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Effect of Prostate Cancer Therapies on Bone Metabolism

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



Transcript: 

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Noel, were you surprised by the results?

Noel Clarke, MBBS, FRCS, ChM: No, I wasn’t surprised at all. We did a lot of basic research on this topic in the late 1980’s and early 1990’s, and published on this. One has to understand the relationship between osteoblast bone formation and osteoclast reabsorption. There’s a thing called a remodeling cycle; it’s like filling the roads: A hole appears and the workmen come along and fill it in. This is a constant replacement process; the whole skeleton is replaced every 2 or 3 years. We looked at this and then after we’d seen data in relation to induced menopause in breast cancer. What was known then was that women suffered an acute loss of bone volume within 6 to 12 months of the hormones being switched off.

We run a control city where we looked at loss of bone volume in men who were having orchidectomy, because that was the treatment at that time. To prevent that, we looked at it in detail: bone biopsies, bone breakdown markers and so on. What we found was that there’s an acute drop in bone volume within 3 months of androgen deprivation therapy [ADT], which is largely produced by an osteoclast surge. You can block that osteoclast surge with a bisphosphonate. At that time it was pamidronate that we used.

What we have in this setting here is a group of men who’ve had a serial insult to the skeleton. They’ve had ADT [androgen deprivation therapy] and abiraterone—super ADT. They’ve had prednisone [Deltasone], and then they get a hit to the bone marrow from radium-223. What these treatments will do is inhibit osteoblast. What the radium will do is inhibit osteoblast precursors in the bone marrow. Osteoblasts are basically fibroblasts. They come out of the fibroblast lineage—all the osteoblast precursors are in the marrow.

You have multiple hits to the skeleton outside of the skeleton affected by the tumor specifically. Now put that to 1 side and then ask the question: What kind of people are these that are actually having treatment? They’re older men, and we know that they are presenting with a degree of osteopenia in a significant number—25% or greater are osteopenic. We also know that when you treat an osteopenic male with ADT, the osteopenia will get worse and become porotic in proportion. This extra insult, for which you stop all of the repair processes and have an osteoblast surge, which you haven’t inhibited because you haven’t given bisphosphonate, is not a surprise to me.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: It has a lot to do with the timing of the abiraterone with the radium because quite a lot of people would have layered radium on top of abiraterone, whereas somebody may have been established on abiraterone therapy and then radium is added after progression. Do you think that’s different than this situation where they’re both being started around the same time?

Noel Clarke, MBBS, FRCS, ChM: It adds insult to insult. You’ll mitigate that to a certain extent but you won’t mitigate it completely. The abiraterone fracture rate was greater, and, again, you’d expect that. Unless an osteoblast bone formation effect occurs, which you’re blocking, you won’t be able to affect that with a bisphosphonate. You’ll affect the resorptive surge which you get with an androgen hit.

Nicholas James, MD: Basically, you’re looking at a bone scan and the osteoblastic response. It’s the osteoblastic response that is the increased uptake of technetium and, when you give it therapeutically, radium. Now we know if you administer it early on and if you looked at bone scans in patients responding to any cancer treatment—it doesn’t matter which one—you get an increase in osteoblastic activity as the bone metastases heal up. You’d be getting a bigger dose of radium if you give it the same time as you start the abiraterone, which you’re not seeing if you layer it. The other thing just to segue slightly into the M0 abiraterone data, is that the patients in whom we saw the biggest benefit in terms of failure-free survival were the men who had abiraterone and radiotherapy. The hazard ratio for the whole trial on failure was about 0.3. The hazard ratio for ABI plus radiotherapy was less than 0.2. And the test for heterogeneity had a clinically significant increase in effect. It looks like there’s synergy between radiotherapy and abiraterone. So we’ve upped the osteoblast reaction—we’ve given a radio-sensitizing agent, and then we’ve given a radiotherapy treatment, and we’re seeing big effects.

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

Nicholas James, MD: I wasn’t so sure that we would see the harm that we saw, but I think you can explain it now. Given the data in ALSYMPCA, it’s a shame that bone protection wasn’t mandated because it looks like the results are generally better if you give zoledronic acid [Zometa] at the same time with extensions of denosumab [Xgeva]

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: There’s some suggestion from the early access program as well that patients who are getting concomitant denosumab or Zometa were also benefitting in terms of survival as well.

Nicholas James, MD: What the Detroit Medical Center [DMC] could have done was insist all patients had bone protection and carry on the randomization in that subgroup. Because I’m not sure what the evidence of harm was in the subgroup, getting bone protection seems sufficient. If you look at some of the cancer-related outcomes like spinal cord protection, it’s reduced in the combination therapy. The data could have been ameliorated by running the study longer, instead of stopping the dangerous bit of it rather than stopping all of it. It kind of muddied the waters, and we’ve ended up not learning what we might have learned from the combination therapy. It was not clear to me that the combination may not in the long run turn out to be better if you ameliorated the early issues.

