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Identifying Bone Progression in Metastatic Prostate Cancer and Treatment Options

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, Feb 15, 2017



Transcript:

Raoul S. Concepcion, MD:
I think it is important—and I think, Alicia, as you pointed out earlier—to say that radium-223 is not a palliative agent. It has a survival benefit. Yes, it will anecdotally, after a couple cycles, help reduce the amount of analgesics that the patient may need. It definitely has a side effect profile that’s superior to the old betas and gammas that we used to use that clearly did not have a survival benefit. And, again, it’s critical for the practitioners to understand that, that they should not look at this as a palliative agent. I think the challenge that people are having with radium-223 is, once again, fitting it into the whole layering schemata of all the different therapies. And I think where most people struggle with this is this definition of “symptomatic.” I think people automatically assume that minimally symptomatic or symptomatic by default means you’ve got to have pain that requires opiate use. Clearly, I think if you wait, if you delay the use of radium to that patient, you’ve probably missed the window. Expand on that. You talked about, “If I’ve got somebody with high volume bone metastases, based upon CHAARTED data, let’s say, I’m going to find something.” For our viewers, give us some indicators of what are the other things we should be looking for.

Alicia K. Morgans, MD, MPH: I can say what I look for are things like an anemia, which I know is, in many cases, indicative of infiltration of the bone marrow with the cancer cells. I also look at alkaline phosphatase because it’s elevated in settings of bone turnover; again indicating that there’s activity in the bone. And certainly there are things like LDH, which Oliver Sartor has talked about multiple times as being something that can help us predict who’s going to be able to respond longest and have the best response to that treatment. And then, my biggest concern, once you find these ways to get what the patient needs to the patient, is re-treatment because it’s not approved—not because I don’t think it’s safe. I was actually just talking to Oliver last weekend about a case that he’s publishing in Clinical Genitourinary Cancer, that he treated a patient with 18 cycles of radium. I had the same expression as you when I heard this. So, he said he initially treated the patient on a clinical trial, I think the expanded access. Then, he treated the patient on the re-treatment protocol that he has had, and then he treated the patient on insurance. This was all separated by time, so it wasn’t 18 cycles in a row. But the patient has done exceedingly well. And if you’re responding to this treatment, to have the opportunity to re-treat I think is really important. Because I’m concerned that if I have a patient who’s doing very well and I’m using whatever criteria I’m using to try to get the patient to therapy, if I need to use it again because I’ve run out of other options and they’re not working, I’m unable at this current time to get that treatment for the patient.

Raoul S. Concepcion, MD: Dan, what about you? Clinically, again, you’ve got a big prostate center. Besides the serologic markers that Alicia talked about, what other clinical symptomatology are you trying to use, trying to elicit from the patient as well as the caregiver, who sometimes is a family member, to really look to get this treatment in the appropriate window of opportunity, if you will?

Daniel R. Saltzstein, MD: Well, like Alicia was alluding to, we also use the alkaline phosphatase, the LDH, and whether you define pain as somebody who is using an opioid versus a nonsteroidal. But fatigue is a big thing. They can’t get off the couch and probably they’re not getting off the couch because they hurt and they just don’t want to say it. Men in Texas are very macho. They’re not going to complain about a lot of things. But the guy who’s sitting there telling me about his mobility issues, “I’m not getting around, there’s a lot of fatigue,” those are the kind of things that we are looking at to try to elicit, do they really have symptomatology so that we can put them on a drug. Because they’re the appropriate patient to get started. Our experience is slightly different in the aspect that I might also combine doing spot radiation because I think that’s more of a therapeutic than a palliative approach. In my clinical experience, I’ve seen maybe 20% to 30%, possibly 35%, get a palliative effect from the Xofigo, and so we will also do spot radiation in some of the areas that they’re very symptomatic.

Raoul S. Concepcion, MD: I know you’ve got a very active bone clinic as well, and probably I would expect most of these patients are already on some element of bone-targeting antiresorptive therapy. I’m assuming you’re using a lot of denosumab (Prolia) or zoledronic acid. Because there are no data on that obviously, especially with DMAB (3,2′-dimethyl-4-aminobiphenyl). Are you continuing them with the denosumab plus radium-223?

Daniel R. Saltzstein, MD: That’s a great question. I’ve sat down with Paul Sieber a number of times because, again, he’s very experienced in bone health. And then some of Saad’s data, when he looked back at that efficacy—and if you could get the number of treatments in—not only was combining with enzalutamide and abiraterone very well tolerated, but also combining with DMAB had an overall improvement in survival. That lends some credence to continuing them on their DMAB and that’s what I’ve been doing at this point in time, again, as long as the insurance company will continue to pay for it in that regard.

Raoul S. Concepcion, MD: Jorge?

