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Practical Applications of ERA 223 in the mCRPC Paradigm

Insights From: Evan Yu, MD, University of Washington; Ulka Vaishampayan, MD, Barbara Ann Karmanos Cancer Institute ; Neeraj Agarwal, MD, Huntsman Cancer Institute
Published: Friday, Dec 21, 2018



Transcript: 

Evan Yu, MD:
In regard to response to ERA 223, the EMA [European Medicines Agency] made some changes that were quite interesting. They actually stated that radium-223 should not be used in combination therapy. They also stated that radium-223 should be used very late in the disease course for patients who have received multiple lines of therapy. They also made the statement that it should be used in patients who have larger volumes of disease.

I’ll go on record as saying that’s not the recommendation I would have made for the reason that the ALSYMPCA trial clearly showed a survival benefit and there were no such data that showed you should be using it at the very end of sequencing, since there’s a survival benefit for patients who are in the predocetaxel setting as well. Additionally, regarding high-volume disease versus low-volume disease, there are no definitive data on that either. Finally, regarding the extrapolation of no combination with any agents, there are no data to show it should be done or that it shouldn’t be done. There are only data to show that there’s no benefit in an upfront combination with abiraterone. I wouldn’t make that extrapolation elsewhere.

Now, in the United States, the FDA recently made a label change. It just stated that you probably shouldn’t give radium-223 in combination with abiraterone up front, and I support that. That would be the recommendation that I would follow. Since I live in the United States, that fits.

Ulka Vaishampayan, MD: The study results of ERA 223 show that abiraterone and radium-223 cannot be combined up front in metastatic CRPC treatment. With the changing paradigm in hormone-sensitive disease, since abiraterone will likely be used in the hormone-sensitive setting of metastatic prostate cancer, chances are you’re going to see patients up front with metastatic CRPC who have already progressed on abiraterone therapy. In this case, to add radium-223, you would need to discontinue abiraterone therapy and then add radium-223.

Similarly, prior to this, the standard way people were using this was at the time of progression on abiraterone therapy, patients were being considered for radium-223. I think that paradigm can still stay, but abiraterone does need to be discontinued when radium-223 is started.

Neeraj Agarwal, MD: The PEACE III trial is a large randomized phase III trial of patients who have metastatic castrate-resistant prostate cancer and who have bone pain or are symptomatic, even minimally symptomatic. They are being randomized to standard therapy with enzalutamide versus enzalutamide plus radium-223. The primary endpoint of this trial is radiographic progression-free survival. Secondary endpoints include overall survival and delay in skeletal-related event, among many other secondary endpoints. We are really looking forward to the results of this trial in the near future. In my view, a combination of radium-223 with enzalutamide will be safe based on our own experience and based on the results of our own phase II trial, which was presented at the ESMO [European Society for Medical Oncology] 2018 meeting. I’m looking forward to the results of the trial, and I think this combination will be safe.

Evan Yu, MD: There is 1 key thing to keep in mind, that many of the fractures in ERA 223 were osteoporotic fractures. Keep in mind that abiraterone is an agent that lowers testosterone 1 to 2 logs lower than standard LHRH [luteinizing hormone-releasing hormone] therapy can. Now, that is different with enzalutamide. With enzalutamide, you’re blocking the androgen receptor, but you’re not lowering testosterone levels. Even though your testosterone levels are already somewhat low from LHRH therapy, they’re not as low as they would be with abiraterone. That’s important because testosterone is converted to estrogen, and estrogen is what builds bone. If I had to take a guess—and this is just a guess, I don’t have a crystal ball—you might not see as many fractures with the combination of enzalutamide and radium-223 because you don’t have as low testosterone and estrogen levels as you do when you lower testosterone 1 to 2 logs with abiraterone.

The other thing to consider with abiraterone and prednisone is the fact that prednisone is also a drug that can worsen bone mineral density and increase the risk of fractures. For instance, if you look at the FRAX [fracture risk assessment tool] score, which helps to prognosticate for risk of fractures, the use of corticosteroids is on there. That’s another good point to think about. With abiraterone and prednisone, you’re lowering testosterone more with abiraterone, which leads to lower estrogen levels, and you’re introducing corticosteroids, all of which will increase the risk of fractures. That may be why we saw so many osteoporotic fractures in ERA 223.


