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Triggers to Initiate Androgen-Deprivation Therapy (ADT) in Prostate Cancer

Panelists: Raoul S. Concepcion, MD, FACS, The Comprehensive Prostate Center; Jorge A. Garcia, MD, FACP, Taussig Cancer Institute; Alicia K. Morgans, MD, MPH, Vanderbilt University Medical Center; Ashley E. Ross, MD, PhD, Johns Hopkins Medical Institution; Daniel R. Saltzstein, MD, Urology San Antonio
Published Online: Wednesday, Nov 30, 2016



Transcript:

Raoul S. Concepcion, MD:
Hello, and thank you for joining this OncLive Peer Exchange® titled “Key Issues Surrounding the Treatment of Prostate Cancer.” We’ve assembled a panel of experts in prostate cancer research to discuss the topics that will cause confusion for physicians treating in 2017 and beyond. We’ll be exchanging opinions on the use of testosterone-blocking therapies in the setting of biochemical recurrence, bone-targeted therapy, and androgen-receptor blocking, with the intention of providing clarity surrounding the challenges that you face in clinical practice.

I am Raoul Concepcion, and I am the editor-in-chief of Urologists in Cancer Care, as well as the director of the Comprehensive Prostate Center in Nashville, Tennessee. Participating today on our distinguished panel are: Dr. Jorge Garcia, director of the Advanced Prostate Cancer Research Program at Taussig Cancer Institute and Glickman Urological & Kidney Institute in Cleveland, Ohio; Dr. Alicia Morgans, assistant professor of medicine and clinical director of Genitourinary Oncology at Vanderbilt University Medical Center in Nashville, TN; Dr. Ashley Ross, director of the Brady Urology Prostate Cancer Program and assistant professor of urology, oncology, and pathology at the John Hopkins Medical Institution in Baltimore, Maryland; and Dr. Daniel Saltzstein, medical director of research and director of the Advanced Therapeutic Clinic at Urology San Antonio in San Antonio, Texas. Thank you, again, for joining us. Let’s go ahead and get started.

I think in this first segment, one of the things that we’ve known about the management of advancing prostate cancer is the dependence upon androgen-deprivation therapy. And, I think, as many of us know, this dates back to Huggins and Hodges doing some of their early work, which, obviously, won them the Nobel Prize. Basically, we know that prostate cancer is an androgen-driven event, and reducing testosterone levels down, to as low as we possibly can, has been the mainstay of therapy. However, one of the things that we also know is that there seems to be this overutilization of LHRH (luteinizing hormone-releasing hormone) analogs, whether it be agonists or antagonists, specifically in the patient who gets definitively treated, whether it be with radical prostatectomy or radiotherapy in that setting of a biochemical recurrence. So, Ash, in your practice, what are the triggers that you use personally, or even at your institution, to try to determine what is the appropriate timing in the patient who has been definitively treated for localized prostate cancer, when to start androgen deprivation therapy in patients with a biochemical recurrence?

Ashley E. Ross, MD, PhD: Thank you very much for the question. I think there are a few considerations. Just going back to Huggins paper, one thing, that he even stated then, is that the androgen deprivation would help halt the cancer, but inevitably, among the majority of patients, there would be progression to the castration-resistant space. And so, the timing of when to initiate therapy becomes beyond just side effects. It becomes more questionable because you’re really temporizing a progression. So, traditionally, at our institution, we would actually wait until metastatic progression, in the majority of cases, watch the PSAs rise, and do routine imaging, sometimes even yearly, sometimes set at a threshold once we got to a certain rise.

There was a paper that came out in our institution several years ago by Freedland et al that looked at predictors of eventual progression to the metastatic state, and among the more powerful ones were things like PSA (prostate-specific antigen) doubling time, or how long it takes a PSA to double. Doubling times that were short, particularly in the 3-month or 6-month window, would portend metastatic progression. And there are certain threshold PSA levels that can also predict that metastatic disease is actually present.

