The luteinizing hormone releasing hormone (LHRH) antagonists in treatment of metastatic prostate cancer

Note: The terms “luteinizing hormone” (LH) and “gonadatropin” (Gn) are variously used by different authorities. Thus, LHRH and GnRH are also interchangeable terms in the medical literature. As far as The “New” Prostate Cancer InfoLink is aware, neither term is considered to be “absolutely correct.” We have chosen to use the terms LH and LHRH throughout this web site as a matter of consistency.

Introduction

The first luteinizing hormone-releasing hormone (LHRH) antagonist (abarelix) was developed in the 1990s and brought to market under the brand name Plenaxis™ in 2003. However, this drug had a number of characteristics that made it unattractive to the medical and the patient community as a treatment for prostate cancer. The most significant of these was a risk for serious and even life-threatening allergic reactions to the drug shortly after its administration. The manufacturer discontinued availability of this drug in the USA in 2005. Abarelix is still available in some other counties around the world, but it is rarely used.

The first “second generation” LHRH antagonist (known as degarelix and marketed under the brand name Firmagon®) was made available in Europe and in the USA by early in 2009. For those who are interested, the full prescribing information for degarelix in the USA is available on the FDA web site.

Unlike abarelix, we expect degarelix to be widely used in the treatment of almost all forms of advanced prostate cancer. Whether it can replace the LHRH agonists over time is a different question that will depend as much on price and cost-effectiveness as on clinical effectiveness.

What are LHRH Antagonists, and How Do They Work?

LHRH antagonists are agents that block the activity of human luteinizing hormone-releasing hormone. In other words, they simply stop the LHRH from stimulating production of luteinizing hormone (LH). Therefore there is no luteinizing hormone available to stimulate the production of testosterone.

The great theoretical benefit of LHRH antagonists as compared to LHRH agonists is that there is no “flare reaction” associated with their use. In other words, there is no short-term boost to testosterone production at initiation of LHRH antagonist therapy. This also means that there is no apparent need for the short-term use of nonsteroidal antiandrogen therapy at the initiation of LHRH antagonist therapy.

The Clinical Effectiveness of LHRH Antagonists in Prostate Cancer

Based on the currently available data from clinical trials, we are able to make the following statements about the clinical effectiveness of degarelix in the treatment of advanced prostate cancer:

  • Degarelix is at least equivalent to leuprolide at maintaining low testosterone levels over a 1-year treatment period in patients with advanced forms of prostate cancer.
  • Degarelix is capable of suppressing testosterone and PSA levels significantly faster than leuprolide.
  • Degarelix does not need to be combined with an antiandrogen such as bicalutamide (Casodex) to prevent the possibility of initial flare.

To date, all completed clinical trials of degarelix have used long-term treatment for up to 1 year using the drug as monotherapy. However, we can expect to see further trials of degarelix in the future, which might include exploring:

  • The combination of degarelix with external beam radiation therapy for treatment of patients with locally advanced prostate cancer
  • The combination of short-term degarelix with external beam radiation for the treatment of patients with biochemical progression after first-line treatment for early stage disease
  • The combination of surgical or external beam radiotherapy with short-term degarelix for the treatment of patients with high-risk, localized prostate cancer

as well as patients with other, more advanced stages of prostate cancer.

The Side Effects of LHRH Antagonist Therapy

We have already noted that the “first generation” LHRH antagonist, abarelix, was associated with a significant risk for serious allergic reactions. It should be emphasized that there are no data from clinical trials to suggest that the second-generation product, degarelix, is associated with any form of allergic reaction.

Degarelix is, however, associated with, or can be expected to be associated with, all of the major adverse reactions that customarily result from testosterone suppression, including:

  • Impotence, because the normal testosterone levels have been reduced to castrate levels
  • Hot flashes, similar to those which occur in women during menopause
  • Gynecomastia or nipple tenderness in which there is mild swelling or at least tenderness of the man’s breasts
  • Depression or depression-like symptoms and
  • Weight gain

The one place where degarelix appears to have a “downside” compared to leuprolide is that (because there is an initial “loading dose” of 240 mg of the drug), it is associated with a high incidence of temporary injection site reactions at the time of the loading dose. Available data suggest, however, that such injection site reactions are far less common at the time of the smaller, monthly injections.

For full information on the possible adverse events associated with any drug, please see the full prescribing information for that specific product.

Content on this page last reviewed and updated January 24, 2010.
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