Practice Profile
A Discussion on the AUA Castrateresistant Prostate Cancer Guidelines David M. Albala, MD,1 David F. Penson, MD, MPH2 1Associated Medical Professionals, Syracuse, NY; 2Vanderbilt University, Nashville, TN [Rev Urol. 2017;19(2):125-128 doi: 10.3909/riu0765] © 2017 MedReviews®, LLC
David Albala: I am speaking with Dr. David Penson, who is currently the chair of the Department of Urologic Surgery at Vanderbilt University Medical Center (Nashville, TN), and we are talking about the castrateresistant prostate cancer guidelines that were developed by the American Urological Association (AUA). These were first published in 2013 and underwent an amendment in 2015. This is a field that has been growing in popularity with the development of advanced prostate cancer clinics throughout the United States. It’s a pleasure to welcome Dr. Penson. David Penson: Thank you, Dr. Albala. It’s a pleasure to be here and I’m happy to have this opportunity to talk about this subject. It’s an important topic for urologists, one that we really need to embrace. David Albala: Tell us a little bit about the history of how these guidelines were developed. Many of us know that guidelines have been developed for other disease states. Why, in 2013, were these guidelines for castrateresistant prostate cancer developed? David Penson: It was a little bit of a perfect storm that the AUA wanted to do this. First and foremost, there were many new agents that had been FDA (US Food and Drug Administration)-approved in the years before that 2013 guideline, in a space where we really didn’t have much. Remember that 2005 was when docetaxel was first approved by the FDA; before that we didn’t have any treatment that had been shown to prolong survival in these patients; by 2013, we had a handful of treatments. In that regard, there was a need for a systemic view of the evidence and a summarization for clinicians.
The other point was that, in the leadership of the AUA, and certainly as well in the leadership of the SUO (Society of Urologic Oncology), there was a feeling that urologists needed to take the lead in this, that we worked closely with medical oncologists—and they certainly do a phenomenal job—but urologists shouldn’t just simply send a patient over to an oncologist when that patient becomes castrate resistant. If we are going to be true prostate cancer caregivers, we need to be able to deal with the entire spectrum of disease. We really, as an organization, had to be the ones who guided our members on how to treat CRPC (castrateresistant prostate cancer). That sort of combination led to the decision to go ahead with the set of guidelines from the AUA, and I think it was a very smart decision. David Albala: Again, you’ve alluded to a question that I wanted to ask: should urologists be managing these patients with CRPC? We started to see, not only in the academic setting, but also in private practices, the establishment of these advanced prostate cancer clinics and bone clinics. Perhaps you could share your insight into whether you think that these are good for group practices to start to undertake? Also, you might suggest on how we go about developing these types of clinics. David Penson: That’s a great question; I’ll tell you up front I have a very strong bias that this is something that urologists should be doing. The irony, David— and you know this—is that the lead for these advanced prostate cancer clinics came in the large community practices. A lot of academic centers were so wrapped up in politics that they were unable to drive this, so it really grew out of these larger practices—community Vol. 19 No. 2 • 2017 • Reviews in Urology • 125
A Discussion on the AUA Castrate-resistant Prostate Cancer Guidelines continued practices—recognizing they had a large group of patients who were still going to need urologic care. Many of these patients have other urologic issues, and these medications are not that difficult to give. And urologists say, “Oh, they’re dangerous. It’s dangerous to give abiraterone. It’s dangerous to give enzalutamide. We don’t have the expertise and these are very strong drugs.” And the answer is, yes, they are very strong drugs but don’t sell yourself short. Urologists give BCG (Bacillus Calmette-Guérin vaccine) in the clinic all the time, and, in my opinion, that’s a much more difficult and dangerous agent to give. In that regard, I think we saw these innovative large group practices saying, “We’re going to do this, we’re going to develop experts in our practices who are going to manage this, and they’re going to do almost everything.” As far as the right size, I do think you need to be in a larger practice. I don’t think this is something that is going to lend itself easily to a two- or a three-[person] group. The reason I say that is because it’s going to be hard to get the expertise and put in the time when you have a very large general practice. In a larger group in which you have some specialization, it lends itself to this, because there is a nuance to giving these drugs, so it does help to make this a clinical focus. A smaller group may have a hard time with that. That being said— I’ll be honest with you—these oral agents are relatively easy to give and you don’t need a whole lot of expertise. David Albala: Thank you very much for that. I’d like to shift to the guidelines that you and many of our colleagues put together, which are very comprehensive. In the guidelines, there are 22 guideline statements looking at 6 index patients.
