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Radium-223 in Combination Therapy for mCRPC

Panelists: Raoul S. Concepcion, MD, Comprehensive Prostate Center in Nashville; Evan Y. Yu, MD, Fred Hutchinson Cancer Research Center; Michael A. Carducci, MD, FACP, Sidney Kimmel Comprehensive Cancer Center of Johns Hopkins Hospital; Neal D. Shore, MD, FACS, Carolina Urologic Research Center; Glen Gejerman, MD, DABR, John Theurer Cancer Center
Published: Tuesday, Aug 08, 2017



Transcript:

Raoul S. Concepcion, MD, FACS: Glen, for the audience, talk about this phenomenon that radiation oncologists have observed over time called the abscopal effect. And then I want Evan and Mike to talk about how the abscopal effect is this going to influence other drugs. Evan, you and I talked earlier about double-stranded DNA hits, which is just what radium-223 does. So, Glen, tell us about the Abscopal effect.


Glen Gejerman, MD, DABR: We know that radiation therapy can affect the immune response, and a lot of the immunomodulators can really be potentiated in patients who have had previous radiation therapy. Thereby, the thought is that as an alfa emitter, radiation therapy can be used in a safe way, and then these additional immune-type drugs can be added. It’s a very safe toxicity profile. We should be combining them early on.

Evan Y. Yu, MD: I’ll just add that the theory makes a lot of sense—you use radiation to induce cell death. More androgens, neo-androgens, are released for the immune system to recognize its targets and to either follow up, or combine, with some of our novel immunotherapies, whether they’re PD-1 or PD-L1 therapies, vaccines, etc. There are a lot of different trials that are happening, or will happen, in combination with radium-223 and potential PD-1/PD-L1 antibodies. I think there’s a lot of excitement there.

I also think, back to the point of DNA repair, it’s not just PARP inhibitors—it’s platinum, it’s radium, and it’s anything that induces a double-strand DNA break that makes it hard for patients with homologous recombination deficiency to repair that. I do think that the future of radium-223 is probably in combination. But, we may have patients who are exquisitely sensitive—who have genetic predispositions based on their germline or somatic alterations that predispose them to respond well to radium-223—because it is the only FDA-approved therapy in prostate cancer that clearly induces double-strand DNA breaks.

Michael A. Carducci, MD, FACP: Again, this whole issue about, “It’s not for palliation, it really is life-prolonging” and “Who’s symptomatic?” If you’re anemic, it’s because you had a big burden of disease—that may be your sign for anemia. We have that wider window of who we can use the therapy in and consider a right time for using it. The concern I have, sometimes, is that patients want their PSA (prostate-specific antigen) to drop. It doesn’t always drop. Many times, it doesn’t. And so, it’s rising. Trying to get them through 6 months of therapy, because that’s where the survival advantage is, does take some handholding—to say, “We do think it’s helping. This is what we know about it.” We can add therapies in, or continue them on other therapies that may affect PSA, to get that sense to make sure that they get the whole course of therapy.

Raoul S. Concepcion, MD, FACS: We do know, in patients who get started on radium-223 and have a generally higher alkaline phosphatase level, that that is a good marker to potentially follow when they get radium-223, right? They get a decrease in their alpha levels, correct?

Michael A. Carducci, MD, FACP: Yes, we do see that.

Glen Gejerman, MD, DABR: I think it’s a key point. By the time I’ve seen these patients, they’ve been living with that number—the PSA number. And their day, their week, or their month, is going to be good based on whether their number is going up or down.

If you use radium-223 alone, I always tell patients, “We’re not going to look at your PSA, because I’m not going to impact your PSA,” in a similar way that immunotherapies in the IMPACT trial wouldn’t really affect the PSA. But we specifically look at the alkaline phosphatase. We track it before each infusion. If they get an infusion 3 weeks later, they get an alkaline phosphatase test. And, invariably, it drops. It sometimes bumps up, but that gets them to a point of looking and focusing on a number so they can kind of track their own progress, and that keeps them in on it.

When we combine it with something else, if we’re talking about some of the androgen receptor inhibitors, then you’ll see an impact in the PSA. In that case, the patient will look at the PSA. But, I always stress to them, “Radium-223 is not designed to impact your PSA. You’ve got to look at something else.”

