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Radium-223 Alone and with Other Agents for 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: Tuesday, Jan 31, 2017


Transcript:

Raoul S. Concepcion, MD:
Let me use that and all these comments, really, as a segue to another agent, which again, mechanistically, is very different: radium-223. We know that radium-223 is an alpha-emitting radiopharmaceutical. It basically got approved based on results from the ALSYMPCA trial. We know that in that trial, it showed a survival benefit. There was no reduction in PSA, and the patients that did better clearly had a survival benefit if they received at least 5 or 6 doses. It’s a 1-minute injection; it’s given 4 weeks apart. We know because it’s an alpha emitter and it seems to have less myelosuppression. It clearly is a bone-targeting agent, and I think it’s a really well-tolerated drug. It’s got a really nice safety profile.

We’re going to talk a little bit more about this, but I really want to dovetail on what you were talking about because we started going down this road, a little bit, of molecular mechanisms. This is a bone-targeting agent, and in ALSYMPCA, we knew that you could not have visceral disease. You could have limited nodal disease of less than 3 cm, and you had to be relatively asymptomatic and were not being considered, at the time, for docetaxel chemotherapy. So, Alicia, in your practice, if you’ve got a patient that you think has, let’s just say, high-volume metastatic disease, is asymptomatic, do you give radium by itself because it’s not attacking the androgen axis? Would you go ahead and start a concomitant abiraterone or enzalutamide?

Alicia K. Morgans, MD, MPH: I think there are situations where I would do both, which is a great nonanswer to your question. But I would say, if the patient has lymph node-positive disease, I actually won’t use an AR-directed therapy with radium because I don’t feel comfortable not treating that and controlling that part of the disease. We know that metastatic disease can feed other metastatic sites, and so I want to control every place that I possibly can. If that patient is completely asymptomatic but has high volume disease, often I can find a symptom even if they don’t have one. Maybe they have low back pain, maybe they have this or that, but if radium is what I need to use next and that’s a decision where I’m asking, “Have I already used chemotherapy? Is the patient not interested in chemotherapy? Where am I in my treatment spectrum?” I will find a symptom and I will treat it. And that symptom may be bone pain, that symptom may be fatigue, that symptom might be anemia, which we know can be related to infiltrative disease in the bone marrow, alkaline phosphatase that’s elevated.

I would say that most people who have bony disease have at least something that justifies that. I believe in using radium not just because I think it relieves bone pain, but because radium is associated with a survival benefit. And that’s why I use radium. So I do want to get it into everyone I think can tolerate it. Where I work it into the spectrum is not necessarily after chemotherapy, it may be before. It really just depends on how that patient is doing and where I am in terms of what is the best treatment for that patient.

Raoul S. Concepcion, MD: Based upon what you just said, if you had some element of soft-tissue disease, limited nodal disease, that would be the appropriate patient also to combine if you could get it covered by insurance?

Alicia K. Morgans, MD, MPH: I have not had trouble with that, actually. Don’t tell the people in Tennessee, but I have not really had trouble with that. Like I said, I just don’t feel comfortable having untreated disease, and I know that radium is not treating the soft tissue.

Raoul S. Concepcion, MD: Dan, what about you?

Daniel R. Saltzstein, MD: What I would add to that is I tend to also combine therapies or layer therapies. I tend to find a way in these patients to document symptoms. But in my patient population, there’s such high PSA anxiety. Treating with Xofigo alone, the conversations for waiting 6 months and their PSA is going up? We’ve done that with Provenge, we’ve done that experiment. So, again, whether I’d layer on an abiraterone or an enzalutamide to maybe help them control the PSA anxiety and also use another mechanism of action to treat their prostate cancer, I think that is a big benefit to these patients.

Raoul S. Concepcion, MD: But, Jorge, should we be worried? Maybe I’m overthinking this because we know that there is, at a cellular level, at a molecular level—the Hopkins data that Emanuel reported out—this treatment pressure selection in patients who have been previously treated with either abiraterone or enzalutamide, that they will get these androgen receptor variants whether it’s V7 or whatever else is out there. Based upon your commentary, which you and I have discussed before, that’s the rationale for checking a PSA very early because if you don’t see a drop in their PSA, you know immediately—clinically, without measuring it serologically—that you probably have a variant that’s not working. So, if you have a patient like we’re talking about, this minimally symptomatic patient who still, for the most part, is pretty active and has predominantly bony metastatic disease, should we be worrying about driving a mutation too early by the layering in of either an abiraterone or an enzalutamide?

