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ERA 223 and Implications for Clinical Practice

Panelists: Joe OSullivan, MD, Queens University; Nicholas James, MBBS, PhD University of Birmingham; Noel Clarke, MBBS, Christie Hospital
Published: Monday, Dec 17, 2018



Transcript: 

Noel Clarke, MBBS, FRCS, ChM: Your point about the effect of elevated osteoblast activity plays into the notion that we don’t understand enough of what’s going on. Osteoblast was described in 1978 as being prevalent in a third of patients, as indicated by bone scans. I suspect that there is an osteoblast overspill, or overaction, in many patients. It may be that that’s where you would use this osteoblast uptake phenomenon in bone metastases. Possibly, if this trial had included abiraterone [Zytiga] and then radium-223 3 months later plus bone protection, we might have seen completely different results.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: I thought there would be synergy. We know that ionizing radiation and targeting the androgen receptor is synergetic in local radiotherapy. Do you know the results of the ERA 223 trial? What does it mean for clinical practice?

Nicholas James, MD: It hasn’t changed the license in North America—Canada, the United States—or Japan, but it has changed the license, to a degree, in Europe. If you look at the European Medicines Agency [EMA] changes, it recommends that you have 2 lines of CRPC [castrate-resistant prostate cancer] treatment; it’s a bit vague as to what that means exactly: It allows you to have only 1 line if you’re not eligible for other lines of therapy. In the United Kingdom, where we can’t use abiraterone and enzalutamide [Xtandi] back to back, it means that if you’re not fit for chemotherapy, you will never receive 2 lines of therapy. I don’t think this changed things much because it’s a slippery concept as to who fits the chemotherapy criteria.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Exactly.

Nicholas James, MD: In reality, that license has changed; the message it sends is not correct. It sends the message that this is a dangerous drug, whereas, actually, the data from the ALSYMPCA trial show it is an effective drug that prolongs survival. And like all drugs, you have to use them carefully and minimize harm. According to the ERA 223 and ALSYMPCA trials, it’s clear that you minimize harm and maximize benefit by giving bone protection; that’s the lesson I would take away, that bone protection provides longer survival. But I don’t think it provides this is a dangerous drug. It provides it’s a dangerous drug if you coadminister it simultaneously with abiraterone.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: That’s not a good idea.

Noel Clarke, MBBS, FRCS, ChM: In a practical sense, this has an effect on what we know: If the natural history of the disease progresses, the number of visceral metastases increases. We have a restriction arbitrarily applied in my view, which is that, if in the United Kingdom a patient has nonbone metastases, the cycle of the ERA 223 treatment is pushed back further in the cycle—more patients become ineligible for it; perhaps they might have benefited if they’d been administered it earlier.

Nicholas James, MD: The EMA license says you shouldn’t give it beyond third line. You’ve kind of got a tight window, which is somewhat artificial, since it is not a terribly evidence-supported rationale. It is supported by the evidence here, but this isn’t what we will do in the future. We definitely won’t do what was done in ERA 223 for all the reasons we’ve just been discussing.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: One of the most disagreeable recommendations in the new label is the idea that patients should have an alkaline phosphatase reading greater than 220, which, as we know, was a stratification factor in the ALSYMPCA trial, which was quite arbitrarily based on the median in the phase II trial. I’m interested to know what you think, Noel. Do you think an alkaline phosphatase reading of 220 is predictive of benefit from radium-223?

Noel Clarke, MBBS, FRCS, ChM: On the basis of the evidence, no. What we can see is that alkaline phosphatase is a predictor of progression and prognosis but not a response to the drug.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Two hundred twenty is quite a reading.

Noel Clarke, MBBS, FRCS, ChM: It is.

Nicholas James, MD: If you take a trial, you power it for an outcome. You’ll need a certain number of patients—say 600—like whatever it was in ALSYMPCA. You then slice the population into subgroups, which are instantly underpowered; in this case, you have the patients with the lower-alkaline phosphatase or the patients with the better prognosis and, therefore, lower event rates. Straightaway, you’re underpowered. What you’re looking for in a forest plot is the evidence that the effect is different in the different subgroups. You’re not looking to see whether the individual hazard ratio crosses 1. You’re looking to see whether the effect is different in the subgroups. In the ALSYMPCA trial, there is no evidence of differential benefit in different subgroups. Of course, the point estimations fluctuate; it’s just random biology.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: It’s statistical illiteracy.

Nicholas James, MD: I hate to say it, but perhaps a regulation body is required.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: It’s the same subgroup analysis, yes.

