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Reducing Risk of Fracture in Metastatic CRPC

Panelists: Judd Moul, MD, Duke Cancer Institute; Neeraj Agarwal, MD, Hunstman Cancer Institute; Tanya Dorff, MD, City of Hope National Medical Center; Alicia Morgans, MD, PhD, Northwestern University Feinberg School of Medicine
Published: Thursday, Sep 12, 2019



Transcript: 

Judd Moul, MD:
Unless there are other comments about that, let’s move on to a therapeutic agent that we haven’t discussed so far, and that’s radium-223. Alicia, could you give a really brief clinical overview of radium-223? Then we can talk about the controversies.

Alicia Morgans, MD, MPH: Of course. Radium-223 is approved. It’s an alpha-particle-emitting pharmaceutical—a radiopharmaceutical—that is approved in patients who have metastatic CRPC [castration-resistant prostate cancer] that is symptomatic, and typically it’s for patients who have only bone metastases. It’s honing to areas where the prostate cancer has integrated itself into the bone, and it delivers this alpha radiation very locally. It does not affect disease in lymph nodes or organs. As I said, it’s for symptomatic patients. Symptoms can be defined more broadly, because there is an associated survival benefit. If I have a patient who has some fatigue or an elevated LDH [lactate dehydrogenase], I would say that’s symptomatic enough for me—if I’m making that therapeutic decision—and this is the next thing that I think is right for the patient in terms of prolonging survival.

Judd Moul, MD: Tanya, what’s the news from ASCO [American Society of Clinical Oncology Annual Meeting] 2019? What have we learned about radium-223 in the context of the other treatments?

Tanya Dorff, MD: Now the question is about combination therapy. Because of the different mechanisms of action, that’s very appealing. Radium-223 was approved on a survival advantage, which is really important. However, the secondary endpoint of the symptomatic skeletal-related event makes us think of it as an agent that reduces fractures and those types of complications.

When ERA 223 had a press release about a year ago showing increased risk of fracture when you added abiraterone with the radium-223, I think many of us were surprised if not shocked. At ASCO 2019, we took a look at the ongoing trial of enzalutamide with radium-223, and lo and behold, they also saw increased risk of fracture. It was 13% with enzalutamide, and 33% with the combination. Because prior experience informed this trial to look at their data safety, they recommended bone-protective agent use, and that completely negated that risk of fracture.

The major take-home message is, for every patient with CRPC who has bone metastases, we need to get thinking about adding either denosumab at the treatment—so 120 mg monthly—or zoledronic acid as a treatment dose, which I would now say is quarterly. I’d be interested in the panel’s thoughts on that. Especially now, when I’m looking at radium-223 for a patient, I revisit that question. I make sure I put them on bone-protective agent.

Judd Moul, MD: To summarize again, this is an important key teaching point. This trial showed that you can combine enzalutamide and radium-223, and if you add bone-protective agents, you’re not getting the increased fracture rate that we saw in the previous trial when abiraterone and radium-223 were combines. Is that correct?

Tanya Dorff, MD: Right. The primary endpoint looking at whether it’s valuable to combine enzalutamide and radium-223 has not read out. We don’t know about that yet. All we know is that we can mitigate that fracture risk. I suspect that could have occurred with abiraterone, too, had they just implemented bone protection.

Neeraj Agarwal, MD: I have a quick point. Regarding the ERA 223 trial, which showed increased factures with the combination of abiraterone and radium, all these trials were historically following the huge dogma, in my view, of not allowing bisphosphonates or denosumab after patients start the trial treatment. This has been studied over last 10 or 15 years, when it was generally conceived that these agents may improve survival. Because of that, these agents were not allowed on any of these trials. Then it was basically followed without much of a rationale.

If you look at any of the trials over the last 3 or 4 years, it is a standard language in the eligibility criteria that patients cannot start bisphosphonates or denosumab after the trial treatment starts. If they were already on a so-called stable dose of bisphosphonates and denosumab, they were fine. However, if you have not started them, then you are not allowed to start them.

We’re dealing with a patient population that has been exposed to years of castration therapy with osteoporosis incidence reaching up to 60% to 70%, regardless of which therapy they’re on, just because they have been on testosterone suppression for the preceding 5 to 10 years. In this study, the prevalence of osteoporosis ranged from 30% to 80%. In this population, you are saying, “You cannot be on bisphosphonates and denosumab.” I think that was a starting point. Once you allow them to get these agents, all the excessive risk gets mitigated.