Jorge A. Garcia, MD: The standard of care for men with metastatic castration-resistant disease today is either abiraterone or enzalutamide or sipuleucel-T, radium-223, or docetaxel. What I have a disagreement with the NCCN guidelines is, remember the IMPACT trial, the COUGAR-302, and PREVAIL, identical patient entry, right? It was basically patients with asymptomatic or minimally symptomatic disease, which meant no opioids. That’s it. Yet, the label for abiraterone and enzalutamide allows them to treat patients with symptomatic disease. Now, I fundamentally don’t have any issues with that, but I do have an issue when our guidelines state that docetaxel should be only used for patients with symptomatic disease. I think it’s incorrect. Because, if you remember, in the TAX-327 and SWOG-9916 trials, we did not mandate for people who have symptomatic disease. It was, you have metastatic castration-resistant disease, you get either mitoxantrone or docetaxel, that’s it. So, I think that’s the battle that I have.

If you remove sipuleucel-T out of that equation for a little bit, then clearly, in the United States, between oral therapy or chemotherapy, oral therapy would win. Chemotherapy or radionucleotide? Radionucleotide therapy would win. I don’t think like that, and I agree with Alicia. It really depends when I see the patient. If the patient comes after chemotherapy, then I structure my treatment differently. Now, I don’t think Xofigo or radium-223 should be thought of as either/or. I think it’s part of the continuum of care.

And, in fact, if you look at the ALSYMPCA best supportive data, it is what I used to be vocal about, using enzalutamide or abiraterone, to pick your oral agent to support in combination therapy. Why? When we look at the best supportive care, we allow Emset, which is an all-nitrogen mustard. We allow radiation therapy. We allow ketoconazole. Well, abiraterone is a better ketoconazole; more selective, less toxic, maybe more expensive. They allow anti-androgen therapy. Well, they didn’t mean enzalutamide; they probably meant bicalutamide, flutamide, nilutamide. But we have a better AR inhibitor, less agonistic. So, I use that data to say, “Listen, I feel very comfortable giving you dual therapy with radium-223 and abiraterone.”

The biggest question in my practice is, when do I pull trigger to start you? Do I start you on abiraterone first or oral therapy first, or do I start radium-223 first? My tendency right now is I start on an oral therapy first and depending on the symptoms, how they’re doing with their “bone disease,” I make that decision to add on. Or, for that matter, if they’re progressing on abiraterone or enzalutamide and they are not ready for chemotherapy or ready to switch to a treatment outside clinical trials and they’re forced, we need to move on to another treatment. And that treatment happens to be an oral agent, which is very uncommon in my practice. But sometimes you have to do it. Then, I will actually do oral therapy in combination with radium-223.

The earlier you do radium-223, you have more likelihood to complete the 6 cycles. And a reminder, in the ALSYMPCA trial, the median number that was given was 6 cycles. If you look at our data, the median number of cycles given in the postchemotherapy space is around 3 to 4. Now, if you have someone with symptomatic disease, I think the biggest question is, could you afford, as a patient, to wait until you have pain relief? Radium-223 doesn’t control pain in a week. Systemic docetaxel chemotherapy does within 48 to 72 hours if you treat the patient really well. So, for me, it is not about waiting until you have a lot of symptoms; it’s earlier because I think you can actually endure that therapy earlier.

Lastly, if I may, a lot of people are concerned about using radium-223 before chemotherapy because of the risk for myelosuppression. The risk of myelosuppression in pre- or postdocetaxel from chemotherapy-naïve patients is around 1%; chemotherapy-treated is around 3% to 4%. I’d remind the audience that the incidence of grade 3 neutropenia with docetaxel alone in any trial that you look at is between 6% to 12%, so that shouldn’t be a reason why one would be concerned about using radium-223 in that context.

And lastly, the median survival difference between placebo and radium-223 is not drastically great. So, urologists may say, “Jorge, a 3-month difference, that’s nothing.” But I’d remind you the hazard ratio that we have had since 1999—when mitoxantrone got approved for pain improvement, symptom improvement—has gone from almost 0.9 to almost 0.66. Radium-223 is 0.69. So, it’s right along with what we have done and developed over the last 5 years. I’d really believe it’s an active agent. We do see PSA responses in around 16% of patients or so forth. The challenge is that I would never talk to my patients and tell them, “I’m going to put you on radium-223, and you should expect to see a PSA decline.” I tell them, “I’m going to put you on radium-223 because I’m going to likely make you live longer, control your symptoms, delay your progression from SSEs, and by default, your PSA may go down, but do not expect to see your PSA down.” Because I don’t have any issues with waiting for PSA, for most people on oral therapy, the PSA issue goes away as with sipuleucel-T when we combine sipuleucel-T with abiraterone or enzalutamide.

