Is treatment with degarelix really “better” than treatment with an LHRH agonist?

One of our regular readers has asked us to comment on a paper suggesting the possibility of “significant improvement” in various outcomes for men initially treated with the LHRH antagonist degarelix as compared to the LHRH agonists leuprolide acetate and goserelin acetate.

There are some things we need to address immediately in the evaluation of the abstract of this paper by Klotz et al. (We have not had the opportunity to review the full text of this paper.)

First, it is a meta-analysis of data from five different studies. Such meta-analyses have to be evaluated with great care because they usually combine data from very different clinical trials in very different types of patients. Second, the men treated in these trials received degarelix or one of the LHRH agonists for very different periods of time. Third, the data presented in the abstract are limited, and it may well be that in the full text of this paper there are specific limitations reported on the accuracy of the data that appear in the abstract. Fourth, we don’t know for sure whether the meta-analysis is based on pooled primary data from the actual trials or on pooled data from the published papers about the five completed trials. (This last fact can significant impact the results of meta-analyses.)

Here is what the paper’s abstract tells us:

  • The study was based on “pooled data” from five randomized, prospective, Phase III trials of ADT.
  • In these five trials, patients were randomized to treatment with either degarelix or an LHRH agonist.
    • 1,458/1,925 patients were on therapy for 12 months.
    • 467/1,925 patients were on therapy for just 3 months.
    • 1,266/1,925 patients were randomized to treatment with degarelix.
    • 201/1,925 patients were randomized to treatment with leuprolide acetate.
    • 458/1,925 patients were randomized to treatment with goserelin acetate.
  • Biochemical progression-free survival was longer in
    • The men treated with degarelix (hazard ratio [HR] = 0.71; p = 0.017).
    • The men treated with degarelix who had a baseline PSA level > 20 ng/ml (HR = 0.47; p = 0.023).
  • Overall survival was “particularly improved in patients with baseline testosterone levels of > 2 ng/ml” (HR = 0.36; p = 0.006)
  • Overall, there were fewer joint-related signs and symptoms, musculoskeletal events, and urinary tract events in the patients treated with degarelix.

Here are some of the important things that the abstract does not tell us:

  • Why the patients were given either degarelix or an LHRH agonist
  • Whether the patients treated with an LHRH agonist were pretreated for at least 2 weeks with an antiandrogen before being given their first injection of an LHRH agonist
  • Whether or not the patients had evident metastatic disease
  • Whether their ADT was being given in combination with another type of treatment
  • Whether some of the patients who were on treatment for 12 months were actually on ADT for longer
  • For how long the patients had been followed post-treatment
  • That under the heading entitled “Results and limitations”, no limitations are listed (but all studies have limitations, particularly meta-analyses like this one)
  • How “baseline testosterone” is being defined (Is this the serum T level after 3 months of treatment with degarelix or an LHRH agonist, or is it the patient’s serum T level prior to any ADT?)

While this paper appears at first sight to offer us the idea that initial treatment with degarelix is likely to be more effective and safer than treatment with an LHRH agonist, the reality is that such a conclusion may only be valid for a subset of patients or because of the way this meta-analysis was carried out.

We do know that degarelix seems to be more efficient at lowering the PSA level of men with prostate cancer into the undetectable range (i.e., to < 0.1 ng/ml) and at lowering the serum T level of men with prostate cancer down to < 20 ng/dl. However, The “New” Prostate Cancer InfoLink is not aware of any single randomized trial of men treated with degarelix as opposed to an LHRH agonist that has shown a true prostate cancer-specific or overall survival benefit for treatment with degarelix, which makes the findings of this meta-analysis more than a little suspect.

For several years now, the manufacturers of degarelix have been supporting the publication of data that seem to endorse the idea that degarelix is at least as effective and potentially more efficient and/or safer than the LHRH agonists in the treatment of prostate cancer. However, to truly demonstrate that this is the case, they would need to do a large, randomized, head to head trial in men who all met the same, pre-specified characteristics and criteria at time of treatment. No such trial has ever been carried out, and the chance to carry out such a trial may now be gone (given the number of other new drugs being tested in progressive treatment of prostate cancer).

There are certainly physicians who believe that, when ADT is initiated, it may be better to start with degarelix than with an LHRH agonist. There are physicians who will switch their patients to degarelix if the patients’ serum T or PSA levels don’t drop low enough or fast enough on initial LHRH agonist therapy. There are physicians who will use degarelix as a second-line form of ADT after initial treatment with an LHRH agonist starts to fail. However, whether there are a significant number of physicians who actually think that treatment with degarelix offers either a prostate cancer-specific or an overall survival benefit compared to an LHRH agonist in the treatment of progressive prostate cancer is something we doubt.

It is still not even clear that treatment with any form of standard ADT offers any prostate cancer-specific or overall survival benefit in the treatment of progressive prostate cancer … with one exception. We do know that there is a survival benefit to addition of an LHRH agonist to radiation therapy in the treatment of men with node-positive prostate cancer. And unless the manufacturers of degarelix can actually prove that this drug offers a true survival benefit compared to some other form of standard ADT in a randomized, Phase III, clinical trial, the U.S. Food & Drug Administration is not going to let them make any such claim in their promotional materials.

One Response

  1. NB: A correspondent has kindly provided us with the full text of this article by Klotz et al. Once we have had a chance to read through this article with care, we will see if we can add any clarifications to the information provided above.

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