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Treatment Challenges in Nonmetastatic CRPC

Panelists: Raoul S. Concepcion, MD, FACS, Comprehensive Prostate Center; Daniel George, MD, Duke Cancer Institute; Alec Koo, MD, Skyline Urology; Phillip Koo, MD, MD Anderson Cancer Center; Neal D. Shore, MD, FACS, Carolina Urologic Research Center
Published: Friday, Apr 13, 2018



Transcript: 

Raoul S. Concepcion, MD, FACS: In this next segment, we’re going to transition. We’ve gone from definitively treated biochemical recurrence, diagnosed metastatic hormone-naïve disease. Most of those patients will get androgen deprivation therapy. And hopefully, for higher-volume, higher-grade disease, they will get some element of an oral agent or chemotherapy. But we know that despite ADT, which is obviously the baseline in managing these diseases, these patients will ultimately fail hormone therapy. We get into this area called castration-resistant prostate cancer. Neal, for the audience, give us a working definition of castration-resistant prostate cancer.

Neal D. Shore, MD, FACS: We’ve gone through all of these iterations of various nomenclature verbiage, and it’s still controversial. Some folks don’t really like the term. They bristle about this word castration. Maybe some would like some other definition for it? But that said, I think it’s gotten its traction because of the trials that we’ve done. It’s been important, and I think the Prostate Cancer Working Groups—1, 2, and 3—have been really helpful in standardizing global trials.

The definition that’s fairly ubiquitously used is, you have to check a testosterone level. Based on our metrics here in North America, it has to be less than 50 ng/dL. It is usually repeated for a second time, but not always. It doesn’t have to be. The prostate-specific antigen has to be rising by 25% or more from the nadir, and then it is repeated for a second time. In real-world practice, most of us would accept that as long as the PSA is going up from nadir, and the T-level is less than 50 ng/dL, it is, indeed, CRPC.

Daniel George, MD: I would just clarify that we do see these cases with these slightly higher testosterone levels. I’m sure you guys have seen these, too. The patients are on a LHRH agonist. Yet, their testosterone is 60 ng/dL or 65 ng/dL. To me, that’s still castration-resistant disease. We draw the line at 50 ng/dL because we have to. We have to draw it somewhere. But to me, it’s more of a guideline.
I’ve had a patient on a LHRH agonist. Their T-level has gone down. Their PSA has dropped. And now, they’ve gone from a nadir and they’re going up. They’re still on that LHRH agonist. For me, for all purposes, that’s going to be castration-resistant, even if the T level is a little bit higher. We’ve actually gone to raising that threshold to 75 ng/dL in some of our protocols, just because we’ve run into this issue. We’ve run into it in some of our minority populations, sometimes, and other populations of which I don’t really know how to explain. I don’t know that it is fundamentally going to prevent us from getting to castration resistance, because I don’t know how to lower it any lower. I’ve done surgical castrations.

Alec Koo, MD: Dan, what is the utility for switching over to degarelix. To try to see if you could reverse that trend and…

Daniel George, MD: It’s a good point, Alec. We’ve tried that. Sometimes it works. But it doesn’t work all the time. I don’t want to get too stuck on it. I think the intent is that most of the patients are less than 50 ng/dL. But it’s not a perfect application.

Neal D. Shore, MD, FACS: Those are just your investigator-initiated protocols. But unfortunately, it’s pretty rigorous, if you don’t get somebody below 50 ng/dL. Oftentimes, for most trials, that’s exclusionary criteria. I think you’re right. Sometimes, you can try a different LHRH agonist, antagonist, bilateral orchiectomy, but I would also suggest looking at your testosterone assay. They’re starting to see a lot of different assays out there, and some of those can be misleading. Today, mass spectrometry is going to give you the best number. We’ve seen this variability. So, I would advise the audience to think about where they’re getting the T-assay.

