Onco Targets and Therapy Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW An update on the use of degarelix in the treatment of advanced hormone-dependent prostate cancer Ferenc G Rick1 Abstract: Androgen deprivation therapy remains the mainstay of medical treatment for Norman L Block1–3 advanced prostate cancer. Commonly, this is achieved with medical androgen deprivation Andrew V Schally1–3 rather than surgical intervention as the permanence and psychological effects of the latter are unacceptable for most patients. Degarelix is a third generation antagonist of luteinizing 1Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical hormone-releasing hormone (LHRH, also termed gonadotropin-releasing hormone) for the Center and South Florida Veterans first-line treatment of androgen-dependent advanced prostate cancer. Degarelix acts directly Affairs Foundation for Research and on the pituitary receptors for LHRH, blocking the action of endogenous LHRH. The use of Education, 2Department of Pathology, University of Miami, Miller School of degarelix eliminates the initial undesirable surge in gonadotropin and testosterone levels, which Medicine, 3Divisions of Hematology/ is produced by agonists of LHRH. Degarelix is the most comprehensively studied and widely Oncology and Endocrinology, For personal use only. Department of Medicine, University available LHRH antagonist worldwide. Clinical trials have demonstrated that degarelix has a of Miami, Miller School of Medicine, long-term efficacy similar to the LHRH agonist leuprolide in achieving testosterone suppres- Miami, Florida, USA sion in patients with prostate cancer. Degarelix, however, produces a faster suppression of testosterone and prostate-specific antigen (PSA), with no testosterone surges or microsurges, and thus prevents the risk of clinical flare in advanced disease. Recent clinical trials demon- strated that treatment with degarelix results in improved disease control when compared with an LHRH agonist in terms of superior PSA progression-free survival, suggesting that degarelix likely delays progression to castration-resistant disease and has a more significant impact on bone serum alkaline phosphatase and follicle-stimulating hormone. Degarelix is usually well tolerated, with limited toxicity and no evidence of systemic allergic reactions in clinical studies. Degarelix thus represents an important addition to the hormonal armamentarium for therapy of OncoTargets and Therapy downloaded from https://www.dovepress.com/ by 54.70.40.11 on 18-May-2018 advanced androgen-dependent prostate cancer. Keywords: degarelix, GnRH, LHRH, metastatic prostate cancer, androgen-dependent prostate cancer, hormonal therapy Introduction The American Cancer Society estimated that there were 241,740 new cases of prostate cancer (PCa) in the United States of America in 2012, accounting for 28.5% of all cancers in men, and 28,170 deaths.1 In addition to morbidity and mortality, the socio- economic burden and the impact of PCa on quality of life are significant.2 The first Correspondence: Ferenc G Rick Veterans Affairs Medical Center milestone for the treatment of PCa was in 1941, when Huggins and Hodges reported and South Florida Veterans Affairs that the growth of PCa cells requires the androgen, testosterone.3 This discovery led Foundation for Research and Education, to the use of orchiectomy or estrogens as the prevalent methods of androgen deprivation 1201 NW 16th St, Research (151), Room 2A103C Miami, FL 33125, USA therapy (ADT) for patients with advanced PCa and remained so until the 1970s.4 Tel +1 305 575 3477 The next major breakthrough in ADT belongs to Andrew Schally and associates, Fax +1 305 575 3126 Email [email protected] who first isolated and described the structure of the hypothalamic neurohormone, submit your manuscript | www.dovepress.com Onco Targets and Therapy 2013:6 391–402 391 Dovepress © 2013 Rick et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article http://dx.doi.org/10.2147/OTT.S32426 which permits unrestricted noncommercial use, provided the original work is properly cited. Powered by TCPDF (www.tcpdf.org) 1 / 1 Rick et al Dovepress luteinizing hormone-releasing hormone (LHRH or The agonists, acting on pituitary LHRH receptors, produce gonadotropin-releasing hormone) in 1971.5 The Schally group an intense initial stimulation of release of LH and FSH and, was also the first to show that both natural and synthetic LHRH as a consequence, cause a discernible rise in testosterone. released luteinizing hormone (LH) and follicle-stimulating Eventually, agonist-induced overstimulation overcomes the hormone (FSH) in humans.6 Over the past 40 years, more than natural pulsatile control of LH release, leading