For these patients who come in with CRPC, the recommendations have been that these patients should be treated with a variety of agents. There is a sequence of different agents that can be used and I wonder if you could quickly summarize how you treat these patients when they come in to see you. David Penson: Right off the bat, one of the nice things about the guidelines, which is unique in certain regards to the AUA guidelines, is the concept of these index patients. It’s very helpful because it represents the spectrum of what you see if you’re going to take care of CRPC. At each step along the way, each index patient almost chronologically represents what is going to happen to the patient over time, and it helps guide decision making. Often, patients walk in and they’ll be asymptomatic and have no evidence of metastasis, so they’ll be M0 CRPC, and that’s a difficult patient for us because, as of 2017, there are no FDAapproved agents in that space. It’s hard to give a lot of strong advice because the guidelines just talk about the recommendation as observation with continued androgen deprivation. There are some options they throw in. What we do at our practice when we see the M0 CRPC patient is try to get him on a clinical trial, because that way we’re pushing the science forward while, at the same time, getting the patient something, because many of these patients are nervous at that point. And then, the next [type] of patient we tend to see—which is the second index patient—is the patient who has metastatic disease now, measurable metastatic disease, but he is asymptomatic or minimally symptomatic and hasn’t seen chemotherapy before.
126 • Vol. 19 No. 2 • 2017 • Reviews in Urology
This is the patient that I see most commonly in my practice in 2017. We have an Advanced Prostate Cancer Clinic here at Vanderbilt, and the guidelines recommend abiraterone, enzalutamide, sipuleucel-T, or docetaxel. I usually don’t go to docetaxel on that patient simply because patients are somewhat reluctant to go to cytotoxic agents at that point. If a patient has particularly aggressive disease, I’ll certainly talk about it, but usually what we’ll do is start with one of the oral agents, whether it’s abiraterone and prednisone, or enzalutamide. My choice of agent really depends on the patient’s comorbid conditions and certain contraindications. For example, if a patient has a seizure history, you don’t want to give him enzalutamide. If he has diabetes that is brittle, the abiraterone-prednisone combination probably is not the best way to go. David Albala: Where you would place sipuleucel-T? Because there are many physicians that feel these patients [who] are asymptomatic or minimally symptomatic upfront should receive this immunotherapy. What is your experience with giving this drug to these patients? As you know, it’s an infusion that is relatively easily done, but, is there a role for this before you go to the oral agents? David Penson: That’s exactly what I was going to mention, and the answer is, yes, absolutely. If you look at the studies of sipuleucel-T, you want to get that into the patient as early in the disease course as possible. If someone comes in with a large volume of metastatic disease or rapidly rising PSA (prostatespecific antigen), sipuleucel-T is probably not the best agent. But in the patient who comes in with lowvolume metastatic disease, and the PSA is rising relatively slowly, I will try to get him sipuleucel-T.