Judd Moul, MD: I want to get Alicia’s point. As a urologist, here’s what I think may have been partially responsible. When denosumab came out, before zoledronic acid, there was an initial enthusiasm. The urologists were being educated a lot on bone health, so there was major progress made. Then the osteonecrosis issue popped into our understanding. Quite frankly, a urologist hears that term and he or she freaks out, thinking “You mean my jaw is going to fall off?” There was a lot of overreaction.

I think the pendulum swung the opposite way where practitioners were thinking, “I can’t use denosumab every month because of the issue with osteonecrosis of the jaw.” Alicia, what’s your comment on that?

Alicia Morgans, MD, MPH: I think you’re exactly right. I think patients also heard about osteonecrosis of the jaw. Their dentists certainly heard about osteonecrosis of the jaw. I have patients whose children are dentists, and they won’t let them near bone health agents. The most important thing that came out of the ERA 223 and then the latest, which Tanya just discussed, is that bone health is critically important. Fractures increase mortality in this population. Men are generally less likely to heal than women, and there is about a 33% mortality in the year after fracture for men who experience it.

Bone health should be something that we consider on the front end. We should not take from this, though, that we should combine enzalutamide and radium or enzalutamide and ABI [abiraterone]. Whether that’s valuable has not been answered yet. In mCRPC [metastatic castration-resistant prostate cancer], we need to think about bone health more strategically and systematically, and we need to get back into our treatment paradigm.

Judd Moul, MD: To recap, in this latest study presented at ASCO, if you combine the bone health agents with enzalutamide and radium concomitantly, there were no fractures using that triple therapy.

Tanya Dorff, MD: There weren’t fractures, but there was no increased risk in the double versus single.

Judd Moul, MD: Yet the counter-argument is that it’s preliminary. We still have this precaution to be concerned with. Alicia is saying that despite ASCO 2019, we still have to be cautious, and the current party line is to avoid using radium-223 concomitantly with abiraterone or enzalutamide. Am I hearing you correctly?

Alicia Morgans, MD, MPH: It’s not just a caution. It’s that we don’t know that there’s additive benefit at this point. We can mitigate a lot of that bone health risk with bone health agents if we get them back into our practices, but we don’t have any evidence that the combination is superior to treatment with 1 of these drugs at a time. Until we have that data, I don’t think any of us would recommend combining those agents.


Transcript Edited for Clarity

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Transcript: 

Judd Moul, MD:
Unless there are other comments about that, let’s move on to a therapeutic agent that we haven’t discussed so far, and that’s radium-223. Alicia, could you give a really brief clinical overview of radium-223? Then we can talk about the controversies.

Alicia Morgans, MD, MPH: Of course. Radium-223 is approved. It’s an alpha-particle-emitting pharmaceutical—a radiopharmaceutical—that is approved in patients who have metastatic CRPC [castration-resistant prostate cancer] that is symptomatic, and typically it’s for patients who have only bone metastases. It’s honing to areas where the prostate cancer has integrated itself into the bone, and it delivers this alpha radiation very locally. It does not affect disease in lymph nodes or organs. As I said, it’s for symptomatic patients. Symptoms can be defined more broadly, because there is an associated survival benefit. If I have a patient who has some fatigue or an elevated LDH [lactate dehydrogenase], I would say that’s symptomatic enough for me—if I’m making that therapeutic decision—and this is the next thing that I think is right for the patient in terms of prolonging survival.

Judd Moul, MD: Tanya, what’s the news from ASCO [American Society of Clinical Oncology Annual Meeting] 2019? What have we learned about radium-223 in the context of the other treatments?

Tanya Dorff, MD: Now the question is about combination therapy. Because of the different mechanisms of action, that’s very appealing. Radium-223 was approved on a survival advantage, which is really important. However, the secondary endpoint of the symptomatic skeletal-related event makes us think of it as an agent that reduces fractures and those types of complications.

When ERA 223 had a press release about a year ago showing increased risk of fracture when you added abiraterone with the radium-223, I think many of us were surprised if not shocked. At ASCO 2019, we took a look at the ongoing trial of enzalutamide with radium-223, and lo and behold, they also saw increased risk of fracture. It was 13% with enzalutamide, and 33% with the combination. Because prior experience informed this trial to look at their data safety, they recommended bone-protective agent use, and that completely negated that risk of fracture.

