Is an LHRH antagonist a better first-line hormone therapy than an LHRH agonist?


The question of whether an LHRH antagonist (such as degarelix) is really a better first-line hormone therapy than an LHRH agonist (e.g., leuprolide acetate) is still not fully answered.

As experienced prostate cancer patients will be aware, an LHRH antagonist (which does not induce a testosterone flare reaction at the time of treatment initiation) has theoretical benefits compared to the LHRH agonists, which normally are given with at least a short, initial course of an antiandrogen — to prevent the aforementioned flare reaction. However, what we do not know is whether there is any “real” long-term benefit (in terms of progression-free or overall survival) from the use of an LHRH antagonist as a first-line form of hormone therapy.

A new paper by Crawford et al. seems to begin to answer this question … although The “New” Prostate Cancer InfoLink thinks we are going to need a good deal more data before there is sufficient information to draw definitive conclusions about the relative merits of the two approaches.

In 2008, Klotz et al. initially reported that degarelix — when given at a loading dose of 240 mg  followed by doses of 80 mg every 28 days — was capable of suppressing testosterone levels to ≤ 50 ng/dl from day 28 to day 365 in 97.2 percent of randomly selected patients (as compared to 96.4 percent of randomly selected patients treated with a monthly dose of 7.5 mg of leuprolide acetate). They concluded that degarelix was “not inferior” to leuprolide at maintaining low testosterone levels for a 1-year treatment period; that degarelix induced testosterone and PSA suppression significantly faster than leuprolide; and that PSA suppression was also maintained throughout the study.

(It should be noted at this point that the finally approved dosing of degarelix — pretty much around the world, as far as we are aware — is a loading dose of 240 mg followed by subsequent doses of 80 mg every 28 days.)

The new paper by Crawford et al. reports data from an extension of that original study. In this extension study, men who had completed the initial trial were invited to do one of three possible things:

  • To continue on the same maintenance dose of degarelix that they received in the original trial (which was either 80 mg or 160 mg every 28 days)
  • To be re-randomized — if they had originally received leuprolide acetate — to degarelix at
    • Either a  loading dose of 240 mg followed by doses of 80 mg every 28 days
    • Or a loading dose of 240 mg followed by doses of 160 mg every 28 days

However, once the maintenance dose of degarelix was approved at 80 mg every 28 days, the study reports states that all patients in the extension trial were switched to this maintenance dose (although the full text is confusing on this point). This fact makes detailed interpretation of some of the complex and dense data available in the full paper difficult. It is unclear exactly how many patients who were originally on leuprolide acetate were on degarelix 24/160 or degarelix 240/80 and for how long. The higher maintenance dose  was associated with more significant side effects in the trial data reported by Klotz et al., which is why the lower maintenance dose was the one approved.

We have been able to review the full next of this paper, not just the abstract, so here are what seem to us to be the key pieces of information:

  • The median follow-up was 27.5 months after the start of the extension trial at 1 year on therapy.
  • Patients who were switched from leuprolide 7.5 mg to degarelix 240/80 at the start of the extension trial had:
    • A median serum testosterone level less than 20 ng/dl during the entire follow-up period and similar to patients who had started out on the degarelix 240/80 dosing schedule
    • A median PSA level that remained below 1.0 ng/ml during the entire follow-up period and similar to patients who started out on the degarelix 240/80 dosing schedule
    • A small but significant overall reduction in their PSA-based rate of biochemical progression-free survival
    • A small but significant reduction in the PSA-based rate of biochemical progression-free survival in the men with an original baseline PSA level of > 20 ng/ml
    • A decrease in their risk for musculoskeletal and connective tissue adverse effects down to a level similar to patients who had started out on the degarelix 240/80 dosing schedule
  • The overall rates of “treatment-emergent” adverse effects was similar between the two sets of patients over the course of all 4 years of the study.
  • Men who were switched from leuprolide acetate to degarelix did report more injection site reactions in year 2 of the study (but these reports declined in years 3 and 4).

The conclusions that can be drawn from this study are that:

  • Degarelix can maintain castrate levels of serum testosterone and related biochemicals over a period of up to 4 years at a loading dose of 240 mg and subsequent doses of 80 mg every 28 days.
  • The statistically significant improvement in biochemical progression-free survival shown by degarelix compared to leuprolide acetate at 12 months appears to be continued over a period of 4 years.
  • Degarelix can be used as an alternative to an LHRH agonist as first-line androgen deprivation therapy (ADT) for at least 4 years.

It would be inappropriate at this stage to conclude that degarelix might actually have either an overall or a progression-free survival benefit compared to an LHRH agonist on the basis of this trial. Proof of such an effect would require a new, appropriately designed, randomized, multi-center trial. Whether the manufacturer of degarelix is willing to commit to such a trial (which might take several years to complete) is not known, but there is no sign of such a trial on the ClinicalTrials.gov web site.

It must also be recognized that — in the “real world”– most patents receiving long-term ADT are being dosed with formulations of LHRH agonists that can be given once every 3, 4, 6, or even 12 months, whereas degarelix must be dosed every month at this time. If formulations of degarelix could be developed that allowed less frequent dosing (i.e., every 3 months at a minimum), then there is a significant possibility that degarelix might become a more widely accepted form of ADT.

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