There have been two new developments that I want to just touch on. One is that we are getting the idea that maybe a lot of these patients are going to be appropriate for some sort of trial, either a consortium trial or a smaller trial going on at these different institutions—some of them using not just traditional hormonal deprivation, but we’ll talk about these newer agents later. Enzalutamide, in the EMBARK trial, and abiraterone, in the AbiCure trial, are looking at can we use these agents that are not only suppressing the growth of the tumor, but might actually destroy tumor when it’s at its small micrometastatic state? And so, with people at PSAs above 1 at our institution, we try to enroll them on a trial like that. And, the second thing, that we’ll touch on later, is where’s the disease coming from? Is it all systemic or are there small islets of disease? Maybe, as we’ll talk about in a little while, perhaps, some of the newer imaging modalities will show us other focuses of disease. As to your main question, really, we wait until metastatic recurrence or, in my patients, if the PSA doubling time is less than 6 months, I’m very worried that they’re having pending progression and will start therapy.

Raoul S. Concepcion, MD: Dan, from your particular standpoint—big group, 20 plus providers, big community practice group, very active in clinical research, a dedicated advanced prostate center—does that fit in terms of what happens in a typical large community practice?

Daniel R. Saltzstein, MD: Yes. I would agree with what Ash is saying, and that is, again, we’re also involved in some of the clinical trials in EMBARK. So, our goal, in some of these gentlemen, is to get them into a clinical trial because, again, we still have not completely developed a landscape of when these patients would be best treated. It’s a balance between the efficacy potential of overall survival benefit. It’s a balance between the toxicity that we know is coming out in a lot of papers. It’s a balance between the cost issue in the number of injections these patients might receive. We have also started to look at the Freedland paper and started to—when patients have a rapid PSA doubling time, a higher Gleason score, higher PSAs—look at that as a trigger to put patients on androgen-deprivation therapy. And, of course, like I said, we want to get patients on trials so we can figure out if there are any advances in that regard.

Raoul S. Concepcion, MD: I know, Alicia, at Vanderbilt, you guys have a multidisciplinary clinic. In that particular setting, which I think is a great setting, and I think a lot of academic centers move in that direction, does that patient start to be seen in that clinic before ADT is started, or is it generally after ADT has already been instituted? In other words, do you have a role, as a medical oncologist, in determining when is the correct time for ADT?

Alicia K. Morgans, MD, MPH: That’s a great question, and it’s one that, even with a multidisciplinary clinic, we’re still trying to find our way with. Because there are some practitioners who feel very comfortable with making that decision, and who’ve been practicing for a long time as amazing urologists. And so, when they feel comfortable with that, they often will take care of that on their own. For others, they really think it’s time to involve medical oncologists and urologists who specialize in the more advanced prostate cancer setting, and so they will pass the baton on that. I think from a medical oncology standpoint, we’re happy to accept patients, at any point, because even from that early time, thinking about the complications of treatment is really important to me. I believe at this point, we don’t have evidence to show that there’s real survival benefit, at least, when we start that therapy earlier rather than later, which is why clinical trials are so important. But, in a setting where we don’t have clinical trials, we do try to delay initiation as long as possible. And, certainly, we consider patient preferences and anxieties in all of that, too. But, when we’re thinking about the things that intermittent therapy or continuous therapy can cause in the long term, it can be devastating to patients, and we try to limit that.

Raoul S. Concepcion, MD: Jorge, what about at the clinic?

Jorge A. Garcia, MD: Let me just take a different approach. Clearly, most of us would prefer to actually put those patients, with a rising PSA syndrome, in a clinical trial, no doubt about that. But, for patients who don’t have access to a clinical trial, then the question becomes, for our community doctors, what are we going to do? And, I think, one has to be practical and pragmatic about these issues. It is very hard to believe, that even in the United States with the challenges in PSA, that you can tell a patient, “Your disease is growing. We haven’t seen it yet, but don’t worry. Let it grow bigger and then we’ll treat you when you have developed metastasis.” It’s a very foreign concept, one that for the last 5 to 10 years we’ve been trying, as a group, to actually address; educating patients about the importance, and perhaps, the imperfections, of PSA.