A Discussion on the AUA Castrate-resistant Prostate Cancer Guidelines Often, if a patient has highvolume disease or rapidly rising PSA, I will try to get him under control with abiraterone-prednisone or with enzalutamide; once we have that under control, we’ll offer him sipuleucel-T after that. Even though it is an off-label use, we often try to give it concurrently because patients do want the sipuleucel-T, and I think there’s a benefit to it if you look at the evidence. However, you must remember that we don’t know exactly how sipuleucel-T works. We think it works by activating the immune system, and so that takes a few months. If you look at the impact study that I was involved in, you see that the survival curves don’t separate until 6 months. So, in the rapidly progressing patient who doesn’t have that 6-month window, you must do something for them right away. That’s the patient I’ll try to get [onto] either one of the oral agents. Once we have him stabilized on the oral agent, it’s completely reasonable and probably a good thing to think about getting the sipuleucel-T in, because you want to get that in as early in the disease course as you can. David Albala: Maybe you could summarize for us the role of docetaxel chemotherapy in patients. When do you start this agent and how do you put it into your practice? There are very few urologists that I’m aware of who give this agent to patients in this castrate-resistant space, so a lot of our patients are referred to oncologists. Maybe you could give us a little bit of history of docetaxel in CRPC patients. David Penson: Sure. You mentioned the history of docetaxel— historically, until about 2010, that was the only agent we had in
CRPC that prolonged survival, and urologists have been reluctant to give cytotoxic agents. I think that’s reasonable. I don’t give docetaxel and I know very few urologists who do. I know a couple but, for the most part, urologists don’t give it. Basically, the history is that we’ve sent those patients away. What changed in 2010, and a few years after that, was the addition of sipuleucel-T, the addition of abiraterone and enzalutamide, which urologists were comfortable giving, and then the approval of radium Ra 223 dichloride in 2013. In my practice, I usually give those agents before I send the patient to a medical oncologist for docetaxel, when he is failing the abiraterone or the enzalutamide. That is usually how it goes, and patients want to go in that direction. As I said before, some patients progress so rapidly—have such a high volume of disease—that I send them for the cytotoxic [agent] up front. However, that is the minority of patients. The other thing we have to consider—and it’s going to be interesting to see how this all plays out—is the CHAARTED (Chemohormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) and the STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy: A Multi-Stage Multi-Arm Randomised Controlled Trial) results, [as well as] the recent results from ASCO (American Society of Clinical Oncology) looking at CHAARTED and STAMPEDE, which look at docetaxel in hormone-sensitive patients. We are going to see more patients in our CRPC practices who have seen docetaxel many years earlier, and docetaxel may not be as effective in those patients.
The other thing we are going to start seeing with this recent presentation at ASCO, that showed that the addition of abiraterone in hormone-sensitive disease prolonged survival, is patients who have already been on abiraterone for some period of time when they become castrate resistant. That’s going to change the way we treat patients. It has been my experience that if a patient fails abiraterone or fails enzalutamide, it is pretty rare that he has a response to the other agent. We still do it because it’s worth a try, but it is the minority of patients who have been on enzalutamide and then are switched to abiraterone after failing enzalutamide. I don’t know how it’s going to play out now that we see abiraterone used even further up. I think it is going to increase the use of enzalutamide in the CRPC setting and probably increase the use of sipuleucel-T. David Albala: For those patients that have metastatic bony disease, what is your experience with radium Ra 223 dichloride, and how do you feel it should be integrated into the treatment plan for our patients? David Penson: Radium Ra 223 dichloride is a terrific agent and it’s FDA approved in patients who are symptomatic with no known visceral disease. It is worth noting that disease of the lymph nodes is different than disease of the viscera (lung, liver, etc), and some lymph node disease is permitted. Where radium Ra 223 dichloride is used in the sequence is generally after patients have been on abiraterone, or on enzalutamide, and are now starting to show symptoms. Because the label includes the need for some degree of symptomatology, it is important to have processes in place to find symptoms
Vol. 19 No. 2 • 2017 • Reviews in Urology • 127
A Discussion on the AUA Castrate-resistant Prostate Cancer Guidelines continued of disease when they arise and document them. Patient questionnaires and robust clinicianpatient dialogue can be leveraged to uncover symptoms in often stoic patients. Furthermore, advanced prostate cancer is preferentially a disease that resides in the bone, and it is good to have a modality that targets this site of disease and extends survival. We often try to go to radium Ra 223 dichloride ahead of the docetaxel if we can, because
patients have a natural fear of cytotoxic chemotherapy and radium Ra 223 dichloride is very well tolerated. In that regard, where we’re using it a fair amount is if you look back to the index patients in the AUA guidelines—we’re going to Index Patient 3, Index Patient 4, and Index Patient 5—these are patients who are symptomatic and usually regardless of whether they’ve seen prior chemotherapy. I think it’s an outstanding drug.
128 • Vol. 19 No. 2 • 2017 • Reviews in Urology
David Albala: I would like to thank Dr. Penson for his time today. I think your comments have been very insightful and been very beneficial, and I know will be of benefit to our audience who treat these patients. Thank you and have a great day. David Penson: Thank you. This transcript has been edited for style and clarity.
