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mCRPC: Design and Results of ERA 223

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: 

Ulka Vaishampayan, MD:
ERA 223 was a trial that was conducted in metastatic CRPC patients who were randomized to get abiraterone and prednisone, plus or minus radium-223. All of the patients received abiraterone and prednisone on the study. The study was looking at overall survival as an endpoint, and the results showed that there was no difference in overall survival between the arms. The addition of radium-223 to abiraterone was not of benefit. There was an increased risk of fractures in the combination arm as compared to the single-agent abiraterone and prednisone arm.

That raises a slight concern about using these therapies in combination. Because of that, the ideal sequencing at present should be if patients are progressing on abiraterone and prednisone, you stop the treatment and start the patient on radium-223 if that is your next therapy of choice. The addition of bone-targeted agents such as denosumab or zoledronic acid was not really mandated on the study. Adding those may reduce the risk of fractures, and that should be considered. About half of the patients in the study did receive bone-targeted agents on either arm, and the fracture risk was somewhat lower in those patients. But again, that is a subset of the entire population.

At present, bone-targeted therapy in conjunction with either of these treatments is something that needs to be strongly considered, in my opinion. Adding one treatment to the other, adding radium-223 to abiraterone, cannot be recommended.

Neeraj Agarwal, MD: The question arises as to why there were increased fractures or skeletal-related events in the combination arm with abiraterone and radium-223, when it was just supposed to do the opposite. Radium-223 is a bone-targeting agent. Radium-223 is known to delay the onset of skeletal-related events by 6 months, based on ALSYMPCA trial. What could have happened here? I don’t think it is possible to explain this from a mechanistic perspective. I cannot think of all the biological rationale behind these findings. One thing I would like to note, which I thought was pretty striking, is that when the patients were enrolled in this trial, a DEXA [dual-energy x-ray absorptiometry] scan to measure osteopenia or osteoporosis was not mandatory. We also know that when patients are progressing on androgen deprivation therapy and getting into the castrate-resistant phase, the prevalence of osteopenia and osteoporosis can range from 25% to 70%, based on various studies. Is it possible that there was a huge imbalance between these 2 arms as far as osteopenia and osteoporosis is concerned?

Another point I would like to bring to your attention is that patients were not allowed to be treated with bisphosphonates like zoledronic acid or RANK [nuclear factor-κB] ligand inhibitors like denosumab once they were started on the trial treatment. Now we are looking at 2 factors. In fact, only 30% of patients in this trial who were already on denosumab, zoledronic acid, or other bisphosphonates were allowed to continue those therapies. But 70% of patients in this trial were not allowed to receive bone-targeting agents.

Think about if it’s possible that there was a huge imbalance in the arm as far as osteopenia and osteoporosis is concerned. If that was the case, and we are looking at patients who had osteopenia and osteoporosis and they were not allowed to be treated with bisphosphonates or denosumab, I would expect them to have fractures. That’s what I think may have happened. In fact, if we look at the presentation from the ESMO [European Society for Medical Oncology] meeting, the fractures that happened in the combination arm or fractures that happen in general in this population—mostly osteoporosis-related fractures—were less likely to be disease progression–related fractures. That is the basis for my hypothesis, that it’s possible there was an imbalance at the time of entry as far as osteopenia and osteoporosis are concerned.

Evan Yu, MD: My key take-home points from ERA 223 are probably that we shouldn’t be combining radium-223 and abiraterone up front. There’s no benefit, at least from the ERA 223 trial data. I wouldn’t go overboard and take that rationale into other settings, saying that you can’t combine it with anything else because there are data in that situation. I think that it emphasizes how important bone health is. In these patients with metastatic castration-resistant prostate cancer, we’re always thinking about skeletal-related events, but osteoporotic fractures happen in these patients as well. There might be something about the biology and the combination that we just don’t understand yet. It is important to always remember bone health and to prevent osteoporotic fractures.