To Ash’s points, waiting until you have metastasis, based on data from MRC (Medical Research Council) back in the 90s, if you have objective disease or if you have objective symptomatic disease, the initial pass of the data is positive in favor for those patients to start hormonal therapy early. The longer the follow-up, it is a washout, no survival difference. Now, how do you think of that for that group of patients, and how do you apply the Messing data, which are imperfect data, as well? Patients who had a radical prostatectomy who were NED (No Evidence of Disease), but who were found to have microscopic disease at the time of surgery, initiated immediate ADT against deferring ADT—granted, this was pre-PSA era, and there were challenging definitions as to the timing of initiation of therapy, clinical progression, radiographic progression, or symptomatic progression. But, that data did demonstrate survival improvement when you started ADT, up front, immediately. Since then, I think, the biggest controversy, that we have had, is most of us do believe that early ADT does impact outcome. However, with the side-effect profile, the question is, how early is early? For instance, the European trial looking at PSA relapse of 3 years, looking at ADT initiation—that data demonstrated that early ADT actually impacts outcome, but yet, we still don’t know what PSA relapse means. Because we don’t know if changing your PSA kinetics, for that matter, will drastically improve your outcome, survival wise. And that’s the biggest challenge in the rising PSA syndrome. How do you actually tell a patient, “We’re going to keep you off therapy, we’re going to wait until you develop metastasis,” when all of us do believe those patients do have metastatic disease? We just simply don’t have the technology perhaps to affect that metastasis objectively. And, I would argue, that if we had such a technology, maybe early interventions, for those in whom we believe have disease, would be actually better than waiting until they have advanced disease.

Alicia K. Morgans, MD, MPH: I would have to agree with that. And, I would say that we also need to identify those patients who will have the most aggressive disease, because just having small-volume micrometastatic disease doesn’t necessarily mean that this will be an aggressive disease. In many cases, it is, but in others, it’s not. And, I think, as we’re making personalized treatment decisions for our patients, it’s important for them to think about the pros and the cons. Ultimately, at the end of the day, outcomes are what matter, and we need to continue to collect the data. So, I strongly encourage everyone, who can, to participate in those trials, but, I agree with you, it is challenging when we think about community settings.

Transcript Edited for Clarity

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Transcript:

Raoul S. Concepcion, MD:
Hello, and thank you for joining this OncLive Peer Exchange® titled “Key Issues Surrounding the Treatment of Prostate Cancer.” We’ve assembled a panel of experts in prostate cancer research to discuss the topics that will cause confusion for physicians treating in 2017 and beyond. We’ll be exchanging opinions on the use of testosterone-blocking therapies in the setting of biochemical recurrence, bone-targeted therapy, and androgen-receptor blocking, with the intention of providing clarity surrounding the challenges that you face in clinical practice.

I am Raoul Concepcion, and I am the editor-in-chief of Urologists in Cancer Care, as well as the director of the Comprehensive Prostate Center in Nashville, Tennessee. Participating today on our distinguished panel are: Dr. Jorge Garcia, director of the Advanced Prostate Cancer Research Program at Taussig Cancer Institute and Glickman Urological & Kidney Institute in Cleveland, Ohio; Dr. Alicia Morgans, assistant professor of medicine and clinical director of Genitourinary Oncology at Vanderbilt University Medical Center in Nashville, TN; Dr. Ashley Ross, director of the Brady Urology Prostate Cancer Program and assistant professor of urology, oncology, and pathology at the John Hopkins Medical Institution in Baltimore, Maryland; and Dr. Daniel Saltzstein, medical director of research and director of the Advanced Therapeutic Clinic at Urology San Antonio in San Antonio, Texas. Thank you, again, for joining us. Let’s go ahead and get started.

