Dr. Charles J. Ryan is the Clinical Program Leader for Genitourinary Medical Oncology at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center.
He primarily treats men with advanced prostate cancer. His research focuses on novel therapies for advanced prostate cancer.
How do Xtandi (enzalutamide) and Zytiga (abiraterone) work? What are the differences between them?
Dr. Ryan: Xtandi (enzalutamide) and Zytiga (abiraterone) have been out on the market for a few years. They are both considered standard therapies in castration-resistant prostate cancer. The hormone receptor interaction is important throughout the progression and natural history of the disease. They are similar, but they are not identical in terms of their mechanism of action.
Zytiga (abiraterone) lowers the levels of androgens; it lowers the levels of testosterone and related molecules that are available for the cancer. Xtandi (enzalutamide) blocks the androgen receptor in a potent way. They both end up reducing hormone signaling in the disease.
Because they have different mechanisms of action, they have different side effects. The generic name of Xtandi is enzalutamide, similar to apalutamide (currently in development). They were invented in the same laboratory at University of California, Los Angeles.
Are they all used in the same set of patients?
Dr. Ryan: For the most part, yes. The initial approvals of the drugs for the disease were in patients with metastatic castration-resistant disease in post-chemotherapy patients (CRPC). Then there were two studies that tested Xtandi (enzalutamide) and Zytiga (abiraterone) respectively in chemotherapy-naïve CRPC patients. Both of those demonstrated a benefit over placebo in terms of delaying the disease, the onset of symptoms, improvements in survival, and a decline in functional status. Now they are standard of care for CRPC patients.
Recent reports of the LATITUDE and STAMPEDE studies done in Europe and Canada demonstrated that Zytiga (abiraterone) offers a survival benefit to patients when added to initial hormonal therapy, so that is a new standard for Zytiga (abiraterone). Similar studies with Xtandi (enzalutamide) are ongoing and could demonstrate a similar result, which is to say, Xtandi (enzalutamide) could be used up-front in initial hormonal therapy.
That’s a big change.
Dr. Ryan: That would be. Yes.
Are some men resistant to these therapies initially, or do they develop resistance? If so, is there any way of telling whether a man will be resistant?
Dr. Ryan: In terms of resistance to these therapies, it is fairly universal that patients will develop resistance to these therapies when they receive it in CRPC. Most CRPC tumors have mutations of one type, and some of them have many mutations that ultimately render them resistant to various therapies. One of the big challenges in the field over the last few years has been this question of whether these two drugs are so similar that we should simply choose one and use it, or whether we can use them in a serial fashion. In other words, we would treat a patient with Zytiga (abiraterone) until the disease becomes resistant, and then treat with Xtandi (enzalutamide).
Overall, the use of the second one of these is less effective. It’s probably best to choose one and, if it’s tolerated well, stick with it. When a patient becomes resistant to one of these drugs, using the other one may be of limited value.
There’s no way to reverse or combat a man’s resistance?
Dr. Ryan: It’s actually quite complicated. In the laboratory, the androgen receptor and the factors that stimulate the androgen receptor are dynamic. It is possible that prostate cancer cells could become re-sensitized to these. There are some experimental suggestions that that could occur.
However, we haven’t really seen that bear out in the clinic. It’s a rare patient who will develop progressive disease on Xtandi (enzalutamide) and then have a significant benefit to Zytiga (abiraterone), for example.
You touched briefly on combining drugs in this class with other types of therapy. Are there any others that appear more or less effective?
Dr. Ryan: The results of studies where Xtandi (enzalutamide) or Zytiga (abiraterone) were combined with other therapies are disappointing. At our center, we have tried to do a couple of these combination studies and have not seen results that would change the standard of care. We don’t combine them with chemotherapy, typically.
There was a study that combined Zytiga (abiraterone) with Xofigo (radium-223); that study closed early due to excessive deaths and fractures. It looked like that combination may be dangerous. We’re not sure why that is. Some more thought is going into that process. There is a study underway that’s maturing, which is a combination of Xtandi (enzalutamide) and Zytiga (abiraterone). We anticipate results in the coming year.
For the time being, these should be given as single agents, not in combination.
Has anybody looked at combining them with immunotherapeutic agents?
Dr. Ryan: The newer PD-1 inhibitor immunotherapies in prostate cancer are probably only active in a small proportion of patients with prostate cancer. And there are some studies underway with those, but no definitive data yet.