Raoul S. Concepcion, MD, FACS: Neal, what do you do terms of when you start radium-223 on a patient? What do you do about imaging? Do you image? I know some institutions will image after 3 cycles and some will wait.

Neal D. Shore, MD, FACS: I think it’s important to, any time you’re switching your antineoplastic therapy, repeat your imaging. I always get the full-body CT scan. We’re also still doing technetium-99m bone scans where I practice—we get that upon initiating therapy. In the 2 phase II studies that we did, I did an open-label trial with abiraterone and radium-223 and a second open label with enzalutamide and radium-223. We repeated those scans at 3 months in everybody, and then 1 month post end of treatment.

My recommendation would be that you don’t need to do that 3-month scan. That’s usually pretty wasteful, unless you have serological markers that are going north in a very bad way or the patient is getting new worsening symptomatology, which, invariably, they’re not. But if they were getting worsening symptoms and I was worried about new lesions—they are really progressive, with poorly differentiated disease; the ALP [alkaline phosphatase] or other LFTs [liver function tests] were going sky high; the hemoglobin was going down; LDH was going up; PSA was skyrocketing, and with the PSAs, you know it when you see it, and a little bit of going up isn’t a worry—that’s when I would get scans. But, other than that, I don’t until I complete the course of therapy. You want to really be a little bit more judicious about avoiding overordering.

Michael A. Carducci, MD, FACP: Absolutely. That’s one of the biggest things I have. People want to check their work. You don’t need these scans, other than if there’s a real reason that they’re clinically symptomatic, or their PSA is going through the roof. But my sense is that people are checking scans way too often and it provides no added benefit.

Raoul S. Concepcion, MD, FACS: In the hypothetical situation, if you had a patient after 3 cycles of radium-223 whose PSA is going north, LDH is going north, and maybe they are a little bit more anemic, but the patient, clinically, is stable, with no increased pain, and you got a scan and maybe you’ve got progression at this point relative to the baseline scan—this whole treatment beyond progression—in that case, Dr Yu, would you give the last 3 cycles of radium-223 knowing the benefit? And then, would you go ahead and layer in something after or during the third dose once you saw this progression on the scan?

Evan Y. Yu, MD: First off, my approach is very similar to Neal and Mike’s approach, which is don’t scan unless you’re going to do something about it, or to only scan if you have a real reason to scan. So, you put me in a tough position. I probably might not have scanned this person. But now I did, and he showed progression. Is his progression new bone metastases or is his progression visceral progression? You have to give me a little more information here, but I’ll just answer to both situations.

Raoul S. Concepcion, MD, FACS: He’s got both. He’s got new lesions, and he’s got some new shotty retroperitoneal nodes that are at about 1.5 cm.

Evan Y. Yu, MD: If he’s got 1 or 2 new bone metastases and a couple small retroperitoneal lymph nodes, I’m going to say, “I wish I didn’t scan him,” and I’m going to push forward and try to get him his full 6 doses. Again, I wouldn’t have scanned him in the first place, probably. If he has new visceral lesions, or lymph nodes that are growing like crazy, then I have to respond to the data that I have. I’d have to change therapy, then. But again, without some really strong reason to image him, I probably wouldn’t have imaged him at that point in time.

Raoul S. Concepcion, MD, FACS: Have you had any experience in giving radium-223 as well as a taxane? Because that was not allowed on trial in ALSYMPCA. If the patient had planned chemotherapy, they were excluded. Just out of curiosity, have either one of you had any experiences with it?

Neal D. Shore, MD, FACS: That’s the 1 contraindication in the label. There’s no other contraindication for any sort of additive combination therapy except for the chemotherapy, taxane-based therapy. Dr Michael Morris and Dr. Oliver Sartor have presented on a trial that was done, which gave radium-223 every 6 weeks and a reduced dose of docetaxel. The results actually showed a pretty good tolerability profile. I know they’re working on some additional studies but, for the audience, that is technically an absolute contraindication.

