Luteinising-hormone-releasing Hormone Antagonists in Prostate Cancer
critical clinical problems such as impending bone fractures, cord compression or ureteric obstruction, where the alternative emergency treatment would be orchidectomy or delayed testosterone suppression with antiandrogen cover using LHRH agonists.15
However, Trachtenberg8 noted that while antagonists
achieved castration levels quickly, both antagonists and agonists were equally effective in terms of reduction of testosterone and prostate-specific antigen (PSA) levels.
LHRH was discovered in 1971 by Andrew Shally and colleagues,16 and the LHRH antagonists developed from this discovery.14
However,
there were problems with early first-generation compounds, and due to a lack of potency these products were not clinically viable. Second-generation drugs included minor structural modifications that resulted in improved efficacy.17
However, moving forward from
these second-generation compounds, severe side effects were a long-standing problem with LHRH antagonists that hindered their widespread application. These side effects were mostly due to histamine-mediated anaphylactic responses that caused severe allergic reactions in a number of patients. Changes were made to third-generation LHRH antagonists to combat these reactions, removing amino acids from the compound in order to eliminate the risk.18
One such third-generation compound is abarelix, which was approved by the US Food and Drug Administration (FDA) in 2003 for patients with advanced prostate cancer who have refused orchidectomy and cannot take other hormones. Patients are monitored closely both during and after administration, as well as during the follow-up months.7
In a study involving 81 patients
with symptomatic prostate cancer, three patients experienced an immediate-onset systemic allergic reaction within minutes of receiving abarelix. Side effects included urticaria, pruritus and hypotension and syncope.19
reported only an acceptable safety profile.20
Other recent studies have additionally Due to the still present
possible allergic reactions, the drug was restricted to being marketed as a voluntary risk management programme only to those patients who fall into the above category, and was never registered or approved on the European market. In 2005, due to serious allergic reactions, abarelix was withdrawn from the US market.21
A newer antagonist, degarelix, was approved by the FDA in 2008.22–24 Compared with the earlier antagonist abarelix, adverse events were mild and relatively uncommon with degarelix. They included flushing reactions, injection-site pain, weight gain and increases in serum transaminase levels. Compared with earlier LHRH antagonists, degarelix was associated with the least amount of histamine release among the LHRH antagonists tested,25
thereby reducing the frequency
and severity of the most common allergic reactions associated with the previous generations of antagonists.
A decade after the development of LHRH antagonists as possible treatment compounds, LHRH agonists were developed in the 1980s as a different treatment option.21
The initial hormonal surge in treatment with LHRH agonists is followed by downregulation of LH and FSH, resulting in decreased testosterone production. The hormonal flare associated with LHRH agonists leads to a testosterone surge in patients, which in turn can produce a temporary increase in tumour growth leading to a worsening of symptoms in approximately 10% of patients with metastatic disease.27
The main symptoms associated with the flare
are bone pain, bladder outlet obstruction, urethral obstruction, spinal cord compression and cardiovascular effects,28 adversely affect the long-term outcome of therapy.
and could
For example, the agonist histrelin is administered by a one-year subcutaneous implant in the upper arm, in contrast to most LHRH antagonists, which are administered through intramuscular injections every two to four weeks.26
The necessity for frequent
administration of LHRH antagonists can limit compliance among patients, as the longest period between treatments can be a maximum of one month, compared with one year for the implant. Although administered only once per year, the implant has been shown to hold the castration level constant throughout weeks four to 52, with no rise in any patients throughout this time. Additionally, compared with other agonists, the testosterone flare was remarkably low with the histrelin implant.29
The histrelin implant can
therefore be seen as a real alternative to treatment with antagonists, as it seems to cause a very similar reduction in testosterone levels. Additionally, agonists have been shown to cause allergic reactions in only 0.6% of cases,30
reducing the fear of histamine-related complications possible with LHRH antagonists.
The area most in need of further investigation is the long-term efficacy of LHRH antagonists and their effect on PSA and patient survival. Since degarelix has only been available since 2009, long-term patient follow-up and effects beyond one year of treatment are so far not known. A study is currently evaluating data from a trial on the long-term effects of degarelix over a study period of up to 60 months.31
by the FDA, who took it into consideration in its licensing recognition of abarelix as well as degarelix. This effect provides antagonists with advantages in everyday use as anti-androgen cover, which is recommended when agonist drugs are initiated, is not required.15
Long-term studies on possible adverse effects in longer-term treatment also remain to be conducted. The relationship between LHRH antagonists and patient survival and quality of life merits additional attention in clinical studies, considering the short time degarelix has been available to patients and its as yet unclear role in the management of patients with prostate cancer. Considering that the newer compound degarelix was able to reduce the allergy-related complications, the further development of a next-generation LHRH antagonist may very well be able to reduce side effects even further, but this remains to be seen. Numerous new LHRH antagonists are in development, but only a small number of these are currently in clinical trials.32
LHRH agonists work by constantly
stimulating the anterior pituitary gland, which decreases LH and thereby testosterone production. After the initiation of treatment, LH is transiently increased up to two weeks after the initial dose, causing what is commonly known as the flare or hormonal surge.26 This two- to four-week delay in the lowering of testosterone levels in treatment with LHRH agonists contrasts with the much faster effective lowering by LHRH antagonists. This was recognised as an advantage
EUROPEAN UROLOGICAL REVIEW
Further study is necessary to answer additional questions regarding the speed of testosterone reduction shown with LHRH antagonists compared with agonists. While it is anticipated that due to the rapid fall in testosterone and PSA concentrations during treatment with LHRH antagonists, tumour growth and prostate volume will also decrease faster, this is yet to be confirmed on a larger scale and with longer follow-up times.7
The lack of long-term follow-up studies on 13
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