Alicia K. Morgans, MD, MPH: I agree, and I think that that discussion is strengthened by the fact that the overall survival improvement is the same as all the other agents. And so, PSA is part of the story, but not necessarily all the story. I tell patients to think about the prostate cancer cells exploding and releasing the PSA, and that’s maybe why we’re seeing those levels rise. But I think with the right encouragement, you can absolutely do that. I also think that it’s important to incorporate another mechanism of action in our armamentarium; not using one of our options is not the right thing to do.

Ashley E. Ross, MD, PhD: And nicely, as I look at subset analyses, it’s just exactly to your point. The people who had less or no opioid use actually did better. The healthier patients that could go through the more cycles had higher hemoglobins on entry, etc; [they] did better. And to me, thinking of it as a scientist, as you mentioned, it is a cidal drug. That alpha particle is so powerful, but it has a short distance of travel compared to beta emissions—it’s not going to cause the myelosuppression. And I’m often conceptually worried, [asking] “Well, how much of this would be needed for this bone remodeling to be happening for it to be incorporated? Should you not give something like abiraterone or enzalutamide because it may slow down the process and you need i, or would a RANK ligand inhibitor be a bad choice?” But it seems like that’s not the case. Abiraterone and enzalutamide work fine. Even people on denosumab do better with radium-223. And so, that’s all very good. Then, finally, we’ll put this back to the radons. It seems that there are data coming that retreatment even is fairly safe, and so you don’t have to pull the trigger once.

Raoul S. Concepcion, MD: I think Oliver said he had a series where that time [from] the end of the first completion of the first cycle to the retreatment was 6 months, and then patients did really well still. So, I think that’s the interesting thing about all these agents. Whether it’s radium-223, whether it’s sipuleucel-T, we know what the first trial did. So, what about retreatment, especially with the immunotherapies?

Transcript Edited for Clarity
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Transcript:

Raoul S. Concepcion, MD:
Let me use that and all these comments, really, as a segue to another agent, which again, mechanistically, is very different: radium-223. We know that radium-223 is an alpha-emitting radiopharmaceutical. It basically got approved based on results from the ALSYMPCA trial. We know that in that trial, it showed a survival benefit. There was no reduction in PSA, and the patients that did better clearly had a survival benefit if they received at least 5 or 6 doses. It’s a 1-minute injection; it’s given 4 weeks apart. We know because it’s an alpha emitter and it seems to have less myelosuppression. It clearly is a bone-targeting agent, and I think it’s a really well-tolerated drug. It’s got a really nice safety profile.

We’re going to talk a little bit more about this, but I really want to dovetail on what you were talking about because we started going down this road, a little bit, of molecular mechanisms. This is a bone-targeting agent, and in ALSYMPCA, we knew that you could not have visceral disease. You could have limited nodal disease of less than 3 cm, and you had to be relatively asymptomatic and were not being considered, at the time, for docetaxel chemotherapy. So, Alicia, in your practice, if you’ve got a patient that you think has, let’s just say, high-volume metastatic disease, is asymptomatic, do you give radium by itself because it’s not attacking the androgen axis? Would you go ahead and start a concomitant abiraterone or enzalutamide?

Alicia K. Morgans, MD, MPH: I think there are situations where I would do both, which is a great nonanswer to your question. But I would say, if the patient has lymph node-positive disease, I actually won’t use an AR-directed therapy with radium because I don’t feel comfortable not treating that and controlling that part of the disease. We know that metastatic disease can feed other metastatic sites, and so I want to control every place that I possibly can. If that patient is completely asymptomatic but has high volume disease, often I can find a symptom even if they don’t have one. Maybe they have low back pain, maybe they have this or that, but if radium is what I need to use next and that’s a decision where I’m asking, “Have I already used chemotherapy? Is the patient not interested in chemotherapy? Where am I in my treatment spectrum?” I will find a symptom and I will treat it. And that symptom may be bone pain, that symptom may be fatigue, that symptom might be anemia, which we know can be related to infiltrative disease in the bone marrow, alkaline phosphatase that’s elevated.

