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2018 Friends of Israel Urological Symposium

FOIU 2018: Agonists vs. Antagonists: Should Antagonists be the Primary Choice for ADT? - YES

Tel-Aviv, Israel (UroToday.com) David Margel, MD debated for the usage of antagonists as the primary choice for androgen deprivation therapy (ADT). GnRH antagonists have several potential advantages over agonists:

  • No flare phenomenon
  • No issues in starting this therapy when baseline testosterone levels are over 5 ng/ml
  • No issues in starting this therapy when baseline PSA levels are over 20 ng/ml
  • Elevated alkaline phosphatase
The use of ADT in prostate cancer (PC) has long been associated with an increased risk of cardiovascular events (CVE), particularly in men with a history of CVE. In 2010 the FDA mandated manufacturers of GnRH agonists to include CV risk as an additional safety information to their drug labels. 

Margel presented his own trial of early cardiovascular morbidity in a randomized trial comparing between LHRH-agonist and LHRH antagonist treatment in patients with advanced PC. The primary aim of this study was to compare endothelial function in patients with advanced PC and pre-existing CVD treated for one year with degarelix vs. LHRH agonist. The secondary endpoint was to compare CVE. This was a bi-central randomized open-label superiority study. Men with advanced PC and pre-existing CVD were included in this study. The men were stratified by cancer status (local vs. metastatic) and by endothelial function (measured by endoPAT). The inclusion and exclusion criteria are shown in Table 1. The outcomes included all cardiovascular events and all major adverse cardiovascular events (MACE) including:

  • Death 
  • Myocardial infarction 
  • Cerebrovascular accident (CVA) 
  • Cardiac catheterization with stent
Additionally, serum hormones and biomarker levels were taken at baseline and every 3 months including CRP, D-dimer, NT-proBNP, and HsTrop. A total of 41 patients were randomized to the GnRH antagonist group and 39 in the agonist group. The characteristic of the patients’ PC is shown in table 2 and CV history in table 3.

Table 1 – Inclusion and exclusion criteria:
UroToday FOIU2018 the Primary Choice for ADT YES 1

Table 2 – Prostate cancer clinical details:
UroToday FOIU2018 the Primary Choice for ADT YES 2

Table 3 – Cardiovascular disease details:
UroToday FOIU2018 the Primary Choice for ADT YES 3

The results of the trial demonstrated that MACE had occurred in 20% of the agonist group compared to 2.4% of the antagonist group. A total of 35% CVE had occurred in the agonist group compared to 7% in the antagonist group. All differences were statistically significant. Interestingly NTproBNP, a well-known CVE predictor, was significantly higher in the agonist group (Figure 1).

Figure 1 – NTproBNP in the agonist and antagonist groups:
UroToday FOIU2018 the Primary Choice for ADT YES 4

Margel suggested that the mechanism underlying these results are the GnRH receptor on the endothelium, macrophages and T-cells, and the fact that higher FSH levels, which are present with agonists, but not with antagonists, result in an increased metabolic risk.

Margel concluded his presentation, stating that most patients with PC die of heart disease. A plethora of evidence, including the presented prospective trial, suggest that antagonists are better than agonists, at least for those with previous ischemic heart disease.

Presented by: David Margel, MD, Rabin Medical Center, Israel

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

Read the Opposing Argument: Should Antagonists be the Primary Choice for ADT? - NO