Jorge A. Garcia, MD: I agree with you. I fundamentally think, in the United States, we overutilize denosumab and zoledronic acid. And I don’t believe with the data that we have that zoledronic has any role in prostate cancer. I think that if you look at the utility and the data, actually we used to approve zoledronic acid from back in the days until now. It used to be that the agent, denosumab, in the CRPC space with metastasis did better than zoledronic acid. Zoledronic acid doesn’t have any phase III data looking at bone loss reduction, and so I think of prostate cancer patients for bone health in 3 ways: those in whom I need to minimize bone loss, those in whom I may want to delay an SRE, and in those who actually may need symptom control for SREs. This is, again, the term that ALSYMPCA used, which is not a skeletal-related event, but a skeletal symptomatic event because we did mandated scans in ALSYMPCA.

I think the challenge is that if you look independently, abiraterone alone has the ability to delay SREs. Enzalutamide alone has the ability to do so and radium-223 alone can do that as well. So, I’m not sure that my first thought when I see a patient with bone metastases is, “Oh, I need to begin denosumab because we’re going to delay your SREs.” I think that I want to actually control this systemically, and I may introduce denosumab over time, but it’s not the first gut reaction that I have when I’m seeing my patient. Now, it is fair to say that some of these people may have come with denosumab given every 6 months for bone loss prevention, and I may just switch them to every month. But, technically, having someone who gets docetaxel every 3 weeks, I’m not going to give them denosumab every 3 weeks. They may get denosumab every 6 weeks instead of 3 weeks.

We don’t have the data that the breast cancer group has with zoledronic acid, which does lead to survival improvement. So, I’m not sure bone-targeted therapy for SRE delay or reduction is the most important for our patients. I think the life-prolonging treatments are number 1, and then you can support them with whatever treatment you may think. But in the context of prostate cancer in any given stage, there is no role for zoledronic acid. And I hope that STAMPEDE will settle that for men who actually have castration-sensitive disease.

Raoul S. Concepcion, MD: We’ve had this explosion of all these new therapies. It’s really hard to make sense of all the data, especially when it’s all monotherapy. And it’s like you said, clearly for DMAB at the XGEVA dosing of 120 mg subQ monthly that its SRE prevention, not only was it not inferior, but it was superior to zoledronic acid. But for the urologists, this concept of SREs, it was difficult for us to grasp for the longest period of time. We haven’t really talked too much about this, but where we really missed the boat is when we do institute ADT and we understand the higher incidence of bone mineral density loss that clearly happens within the first couple of years, we don’t do a good enough job of managing those patients. I think that’s a real problem that we have. We know that when you look at the PROCEED registry, which is the postmarketing trial that Dendreon had to do, in the first 2000 patients—and I think Matt Cooperberg, he’s looking at this data—if you say that 90% of patients with metastatic castration-resistant prostate cancer had bony metastases, only 30% of those patients were actually getting antiresorptive therapy, which is pretty dismal, I think. Again, I think with this whole bone microenvironment, there are lots of questions, there are lots of intriguing possibilities in terms of combining therapies with immunotherapy. Dan, I think Neal did a study looking at abiraterone and radium-223, correct? It was a study showing that, actually, it can be safely combined. Comment, if you will, about that trial, if you can.

Daniel R. Saltzstein, MD: Well, again, I think it was a small N. I think it was something like 35 or 40 patients. But what he mainly found was that the side effect profile was minimally changed from what we had known if you had used one agent on their own. So, again, it was a very good safety profile. And then, in addition to what Saad was telling us from the early access program, their overall survival was improved and also when we looked at the data going forward.

Jorge A. Garcia, MD: To your point, the issue with the Saad data is only 20% of the patients actually were on abiraterone and less than 5% or 7% were taking enzalutamide. So, really, it actually doesn’t reflect. Even though it’s retrospective, I think our series in America is probably the largest series looking at the combination therapy and what do you do. And I think that it does appear that mathematically, people on combined therapy have a better survival, longer for that matter than historical radium-223 alone, and it clearly settles the issue with PSA and soft tissue disease because you don’t have to be that dramatically worried if, indeed, you’re taking an oral agent that has been effective for that patient.

Raoul S. Concepcion, MD: And didn’t Fred Saad also report at ASCO this year that it’s critical that you get in at least 5 or 6 injections of radium? That basically gets you to that survival benefit versus patients that got 4 injections or less. I think he reported that at ASCO this year.

Alicia K. Morgans, MD, MPH: He did, and I think that that was really important in terms of where we’re aiming with these patients. But I would also say it may be, too, that the sicker patients received fewer cycles. I would keep that in mind as I interpret that data. Of course, if we have something that improves survival, we have a goal of 6 injections, and it looks like they’re doing better, then certainly we should aim for that.

