Przemyslaw W. Twardowski, MD
While there has been some progress with treating prostate cancer, how to prevent the progression of metastatic prostate cancer is still unclear, according to Przemyslaw W. Twardowski, MD.
While agents such as abiraterone acetate (Zytiga) and enzalutamide (Xtandi), LHRH antagonists such as degarelix (Firmagon), and bone-targeted therapies such as radium-223 dichloride (Xofigo) have led to significant advancements in the paradigm, researchers are continuing to evaluate them in an effort to improve outcomes.
“As good as these drugs are that we have right now, unfortunately, none of them provides a curative effect in metastatic advanced disease,” said Twardowski. “Ultimately, over a period of time, they fail. This is when the patients start developing symptoms and developing new metastatic sites. That’s when we know that the cancer is entering into a more ominous phase—the potentially life-threatening phase.”
In an interview during the 2017 OncLive®
State of the Science SummitTM
on Genitourinary Cancers, Twardowski, professor of medical oncology at John Wayne Cancer Institute (JWCI), discussed a variety of factors to consider when treating patients with prostate cancer.
OncLive: What are some factors that you take into consideration when choosing which androgen-receptor (AR) targeted therapy is best for patients with prostate cancer?
That’s a great question and not easy to answer because we don't really have any laboratory molecular biomarkers that would guide us. I sometimes joke that, in many ways, for me, in the regular practice setting, the choice between the key second-generation androgen pathway inhibitors, such as abiraterone acetate and enzalutamide, is almost like flipping a coin, essentially. There are very subtle nuanced clinical factors that may influence one agent over the other.
For example, enzalutamide has been associated with more side effects related to neurological abnormalities like very rare incidents of seizures, falls, and perhaps, a little bit more fatigue. In my practice, certainly in patients who are at risk for these side effects or have a history of seizure, falls, or maybe some performance status issues that may predispose them to that, I would potentially consider using the alternative of abiraterone acetate.
On the other hand, in patients who have brittle diabetes, a history of liver problems, or congestive heart failure, they would potentially sway me to use the alternative drug, enzalutamide. As you can see, those are relatively subtle nuanced clinical factors that can influence the decision making, but, honestly, for a majority of patients, they don’t really apply. We really need better ways to select these agents in an academic institution.
In many cases, we are also influenced by potential availability of subsequent clinical trials, so that may also play a role in consideration. For example, we have clinical trials that particularly look at patients who are failing abiraterone acetate therapy. That may sway us to use that agent versus the other one, but that may not apply, of course, to the community setting that much.
How does degarelix fit into the paradigm?
That’s also a very good question. Degarelix was approved in 2008 for the treatment of patients with prostate cancer. It is an agent that blocks the production of testosterone in the testicle in a slightly different way that may be more like traditional, older-generation agents. The main difference, without going into details of the pathophysiology of degarelix, is that degarelix causes more rapid suppression of testosterone production in the testicle. It is usually within 1 or 2 days versus 10 to 20 days for these other agents.
Also, the other agents tend to have this paradoxical effect initially that they cause what is called “testosterone surge,” which is the initial increase of testosterone that takes place over a few days. Then, ultimately, testosterone goes down. However, in this initial period, that may be detrimental—especially in patients who have very large-volume metastatic disease symptomatic perhaps at risk of spinal cord compression or urinary retention.
That leads me to the logical conclusion that, in those kinds of patients with high-volume metastatic disease who are at risk of significant deterioration through that initial testosterone surge process, I would potentially favor degarelix. Now, in the long run, it’s a very debatable question whether degarelix provides any long-term advantage over agents like leuprolide or goserelin. It’s slightly less convenient because it only comes in monthly injections versus longer-acting injections. One strategy would be to use degarelix initially in these patients and then switch them to more traditional agents.