I would say that most people who have bony disease have at least something that justifies that. I believe in using radium not just because I think it relieves bone pain, but because radium is associated with a survival benefit. And that’s why I use radium. So I do want to get it into everyone I think can tolerate it. Where I work it into the spectrum is not necessarily after chemotherapy, it may be before. It really just depends on how that patient is doing and where I am in terms of what is the best treatment for that patient.

Raoul S. Concepcion, MD: Based upon what you just said, if you had some element of soft-tissue disease, limited nodal disease, that would be the appropriate patient also to combine if you could get it covered by insurance?

Alicia K. Morgans, MD, MPH: I have not had trouble with that, actually. Don’t tell the people in Tennessee, but I have not really had trouble with that. Like I said, I just don’t feel comfortable having untreated disease, and I know that radium is not treating the soft tissue.

Raoul S. Concepcion, MD: Dan, what about you?

Daniel R. Saltzstein, MD: What I would add to that is I tend to also combine therapies or layer therapies. I tend to find a way in these patients to document symptoms. But in my patient population, there’s such high PSA anxiety. Treating with Xofigo alone, the conversations for waiting 6 months and their PSA is going up? We’ve done that with Provenge, we’ve done that experiment. So, again, whether I’d layer on an abiraterone or an enzalutamide to maybe help them control the PSA anxiety and also use another mechanism of action to treat their prostate cancer, I think that is a big benefit to these patients.

Raoul S. Concepcion, MD: But, Jorge, should we be worried? Maybe I’m overthinking this because we know that there is, at a cellular level, at a molecular level—the Hopkins data that Emanuel reported out—this treatment pressure selection in patients who have been previously treated with either abiraterone or enzalutamide, that they will get these androgen receptor variants whether it’s V7 or whatever else is out there. Based upon your commentary, which you and I have discussed before, that’s the rationale for checking a PSA very early because if you don’t see a drop in their PSA, you know immediately—clinically, without measuring it serologically—that you probably have a variant that’s not working. So, if you have a patient like we’re talking about, this minimally symptomatic patient who still, for the most part, is pretty active and has predominantly bony metastatic disease, should we be worrying about driving a mutation too early by the layering in of either an abiraterone or an enzalutamide?

Jorge A. Garcia, MD: The standard of care for men with metastatic castration-resistant disease today is either abiraterone or enzalutamide or sipuleucel-T, radium-223, or docetaxel. What I have a disagreement with the NCCN guidelines is, remember the IMPACT trial, the COUGAR-302, and PREVAIL, identical patient entry, right? It was basically patients with asymptomatic or minimally symptomatic disease, which meant no opioids. That’s it. Yet, the label for abiraterone and enzalutamide allows them to treat patients with symptomatic disease. Now, I fundamentally don’t have any issues with that, but I do have an issue when our guidelines state that docetaxel should be only used for patients with symptomatic disease. I think it’s incorrect. Because, if you remember, in the TAX-327 and SWOG-9916 trials, we did not mandate for people who have symptomatic disease. It was, you have metastatic castration-resistant disease, you get either mitoxantrone or docetaxel, that’s it. So, I think that’s the battle that I have.

If you remove sipuleucel-T out of that equation for a little bit, then clearly, in the United States, between oral therapy or chemotherapy, oral therapy would win. Chemotherapy or radionucleotide? Radionucleotide therapy would win. I don’t think like that, and I agree with Alicia. It really depends when I see the patient. If the patient comes after chemotherapy, then I structure my treatment differently. Now, I don’t think Xofigo or radium-223 should be thought of as either/or. I think it’s part of the continuum of care.

And, in fact, if you look at the ALSYMPCA best supportive data, it is what I used to be vocal about, using enzalutamide or abiraterone, to pick your oral agent to support in combination therapy. Why? When we look at the best supportive care, we allow Emset, which is an all-nitrogen mustard. We allow radiation therapy. We allow ketoconazole. Well, abiraterone is a better ketoconazole; more selective, less toxic, maybe more expensive. They allow anti-androgen therapy. Well, they didn’t mean enzalutamide; they probably meant bicalutamide, flutamide, nilutamide. But we have a better AR inhibitor, less agonistic. So, I use that data to say, “Listen, I feel very comfortable giving you dual therapy with radium-223 and abiraterone.”

The biggest question in my practice is, when do I pull trigger to start you? Do I start you on abiraterone first or oral therapy first, or do I start radium-223 first? My tendency right now is I start on an oral therapy first and depending on the symptoms, how they’re doing with their “bone disease,” I make that decision to add on. Or, for that matter, if they’re progressing on abiraterone or enzalutamide and they are not ready for chemotherapy or ready to switch to a treatment outside clinical trials and they’re forced, we need to move on to another treatment. And that treatment happens to be an oral agent, which is very uncommon in my practice. But sometimes you have to do it. Then, I will actually do oral therapy in combination with radium-223.

