Crawford Highlights Role of Degarelix in Prostate Cancer

E. David Crawford, MD

As a GnRH antagonist available for patients with advanced prostate cancer, degarelix (Firmagon) has proven to be a solid option with its tolerable safety profile and rapid reduction in testosterone suppression, explains E. David Crawford, MD.

The 2008 FDA approval of degarelix was based off of findings from a phase III study that compared the safety and efficacy of the antagonist with leuprolide. Here, researchers evaluated the ability to maintain suppression of testosterone for up to 1 year; results showed that there were no rises in testosterone in the degarelix arm and that 96% of patients attained medical castration 3 days following the first dose.

Degarelix is currently being explored for its efficacy in patients who have prostate cancer and cardiovascular disease (NCT02663908). The ongoing phase III PRONOUNCE trial is comparing degarelix with leuprolide to see which of the 2 agents leads to a greater reduction in the risk of cardiovascular complications for patients with both conditions.

OncLive: When you have a patient with prostate cancer, where do therapies like degarelix fit into their treatment course?

In an interview with OncLive, Crawford, a professor of radiation oncology at the University of Colorado Denver, shares insight on incorporating ADT—specifically degarelix—into the prostate cancer landscape and why it remains to be a standard go-to approach for patients.Crawford: Degarelix is a GnRH antagonist. What Dr Andrew Schally, who received the Nobel Prize in Physiology or Medicine in 1977, was working on was trying to develop an antagonist to shut down the hypothalamic pituitary testicular axis. We never could quite get there because of molecule-delivery systems, as well as histamine release and allergic reactions. We actually settled for an agonist, which have paradoxical effects and raise testosterone before they lower it. However, the good things were that they were depots that could be 1 month, 3 months, or 6 months. Therefore, there are people who continue to pave the way to develop an antagonist [like that].

One of the first ones was cetrorelix (Cetrotide), then abarelix (Plenaxis), and now degarelix. Degarelix had solved some of the issues with the earlier ones, such as escapes and histamine release and things like that; however, it is still a 1-month depot. We sort of live in a 3-month, 4-month depot arena, but, nevertheless, when you start focusing on the attributes of degarelix compared with an agonist, what you end up seeing are some real benefits [with degarelix] that probably outweigh the monthly depot.

What patients would be appropriate to receive degarelix?

Degarelix gives a rapid reduction in testosterone and has some other attributes, including a lack of flares with testosterone except in between injections. There are some interesting effects on follicle-stimulating hormone (FSH) and a bunch of other things. I would use it in patients who would be candidates for ADT—almost anybody I would give it to. Particularly, I would focus on patients who had a lot of disease or flare of the disease, and could have spinal cord or urinary problems. It also gives more rapid volume reduction in the prostate. When you give radiation or an agonist, you’re actually wasting a couple of months because of the flare of testosterone. You can block it with an antiandrogen agent, but some of that still occurs.

What are the adverse events, if any, associated with degarelix?

A lot of times, the big drawback [with degarelix] is that it is 1 month. So, if I have patients at the University of Colorado Denver who are coming from Idaho or Wyoming, and they have a 4- to 6-hour drive once a month, it becomes much more problematic. We find ways around it. It is basically just one: injection site reaction. We know that about one-third of the patients who get their first injection and they have to get a loading dose—2 injection sites in the abdomen—will get some redness or feel some pain. It can be relatively severe in some patients. Then, after that, there are monthly maintenance doses and then that cuts down by a few percent, but not as high as the 30% [with the loading dose].

Do you believe that this drug is underutilized in practice?

There are a lot of issues that have to do with why patients get injection site reaction. Some of it has to do with injection technique. It’s a subcutaneous drug and most people think that subcutaneous is right under your skin. However, it’s a deep subcutaneous drug, so we don’t want the peptide in contact with the epidermis.It is under utilized because it’s only for 1 month; patients are sort of sold on 3- and 4- month depots. However, when you talk to patients about the ability to suppress testosterone and all of the other stuff that goes along with it that’s positive, people understand. A lot of the drugs we use in cancer therapy are every 3 weeks or every month, anyway.

How does ADT compare with other prostate cancer therapies?

We really need to monitor testosterone with these drugs. Antagonists like degarelix are good drugs, but there are some agonists that work very well at keeping testosterone down and not having many flares. We have done some work with leuprolide; that is a good drug. That has different depots, such as 1 month, 3 months, 4 months, and 6 months. You can weigh the risks and benefits but, at the end of the day, you want to give a drug that gets testosterone down and keeps it down. What we have learned in the past couple of years is that ADT has some baggage, and the baggage used to be hot flashes, lost libido, weight gain, osteoporosis, and things like that. There were explanations for that.

Then, a few years ago, some people started reporting an increased risk of cardiovascular disease when on ADT. There were some parallels that existed. This led to a question of why this is occurring and an understanding of it. Part of it may be related to the drug you use—is it an agonist or antagonist and FSH? FSH actually has some very interesting effects. It can stimulate the tumor growth and lipid in blood vessels that can lead to atherosclerosis. GnRH receptors and agonists, for instance, can stimulate T cells and cytokine-release syndrome, whereas antagonists might not. That is one of the other mechanisms.

The bottom line is that men who have a preexisting cardiovascular disease have that exacerbated with ADT. Therefore, you need to watch for it. We preach this shared care that we work with our family practice cardiologist with these patients to deal with any cardiac risk and stuff like that. We will control blood pressure, lipids, and have them do exercise to try to avert this.

However, we have to be very careful in using ADT in men who have prior cardiovascular disease. Right now, there are retrospective studies that show that there may be less risk with an antagonist. I have written about that and others have, too. Again, these are retrospective studies, and a prospective study needs to be done. There are 2 ongoing now; 1 in the United States and 1 in Canada.

Klotz L, Boccon-Gibod L, Shore ND, et al. The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int. 2008;102(11):1531-1538.