Transcript Edited for Clarity

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Transcript:

Raoul S. Concepcion, MD:
I think it is important—and I think, Alicia, as you pointed out earlier—to say that radium-223 is not a palliative agent. It has a survival benefit. Yes, it will anecdotally, after a couple cycles, help reduce the amount of analgesics that the patient may need. It definitely has a side effect profile that’s superior to the old betas and gammas that we used to use that clearly did not have a survival benefit. And, again, it’s critical for the practitioners to understand that, that they should not look at this as a palliative agent. I think the challenge that people are having with radium-223 is, once again, fitting it into the whole layering schemata of all the different therapies. And I think where most people struggle with this is this definition of “symptomatic.” I think people automatically assume that minimally symptomatic or symptomatic by default means you’ve got to have pain that requires opiate use. Clearly, I think if you wait, if you delay the use of radium to that patient, you’ve probably missed the window. Expand on that. You talked about, “If I’ve got somebody with high volume bone metastases, based upon CHAARTED data, let’s say, I’m going to find something.” For our viewers, give us some indicators of what are the other things we should be looking for.

Alicia K. Morgans, MD, MPH: I can say what I look for are things like an anemia, which I know is, in many cases, indicative of infiltration of the bone marrow with the cancer cells. I also look at alkaline phosphatase because it’s elevated in settings of bone turnover; again indicating that there’s activity in the bone. And certainly there are things like LDH, which Oliver Sartor has talked about multiple times as being something that can help us predict who’s going to be able to respond longest and have the best response to that treatment. And then, my biggest concern, once you find these ways to get what the patient needs to the patient, is re-treatment because it’s not approved—not because I don’t think it’s safe. I was actually just talking to Oliver last weekend about a case that he’s publishing in Clinical Genitourinary Cancer, that he treated a patient with 18 cycles of radium. I had the same expression as you when I heard this. So, he said he initially treated the patient on a clinical trial, I think the expanded access. Then, he treated the patient on the re-treatment protocol that he has had, and then he treated the patient on insurance. This was all separated by time, so it wasn’t 18 cycles in a row. But the patient has done exceedingly well. And if you’re responding to this treatment, to have the opportunity to re-treat I think is really important. Because I’m concerned that if I have a patient who’s doing very well and I’m using whatever criteria I’m using to try to get the patient to therapy, if I need to use it again because I’ve run out of other options and they’re not working, I’m unable at this current time to get that treatment for the patient.

Raoul S. Concepcion, MD: Dan, what about you? Clinically, again, you’ve got a big prostate center. Besides the serologic markers that Alicia talked about, what other clinical symptomatology are you trying to use, trying to elicit from the patient as well as the caregiver, who sometimes is a family member, to really look to get this treatment in the appropriate window of opportunity, if you will?

Daniel R. Saltzstein, MD: Well, like Alicia was alluding to, we also use the alkaline phosphatase, the LDH, and whether you define pain as somebody who is using an opioid versus a nonsteroidal. But fatigue is a big thing. They can’t get off the couch and probably they’re not getting off the couch because they hurt and they just don’t want to say it. Men in Texas are very macho. They’re not going to complain about a lot of things. But the guy who’s sitting there telling me about his mobility issues, “I’m not getting around, there’s a lot of fatigue,” those are the kind of things that we are looking at to try to elicit, do they really have symptomatology so that we can put them on a drug. Because they’re the appropriate patient to get started. Our experience is slightly different in the aspect that I might also combine doing spot radiation because I think that’s more of a therapeutic than a palliative approach. In my clinical experience, I’ve seen maybe 20% to 30%, possibly 35%, get a palliative effect from the Xofigo, and so we will also do spot radiation in some of the areas that they’re very symptomatic.

Raoul S. Concepcion, MD: I know you’ve got a very active bone clinic as well, and probably I would expect most of these patients are already on some element of bone-targeting antiresorptive therapy. I’m assuming you’re using a lot of denosumab (Prolia) or zoledronic acid. Because there are no data on that obviously, especially with DMAB (3,2′-dimethyl-4-aminobiphenyl). Are you continuing them with the denosumab plus radium-223?

Daniel R. Saltzstein, MD: That’s a great question. I’ve sat down with Paul Sieber a number of times because, again, he’s very experienced in bone health. And then some of Saad’s data, when he looked back at that efficacy—and if you could get the number of treatments in—not only was combining with enzalutamide and abiraterone very well tolerated, but also combining with DMAB had an overall improvement in survival. That lends some credence to continuing them on their DMAB and that’s what I’ve been doing at this point in time, again, as long as the insurance company will continue to pay for it in that regard.

Raoul S. Concepcion, MD: Jorge?

