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The Canadian Journal of Urology Apr 2014Androgen deprivation therapy (ADT) is the lynchpin of treatment for advanced prostate cancer. Prescribing physicians and patients have a choice between orchiectomy,... (Review)
Review
INTRODUCTION
Androgen deprivation therapy (ADT) is the lynchpin of treatment for advanced prostate cancer. Prescribing physicians and patients have a choice between orchiectomy, luteinizing hormone releasing hormone (LHRH) agonists, combined androgen deprivation (CAD) or LHRH antagonists.
MATERIALS AND METHODS
Literature relating to the use of LHRH antagonists in the management of prostate cancer was reviewed.
RESULTS
Abarelix was the first-in-class LHRH pure antagonist that was Food and Drug Administration (FDA) approved in 2003. Due to a variety of concerns including hypersensitivity reactions it was withdrawn from the United States (U.S.) market in 2005. The only currently commercially available LHRH antagonist in the U.S. is degarelix available as a once-a-month depot injection. The potential clinical advantage of degarelix compared to the LHRH agonists is the very rapid and sustained testosterone suppression with no identifiable physiological or clinical testosterone surge or flare. The main disadvantage of degarelix compared to the LHRH agonists is the monthly dosing and the inconvenience for some patients and practices. Recent studies tout improved disease control for degarelix compared to monthly leuprolide acetate; however, these results remain controversial.
CONCLUSIONS
The rapid T-suppression achieved with degarelix may provide a clinical benefit for various groups of men with advanced or locally advanced disease.
Topics: Antineoplastic Agents; Cost-Benefit Analysis; Disease Progression; Gonadotropin-Releasing Hormone; Humans; Male; Neoplasm Staging; Oligopeptides; Prostatic Neoplasms; Testosterone
PubMed: 24775720
DOI: No ID Found -
Reviews in Urology 2001The last decade has seen explosive growth in the therapy of prostate cancer. Three areas of therapeutics are emerging: 1) new compounds with novel uses; 2) available...
The last decade has seen explosive growth in the therapy of prostate cancer. Three areas of therapeutics are emerging: 1) new compounds with novel uses; 2) available compounds with new applications; and 3) new compounds applied to established indications. The novel compounds target specific receptor sites of cancer pathways and attack cancer cells with less effect on normal tissue. Earlyphase trials with compounds targeting the endothelin-A and EGF receptors have shown encouraging results in hormone-refractory prostate cancer. In addition, the Early Prostate Cancer Trial of over 8000 men is currently underway to determine the benefit of adjuvant androgen ablation with bicalutamide in men with localized prostate cancer. Early results show a significant 42% reduction in the progression of the disease in the bicalutamide treatment arm. Further, in large, phase 3 clinical trials in patients needing androgen ablation, the GnRH antagonist abarelix caused no testosterone surge and demonstrated a significantly more rapid decline in serum testosterone to the castrate level than did an LHRH agonist analogue. Abarelix should thus have application as a monotherapy in patients who need a rapid onset of action or are at high risk of complications from the clinical flare seen with LHRH agonists. Abarelix also uniquely caused a sustained decline in serum FSH levels, which have been shown in vitro to stimulate prostate cancer cell growth. If these favorable effects can be duplicated in patients, abarelix might also offer a survival benefit.
PubMed: 16986005
DOI: No ID Found -
The Oncologist 2000Prostate cancer has become the most common cancer among American men and is second only to lung cancer as a cause of male cancer-related death. Several treatment options... (Review)
Review
Prostate cancer has become the most common cancer among American men and is second only to lung cancer as a cause of male cancer-related death. Several treatment options exist for different stages of prostate cancer including observation, prostatectomy, radiation therapy, chemotherapy, and hormone therapy. Hormone therapy has evolved from the use of estrogens to gonadotropin-releasing hormone (GnRH) agonists and recently, investigational GnRH antagonists. GnRH receptor agonists such as leuprolide, bruserelin and goserelin have been used for the treatment of prostate cancer. These agonists eventually cause the inhibition of lutenizing hormone production, which in turn causes a suppression of testosterone and dihydrotestosterone, on which continued growth of prostate cancer cells depend. Several comparative studies of leuprorelin administered as daily injections or monthly depot injections have been reported. Disease progression was prevented in more than 72% of men administered daily leuprorelin, and in 82% to 89% of those receiving monthly depots. Another synthetic GnRH analog, goserelin, has been studied in a similar population of men with daily injections producing partial responses in 60% to 80% of men with previously untreated prostate cancer. Abarelix, a peptide antagonist of GnRH receptor, is also being studied for the treatment of prostate cancer. The discovery and development of GnRH antagonists may provide an important advance for patients with prostate cancer. Clearly the studies described herein, as well as many others, outline an exciting era of research to define the optimal use of hormonal therapy in prostate cancer.
