Understanding Nonmetastatic CRPC: An Overview

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


Judd W. Moul, MD: Nonmetastatic castrate-resistant prostate cancer is prostate cancer that is no longer responding to hormone therapy, but the patient does not have metastases. Stepping back a little bit, let’s first talk about castrate-resistant prostate cancer, or CRPC, which we used to refer to as hormone-refractory prostate cancer. It’s basically a gentleman in our practice who has been on hormone therapy or androgen deprivation therapy and now has a rising PSA or clinical progression of the disease. He also has to have a low testosterone level, classically less than 50 ng/dL or even less than 20 ng/dL. His PSA has to be rising.

This has been a frustration because nonmetastatic castrate-resistant prostate cancer doesn’t really have any current FDA-approved treatments. We have this condition of men with a rising PSA on androgen deprivation therapy. The men are very concerned about their rising PSA, and in general most of them would like something done. Yet we have this black box right now remaining in 2017, where we don’t have any FDA-approved drugs specifically for this condition. Now on the other hand, metastatic castrate-resistant prostate cancer, or M1 CRPC, has been in the news for the last 10 years. Since 2010, we’ve had multiple treatments approved for men who have metastatic disease. But for this M0, or nonmetastatic group of patients, up until now we just haven’t had a new treatment to offer these gentlemen.

Nonmetastatic castrate-resistant prostate cancer is common, although it’s not crystal clear how common it is. I did some recent literature searches trying to answer that question. One European paper I found said that in the European Union, potentially 4% to 7% of prostate cancer patients who are living would have nonmetastatic castrate-resistant prostate cancer. Then I looked at data from the United States, and recently the American Cancer Society suggested there may be some 20 million, or up to 29 million, men—which seems crazy high—living in the United States who are survivors of prostate cancer.

If you multiply that 3% to 7%, or the 4% to 7%, you could have anywhere from half a million to over 2 million men in the United States who theoretically could have nonmetastatic castrate-resistant prostate cancer. In my own practice, or in my experience as a clinician, I would personally estimate that there are probably half a million men in the United States who have this nonmetastatic castrate-resistant prostate cancer. And up until recently, you would have said, “Well, who cares how many there are, because we really don’t have any treatments for it.” But as of now, there are some treatments coming down the pike. And again, we could be looking to identify up to a half-million men, and we would like to determine if they’re eligible for some of these new treatments that may be coming on line.

When we have a patient who has M0 CRPC, the first thing we need to do with that patient is determine how risky his condition is. How likely is his cancer to progress to metastatic disease, and how long will that take? It is appearing from the literature that a key factor is PSA doubling time and absolute PSA. The clinical trials testing some of these new agents like enzalutamide, apalutamide, and darolutamide all used a PSA doubling time of 10 months or less, along with a PSA typically in the 2 ng/mL to 5 ng/mL range.

In plain English, when we have these patients with M0 disease, it may be appropriate to follow them for a while, monitor a series of PSAs, go to the internet, go to Google, do a PSA doubling time calculator, punch in those PSAs and dates, and try to get a sense of what that PSA doubling time is. If the PSA doubling time in that patient is still greater than 10 months, you might be able to just monitor that patient with further active surveillance. But the red flag seems to be when that PSA doubling time falls below 10 months. That’s a harbinger of more severe disease and may be a trigger point for us to consider these novel hormonal therapy agents once they become FDA approved.

When a doctor is in his clinic, let’s just take an example of a patient. A patient has prostate cancer and gets treatment for localized disease with surgery or radiation. Later, some of those patients develop a recurrence and then have a rising PSA level. At some point the patient gets nervous, the doctor gets nervous, and those men are put on traditional hormone therapy or androgen deprivation therapy. And most of them go on for a period of years, maybe multiple years, where they’re doing fine.

Then they have a rise in PSA, again, while they’re on this hormone therapy and have a castrate testosterone level. That’s the first sign of this nonmetastatic castrate-resistant prostate cancer. The challenge is that we’re not sure when and how often to image them to look for metastatic disease. And so many times, there’s a delay in recognition of this condition and a delay in treatment. The delay in treatment is understandable because, as of this current point in time in late 2017, we have no FDA-approved treatments. But once we have FDA-approved treatments, it’ll be more critical for doctors to identify these patients with M0 disease; talk to them; counsel them about available treatments; and in many cases, if there’s effective treatments available, start those treatments.

Transcript Edited for Clarity 
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