Degarelix as second-line ADT in men not responsive to LHRH agonist therapy


First-line androgen deprivation therapy (ADT) for a man with metastatic prostate cancer has long been been either surgical or medical castration. In the case of medical castatration, the form of medication most commonly used since the mid to late 1980s has been an LHRH agonist (e.g., leuprolide acetate). In the early 1990s it became customary to combine an LHRH agonist with at least a brief period of antiandrogen therapy (as “combined androgen deprivation” [CAD] or “maximal androgen suppression” [MAS]) to suppress the initial testosterone “flare” reaction associated with initiation of LHRH agonist therapy.

LHRH agonist therapy — with or without the use of an antiandrogen — will normally allow patients to initially achieve and subsequently maintain a serum testosterone level of < 50 ng/dl. However, it is well known that as many as 10 percent of all men started on medical castration with an LHRH agonist will not respond with an appropriate drop in the serum testosterone level.

Raddin et al. have now reported two case studies of patients who failed to respond appropriately to first-line LHRH agonist therapy who were successfully switched to treatment with the second generation LHRH antagonist degarelix.

The first patient is reported to be a 63-year-old man, initially treated with leuprolide acetate for metastatic prostate cancer. His PSA promptly fell to 0.6 ng/ml, but after 15 months of therapy, it rose again to to 18.3 ng/ml and his serum testosterone level was 208 ng/dl. Four weeks after initiation of degarelix, his testosterone was adequately suppressed at 16 ng/dl.

The second patient was significantly younger, at just 41 years of age. In this case the patient was again started on leuprolide for treatment of metastatic prostate cancer, but after 3 months of treatment he had a rising PSA and a serum testosterone level of 96 ng/dl. In this patient, again after just 4 weeks on degarelix, his testosterone was 18 ng/dl and his PSA had decreased “concordantly.” After 7 months on degarleix, the patient’s serum testosterone has consistently remained at < 20 ng/dl.

The idea that an LHRH antagonist like degarelix should be effective for at least some men as second-line ADT when standard LHRH agonist therapy is unable to control PSA and serum testosterone levels is hardly a big surprise. The questions that do need to be resolved, however, are the following:

  • In what percentage of men progressing on standard, first-line hormone therapy does degarelix successfully bring PSA and serum testposterone levels back under control?
  • Does degarelix demonstrate the same effects in men whose PSA and serum testosterone had previously been controlled with ADT2 (an LHRH agonist + an antiadrogen) or ADT3 (usually an LHRH agonist + bicalutamide + dutasteride)?
  • Is there any significant delay in disease progression or survival benefit associated with the second-line use of degaralix in this manner?
  • Should LHRH antagonist therapy be “reserved” for use as a standard form of second-line hormone therapy in all men who progress on LHRH monotherapy?

As we have stated several times before, the increasing number of therapeutic agents that are now showing meaningful activity in the management of advanced prostate cancer is raising serious questions about “the best” way to sequence these drugs to achieve both extent and quality of survival for men with evident metastatic or micrometastatic disease. There will be a lot more questions of this type that need to be resolved over the next decade or two.

2 Responses

  1. I write today to share my experience with degarelix, aka Firmagon.

    For about 18 months I was on Lupron with adjuvant Taxotere at the beginining of that course of treatment. At the 18-month point my PSA began rising and my oncologist added ketoconazole. Lupron and keto worked for me for another 18 months and then my PSA started to rise again, with a doubling time of < 30 days, as it had been before Lupron. Testosterone at this time was around 53 ng/dl. We discontinued Lupron and went to degarelix. It was very hard to find the starter dose and syringes to administer the stuff, but my daughter, an internal medicine doctor, hooked me up and taught me how to inject it (subcutaneously). For the first month, my testosterone stayed about the same, and PSA doubled. At that point we discontinued the keto. Second month, PSA doubled again and testosterone was 58; I stayed with the degarelix and added DES at 1 mg/day. Third month, PSA had increased only 20 percent of doubling and testosterone fell to 22 ng/dl. Degarelix hurts at the injection site for a couple of days and the first day after injection I'm a little light-headed, lack energy, etc. So, degarelix is hard to get started with, not much fun to use, and appears to be working. If anyone wants to know, I'll update — my next blood test is next week.

    Luck All,

    Coop

  2. Coop — Sounds like you have a doctor who is more up to speed / thoughful / creative than many. I wonder whether its the degarelix that is helping you. Or the DES. Or the combination.

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