Topics: Antineoplastic Agents, Hormonal; Buserelin; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Prostatic Neoplasms; Testosterone
PubMed: 10794807
DOI: 10.1634/theoncologist.5-2-162 -
Reviews in Urology 2004The hypothesis that follicle-stimulating hormone (FSH) signaling contributes to the progression of androgen-independent prostate cancer (AIPC) is supported by...
The hypothesis that follicle-stimulating hormone (FSH) signaling contributes to the progression of androgen-independent prostate cancer (AIPC) is supported by preclinical evidence. Therefore, abarelix, a gonadotropin-releasing hormone antagonist that suppresses circulating FSH more effectively than standard hormone therapies, would be expected to reduce FSH without altering testosterone, thereby testing the hypothesis that circulating FSH supports the progression of AIPC. The authors tested abarelix on 2 groups of men with early AIPC: 1 group had undergone luteinizing hormone-releasing hormone agonist therapy and the other had undergone orchiectomy. Although there was no confirmed response in either group, the investigators found the time to progression, fraction of patients progression-free at the end of therapy, and fraction of patients with confirmed prostate-specific antigen reductions less than 50% were all higher in the orchiectomy-treated patients. This hypothesis-generating observation has led to a phase I trial to determine whether an escalation in the dosage of abarelix is safe and will produce more complete suppression of FSH.
PubMed: 16985935
DOI: No ID Found -
British Journal of Clinical Pharmacology Oct 2010Early studies on gonadotrophin-releasing hormone (GnRH) antagonists pointed out histamine-mediated anaphylactic reactions as a potential adverse effect of these drug...
AIMS
Early studies on gonadotrophin-releasing hormone (GnRH) antagonists pointed out histamine-mediated anaphylactic reactions as a potential adverse effect of these drug candidates. In this study we have compared the histamine-releasing potential of four approved and marketed antagonists, degarelix, cetrorelix, abarelix and ganirelix in an ex vivo model of human skin samples.
METHODS
Human skin samples were obtained during cosmetic plastic surgery and kept in oxygenated saline solution. The samples were incubated either without or at different concentrations of the antagonists (3, 30 or 300 µg ml(-1) for all, except for ganirelix 1, 10 or 100 µg ml(-1) ). The drug-induced effect was expressed as the increase relative to basal release. The histamine-releasing capacity of the skin was verified by a universal histamine releaser, compound 40/80.
RESULTS
Degarelix had no significant effect on basal histamine release in the 3 to 300 µg ml(-1) concentration range. The effect of ganirelix was moderate causing a nonsignificant increase of 81 ± 27% at the 100 µg ml(-1) concentration. At 30 and 300 µg ml(-1) concentrations abarelix (143 ± 29% and 362 ± 58%, respectively, P < 0.05) and cetrorelix (228 ± 111% and 279 ± 46%, respectively, P < 0.05) caused significantly increased histamine release.
CONCLUSIONS
In this ex vivo human skin model, degarelix displayed the lowest capacity to release histamine followed by ganirelix, abarelix and cetrorelix. These findings may provide indirect hints as to the relative likelihood of systemic anaphylactic reactions in clinical settings.
Topics: Gonadotropin-Releasing Hormone; Histamine; Histamine Release; Humans; Oligopeptides; Skin
PubMed: 20840449
DOI: 10.1111/j.1365-2125.2010.03730.x -
Therapeutic Advances in Urology Jun 2011Androgen deprivation therapy (ADT) is the main treatment approach in advanced prostate cancer and in recent years has primarily involved the use of...
Androgen deprivation therapy (ADT) is the main treatment approach in advanced prostate cancer and in recent years has primarily involved the use of gonadotropin-releasing hormone (GnRH) agonists. However, despite their efficacy, GnRH agonists have several drawbacks associated with their mode of action. These include an initial testosterone surge and testosterone microsurges on repeat administration. GnRH antagonists provide an alternative approach to ADT with a more direct mode of action that involves immediate blockade of GnRH receptors. Antagonists produce a more rapid suppression of testosterone (and prostate-specific antigen [PSA]) without a testosterone surge or microsurges and appear to offer an effective and well tolerated option for the hormonal treatment of prostate cancer. Comparisons with GnRH agonists have shown GnRH antagonists to be at least as effective in achieving and maintaining castrate testosterone levels in patients with prostate cancer. Furthermore, with antagonists, the lack of an initial testosterone surge (which may cause clinical flare) may allow more rapid relief of symptoms related to prostate cancer, avoid the need for concomitant antiandrogens to prevent clinical flare (so avoiding any antiandrogen-associated adverse events) and allow GnRH antagonist use in patients with high tumour burden and/or acute problems such as spinal cord compression. Although several antagonists have been investigated, only degarelix and abarelix are currently available for clinical use in prostate cancer. Currently, degarelix is the most extensively studied and widely available agent in this class. Degarelix is one of a newer generation of antagonists which, in a comprehensive and ongoing clinical development programme, has been shown to provide rapid, profound and sustained testosterone suppression without the systemic allergic reactions associated with earlier antagonists. This review examines the currently available data on GnRH antagonists in prostate cancer.
