FOIU 2018: Agonists vs. Antagonists: Should Antagonists be the Primary Choice for ADT? - NO

Tel-Aviv, Israel (UroToday.com) Igor Tsaur, MD debated against the usage of LHRH antagonists as the primary form of androgen deprivation therapy (ADT). LHRH agonists have an increased risk for cardiovascular disease (CVD), diabetes, myocardial infarction and sudden death (Table 1). The different mechanisms of action of agonists and antagonists are demonstrated in figure 1. 

Table 1 – Increased risk for a cardiovascular event with hormonal treatment:
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Figure 1 – The working mechanism of agonists vs. antagonists
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There is a known correlation of CVD with agonists and higher risk for orchiectomy. The risk is highest for patients with previous CVD. Antagonists cause less arterial plaque rupture than agonists, and there is more FSH decline, which might have a protective role (figure 2). Pooled data analyses of 6 randomized controlled trials have attempted to study the association of CVD with agonists and antagonists (Table 2). In these pooled analyses, 1491 patients on the antagonist degarelix were compared to 837 patients who were on a GnRH agonist. Pre-existing CVD was present in approximately 30% of patients in both groups. CVD was defined as either arterial embolic or thrombotic event, hemorrhagic and ischemic CV condition, myocardial infarction, or another ischemic heart disease. The primary endpoint was a CV event or death. The results demonstrated no difference in men without pre-existing CV conditions. 1 However, in men with pre-existing CV conditions, there was a clear difference favoring degarelix (Figure 3).

Figure 2 – The atherosclerotic plaque and the effect GnRH agonists and antagonists have:
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Table 2- Pooled analyses of 6 randomized trials on GnRH agonists:
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Figure 3 – Comparison of antagonists vs. agonists in patients with pre-existing cardiovascular conditions:
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Tsaur argued that although this study is a hypothesis-generating study, it is not practiced changing. This was a retrospective post hoc analysis, and the CV events were reported as adverse events and not as primary endpoints. Additionally, this is short-term data with a small number of events, with a high suspicion of underreporting adverse events. This analysis showed a benefit for antagonists only if the patient had a pre-existent CV condition (representing only a third of the patients in the cohort).  According to Tsaur, this evidence is not enough to convince us to start using antagonists.

Another study, which was a population-based study with a primary endpoint of the hazard ratio for myocardial infarction or ischemic stroke requiring hospitalization, did not show a meaningful difference between antagonists and agonists 2 The median time to ischemic event was 478 days and the CV profile of agonists and antagonists was similar. Lastly, a meta-analysis of randomized controlled trials of antagonists vs. degarelix did not demonstrate significant differences between these two drug classes.3

Tsaur pointed out that the EAU guidelines state that although it has been suggested that antagonists might be associated with fewer CV events, the methodology used in the studies comparing agonists and antagonists does not provide convincing evidence to show a clear superiority of the antagonists. In conclusion, antagonists are not the primary choice of ADT in all patients. There is poor evidence to favor antagonists over agonists for CV safety. Antagonists might be considered in patients with pre-existing CV and should be considered in patients requiring rapid remission. The prospective randomized controlled trial, comparing agonists and antagonists, the PRONOUNCE trial, is still ongoing, and we will need to patiently await its results to have a clear answer to this debate.

References:
1. Albertsen PC, et al. Eur Urol 2014
2. Scailteux LM et al. European J of Cancer 2017
3. Sciarra A, et al. Medicine 2016

Presented by: Igor Tsaur, MD, Mainz Germany

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre @GoldbergHanan  at the 2018 FOIU 4th Friends of Israel Urological Symposium, July 3-5. 2018, Tel-Aviv, Israel

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