to receptor 3000 agonistic analogs of LHRH have been synthesized. Of desensitization or downregulation, which in turn sup- these analogs, the most important are triptorelin, leuprolide, presses LH and FSH secretion and consequently reduces buserelin, nafarelin, and goserelin, which are 50–100 times testosterone to castrate levels.18 Antagonists of LHRH, in more potent than LHRH itself.7 Endocrine therapy for PCa, contrast, exert their effect directly, competitively binding based on such agonistic analogs of LHRH, was also developed to and blocking pituitary LHRH receptors and causing an by the Schally laboratory.8,9 Schally and colleagues found that immediate blockade of LH and FSH secretion.7 This results long-term administration of LHRH agonists downregulates in immediate testosterone suppression, without any initial pituitary receptors for LHRH, which results in substantially stimulation or surge.19 decreased levels of LH, FSH, and testosterone, providing Animal studies showed not only that administration palliation for patients with advanced PCa.8,9 Agonists of LHRH of LHRH antagonists suppresses LH and testosterone to were found to be safer and equally effective as estrogen.10 castrate levels but also that administration of an LHRH This groundbreaking work by Schally and the subsequent antagonist before an agonist will blunt the expected charac- development of depot formulations of LHRH agonists laid teristic LH and testosterone surge induced by the agonist.20,21 the foundation for current ADT.4 Furthermore, recent in vivo studies in rats suggest that Despite their efficacy, however, LHRH agonists were LHRH antagonists, at doses which do not induce castration found to have several disadvantages associated with their levels of testosterone, can shrink experimentally enlarged mode of action. The initial stimulation of pituitary LHRH LHRH-receptor-expressing benign prostatic tissue. This receptors, in particular, causes a testosterone surge which inhibition is possibly due to the direct inhibitory effects of For personal use only. delays the achievement of castrate testosterone levels for LHRH antagonists exerted through prostatic LHRH recep- about 2–4 weeks.11 This surge may also lead to an exacerba- tors directly on the tissue concerned.22–24 Beneficial effects tion of clinical symptoms (flare effects) in advanced disease, of antagonists of the hypothalamic neurohormones, LHRH including increased bone pain, spinal cord compression, and growth hormone-releasing hormone, on experimental ureteral obstruction, urethral obstruction, and even death.12,13 models of benign prostatic hyperplasia and PCa have been Furthermore, LHRH agonists may also cause testosterone recently reported.25–29 microsurges after each dose administration.14 More recently, a new approach to ADT has emerged Development of LHRH antagonists with the development of antagonists of LHRH. This class Cetrorelix was the first LHRH antagonist tested clinically of agents exerts a direct and immediate blockade of LHRH in patients with PCa and was shown to induce clinical OncoTargets and Therapy downloaded from https://www.dovepress.com/ by 54.70.40.11 on 18-May-2018 pituitary receptors and produces rapid testosterone suppres- improvement.30,31 Abarelix, the first antagonist available sion without an initial surge or subsequent microsurges.15 clinically for treatment of PCa, displayed a safety profile Degarelix, a clinically effective third generation LHRH comparable to that of the LHRH agonist, leuprolide, with antagonist, is currently available for therapy of advanced PCa or without the antiandrogen, bicalutamide.32 However, in the US; it is also available in several countries in North immediate-onset systemic allergic reactions (1.1%) were a and South America, Japan, and most European countries.16 major concern with abarelix.16 This reaction was related to This review evaluates the efficacy and safety of the LHRH histamine release. The manufacturer withdrew abarelix from antagonist, degarelix, and collates recently published addi- the US market for related commercial reasons. It is currently tional clinical and experimental data. available in Germany and its launch in other European coun- tries is underway.16 Mechanism of action of LHRH The third generation LHRH antagonist, degarelix, was (gonadotropin-releasing hormone) synthetically modified with a view toward reducing this antagonists histamine-releasing activity. Degarelix showed only very Antagonists of LHRH induce chemical castration by a weak histamine-releasing properties and the lowest capacity mechanism that is different than that of LHRH agonists.17 for histamine release among the antagonists of LHRH, 392 submit your manuscript | www.dovepress.com Onco