Jorge A. Garcia, MD: I agree with you. I fundamentally think, in the United States, we overutilize denosumab and zoledronic acid. And I don’t believe with the data that we have that zoledronic has any role in prostate cancer. I think that if you look at the utility and the data, actually we used to approve zoledronic acid from back in the days until now. It used to be that the agent, denosumab, in the CRPC space with metastasis did better than zoledronic acid. Zoledronic acid doesn’t have any phase III data looking at bone loss reduction, and so I think of prostate cancer patients for bone health in 3 ways: those in whom I need to minimize bone loss, those in whom I may want to delay an SRE, and in those who actually may need symptom control for SREs. This is, again, the term that ALSYMPCA used, which is not a skeletal-related event, but a skeletal symptomatic event because we did mandated scans in ALSYMPCA.

I think the challenge is that if you look independently, abiraterone alone has the ability to delay SREs. Enzalutamide alone has the ability to do so and radium-223 alone can do that as well. So, I’m not sure that my first thought when I see a patient with bone metastases is, “Oh, I need to begin denosumab because we’re going to delay your SREs.” I think that I want to actually control this systemically, and I may introduce denosumab over time, but it’s not the first gut reaction that I have when I’m seeing my patient. Now, it is fair to say that some of these people may have come with denosumab given every 6 months for bone loss prevention, and I may just switch them to every month. But, technically, having someone who gets docetaxel every 3 weeks, I’m not going to give them denosumab every 3 weeks. They may get denosumab every 6 weeks instead of 3 weeks.

We don’t have the data that the breast cancer group has with zoledronic acid, which does lead to survival improvement. So, I’m not sure bone-targeted therapy for SRE delay or reduction is the most important for our patients. I think the life-prolonging treatments are number 1, and then you can support them with whatever treatment you may think. But in the context of prostate cancer in any given stage, there is no role for zoledronic acid. And I hope that STAMPEDE will settle that for men who actually have castration-sensitive disease.

Raoul S. Concepcion, MD: We’ve had this explosion of all these new therapies. It’s really hard to make sense of all the data, especially when it’s all monotherapy. And it’s like you said, clearly for DMAB at the XGEVA dosing of 120 mg subQ monthly that its SRE prevention, not only was it not inferior, but it was superior to zoledronic acid. But for the urologists, this concept of SREs, it was difficult for us to grasp for the longest period of time. We haven’t really talked too much about this, but where we really missed the boat is when we do institute ADT and we understand the higher incidence of bone mineral density loss that clearly happens within the first couple of years, we don’t do a good enough job of managing those patients. I think that’s a real problem that we have. We know that when you look at the PROCEED registry, which is the postmarketing trial that Dendreon had to do, in the first 2000 patients—and I think Matt Cooperberg, he’s looking at this data—if you say that 90% of patients with metastatic castration-resistant prostate cancer had bony metastases, only 30% of those patients were actually getting antiresorptive therapy, which is pretty dismal, I think. Again, I think with this whole bone microenvironment, there are lots of questions, there are lots of intriguing possibilities in terms of combining therapies with immunotherapy. Dan, I think Neal did a study looking at abiraterone and radium-223, correct? It was a study showing that, actually, it can be safely combined. Comment, if you will, about that trial, if you can.

Daniel R. Saltzstein, MD: Well, again, I think it was a small N. I think it was something like 35 or 40 patients. But what he mainly found was that the side effect profile was minimally changed from what we had known if you had used one agent on their own. So, again, it was a very good safety profile. And then, in addition to what Saad was telling us from the early access program, their overall survival was improved and also when we looked at the data going forward.

Jorge A. Garcia, MD: To your point, the issue with the Saad data is only 20% of the patients actually were on abiraterone and less than 5% or 7% were taking enzalutamide. So, really, it actually doesn’t reflect. Even though it’s retrospective, I think our series in America is probably the largest series looking at the combination therapy and what do you do. And I think that it does appear that mathematically, people on combined therapy have a better survival, longer for that matter than historical radium-223 alone, and it clearly settles the issue with PSA and soft tissue disease because you don’t have to be that dramatically worried if, indeed, you’re taking an oral agent that has been effective for that patient.

Raoul S. Concepcion, MD: And didn’t Fred Saad also report at ASCO this year that it’s critical that you get in at least 5 or 6 injections of radium? That basically gets you to that survival benefit versus patients that got 4 injections or less. I think he reported that at ASCO this year.

Alicia K. Morgans, MD, MPH: He did, and I think that that was really important in terms of where we’re aiming with these patients. But I would also say it may be, too, that the sicker patients received fewer cycles. I would keep that in mind as I interpret that data. Of course, if we have something that improves survival, we have a goal of 6 injections, and it looks like they’re doing better, then certainly we should aim for that.

Transcript Edited for Clarity
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