The major take-home message is, for every patient with CRPC who has bone metastases, we need to get thinking about adding either denosumab at the treatment—so 120 mg monthly—or zoledronic acid as a treatment dose, which I would now say is quarterly. I’d be interested in the panel’s thoughts on that. Especially now, when I’m looking at radium-223 for a patient, I revisit that question. I make sure I put them on bone-protective agent.

Judd Moul, MD: To summarize again, this is an important key teaching point. This trial showed that you can combine enzalutamide and radium-223, and if you add bone-protective agents, you’re not getting the increased fracture rate that we saw in the previous trial when abiraterone and radium-223 were combines. Is that correct?

Tanya Dorff, MD: Right. The primary endpoint looking at whether it’s valuable to combine enzalutamide and radium-223 has not read out. We don’t know about that yet. All we know is that we can mitigate that fracture risk. I suspect that could have occurred with abiraterone, too, had they just implemented bone protection.

Neeraj Agarwal, MD: I have a quick point. Regarding the ERA 223 trial, which showed increased factures with the combination of abiraterone and radium, all these trials were historically following the huge dogma, in my view, of not allowing bisphosphonates or denosumab after patients start the trial treatment. This has been studied over last 10 or 15 years, when it was generally conceived that these agents may improve survival. Because of that, these agents were not allowed on any of these trials. Then it was basically followed without much of a rationale.

If you look at any of the trials over the last 3 or 4 years, it is a standard language in the eligibility criteria that patients cannot start bisphosphonates or denosumab after the trial treatment starts. If they were already on a so-called stable dose of bisphosphonates and denosumab, they were fine. However, if you have not started them, then you are not allowed to start them.

We’re dealing with a patient population that has been exposed to years of castration therapy with osteoporosis incidence reaching up to 60% to 70%, regardless of which therapy they’re on, just because they have been on testosterone suppression for the preceding 5 to 10 years. In this study, the prevalence of osteoporosis ranged from 30% to 80%. In this population, you are saying, “You cannot be on bisphosphonates and denosumab.” I think that was a starting point. Once you allow them to get these agents, all the excessive risk gets mitigated.

Judd Moul, MD: I want to get Alicia’s point. As a urologist, here’s what I think may have been partially responsible. When denosumab came out, before zoledronic acid, there was an initial enthusiasm. The urologists were being educated a lot on bone health, so there was major progress made. Then the osteonecrosis issue popped into our understanding. Quite frankly, a urologist hears that term and he or she freaks out, thinking “You mean my jaw is going to fall off?” There was a lot of overreaction.

I think the pendulum swung the opposite way where practitioners were thinking, “I can’t use denosumab every month because of the issue with osteonecrosis of the jaw.” Alicia, what’s your comment on that?

Alicia Morgans, MD, MPH: I think you’re exactly right. I think patients also heard about osteonecrosis of the jaw. Their dentists certainly heard about osteonecrosis of the jaw. I have patients whose children are dentists, and they won’t let them near bone health agents. The most important thing that came out of the ERA 223 and then the latest, which Tanya just discussed, is that bone health is critically important. Fractures increase mortality in this population. Men are generally less likely to heal than women, and there is about a 33% mortality in the year after fracture for men who experience it.

Bone health should be something that we consider on the front end. We should not take from this, though, that we should combine enzalutamide and radium or enzalutamide and ABI [abiraterone]. Whether that’s valuable has not been answered yet. In mCRPC [metastatic castration-resistant prostate cancer], we need to think about bone health more strategically and systematically, and we need to get back into our treatment paradigm.

Judd Moul, MD: To recap, in this latest study presented at ASCO, if you combine the bone health agents with enzalutamide and radium concomitantly, there were no fractures using that triple therapy.

Tanya Dorff, MD: There weren’t fractures, but there was no increased risk in the double versus single.

Judd Moul, MD: Yet the counter-argument is that it’s preliminary. We still have this precaution to be concerned with. Alicia is saying that despite ASCO 2019, we still have to be cautious, and the current party line is to avoid using radium-223 concomitantly with abiraterone or enzalutamide. Am I hearing you correctly?

Alicia Morgans, MD, MPH: It’s not just a caution. It’s that we don’t know that there’s additive benefit at this point. We can mitigate a lot of that bone health risk with bone health agents if we get them back into our practices, but we don’t have any evidence that the combination is superior to treatment with 1 of these drugs at a time. Until we have that data, I don’t think any of us would recommend combining those agents.


Transcript Edited for Clarity
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