An update on the use of gonadotropin-releasing hormone antagonists in prostate cancer

Abstract

Androgen deprivation therapy (ADT) is the main treatment approach in advanced prostate cancer and in recent years has primarily involved the use of gonadotropin-releasing hormone (GnRH) agonists. However, despite their efficacy, GnRH agonists have several drawbacks associated with their mode of action. These include an initial testosterone surge and testosterone microsurges on repeat administration. GnRH antagonists provide an alternative approach to ADT with a more direct mode of action that involves immediate blockade of GnRH receptors. Antagonists produce a more rapid suppression of testosterone (and prostate-specific antigen [PSA]) without a testosterone surge or microsurges and appear to offer an effective and well tolerated option for the hormonal treatment of prostate cancer. Comparisons with GnRH agonists have shown GnRH antagonists to be at least as effective in achieving and maintaining castrate testosterone levels in patients with prostate cancer. Furthermore, with antagonists, the lack of an initial testosterone surge (which may cause clinical flare) may allow more rapid relief of symptoms related to prostate cancer, avoid the need for concomitant antiandrogens to prevent clinical flare (so avoiding any antiandrogen-associated adverse events) and allow GnRH antagonist use in patients with high tumour burden and/or acute problems such as spinal cord compression. Although several antagonists have been investigated, only degarelix and abarelix are currently available for clinical use in prostate cancer. Currently, degarelix is the most extensively studied and widely available agent in this class. Degarelix is one of a newer generation of antagonists which, in a comprehensive and ongoing clinical development programme, has been shown to provide rapid, profound and sustained testosterone suppression without the systemic allergic reactions associated with earlier antagonists. This review examines the currently available data on GnRH antagonists in prostate cancer.

Keywords: GnRH agonist; GnRH antagonist; abarelix; degarelix; prostate cancer.

Figure 1.

Mean (+SE) of serum bioactive luteinizing hormone (LH; open circles) and testosterone (filled circles) of adult male monkeys (five per group) receiving an implant loaded with the gonadotropin (GnRH) agonist (buserelin) on day 7. On days 0–15 animals were treated, in addition to the GnRH agonist, with GnRH antagonist vehicle (upper panel) or Nal-Glu GnRH antagonist at a dose of 2250 µg/kg daily (bottom panel). ANT, antagonist. (Reproduced with permission from Sharma et al. [1992]).

Figure 2.

Percentage of patients with testosterone ≤0.5 ng/ml during the first month of treatment in the phase III comparative study CS21. *p < 0.001 versus leuprolide (pairwise comparisons by Fisher’s exact test) [Adapted from Persson et al. 2009].

Figure 3.

Median percentage change in prostate-specific antigen (PSA) from baseline for degarelix 240/80 mg versus leuprolide.

Figure 4.

Mean (± standard error) percentage change in prostate-specific antigen from baseline during the first 28 days of treatment in patients with metastatic disease receiving degarelix 240/80 mg and in those who received leuprolide with or without antiandrogens (AA) in the phase III CS21 trial.

Figure 5.

The probability of freedom from prostate-specific antigen (PSA) failure or death over time for patients with baseline PSA ≥20 ng/ml in the CS21 and CS21a trials. The magnified area of the graph shows the time for 25% of patients with baseline PSA ≥20 ng/ml to experience PSA failure or death (TTP_25%).