Therapeutic Options in Metastatic CRPC

Transcript:Charles J. Ryan, MD: We’re fortunate that today there are many treatment options available for men with castration-resistant prostate cancer, and it’s likely we’re going to have even more in the coming years. Right now, we have a menu of therapies available for our patients that are used in a variety of different contexts and have a variety of different mechanisms of action. For over a decade, we’ve had chemotherapy, we’ve had docetaxel, and we’ve recently added cabazitaxel to that list. So, we have two taxane-based chemotherapies. We also have radium-223, also known as Xofigo. This is an intravenously administered radioisotope that’s indicated for men who have symptomatic bony disease—it’s really for patients who have bone-only disease and pain from that. These can be patients who’ve already had chemotherapy or who are unfit for chemotherapy. Then we have the two AR-directed therapies—abiraterone and enzalutamide—and those are both available for patients who are chemotherapy-naïve or who have already been treated with chemotherapy. And finally, we have sipuleucel-T, a cellular immunotherapy which is really a treatment that’s designed for patients with metastatic castration-resistant prostate cancer and who have a more slowly progressing form of the disease.

Enzalutamide has been shown to improve survival and delay disease progression in two contexts. In one, it was in patients who had previously received docetaxel. That was a study that was called the AFFIRM study, and it was reported a few years ago. It led to the approval of enzalutamide. This was followed up with a study called PREVAIL, which was enzalutamide versus placebo in patients with chemotherapy-naïve castration-resistant prostate cancer. In that study, enzalutamide demonstrated a clearly significant benefit in terms of progression-free survival compared to placebo. The median progression-free survival in that study was about 18 months, and the median survival was about 33 months. Both of those were statistically significantly better than the placebo arm. So, in that context, enzalutamide has really become a very logical choice backed by level 1 evidence for use in the chemotherapy-naïve patient population.

In general, enzalutamide is quite safe for most people who take it. There is an interesting story about enzalutamide and the potential safety issues that pertain to its penetration into the central nervous system. At high doses that we don’t use anymore, there were seizures seen with this drug. At the current standard dose of 160 mg/day, we don’t see seizures, but what we have seen is a definite fatigue-type of a syndrome. Falls have been reported with this drug, and there is some speculation that there might be some neurocognitive deficits that occur, such as memory, even depressive symptoms in a certain group of patients. That’s something that’s been recently reported.

Abiraterone has been shown to be effective in both delaying disease progression and improving survival in both chemotherapy-treated and chemotherapy-naïve patients with metastatic castration-resistant prostate cancer. This was based on two phase III studies. We call them the COU-AA-301 study, which was the post-chemotherapy group, and the COU-AA-302 study, which was the chemotherapy-naïve group. In the chemotherapy-naïve group of patients, the median progression-free survival is about 17 months and the median survival when treated with abiraterone is over 35 months. And, so, this is now backed by level-1 evidence and is considered one of the standard therapies for castration-resistant prostate cancer.

Abiraterone’s mechanism of action is to impair androgen production in the tumor and in the adrenal glands. But, what was noted very early on in its development is that it can cause a reflexive mineralocorticoid excess. And what can happen is patients can develop retained sodium, which typically manifests itself as edema and loss of potassium. So, hypokalemia is a risk when a patient takes abiraterone by itself. When a patient takes low-dose prednisone, those mineralocorticoid levels and the mineralocorticoid side effects are drastically reduced. Yet, patients do continue to need to be monitored, and so the monitoring for a patient treated with abiraterone would have to do with potassium levels. Certainly, patients then who are taking low-dose prednisone would need to have blood glucose monitored from time to time, and liver function tests need to be monitored as well.

Transcript Edited for Clarity