Insights From: Julie Graff, MD, Oregon Health and Science University; Judd W. Moul, MD, Duke University Medical Center; Charles J. Ryan, MD, UCSF Helen Diller Comprehensive Cancer Center
Charles J. Ryan, MD: It’s actually a complicated decision about when to treat a patient with nonmetastatic castration-resistant prostate cancer, because some of them can go a long time on no treatment and have a very good prognosis. Others on the other end of the spectrum may actually have a fair amount of disease that is not forming 3-dimensional tumors that show up on scans. They may have bone marrow-based disease, for example.
Of course, in prostate cancer the best marker of disease pace is a change in PSA. Generally, what I do is if a patient has a PSA doubling time that’s less than 9 months, or around 9 months, is watch them quite vigilantly. We do use, and have used over the years, many secondary hormonal therapies in this space simply with the goal of reducing PSA, because we felt generally that reducing PSA is a good thing in that it prevents metastases from forming. So, I look at the patient with the PSA, I scan frequently, and of course I try to read the patient’s anxiety about the situation and look at where prostate cancer is in the context of their other medical illnesses, if there are any.
For patients who become castration resistant, until quite recently the only treatment that patients were typical on would have been a therapy like an LHRH (luteinizing hormone-releasing hormone) agonist or an LHRH antagonist, and perhaps an oral androgen receptor antagonist such as bicalutamide. Now many patients are receiving abiraterone as part of their initial androgen deprivation therapy. And so, many patients who are coming into castration resistance at this time have received abiraterone. I should say not necessarily at this time, but in the future, they will have received abiraterone. Similarly, many patients are receiving docetaxel in the context of castration-sensitive metastatic disease. Now many of those patients when they progress to CRPC will have metastatic CRPC, not nonmetastatic CRPC.
Julie Graff, MD: The current treatments available for nonmetastatic castration-resistant prostate cancer are pretty antiquated. We have ketoconazole that basically turns off the adrenal glands and reduces one source of androgens, but it has never been approved in prostate cancer. It’s an old-fashioned fungal drug, an antifungal medication. We also have estrogens, and we can give those by patch or by mouth, but they can cause blood clots and breast enlargement and tenderness, so patients don’t really like them.
We also have first-generation androgen receptor antagonists such as bicalutamide, flutamide, and nilutamide. The cancer can be resistant to those when it upregulates its androgen receptor. Sometimes, we double up on some of those agents or rotate through them trying to get some effect, but there are no real data saying that they help people live longer or that they increase the time to metastatic disease. In that situation, we’re trying to lower the PSA, but not very successfully.
The rationale of using AR-targeted therapy is to block the actions of the remaining androgens. I say androgens meaning male hormones. When we turn off the testicles, we’re only blocking about 90% of androgens, but the cancer itself can produce some, as can the adrenal glands. So, the rationale is to block the actions of those androgens by making them unable to bind to the androgen receptor. I use these types of agents all the time, from the first-generation drugs that I described, such as bicalutamide, to the second-generation androgen receptor antagonists that are currently only approved for metastatic prostate cancer.
GnRH (gonadotropin-releasing hormone) agonists are those drugs that don’t have the testosterone flair. Most of what we use, such as Lupron (leuprolide), Eligard (leuprolide), or Zoladex (goserelin), are LHRH or GNRH antagonists. They cause an initial flare in the testosterone before they block it. There’s some thought that maybe antagonists are better than agonists, although there are not conclusive data on that. So, when we use the antagonists, we’re mostly using it in the upfront setting in newly diagnosed metastatic prostate cancer.
The unmet needs in nonmetastatic castration resistant prostate cancer are huge. There are no therapies in that space currently that have been shown to improve survival or decrease the risk of metastatic disease. Currently, we have some old-fashioned drugs that we play with in this space, such as ketoconazole, doubling up bicalutamide, or trying estrogens, but all of those have very scant data and we don’t know that they’re doing the patient any good.
Prostate cancer becomes symptomatic when it’s metastatic. Prior to that in the nonmetastatic space, we were only treating the PSA, which is a lab result. So, anything we can do to delay metastatic disease could be beneficial for the patient, particularly because the metastases go to the bones, which can be quite painful.
Charles J. Ryan, MD: The unmet need in nonmetastatic prostate cancer for the current time is a therapy that can prevent metastases. We generally think that preventing metastases is a good thing, and there are papers that show that delays in metastases delay death from the disease or improve survival. So, that’s the goal of therapy. The unmet need would be to find a therapy with a very good safety profile, where we can administer it without significant side effects and prevent metastases from forming.