GnRH agonists or GnRH antagonists: The risks and benefits

This review compared the potential risks and benefits of two hormone therapies available for androgen deprivation therapy (ADT). Authors concluded that GnRH antagonists offer a safe and effective alternative to GnRH agonists.

ADT is a type of hormone therapy commonly used to treat advanced prostate cancer. ADT targets male sex hormones (such as testosterone) and reduces their effect on cancer cell growth. Reducing testosterone to very low (castration) levels is often the treatment goal of ADT. This can be achieved by removal of the testicles (also called orchiectomy) or by drug therapy.

Gonadotropin-releasing hormone (GnRH) agonists are hormone therapy drugs that lower the production of testosterone. When GnRH agonists are first given, testosterone levels initially go up before falling to very low levels. This surge in testosterone may last up to 30 days and can lead to a flare-up of the tumor or other complications. For example, men whose cancer has spread to the bones (bone metastasis) may have bone pain or spinal cord compression during a flare. GnRH antagonists have been developed as an alternative. They provide fast suppression of testosterone without the initial flare. How these different forms of ADT compare in terms of treatment outcomes and side effects is still being investigated.

The aim of this review was to summarize recent findings on the potential risks and benefits of different forms of ADT.

One study directly compared a GnRH antagonist (Firmagon) with a GnRH agonist (Eligard) over the course of 12 months. The GnRH antagonist achieved testosterone suppression to near castration levels within 3 days in 96.1% of men. None of the men receiving the GnRH agonist showed signs of testosterone suppression after 3 days. Importantly, the level of suppression in the group receiving the GnRH antagonist was maintained until the end of the study. Men that switched from the GnRH agonist to the antagonist also achieved fast testosterone suppression.

Two separate trials found that a GnRH antagonist delayed disease progression longer than the GnRH agonist. The time until men became resistant (no longer responded) to treatment was also significantly longer. Another study noted that the GnRH antagonist was more protective against cancer recurrence and death. On average, disease progression or death was delayed by an additional 7 months compared to the GnRH agonist. In a further study, GnRH antagonists were noted to offer better control of bone metastases over a 1-year period.

GnRH agonists and antagonists were both well-tolerated with a similar rate of side effects. Sexual dysfunction and metabolic syndrome (high cholesterol levels, insulin resistance, and diabetes) were among the most commonly reported.

Metabolic syndrome can increase the risk of cardiovascular disease (CVD; heart or blood vessel disease). In one study involving 2,300 men, GnRH antagonists were associated with half as many CVD events during the first year of treatment compared to GnRH agonists. In men with a pre-existing heart condition, the risk of CVD was 56% lower with GnRH antagonists.  

The authors concluded that GnRH antagonists offer faster testosterone suppression and improved disease control, as well as a reduced risk of CVD events, compared to GnRH agonists.