Transcript Edited for Clarity 
 
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Transcript: 

Evan Yu, MD:
In regard to response to ERA 223, the EMA [European Medicines Agency] made some changes that were quite interesting. They actually stated that radium-223 should not be used in combination therapy. They also stated that radium-223 should be used very late in the disease course for patients who have received multiple lines of therapy. They also made the statement that it should be used in patients who have larger volumes of disease.

I’ll go on record as saying that’s not the recommendation I would have made for the reason that the ALSYMPCA trial clearly showed a survival benefit and there were no such data that showed you should be using it at the very end of sequencing, since there’s a survival benefit for patients who are in the predocetaxel setting as well. Additionally, regarding high-volume disease versus low-volume disease, there are no definitive data on that either. Finally, regarding the extrapolation of no combination with any agents, there are no data to show it should be done or that it shouldn’t be done. There are only data to show that there’s no benefit in an upfront combination with abiraterone. I wouldn’t make that extrapolation elsewhere.

Now, in the United States, the FDA recently made a label change. It just stated that you probably shouldn’t give radium-223 in combination with abiraterone up front, and I support that. That would be the recommendation that I would follow. Since I live in the United States, that fits.

Ulka Vaishampayan, MD: The study results of ERA 223 show that abiraterone and radium-223 cannot be combined up front in metastatic CRPC treatment. With the changing paradigm in hormone-sensitive disease, since abiraterone will likely be used in the hormone-sensitive setting of metastatic prostate cancer, chances are you’re going to see patients up front with metastatic CRPC who have already progressed on abiraterone therapy. In this case, to add radium-223, you would need to discontinue abiraterone therapy and then add radium-223.

Similarly, prior to this, the standard way people were using this was at the time of progression on abiraterone therapy, patients were being considered for radium-223. I think that paradigm can still stay, but abiraterone does need to be discontinued when radium-223 is started.

Neeraj Agarwal, MD: The PEACE III trial is a large randomized phase III trial of patients who have metastatic castrate-resistant prostate cancer and who have bone pain or are symptomatic, even minimally symptomatic. They are being randomized to standard therapy with enzalutamide versus enzalutamide plus radium-223. The primary endpoint of this trial is radiographic progression-free survival. Secondary endpoints include overall survival and delay in skeletal-related event, among many other secondary endpoints. We are really looking forward to the results of this trial in the near future. In my view, a combination of radium-223 with enzalutamide will be safe based on our own experience and based on the results of our own phase II trial, which was presented at the ESMO [European Society for Medical Oncology] 2018 meeting. I’m looking forward to the results of the trial, and I think this combination will be safe.

Evan Yu, MD: There is 1 key thing to keep in mind, that many of the fractures in ERA 223 were osteoporotic fractures. Keep in mind that abiraterone is an agent that lowers testosterone 1 to 2 logs lower than standard LHRH [luteinizing hormone-releasing hormone] therapy can. Now, that is different with enzalutamide. With enzalutamide, you’re blocking the androgen receptor, but you’re not lowering testosterone levels. Even though your testosterone levels are already somewhat low from LHRH therapy, they’re not as low as they would be with abiraterone. That’s important because testosterone is converted to estrogen, and estrogen is what builds bone. If I had to take a guess—and this is just a guess, I don’t have a crystal ball—you might not see as many fractures with the combination of enzalutamide and radium-223 because you don’t have as low testosterone and estrogen levels as you do when you lower testosterone 1 to 2 logs with abiraterone.

The other thing to consider with abiraterone and prednisone is the fact that prednisone is also a drug that can worsen bone mineral density and increase the risk of fractures. For instance, if you look at the FRAX [fracture risk assessment tool] score, which helps to prognosticate for risk of fractures, the use of corticosteroids is on there. That’s another good point to think about. With abiraterone and prednisone, you’re lowering testosterone more with abiraterone, which leads to lower estrogen levels, and you’re introducing corticosteroids, all of which will increase the risk of fractures. That may be why we saw so many osteoporotic fractures in ERA 223.


Transcript Edited for Clarity 
 
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