Michael A. Carducci, MD, FACP: Yes, and I think, as Neal said, that study was when you started them together—it wasn’t via layering. So, here you’re on radium-223 and you add docetaxel. In that particular case, if there were any visceral disease, I probably would switch therapies. But as a combination, I think it is certainly something we have to explore.

Transcript Edited for Clarity

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Transcript:

Raoul S. Concepcion, MD, FACS: Glen, for the audience, talk about this phenomenon that radiation oncologists have observed over time called the abscopal effect. And then I want Evan and Mike to talk about how the abscopal effect is this going to influence other drugs. Evan, you and I talked earlier about double-stranded DNA hits, which is just what radium-223 does. So, Glen, tell us about the Abscopal effect.


Glen Gejerman, MD, DABR: We know that radiation therapy can affect the immune response, and a lot of the immunomodulators can really be potentiated in patients who have had previous radiation therapy. Thereby, the thought is that as an alfa emitter, radiation therapy can be used in a safe way, and then these additional immune-type drugs can be added. It’s a very safe toxicity profile. We should be combining them early on.

Evan Y. Yu, MD: I’ll just add that the theory makes a lot of sense—you use radiation to induce cell death. More androgens, neo-androgens, are released for the immune system to recognize its targets and to either follow up, or combine, with some of our novel immunotherapies, whether they’re PD-1 or PD-L1 therapies, vaccines, etc. There are a lot of different trials that are happening, or will happen, in combination with radium-223 and potential PD-1/PD-L1 antibodies. I think there’s a lot of excitement there.

I also think, back to the point of DNA repair, it’s not just PARP inhibitors—it’s platinum, it’s radium, and it’s anything that induces a double-strand DNA break that makes it hard for patients with homologous recombination deficiency to repair that. I do think that the future of radium-223 is probably in combination. But, we may have patients who are exquisitely sensitive—who have genetic predispositions based on their germline or somatic alterations that predispose them to respond well to radium-223—because it is the only FDA-approved therapy in prostate cancer that clearly induces double-strand DNA breaks.

Michael A. Carducci, MD, FACP: Again, this whole issue about, “It’s not for palliation, it really is life-prolonging” and “Who’s symptomatic?” If you’re anemic, it’s because you had a big burden of disease—that may be your sign for anemia. We have that wider window of who we can use the therapy in and consider a right time for using it. The concern I have, sometimes, is that patients want their PSA (prostate-specific antigen) to drop. It doesn’t always drop. Many times, it doesn’t. And so, it’s rising. Trying to get them through 6 months of therapy, because that’s where the survival advantage is, does take some handholding—to say, “We do think it’s helping. This is what we know about it.” We can add therapies in, or continue them on other therapies that may affect PSA, to get that sense to make sure that they get the whole course of therapy.

Raoul S. Concepcion, MD, FACS: We do know, in patients who get started on radium-223 and have a generally higher alkaline phosphatase level, that that is a good marker to potentially follow when they get radium-223, right? They get a decrease in their alpha levels, correct?

Michael A. Carducci, MD, FACP: Yes, we do see that.

Glen Gejerman, MD, DABR: I think it’s a key point. By the time I’ve seen these patients, they’ve been living with that number—the PSA number. And their day, their week, or their month, is going to be good based on whether their number is going up or down.

If you use radium-223 alone, I always tell patients, “We’re not going to look at your PSA, because I’m not going to impact your PSA,” in a similar way that immunotherapies in the IMPACT trial wouldn’t really affect the PSA. But we specifically look at the alkaline phosphatase. We track it before each infusion. If they get an infusion 3 weeks later, they get an alkaline phosphatase test. And, invariably, it drops. It sometimes bumps up, but that gets them to a point of looking and focusing on a number so they can kind of track their own progress, and that keeps them in on it.

When we combine it with something else, if we’re talking about some of the androgen receptor inhibitors, then you’ll see an impact in the PSA. In that case, the patient will look at the PSA. But, I always stress to them, “Radium-223 is not designed to impact your PSA. You’ve got to look at something else.”

Raoul S. Concepcion, MD, FACS: Neal, what do you do terms of when you start radium-223 on a patient? What do you do about imaging? Do you image? I know some institutions will image after 3 cycles and some will wait.