Transcript Edited for Clarity 
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Transcript: 

Ulka Vaishampayan, MD:
ERA 223 was a trial that was conducted in metastatic CRPC patients who were randomized to get abiraterone and prednisone, plus or minus radium-223. All of the patients received abiraterone and prednisone on the study. The study was looking at overall survival as an endpoint, and the results showed that there was no difference in overall survival between the arms. The addition of radium-223 to abiraterone was not of benefit. There was an increased risk of fractures in the combination arm as compared to the single-agent abiraterone and prednisone arm.

That raises a slight concern about using these therapies in combination. Because of that, the ideal sequencing at present should be if patients are progressing on abiraterone and prednisone, you stop the treatment and start the patient on radium-223 if that is your next therapy of choice. The addition of bone-targeted agents such as denosumab or zoledronic acid was not really mandated on the study. Adding those may reduce the risk of fractures, and that should be considered. About half of the patients in the study did receive bone-targeted agents on either arm, and the fracture risk was somewhat lower in those patients. But again, that is a subset of the entire population.

At present, bone-targeted therapy in conjunction with either of these treatments is something that needs to be strongly considered, in my opinion. Adding one treatment to the other, adding radium-223 to abiraterone, cannot be recommended.

Neeraj Agarwal, MD: The question arises as to why there were increased fractures or skeletal-related events in the combination arm with abiraterone and radium-223, when it was just supposed to do the opposite. Radium-223 is a bone-targeting agent. Radium-223 is known to delay the onset of skeletal-related events by 6 months, based on ALSYMPCA trial. What could have happened here? I don’t think it is possible to explain this from a mechanistic perspective. I cannot think of all the biological rationale behind these findings. One thing I would like to note, which I thought was pretty striking, is that when the patients were enrolled in this trial, a DEXA [dual-energy x-ray absorptiometry] scan to measure osteopenia or osteoporosis was not mandatory. We also know that when patients are progressing on androgen deprivation therapy and getting into the castrate-resistant phase, the prevalence of osteopenia and osteoporosis can range from 25% to 70%, based on various studies. Is it possible that there was a huge imbalance between these 2 arms as far as osteopenia and osteoporosis is concerned?

Another point I would like to bring to your attention is that patients were not allowed to be treated with bisphosphonates like zoledronic acid or RANK [nuclear factor-κB] ligand inhibitors like denosumab once they were started on the trial treatment. Now we are looking at 2 factors. In fact, only 30% of patients in this trial who were already on denosumab, zoledronic acid, or other bisphosphonates were allowed to continue those therapies. But 70% of patients in this trial were not allowed to receive bone-targeting agents.

Think about if it’s possible that there was a huge imbalance in the arm as far as osteopenia and osteoporosis is concerned. If that was the case, and we are looking at patients who had osteopenia and osteoporosis and they were not allowed to be treated with bisphosphonates or denosumab, I would expect them to have fractures. That’s what I think may have happened. In fact, if we look at the presentation from the ESMO [European Society for Medical Oncology] meeting, the fractures that happened in the combination arm or fractures that happen in general in this population—mostly osteoporosis-related fractures—were less likely to be disease progression–related fractures. That is the basis for my hypothesis, that it’s possible there was an imbalance at the time of entry as far as osteopenia and osteoporosis are concerned.

Evan Yu, MD: My key take-home points from ERA 223 are probably that we shouldn’t be combining radium-223 and abiraterone up front. There’s no benefit, at least from the ERA 223 trial data. I wouldn’t go overboard and take that rationale into other settings, saying that you can’t combine it with anything else because there are data in that situation. I think that it emphasizes how important bone health is. In these patients with metastatic castration-resistant prostate cancer, we’re always thinking about skeletal-related events, but osteoporotic fractures happen in these patients as well. There might be something about the biology and the combination that we just don’t understand yet. It is important to always remember bone health and to prevent osteoporotic fractures.


Transcript Edited for Clarity 
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