The earlier you do radium-223, you have more likelihood to complete the 6 cycles. And a reminder, in the ALSYMPCA trial, the median number that was given was 6 cycles. If you look at our data, the median number of cycles given in the postchemotherapy space is around 3 to 4. Now, if you have someone with symptomatic disease, I think the biggest question is, could you afford, as a patient, to wait until you have pain relief? Radium-223 doesn’t control pain in a week. Systemic docetaxel chemotherapy does within 48 to 72 hours if you treat the patient really well. So, for me, it is not about waiting until you have a lot of symptoms; it’s earlier because I think you can actually endure that therapy earlier.

Lastly, if I may, a lot of people are concerned about using radium-223 before chemotherapy because of the risk for myelosuppression. The risk of myelosuppression in pre- or postdocetaxel from chemotherapy-naïve patients is around 1%; chemotherapy-treated is around 3% to 4%. I’d remind the audience that the incidence of grade 3 neutropenia with docetaxel alone in any trial that you look at is between 6% to 12%, so that shouldn’t be a reason why one would be concerned about using radium-223 in that context.

And lastly, the median survival difference between placebo and radium-223 is not drastically great. So, urologists may say, “Jorge, a 3-month difference, that’s nothing.” But I’d remind you the hazard ratio that we have had since 1999—when mitoxantrone got approved for pain improvement, symptom improvement—has gone from almost 0.9 to almost 0.66. Radium-223 is 0.69. So, it’s right along with what we have done and developed over the last 5 years. I’d really believe it’s an active agent. We do see PSA responses in around 16% of patients or so forth. The challenge is that I would never talk to my patients and tell them, “I’m going to put you on radium-223, and you should expect to see a PSA decline.” I tell them, “I’m going to put you on radium-223 because I’m going to likely make you live longer, control your symptoms, delay your progression from SSEs, and by default, your PSA may go down, but do not expect to see your PSA down.” Because I don’t have any issues with waiting for PSA, for most people on oral therapy, the PSA issue goes away as with sipuleucel-T when we combine sipuleucel-T with abiraterone or enzalutamide.

Alicia K. Morgans, MD, MPH: I agree, and I think that that discussion is strengthened by the fact that the overall survival improvement is the same as all the other agents. And so, PSA is part of the story, but not necessarily all the story. I tell patients to think about the prostate cancer cells exploding and releasing the PSA, and that’s maybe why we’re seeing those levels rise. But I think with the right encouragement, you can absolutely do that. I also think that it’s important to incorporate another mechanism of action in our armamentarium; not using one of our options is not the right thing to do.

Ashley E. Ross, MD, PhD: And nicely, as I look at subset analyses, it’s just exactly to your point. The people who had less or no opioid use actually did better. The healthier patients that could go through the more cycles had higher hemoglobins on entry, etc; [they] did better. And to me, thinking of it as a scientist, as you mentioned, it is a cidal drug. That alpha particle is so powerful, but it has a short distance of travel compared to beta emissions—it’s not going to cause the myelosuppression. And I’m often conceptually worried, [asking] “Well, how much of this would be needed for this bone remodeling to be happening for it to be incorporated? Should you not give something like abiraterone or enzalutamide because it may slow down the process and you need i, or would a RANK ligand inhibitor be a bad choice?” But it seems like that’s not the case. Abiraterone and enzalutamide work fine. Even people on denosumab do better with radium-223. And so, that’s all very good. Then, finally, we’ll put this back to the radons. It seems that there are data coming that retreatment even is fairly safe, and so you don’t have to pull the trigger once.

Raoul S. Concepcion, MD: I think Oliver said he had a series where that time [from] the end of the first completion of the first cycle to the retreatment was 6 months, and then patients did really well still. So, I think that’s the interesting thing about all these agents. Whether it’s radium-223, whether it’s sipuleucel-T, we know what the first trial did. So, what about retreatment, especially with the immunotherapies?

Transcript Edited for Clarity
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Community Practice Connections™: Personalized Sequencing in Castration-Resistant Prostate Cancer: Bridging the Latest Evidence to the Bedside in Clinical ManagementAug 25, 20181.5
Community Practice Connections™: Precision Medicine for Community Oncologists: Assessing the Role of Tumor-Testing Technologies in Cancer CareNov 30, 20181.0
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