Efficacy and safety of the LHRH antagonist degarelix

Klotz et al. have now published the complete results of one of the Phase III clinical trials designed to evaluate the effectiveness and the safety of degarelix — a second-generation LHRH antagonist — in the management of hormone-sensitive prostate cancer.

LHRH agonists like leuprolide acetate (Lupron, Eligard, Viadur), goserelin acetate (Zoladex), and triptorelin pamoate (Trelstar) work by swamping the pituitary-adrenocortical-hypothalmic axis with excessive amounts of LHRH-like biologics. This results in a shut-down of the hormonal feedback loop that normally controls testosterone production, and thus a shut-down in the production of testosterone and its metabolite (dihydrotestosterone) that significantly impact growth of prostate and prostate cancer cells.

By contrast, the LHRH antagonists actually block the activity of LHRH without swamping the system with excessive amounts of LHRH-like agents. One of the key theoretical benefits of such a process is that it avoids the so-called “flare” reaction associated with the initiation of LHRH agonist therapy, in which there is a significant initial increase in testosterone production before the system is shut down.

A first-generation LHRH agonist known as abarelix (Plenaxis) was approved by the US Food and Drug Administration some years ago. However, it was associated with a significant risk for severe allergic reactions in a number of patients that included a small number of deaths. The product was withdrawn from the market by the manufacturer after a relatively short period of time. Thus, in the development of the first second-generation product, degarelix, the safety of the product has been considered a critical issue to its clinical potential.

The data from the study published by Klotz et al. certainly appear to confirm both the safety and the effectiveness of degarelix in direct comparison to leuprolide acetate.

The fundamental objective of this trial was to evaluate the efficacy and safety of degarelix for achieving and maintaining testosterone suppression in a randomized, 1-year, phase III trial involving patients with prostate cancer. The results of the trial may be summarized as follows:

  • 610 patients with adenocarcinoma of the prostate (any stage; median age 72 years; median testosterone 3.93 ng/ml, median PSA level 19.0 ng/ml) were randomized and received study treatment.
  • Androgen-deprivation therapy was carried out according to the investigator’s assessment — but could not include neoadjuvant hormonal treatment.
  • Three dosing regimens were evaluated:
    • a starting dose of 240 mg of subcutaneous degarelix for 1 month, followed by subcutaneous maintenance doses of 80 mg or 160 mg monthly, or
    • intramuscular leuprolide doses of 7.5 mg monthly
  • The primary endpoint of the trial was suppression of testosterone to ≤ 0.5 ng/ml at all monthly measurements from day 28 to day 364; this outcome was achieved by
    • 97.2 percent of patients in the degarelix 240/80 mg  arm
    • 98.3 percent of patients in the degarelix 240/160 mg arm
    • 96.4 percent of patients in the leuprolide 7.5 mg
  • At 3 days after starting treatment, testosterone levels were ≤ 0.5 ng/ml in
    • 96.1 percent of patinets in the degarelix 240/80 mg arm
    • 95.5 percent of patients in the degarelix 240/160 mg arm
    • none of the patients in the leuprolide 7.5 mg arm
  • The median PSA levels at 14 and 28 days were significantly lower in the two degarelix groups than in the leuprolide group.
  • The hormonal side-effect profiles of the three treatment groups were similar to previously reported effects for androgen-deprivation therapy.
  • The subcutaneous degarelix injection was associated with a significantly higher rate of injection-site reactions than with the intramuscular leuprolide injection (40 vs <1 percent, respectively).
  • Other reported differences in adverse events between the groups included
    • A lower incidence of urinary tract infections in the degarelix groups as compared to the leuprolide group (3 vs 9 percent, respectively)
    • A lower incidence of arthralgia (pain in the joints) in the degarelix groups compared to the leuprolide group (4 vs 9 percent, respectively)
    • A higher incidence of chills in the degarelix groups compared to the leuprolide group (4 vs 0 percent, respectively).
  • There were no reports of systemic allergic reactions.

Based on these data, it certainly appears that:

  • Degarelix is at least equivalent to leuprolide at maintaining low testosterone levels over a 1-year treatment period.
  • 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.
  • Degarelix shows no risk of the allergic reactions associated with the first-generation LHRH antagonists.

Having said that, it is also clear that degarelix is associated with a relatively high degree of injection site reactions compared to leuprolide. Whether this level of injection site reactions will be acceptable to and manageable by patients and their doctors in long-term use of degarelix is an unanswered question at this time.

At this time, degarelix is still under evaluation by regulatory authorities as an agent for the treatment of prostate cancer.

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