A Discussion on the AUA Castrateresistant Prostate Cancer Guidelines David M. Albala, MD,1 David F. Penson, MD, MPH2 1Associated Medical Professionals, Syracuse, NY; 2Vanderbilt University, Nashville, TN [Rev Urol. 2017;19(2):125-128 doi: 10.3909/riu0765] © 2017 MedReviews®, LLC
David Albala: I am speaking with Dr. David Penson, who is currently the chair of the Department of Urologic Surgery at Vanderbilt University Medical Center (Nashville, TN), and we are talking about the castrateresistant prostate cancer guidelines that were developed by the American Urological Association (AUA). These were first published in 2013 and underwent an amendment in 2015. This is a field that has been growing in popularity with the development of advanced prostate cancer clinics throughout the United States. It’s a pleasure to welcome Dr. Penson. David Penson: Thank you, Dr. Albala. It’s a pleasure to be here and I’m happy to have this opportunity to talk about this subject. It’s an important topic for urologists, one that we really need to embrace. David Albala: Tell us a little bit about the history of how these guidelines were developed. Many of us know that guidelines have been developed for other disease states. Why, in 2013, were these guidelines for castrateresistant prostate cancer developed? David Penson: It was a little bit of a perfect storm that the AUA wanted to do this. First and foremost, there were many new agents that had been FDA (US Food and Drug Administration)-approved in the years before that 2013 guideline, in a space where we really didn’t have much. Remember that 2005 was when docetaxel was first approved by the FDA; before that we didn’t have any treatment that had been shown to prolong survival in these patients; by 2013, we had a handful of treatments. In that regard, there was a need for a systemic view of the evidence and a summarization for clinicians.
The other point was that, in the leadership of the AUA, and certainly as well in the leadership of the SUO (Society of Urologic Oncology), there was a feeling that urologists needed to take the lead in this, that we worked closely with medical oncologists—and they certainly do a phenomenal job—but urologists shouldn’t just simply send a patient over to an oncologist when that patient becomes castrate resistant. If we are going to be true prostate cancer caregivers, we need to be able to deal with the entire spectrum of disease. We really, as an organization, had to be the ones who guided our members on how to treat CRPC (castrateresistant prostate cancer). That sort of combination led to the decision to go ahead with the set of guidelines from the AUA, and I think it was a very smart decision. David Albala: Again, you’ve alluded to a question that I wanted to ask: should urologists be managing these patients with CRPC? We started to see, not only in the academic setting, but also in private practices, the establishment of these advanced prostate cancer clinics and bone clinics. Perhaps you could share your insight into whether you think that these are good for group practices to start to undertake? Also, you might suggest on how we go about developing these types of clinics. David Penson: That’s a great question; I’ll tell you up front I have a very strong bias that this is something that urologists should be doing. The irony, David— and you know this—is that the lead for these advanced prostate cancer clinics came in the large community practices. A lot of academic centers were so wrapped up in politics that they were unable to drive this, so it really grew out of these larger practices—community Vol. 19 No. 2 • 2017 • Reviews in Urology • 125
A Discussion on the AUA Castrate-resistant Prostate Cancer Guidelines continued practices—recognizing they had a large group of patients who were still going to need urologic care. Many of these patients have other urologic issues, and these medications are not that difficult to give. And urologists say, “Oh, they’re dangerous. It’s dangerous to give abiraterone. It’s dangerous to give enzalutamide. We don’t have the expertise and these are very strong drugs.” And the answer is, yes, they are very strong drugs but don’t sell yourself short. Urologists give BCG (Bacillus Calmette-Guérin vaccine) in the clinic all the time, and, in my opinion, that’s a much more difficult and dangerous agent to give. In that regard, I think we saw these innovative large group practices saying, “We’re going to do this, we’re going to develop experts in our practices who are going to manage this, and they’re going to do almost everything.” As far as the right size, I do think you need to be in a larger practice. I don’t think this is something that is going to lend itself easily to a two- or a three-[person] group. The reason I say that is because it’s going to be hard to get the expertise and put in the time when you have a very large general practice. In a larger group in which you have some specialization, it lends itself to this, because there is a nuance to giving these drugs, so it does help to make this a clinical focus. A smaller group may have a hard time with that. That being said— I’ll be honest with you—these oral agents are relatively easy to give and you don’t need a whole lot of expertise. David Albala: Thank you very much for that. I’d like to shift to the guidelines that you and many of our colleagues put together, which are very comprehensive. In the guidelines, there are 22 guideline statements looking at 6 index patients.