I think in this first segment, one of the things that we’ve known about the management of advancing prostate cancer is the dependence upon androgen-deprivation therapy. And, I think, as many of us know, this dates back to Huggins and Hodges doing some of their early work, which, obviously, won them the Nobel Prize. Basically, we know that prostate cancer is an androgen-driven event, and reducing testosterone levels down, to as low as we possibly can, has been the mainstay of therapy. However, one of the things that we also know is that there seems to be this overutilization of LHRH (luteinizing hormone-releasing hormone) analogs, whether it be agonists or antagonists, specifically in the patient who gets definitively treated, whether it be with radical prostatectomy or radiotherapy in that setting of a biochemical recurrence. So, Ash, in your practice, what are the triggers that you use personally, or even at your institution, to try to determine what is the appropriate timing in the patient who has been definitively treated for localized prostate cancer, when to start androgen deprivation therapy in patients with a biochemical recurrence?

Ashley E. Ross, MD, PhD: Thank you very much for the question. I think there are a few considerations. Just going back to Huggins paper, one thing, that he even stated then, is that the androgen deprivation would help halt the cancer, but inevitably, among the majority of patients, there would be progression to the castration-resistant space. And so, the timing of when to initiate therapy becomes beyond just side effects. It becomes more questionable because you’re really temporizing a progression. So, traditionally, at our institution, we would actually wait until metastatic progression, in the majority of cases, watch the PSAs rise, and do routine imaging, sometimes even yearly, sometimes set at a threshold once we got to a certain rise.

There was a paper that came out in our institution several years ago by Freedland et al that looked at predictors of eventual progression to the metastatic state, and among the more powerful ones were things like PSA (prostate-specific antigen) doubling time, or how long it takes a PSA to double. Doubling times that were short, particularly in the 3-month or 6-month window, would portend metastatic progression. And there are certain threshold PSA levels that can also predict that metastatic disease is actually present.

There have been two new developments that I want to just touch on. One is that we are getting the idea that maybe a lot of these patients are going to be appropriate for some sort of trial, either a consortium trial or a smaller trial going on at these different institutions—some of them using not just traditional hormonal deprivation, but we’ll talk about these newer agents later. Enzalutamide, in the EMBARK trial, and abiraterone, in the AbiCure trial, are looking at can we use these agents that are not only suppressing the growth of the tumor, but might actually destroy tumor when it’s at its small micrometastatic state? And so, with people at PSAs above 1 at our institution, we try to enroll them on a trial like that. And, the second thing, that we’ll touch on later, is where’s the disease coming from? Is it all systemic or are there small islets of disease? Maybe, as we’ll talk about in a little while, perhaps, some of the newer imaging modalities will show us other focuses of disease. As to your main question, really, we wait until metastatic recurrence or, in my patients, if the PSA doubling time is less than 6 months, I’m very worried that they’re having pending progression and will start therapy.

Raoul S. Concepcion, MD: Dan, from your particular standpoint—big group, 20 plus providers, big community practice group, very active in clinical research, a dedicated advanced prostate center—does that fit in terms of what happens in a typical large community practice?

Daniel R. Saltzstein, MD: Yes. I would agree with what Ash is saying, and that is, again, we’re also involved in some of the clinical trials in EMBARK. So, our goal, in some of these gentlemen, is to get them into a clinical trial because, again, we still have not completely developed a landscape of when these patients would be best treated. It’s a balance between the efficacy potential of overall survival benefit. It’s a balance between the toxicity that we know is coming out in a lot of papers. It’s a balance between the cost issue in the number of injections these patients might receive. We have also started to look at the Freedland paper and started to—when patients have a rapid PSA doubling time, a higher Gleason score, higher PSAs—look at that as a trigger to put patients on androgen-deprivation therapy. And, of course, like I said, we want to get patients on trials so we can figure out if there are any advances in that regard.

Raoul S. Concepcion, MD: I know, Alicia, at Vanderbilt, you guys have a multidisciplinary clinic. In that particular setting, which I think is a great setting, and I think a lot of academic centers move in that direction, does that patient start to be seen in that clinic before ADT is started, or is it generally after ADT has already been instituted? In other words, do you have a role, as a medical oncologist, in determining when is the correct time for ADT?