Nicholas James, MD: The whole trial is positive. It’s positive for all the patients in the trial unless you’ve got convincing evidence of heterogeneity of effect, of which there was no evidence.

Transcript Edited for Clarity

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Transcript: 

Noel Clarke, MBBS, FRCS, ChM: Your point about the effect of elevated osteoblast activity plays into the notion that we don’t understand enough of what’s going on. Osteoblast was described in 1978 as being prevalent in a third of patients, as indicated by bone scans. I suspect that there is an osteoblast overspill, or overaction, in many patients. It may be that that’s where you would use this osteoblast uptake phenomenon in bone metastases. Possibly, if this trial had included abiraterone [Zytiga] and then radium-223 3 months later plus bone protection, we might have seen completely different results.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: I thought there would be synergy. We know that ionizing radiation and targeting the androgen receptor is synergetic in local radiotherapy. Do you know the results of the ERA 223 trial? What does it mean for clinical practice?

Nicholas James, MD: It hasn’t changed the license in North America—Canada, the United States—or Japan, but it has changed the license, to a degree, in Europe. If you look at the European Medicines Agency [EMA] changes, it recommends that you have 2 lines of CRPC [castrate-resistant prostate cancer] treatment; it’s a bit vague as to what that means exactly: It allows you to have only 1 line if you’re not eligible for other lines of therapy. In the United Kingdom, where we can’t use abiraterone and enzalutamide [Xtandi] back to back, it means that if you’re not fit for chemotherapy, you will never receive 2 lines of therapy. I don’t think this changed things much because it’s a slippery concept as to who fits the chemotherapy criteria.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Exactly.

Nicholas James, MD: In reality, that license has changed; the message it sends is not correct. It sends the message that this is a dangerous drug, whereas, actually, the data from the ALSYMPCA trial show it is an effective drug that prolongs survival. And like all drugs, you have to use them carefully and minimize harm. According to the ERA 223 and ALSYMPCA trials, it’s clear that you minimize harm and maximize benefit by giving bone protection; that’s the lesson I would take away, that bone protection provides longer survival. But I don’t think it provides this is a dangerous drug. It provides it’s a dangerous drug if you coadminister it simultaneously with abiraterone.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: That’s not a good idea.

Noel Clarke, MBBS, FRCS, ChM: In a practical sense, this has an effect on what we know: If the natural history of the disease progresses, the number of visceral metastases increases. We have a restriction arbitrarily applied in my view, which is that, if in the United Kingdom a patient has nonbone metastases, the cycle of the ERA 223 treatment is pushed back further in the cycle—more patients become ineligible for it; perhaps they might have benefited if they’d been administered it earlier.

Nicholas James, MD: The EMA license says you shouldn’t give it beyond third line. You’ve kind of got a tight window, which is somewhat artificial, since it is not a terribly evidence-supported rationale. It is supported by the evidence here, but this isn’t what we will do in the future. We definitely won’t do what was done in ERA 223 for all the reasons we’ve just been discussing.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: One of the most disagreeable recommendations in the new label is the idea that patients should have an alkaline phosphatase reading greater than 220, which, as we know, was a stratification factor in the ALSYMPCA trial, which was quite arbitrarily based on the median in the phase II trial. I’m interested to know what you think, Noel. Do you think an alkaline phosphatase reading of 220 is predictive of benefit from radium-223?

Noel Clarke, MBBS, FRCS, ChM: On the basis of the evidence, no. What we can see is that alkaline phosphatase is a predictor of progression and prognosis but not a response to the drug.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Two hundred twenty is quite a reading.

Noel Clarke, MBBS, FRCS, ChM: It is.

Nicholas James, MD: If you take a trial, you power it for an outcome. You’ll need a certain number of patients—say 600—like whatever it was in ALSYMPCA. You then slice the population into subgroups, which are instantly underpowered; in this case, you have the patients with the lower-alkaline phosphatase or the patients with the better prognosis and, therefore, lower event rates. Straightaway, you’re underpowered. What you’re looking for in a forest plot is the evidence that the effect is different in the different subgroups. You’re not looking to see whether the individual hazard ratio crosses 1. You’re looking to see whether the effect is different in the subgroups. In the ALSYMPCA trial, there is no evidence of differential benefit in different subgroups. Of course, the point estimations fluctuate; it’s just random biology.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: It’s statistical illiteracy.

Nicholas James, MD: I hate to say it, but perhaps a regulation body is required.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: It’s the same subgroup analysis, yes.

Nicholas James, MD: The whole trial is positive. It’s positive for all the patients in the trial unless you’ve got convincing evidence of heterogeneity of effect, of which there was no evidence.

Transcript Edited for Clarity
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