For these patients who come in with CRPC, the recommendations have been that these patients should be treated with a variety of agents. There is a sequence of different agents that can be used and I wonder if you could quickly summarize how you treat these patients when they come in to see you. David Penson: Right off the bat, one of the nice things about the guidelines, which is unique in certain regards to the AUA guidelines, is the concept of these index patients. It’s very helpful because it represents the spectrum of what you see if you’re going to take care of CRPC. At each step along the way, each index patient almost chronologically represents what is going to happen to the patient over time, and it helps guide decision making. Often, patients walk in and they’ll be asymptomatic and have no evidence of metastasis, so they’ll be M0 CRPC, and that’s a difficult patient for us because, as of 2017, there are no FDAapproved agents in that space. It’s hard to give a lot of strong advice because the guidelines just talk about the recommendation as observation with continued androgen deprivation. There are some options they throw in. What we do at our practice when we see the M0 CRPC patient is try to get him on a clinical trial, because that way we’re pushing the science forward while, at the same time, getting the patient something, because many of these patients are nervous at that point. And then, the next [type] of patient we tend to see—which is the second index patient—is the patient who has metastatic disease now, measurable metastatic disease, but he is asymptomatic or minimally symptomatic and hasn’t seen chemotherapy before.
126 • Vol. 19 No. 2 • 2017 • Reviews in Urology
This is the patient that I see most commonly in my practice in 2017. We have an Advanced Prostate Cancer Clinic here at Vanderbilt, and the guidelines recommend abiraterone, enzalutamide, sipuleucel-T, or docetaxel. I usually don’t go to docetaxel on that patient simply because patients are somewhat reluctant to go to cytotoxic agents at that point. If a patient has particularly aggressive disease, I’ll certainly talk about it, but usually what we’ll do is start with one of the oral agents, whether it’s abiraterone and prednisone, or enzalutamide. My choice of agent really depends on the patient’s comorbid conditions and certain contraindications. For example, if a patient has a seizure history, you don’t want to give him enzalutamide. If he has diabetes that is brittle, the abiraterone-prednisone combination probably is not the best way to go. David Albala: Where you would place sipuleucel-T? Because there are many physicians that feel these patients [who] are asymptomatic or minimally symptomatic upfront should receive this immunotherapy. What is your experience with giving this drug to these patients? As you know, it’s an infusion that is relatively easily done, but, is there a role for this before you go to the oral agents? David Penson: That’s exactly what I was going to mention, and the answer is, yes, absolutely. If you look at the studies of sipuleucel-T, you want to get that into the patient as early in the disease course as possible. If someone comes in with a large volume of metastatic disease or rapidly rising PSA (prostatespecific antigen), sipuleucel-T is probably not the best agent. But in the patient who comes in with lowvolume metastatic disease, and the PSA is rising relatively slowly, I will try to get him sipuleucel-T.
