Landmarks in hormonal therapy for prostate cancer



We read with great interest the review by Hammerer and Madersbacher [1] and we would like to congratulate the authors for their work; however, we would like to bring to your attention some important misconceptions in their paper, which we believe require clarification and warrant further discussion to ensure that readers receive an unbiased view from the journal.

In the section of the article that discusses GnRH antagonists, the authors describe degarelix as ‘another LHRH antagonist that is available as a monthly s.c. formulation, with outcome reported in a small scale phase III study’. It should be noted that the phase III study in question was a randomised, US Food and Drug Administration- and European Medicines Agency-approved, comparative pivotal registration trial, which included 610 patients and was conducted over 1 year [2]. It is also interesting to note that while the authors use the term ‘small’ to describe a trial of an antagonist that includes >600 patients, later in the article they mention that ‘Two large scale prospective studies have compared bicalutamide with medical or surgical castration … ’, yet, one of these ‘large scale’ trials included 480 patients who were randomised to treatment [3].

We were equally puzzled by the amalgam between antagonists on the histamine-mediates side effects, the authors stating that ‘Many LHRH antagonists have been associated with serious and life-threatening histamine-mediated side-effects … ’. The histamine-releasing potential of earlier generations of GnRH antagonists is well recognised [4]. While systemic allergic reactions have been reported with abarelix [5], published trials of degarelix show no reports of systemic allergic reactions [2, 6-8]. In fact, degarelix displays only weak histamine-releasing properties, and in studies in animals [9] and in a human skin model [10] degarelix displayed the lowest propensity for histamine release among the GnRH antagonists tested. Indeed, the European summary of product characteristics of degarelix mentions hypersensitivity reaction as uncommon [11].

The authors also state that in regard to LHRH agonists, ‘… suppression of the initial flare up with monotherapy may only be clinically relevant in a few, symptomatic, metastatic patients.’ This is, we believe, a major misinterpretation of the characteristics of degarelix. The absence of testosterone flare is the pharmacological signature of a different mechanism of action. In pre-planned analyses of the pivotal registration trial, in which degarelix was compared with leuprolide, this different mechanism of action translated into a difference in time to PSA progression or death and time to alkaline phosphatase escape, both being significant in patients with a PSA level >20 ng/mL or M1 stage at trial inclusion [12-14]. In a study assessing the benefit of degarelix vs. goserelin on LUTS of locally advanced PCa, degarelix has been shown to offer superior LUTS control over goserelin [15].

In the discussion of intermittent androgen deprivation therapy (ADT), while referring to the study by Calais da Silva et al. (2009), the article incorrectly cites the number of patients randomised to intermittent or continuous ADT as 127 and 107, respectively. The actual number of patients randomised to these treatment groups was 314 and 312, respectively. This clarification may help to put into context more effectively the number of deaths subsequently cited for this trial.

Finally, in Table 1, ‘Hormonal agents used in the management of prostate cancer’, the authors include the GnRH antagonist cetrorelix, but this agent is not approved for use in prostate cancer. Also, it appears curious that a study with MDV3100 (now called enzalutamide), is referenced as ‘Takeda, data on file’ when this agent is being developed by Medivation, in collaboration with Astellas.

In conclusion, we hope that by clarifying and expanding on the above issues, we have helped to broaden the scientific context within which we believe the content of this article should be viewed.