Daniel George, MD: That’s a good point. It’s all kind of arbitrary. At the end of the day, I don’t want people to hold back on using drugs for castration resistance because of something like this. So, if you don’t have access to those kinds of things, I don’t want you to feel restricted by it.

Transcript Edited for Clarity 

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Transcript: 

Raoul S. Concepcion, MD, FACS: In this next segment, we’re going to transition. We’ve gone from definitively treated biochemical recurrence, diagnosed metastatic hormone-naïve disease. Most of those patients will get androgen deprivation therapy. And hopefully, for higher-volume, higher-grade disease, they will get some element of an oral agent or chemotherapy. But we know that despite ADT, which is obviously the baseline in managing these diseases, these patients will ultimately fail hormone therapy. We get into this area called castration-resistant prostate cancer. Neal, for the audience, give us a working definition of castration-resistant prostate cancer.

Neal D. Shore, MD, FACS: We’ve gone through all of these iterations of various nomenclature verbiage, and it’s still controversial. Some folks don’t really like the term. They bristle about this word castration. Maybe some would like some other definition for it? But that said, I think it’s gotten its traction because of the trials that we’ve done. It’s been important, and I think the Prostate Cancer Working Groups—1, 2, and 3—have been really helpful in standardizing global trials.

The definition that’s fairly ubiquitously used is, you have to check a testosterone level. Based on our metrics here in North America, it has to be less than 50 ng/dL. It is usually repeated for a second time, but not always. It doesn’t have to be. The prostate-specific antigen has to be rising by 25% or more from the nadir, and then it is repeated for a second time. In real-world practice, most of us would accept that as long as the PSA is going up from nadir, and the T-level is less than 50 ng/dL, it is, indeed, CRPC.

Daniel George, MD: I would just clarify that we do see these cases with these slightly higher testosterone levels. I’m sure you guys have seen these, too. The patients are on a LHRH agonist. Yet, their testosterone is 60 ng/dL or 65 ng/dL. To me, that’s still castration-resistant disease. We draw the line at 50 ng/dL because we have to. We have to draw it somewhere. But to me, it’s more of a guideline.
I’ve had a patient on a LHRH agonist. Their T-level has gone down. Their PSA has dropped. And now, they’ve gone from a nadir and they’re going up. They’re still on that LHRH agonist. For me, for all purposes, that’s going to be castration-resistant, even if the T level is a little bit higher. We’ve actually gone to raising that threshold to 75 ng/dL in some of our protocols, just because we’ve run into this issue. We’ve run into it in some of our minority populations, sometimes, and other populations of which I don’t really know how to explain. I don’t know that it is fundamentally going to prevent us from getting to castration resistance, because I don’t know how to lower it any lower. I’ve done surgical castrations.

Alec Koo, MD: Dan, what is the utility for switching over to degarelix. To try to see if you could reverse that trend and…

Daniel George, MD: It’s a good point, Alec. We’ve tried that. Sometimes it works. But it doesn’t work all the time. I don’t want to get too stuck on it. I think the intent is that most of the patients are less than 50 ng/dL. But it’s not a perfect application.

Neal D. Shore, MD, FACS: Those are just your investigator-initiated protocols. But unfortunately, it’s pretty rigorous, if you don’t get somebody below 50 ng/dL. Oftentimes, for most trials, that’s exclusionary criteria. I think you’re right. Sometimes, you can try a different LHRH agonist, antagonist, bilateral orchiectomy, but I would also suggest looking at your testosterone assay. They’re starting to see a lot of different assays out there, and some of those can be misleading. Today, mass spectrometry is going to give you the best number. We’ve seen this variability. So, I would advise the audience to think about where they’re getting the T-assay.

Daniel George, MD: That’s a good point. It’s all kind of arbitrary. At the end of the day, I don’t want people to hold back on using drugs for castration resistance because of something like this. So, if you don’t have access to those kinds of things, I don’t want you to feel restricted by it.

Transcript Edited for Clarity 
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