normality during the 6-month period.

The pharmacokinetics and pharmacodynamics of a continuous infusion of abarelix have been evaluated [22] and these were found to be comparable to those seen using i.m. administration. In this multicentre, open-label study, 36 men with clinically localized or advanced prostate cancer received a continuous infusion of 50 µg/kg/day of abarelix for up to 12 weeks. Peak serum concentrations were reached at ≈28 days and maximum inhibition of testosterone, DHT, FSH and LH was achieved and maintained from day 15. Inhibition of PSA was 52.5% at day 28, increasing to 81.9% after 12 weeks, reaching 94.6% in the 4–7 week follow-up period. Prostate gland size was reduced by 35% at the end of the study treatment phase.

SAFETY

Early studies on abarelix reported an acceptable safety profile [17]. Questions have been raised about hypersensitivity reactions in a small percentage of patients receiving abarelix [23] and these have been re-stated in review articles [10]; however, further scrutiny of the evidence is more reassuring. Reports of systemic hypersensitivity reactions have been uncommon and self-limiting, but they were associated with hypotension and syncope in some cases. A phase III study of 242 men [19] showed that hypersensitivity occurred at ≈1%, a rate which was only marginally higher than that seen with leuprolide. One event of an allergic reaction (generalized erythematous rash with pruritus) and one event of increased transaminases with adverse sequelae were reported as serious and related to abarelix. No anti-abarelix antibodies were detected in men treated with abarelix. The comparative safety of abarelix and leuprolide plus bicalutamide [21] showed a similar adverse-event rate in the two treatment arms. These incidents included allergic events such as urticaria and pruritis, but resolved without treatment. Overall, of the 1397 patients who have received abarelix in clinical studies to date, 15 (1.1%) have had immediate-onset systemic injection reactions [24] and in seven of these (0.5%), hypotension or syncope was part of the reaction. Allergic reactions with LHRH agonists also occur in ≈0.6%, which often interrupt treatment and require medical intervention. Investigation of this phenomenon immunologically has failed to reveal changes in immune status, and abarelix-treated men do not show antibody formation. Human volunteer skin-testing studies with abarelix have shown a histamine-release reaction, and this was also reported in one of the eight patients who had an injection reaction [25]. Skin reactions are also a feature of the later GnRH antagonists [26] and it is possible that histamine release is a class effect.

ADVANTAGES OF ABARELIX TREATMENT

Abarelix was the first GnRH antagonist to be approved by the USA Food and Drug Administration in 2004. Specifically for the USA, physicians are required to register with a user-safety programme to prescribe the drug. Abarelix is approved in Germany for the initiation of hormonal castration in advanced or metastatic hormone-dependent prostate carcinoma when androgen suppression is necessary.

One of the key advantages it has over the LHRH agonists is that there is no testosterone flare. It has been shown that with LHRH agonists, LH peaks at about three times the baseline value at 24 h after administration [27]. The testosterone increase is delayed, with a peak being reached at day 3 and a subsequent decline to pretreatment levels by day 7. Castrate levels are achieved after 3 weeks of therapy. In a study by Waxman et al.[28], the appearance of symptoms appeared to follow the changes in LH and testosterone, with pain first occurring at 12 h after the start of therapy and peaking at 36 h.

LHRH agonists should not be used in patients with metastatic disease at high risk of the testosterone flare phenomenon. Patients in this category are those with metastatic disease who are at risk of a catastrophic event from transient disease flare, such as those with impending spinal cord compression, with significant obstructive voiding symptoms or with early neurological sequelae. Flare should also be avoided in patients with asymptomatic advanced disease, to avoid the induction of symptoms. It is essential that a form of blocking therapy is added in conjunction with LHRH agonists if such a therapy is given to such patients.

Another advantage of GnRH antagonists over the agonists is the attainment of a faster medical castration through a more pronounced down-regulation of testosterone. Faster control of testosterone levels also removes the risk of tumour stimulation. Such control has been accompanied by a reduction in risk of spinal cord compression, improvements in bladder neck outlet obstruction, reduced need of catheterization and reduced bone pain [18].

CONCLUSION

Abarelix has the potential to give an effective treatment to patients with advanced prostate cancer while avoiding the risk of worsening of symptoms due to testosterone flare. The use of abarelix has the possibility of improving compliance, because the concept of a pure antagonist is easier for patients and their relatives to grasp than that of an agonist, which first stimulates then subsequently blocks androgen production. The simplified dosing regimen that does not require the previous use of an antiandrogen is also more convenient for both patients and clinicians. Importantly, no additional physician visits are required compared with the LHRH agonist regimen. Abarelix presents a new viable alternative for patients with advanced and metastatic prostate cancer.

ACKNOWLEDGEMENTS

This paper was supported by an unrestricted educational grant from Speciality European Pharma. The authors would like to acknowledge the editorial support provided by Dr Christine McKillop. Drs Kirby and Clarke have presented at SEP sponsored symposia.

CONFLICT OF INTEREST

Roger S. Kirby is Chairman at Symposium, John M. Fitzpatrick is on the Advisory Boards for GSK, Sanofi-aventis, Ferring and Pfizer, and Noel Clarke is a Speaker at Symposium.

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