PubMed: 21904569
DOI: 10.1177/1756287211414457 -
American Journal of Physiology.... Jul 2020We have previously shown that systemic injection of erythropoietin-producing hepatocellular receptor A7 (EPHA7)-Fc raises serum luteinizing hormone (LH) levels before...
We have previously shown that systemic injection of erythropoietin-producing hepatocellular receptor A7 (EPHA7)-Fc raises serum luteinizing hormone (LH) levels before ovulation in female rats, indicating the induction of EPHA7 in ovulation. In this study, we aimed to identify the mechanism and hypothalamus-pituitary-ovary (HPO) axis level underlying the promotion of LH secretion by EPHA7. Using an ovariectomized (OVX) rat model, in conjunction with low-dose 17β-estradiol (E) treatment, we investigated the association between EPHA7-ephrin (EFN)A5 signaling and E negative feedback. Various rat models (OVX, E-treated OVX, and abarelix treated) were injected with the recombinant EPHA7-Fc protein through the caudal vein to investigate the molecular mechanism underlying the promotion of LH secretion by EPHA7. was observed strongly expressed in the arcuate nucleus of the female rat by using RNAscope in situ hybridization. Our results indicated that E, combined with estrogen receptor (ER)α, but not ERβ, inhibited and gonadotropin-releasing hormone 1 ( expressions in the hypothalamus. In addition, the systemic administration of EPHA7-Fc restrained the inhibition of and by E, resulting in increased and expressions in the hypothalamus as well as increased serum LH levels. Collectively, our findings demonstrated the involvement of EPHA7-EFNA5 signaling in the regulation of LH and the E negative feedback pathway in the hypothalamus, highlighting the functional role of EPHA7 in female reproduction.
Topics: Animals; Arcuate Nucleus of Hypothalamus; Ephrin-A5; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens; Feedback, Physiological; Female; Gonadotropin-Releasing Hormone; Hormone Antagonists; Hypothalamo-Hypophyseal System; Hypothalamus; Luteinizing Hormone; Oligopeptides; Ovariectomy; Ovary; Protein Precursors; Rats; Receptor, EphA7; Recombinant Proteins
PubMed: 32396496
DOI: 10.1152/ajpendo.00046.2020 -
Reviews in Urology 2004Luteinizing hormone-releasing hormone (LHRH) agonist therapy to induce medical castration has become the most common form of hormonal therapy for advanced and metastatic...
Luteinizing hormone-releasing hormone (LHRH) agonist therapy to induce medical castration has become the most common form of hormonal therapy for advanced and metastatic prostate cancer. When treatment is started, LHRH agonists initially stimulate the release of LH, causing a surge in serum testosterone that can precipitate a "flare" phenomenon or worsening of disease, particularly in patients with bone metastatic disease. Gonadotropin-releasing hormone (GnRH) receptor antagonism represents a newer approach to medical castration. Abarelix is a pure GnRH receptor antagonist that is devoid of any LHRH agonist activity. Results from 1 phase II and 3 phase III clinical trials demonstrate that abarelix produces medical castration more quickly and without causing testosterone surge, as compared with LHRH agonists with or without a nonsteroidal antagonist. The safety profile in terms of adverse events is comparable between the 2 types of treatment, but the lack of testosterone surge with abarelix might confer a safety advantage by abolishing the risk of a disease flare.
PubMed: 16985933
DOI: No ID Found -
FDA Consumer 2004
Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Humans; Male; Oligopeptides; Prostatic Neoplasms
PubMed: 15101352
DOI: No ID Found -
Reviews in Urology 2001It is well recognized that testosterone has a number of untoward effects on prostatic carcinoma and that castration is associated with significant tumor shrinkage and...
It is well recognized that testosterone has a number of untoward effects on prostatic carcinoma and that castration is associated with significant tumor shrinkage and resolution of symptoms of advanced prostatic carcinoma. Approaches to hormonal therapy have evolved significantly over the last several decades. Initially castration was utilized, which provided effective reduction of testicular androgens, but with adverse psychological factors. The next approach was utilization of diethylstilbestrol, but with significant cardiovascular toxicity in higher doses. The development of the luteinizing hormone-releasing hormone agonists provided an improvement in pharmacologic castration; however, they are associated with a transient testosterone surge and the potential for exacerbation of clinical manifestations of advanced prostate carcinoma (the so-called "testosterone flare"). Recently, gonadotropin-releasing hormone (GnRH) antagonists have been investigated. Abarelix is a pure GnRH antagonist that blocks the anterior pituitary receptor, resulting in prompt and significant reduction not only of luteinizing hormone but also follicle-stimulating hormone. This results in castrate levels of testosterone while avoiding the testosterone surge.
PubMed: 16986002
DOI: No ID Found