Neal D. Shore, MD, FACS: I think it’s important to, any time you’re switching your antineoplastic therapy, repeat your imaging. I always get the full-body CT scan. We’re also still doing technetium-99m bone scans where I practice—we get that upon initiating therapy. In the 2 phase II studies that we did, I did an open-label trial with abiraterone and radium-223 and a second open label with enzalutamide and radium-223. We repeated those scans at 3 months in everybody, and then 1 month post end of treatment.

My recommendation would be that you don’t need to do that 3-month scan. That’s usually pretty wasteful, unless you have serological markers that are going north in a very bad way or the patient is getting new worsening symptomatology, which, invariably, they’re not. But if they were getting worsening symptoms and I was worried about new lesions—they are really progressive, with poorly differentiated disease; the ALP [alkaline phosphatase] or other LFTs [liver function tests] were going sky high; the hemoglobin was going down; LDH was going up; PSA was skyrocketing, and with the PSAs, you know it when you see it, and a little bit of going up isn’t a worry—that’s when I would get scans. But, other than that, I don’t until I complete the course of therapy. You want to really be a little bit more judicious about avoiding overordering.

Michael A. Carducci, MD, FACP: Absolutely. That’s one of the biggest things I have. People want to check their work. You don’t need these scans, other than if there’s a real reason that they’re clinically symptomatic, or their PSA is going through the roof. But my sense is that people are checking scans way too often and it provides no added benefit.

Raoul S. Concepcion, MD, FACS: In the hypothetical situation, if you had a patient after 3 cycles of radium-223 whose PSA is going north, LDH is going north, and maybe they are a little bit more anemic, but the patient, clinically, is stable, with no increased pain, and you got a scan and maybe you’ve got progression at this point relative to the baseline scan—this whole treatment beyond progression—in that case, Dr Yu, would you give the last 3 cycles of radium-223 knowing the benefit? And then, would you go ahead and layer in something after or during the third dose once you saw this progression on the scan?

Evan Y. Yu, MD: First off, my approach is very similar to Neal and Mike’s approach, which is don’t scan unless you’re going to do something about it, or to only scan if you have a real reason to scan. So, you put me in a tough position. I probably might not have scanned this person. But now I did, and he showed progression. Is his progression new bone metastases or is his progression visceral progression? You have to give me a little more information here, but I’ll just answer to both situations.

Raoul S. Concepcion, MD, FACS: He’s got both. He’s got new lesions, and he’s got some new shotty retroperitoneal nodes that are at about 1.5 cm.

Evan Y. Yu, MD: If he’s got 1 or 2 new bone metastases and a couple small retroperitoneal lymph nodes, I’m going to say, “I wish I didn’t scan him,” and I’m going to push forward and try to get him his full 6 doses. Again, I wouldn’t have scanned him in the first place, probably. If he has new visceral lesions, or lymph nodes that are growing like crazy, then I have to respond to the data that I have. I’d have to change therapy, then. But again, without some really strong reason to image him, I probably wouldn’t have imaged him at that point in time.

Raoul S. Concepcion, MD, FACS: Have you had any experience in giving radium-223 as well as a taxane? Because that was not allowed on trial in ALSYMPCA. If the patient had planned chemotherapy, they were excluded. Just out of curiosity, have either one of you had any experiences with it?

Neal D. Shore, MD, FACS: That’s the 1 contraindication in the label. There’s no other contraindication for any sort of additive combination therapy except for the chemotherapy, taxane-based therapy. Dr Michael Morris and Dr. Oliver Sartor have presented on a trial that was done, which gave radium-223 every 6 weeks and a reduced dose of docetaxel. The results actually showed a pretty good tolerability profile. I know they’re working on some additional studies but, for the audience, that is technically an absolute contraindication.

Michael A. Carducci, MD, FACP: Yes, and I think, as Neal said, that study was when you started them together—it wasn’t via layering. So, here you’re on radium-223 and you add docetaxel. In that particular case, if there were any visceral disease, I probably would switch therapies. But as a combination, I think it is certainly something we have to explore.

Transcript Edited for Clarity
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