Alicia K. Morgans, MD, MPH: That’s a great question, and it’s one that, even with a multidisciplinary clinic, we’re still trying to find our way with. Because there are some practitioners who feel very comfortable with making that decision, and who’ve been practicing for a long time as amazing urologists. And so, when they feel comfortable with that, they often will take care of that on their own. For others, they really think it’s time to involve medical oncologists and urologists who specialize in the more advanced prostate cancer setting, and so they will pass the baton on that. I think from a medical oncology standpoint, we’re happy to accept patients, at any point, because even from that early time, thinking about the complications of treatment is really important to me. I believe at this point, we don’t have evidence to show that there’s real survival benefit, at least, when we start that therapy earlier rather than later, which is why clinical trials are so important. But, in a setting where we don’t have clinical trials, we do try to delay initiation as long as possible. And, certainly, we consider patient preferences and anxieties in all of that, too. But, when we’re thinking about the things that intermittent therapy or continuous therapy can cause in the long term, it can be devastating to patients, and we try to limit that.

Raoul S. Concepcion, MD: Jorge, what about at the clinic?

Jorge A. Garcia, MD: Let me just take a different approach. Clearly, most of us would prefer to actually put those patients, with a rising PSA syndrome, in a clinical trial, no doubt about that. But, for patients who don’t have access to a clinical trial, then the question becomes, for our community doctors, what are we going to do? And, I think, one has to be practical and pragmatic about these issues. It is very hard to believe, that even in the United States with the challenges in PSA, that you can tell a patient, “Your disease is growing. We haven’t seen it yet, but don’t worry. Let it grow bigger and then we’ll treat you when you have developed metastasis.” It’s a very foreign concept, one that for the last 5 to 10 years we’ve been trying, as a group, to actually address; educating patients about the importance, and perhaps, the imperfections, of PSA.

To Ash’s points, waiting until you have metastasis, based on data from MRC (Medical Research Council) back in the 90s, if you have objective disease or if you have objective symptomatic disease, the initial pass of the data is positive in favor for those patients to start hormonal therapy early. The longer the follow-up, it is a washout, no survival difference. Now, how do you think of that for that group of patients, and how do you apply the Messing data, which are imperfect data, as well? Patients who had a radical prostatectomy who were NED (No Evidence of Disease), but who were found to have microscopic disease at the time of surgery, initiated immediate ADT against deferring ADT—granted, this was pre-PSA era, and there were challenging definitions as to the timing of initiation of therapy, clinical progression, radiographic progression, or symptomatic progression. But, that data did demonstrate survival improvement when you started ADT, up front, immediately. Since then, I think, the biggest controversy, that we have had, is most of us do believe that early ADT does impact outcome. However, with the side-effect profile, the question is, how early is early? For instance, the European trial looking at PSA relapse of 3 years, looking at ADT initiation—that data demonstrated that early ADT actually impacts outcome, but yet, we still don’t know what PSA relapse means. Because we don’t know if changing your PSA kinetics, for that matter, will drastically improve your outcome, survival wise. And that’s the biggest challenge in the rising PSA syndrome. How do you actually tell a patient, “We’re going to keep you off therapy, we’re going to wait until you develop metastasis,” when all of us do believe those patients do have metastatic disease? We just simply don’t have the technology perhaps to affect that metastasis objectively. And, I would argue, that if we had such a technology, maybe early interventions, for those in whom we believe have disease, would be actually better than waiting until they have advanced disease.

Alicia K. Morgans, MD, MPH: I would have to agree with that. And, I would say that we also need to identify those patients who will have the most aggressive disease, because just having small-volume micrometastatic disease doesn’t necessarily mean that this will be an aggressive disease. In many cases, it is, but in others, it’s not. And, I think, as we’re making personalized treatment decisions for our patients, it’s important for them to think about the pros and the cons. Ultimately, at the end of the day, outcomes are what matter, and we need to continue to collect the data. So, I strongly encourage everyone, who can, to participate in those trials, but, I agree with you, it is challenging when we think about community settings.

Transcript Edited for Clarity
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Online CME Activities
TitleExpiration DateCME Credits
Community Practice Connections™: New York GU™: 9th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary MalignanciesMay 27, 20171.5
Cancer Summaries and Commentaries™: Update from Chicago: Advances in the Treatment of Genitourinary CancersJul 28, 20171.5
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