A Discussion on the AUA Castrate-resistant Prostate Cancer Guidelines Often, if a patient has highvolume disease or rapidly rising PSA, I will try to get him under control with abiraterone-prednisone or with enzalutamide; once we have that under control, we’ll offer him sipuleucel-T after that. Even though it is an off-label use, we often try to give it concurrently because patients do want the sipuleucel-T, and I think there’s a benefit to it if you look at the evidence. However, you must remember that we don’t know exactly how sipuleucel-T works. We think it works by activating the immune system, and so that takes a few months. If you look at the impact study that I was involved in, you see that the survival curves don’t separate until 6 months. So, in the rapidly progressing patient who doesn’t have that 6-month window, you must do something for them right away. That’s the patient I’ll try to get [onto] either one of the oral agents. Once we have him stabilized on the oral agent, it’s completely reasonable and probably a good thing to think about getting the sipuleucel-T in, because you want to get that in as early in the disease course as you can. David Albala: Maybe you could summarize for us the role of docetaxel chemotherapy in patients. When do you start this agent and how do you put it into your practice? There are very few urologists that I’m aware of who give this agent to patients in this castrate-resistant space, so a lot of our patients are referred to oncologists. Maybe you could give us a little bit of history of docetaxel in CRPC patients. David Penson: Sure. You mentioned the history of docetaxel— historically, until about 2010, that was the only agent we had in
CRPC that prolonged survival, and urologists have been reluctant to give cytotoxic agents. I think that’s reasonable. I don’t give docetaxel and I know very few urologists who do. I know a couple but, for the most part, urologists don’t give it. Basically, the history is that we’ve sent those patients away. What changed in 2010, and a few years after that, was the addition of sipuleucel-T, the addition of abiraterone and enzalutamide, which urologists were comfortable giving, and then the approval of radium Ra 223 dichloride in 2013. In my practice, I usually give those agents before I send the patient to a medical oncologist for docetaxel, when he is failing the abiraterone or the enzalutamide. That is usually how it goes, and patients want to go in that direction. As I said before, some patients progress so rapidly—have such a high volume of disease—that I send them for the cytotoxic [agent] up front. However, that is the minority of patients. The other thing we have to consider—and it’s going to be interesting to see how this all plays out—is the CHAARTED (Chemohormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) and the STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy: A Multi-Stage Multi-Arm Randomised Controlled Trial) results, [as well as] the recent results from ASCO (American Society of Clinical Oncology) looking at CHAARTED and STAMPEDE, which look at docetaxel in hormone-sensitive patients. We are going to see more patients in our CRPC practices who have seen docetaxel many years earlier, and docetaxel may not be as effective in those patients.
The other thing we are going to start seeing with this recent presentation at ASCO, that showed that the addition of abiraterone in hormone-sensitive disease prolonged survival, is patients who have already been on abiraterone for some period of time when they become castrate resistant. That’s going to change the way we treat patients. It has been my experience that if a patient fails abiraterone or fails enzalutamide, it is pretty rare that he has a response to the other agent. We still do it because it’s worth a try, but it is the minority of patients who have been on enzalutamide and then are switched to abiraterone after failing enzalutamide. I don’t know how it’s going to play out now that we see abiraterone used even further up. I think it is going to increase the use of enzalutamide in the CRPC setting and probably increase the use of sipuleucel-T. David Albala: For those patients that have metastatic bony disease, what is your experience with radium Ra 223 dichloride, and how do you feel it should be integrated into the treatment plan for our patients? David Penson: Radium Ra 223 dichloride is a terrific agent and it’s FDA approved in patients who are symptomatic with no known visceral disease. It is worth noting that disease of the lymph nodes is different than disease of the viscera (lung, liver, etc), and some lymph node disease is permitted. Where radium Ra 223 dichloride is used in the sequence is generally after patients have been on abiraterone, or on enzalutamide, and are now starting to show symptoms. Because the label includes the need for some degree of symptomatology, it is important to have processes in place to find symptoms
Vol. 19 No. 2 • 2017 • Reviews in Urology • 127
A Discussion on the AUA Castrate-resistant Prostate Cancer Guidelines continued of disease when they arise and document them. Patient questionnaires and robust clinicianpatient dialogue can be leveraged to uncover symptoms in often stoic patients. Furthermore, advanced prostate cancer is preferentially a disease that resides in the bone, and it is good to have a modality that targets this site of disease and extends survival. We often try to go to radium Ra 223 dichloride ahead of the docetaxel if we can, because
patients have a natural fear of cytotoxic chemotherapy and radium Ra 223 dichloride is very well tolerated. In that regard, where we’re using it a fair amount is if you look back to the index patients in the AUA guidelines—we’re going to Index Patient 3, Index Patient 4, and Index Patient 5—these are patients who are symptomatic and usually regardless of whether they’ve seen prior chemotherapy. I think it’s an outstanding drug.
128 • Vol. 19 No. 2 • 2017 • Reviews in Urology
David Albala: I would like to thank Dr. Penson for his time today. I think your comments have been very insightful and been very beneficial, and I know will be of benefit to our audience who treat these patients. Thank you and have a great day. David Penson: Thank you. This transcript has been edited for style and clarity.