Noel Clarke, MBBS, FRCS, ChM: The baby is being thrown out in the bath water right now. It’s like the 70’s bio-study with estrogens. When you look at the data, that study was 1700 patients and was quite fascinating because the prostate-cancer specific survival was much better with estrogens than it was. But you may lose it on the cardiovascular events. What we’re re-examining with the estrogen trial and STAMPEDE trial is whether the estrogen is using patches as a primary androgen deprivation, and whether metabolically it is less harmful, and lowering cholesterol, blood pressure, and raising bone preservation. What we don’t know is whether there’s a cancer benefit from that end. We’ve had an interval from 1976 to the PATCH trial report. That’s largely from the same phenomenon, which is a positive anti-cancer effect being ignored because of the toxicity issue, which is probably avoidable.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Which could have been covered.

Nicholas James, MD: You’re involved with both the PATCH trial and of course the STAMPEDE trial. I think it’s going to be very interesting to see how that pans out. There’s obviously no pharmaceutical support for estrogen patches.

Transcript Edited for Clarity 

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Transcript: 

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Noel, were you surprised by the results?

Noel Clarke, MBBS, FRCS, ChM: No, I wasn’t surprised at all. We did a lot of basic research on this topic in the late 1980’s and early 1990’s, and published on this. One has to understand the relationship between osteoblast bone formation and osteoclast reabsorption. There’s a thing called a remodeling cycle; it’s like filling the roads: A hole appears and the workmen come along and fill it in. This is a constant replacement process; the whole skeleton is replaced every 2 or 3 years. We looked at this and then after we’d seen data in relation to induced menopause in breast cancer. What was known then was that women suffered an acute loss of bone volume within 6 to 12 months of the hormones being switched off.

We run a control city where we looked at loss of bone volume in men who were having orchidectomy, because that was the treatment at that time. To prevent that, we looked at it in detail: bone biopsies, bone breakdown markers and so on. What we found was that there’s an acute drop in bone volume within 3 months of androgen deprivation therapy [ADT], which is largely produced by an osteoclast surge. You can block that osteoclast surge with a bisphosphonate. At that time it was pamidronate that we used.

What we have in this setting here is a group of men who’ve had a serial insult to the skeleton. They’ve had ADT [androgen deprivation therapy] and abiraterone—super ADT. They’ve had prednisone [Deltasone], and then they get a hit to the bone marrow from radium-223. What these treatments will do is inhibit osteoblast. What the radium will do is inhibit osteoblast precursors in the bone marrow. Osteoblasts are basically fibroblasts. They come out of the fibroblast lineage—all the osteoblast precursors are in the marrow.

You have multiple hits to the skeleton outside of the skeleton affected by the tumor specifically. Now put that to 1 side and then ask the question: What kind of people are these that are actually having treatment? They’re older men, and we know that they are presenting with a degree of osteopenia in a significant number—25% or greater are osteopenic. We also know that when you treat an osteopenic male with ADT, the osteopenia will get worse and become porotic in proportion. This extra insult, for which you stop all of the repair processes and have an osteoblast surge, which you haven’t inhibited because you haven’t given bisphosphonate, is not a surprise to me.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: It has a lot to do with the timing of the abiraterone with the radium because quite a lot of people would have layered radium on top of abiraterone, whereas somebody may have been established on abiraterone therapy and then radium is added after progression. Do you think that’s different than this situation where they’re both being started around the same time?

Noel Clarke, MBBS, FRCS, ChM: It adds insult to insult. You’ll mitigate that to a certain extent but you won’t mitigate it completely. The abiraterone fracture rate was greater, and, again, you’d expect that. Unless an osteoblast bone formation effect occurs, which you’re blocking, you won’t be able to affect that with a bisphosphonate. You’ll affect the resorptive surge which you get with an androgen hit.

Nicholas James, MD: Basically, you’re looking at a bone scan and the osteoblastic response. It’s the osteoblastic response that is the increased uptake of technetium and, when you give it therapeutically, radium. Now we know if you administer it early on and if you looked at bone scans in patients responding to any cancer treatment—it doesn’t matter which one—you get an increase in osteoblastic activity as the bone metastases heal up. You’d be getting a bigger dose of radium if you give it the same time as you start the abiraterone, which you’re not seeing if you layer it. The other thing just to segue slightly into the M0 abiraterone data, is that the patients in whom we saw the biggest benefit in terms of failure-free survival were the men who had abiraterone and radiotherapy. The hazard ratio for the whole trial on failure was about 0.3. The hazard ratio for ABI plus radiotherapy was less than 0.2. And the test for heterogeneity had a clinically significant increase in effect. It looks like there’s synergy between radiotherapy and abiraterone. So we’ve upped the osteoblast reaction—we’ve given a radio-sensitizing agent, and then we’ve given a radiotherapy treatment, and we’re seeing big effects.

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

Nicholas James, MD: I wasn’t so sure that we would see the harm that we saw, but I think you can explain it now. Given the data in ALSYMPCA, it’s a shame that bone protection wasn’t mandated because it looks like the results are generally better if you give zoledronic acid [Zometa] at the same time with extensions of denosumab [Xgeva]

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: There’s some suggestion from the early access program as well that patients who are getting concomitant denosumab or Zometa were also benefitting in terms of survival as well.

Nicholas James, MD: What the Detroit Medical Center [DMC] could have done was insist all patients had bone protection and carry on the randomization in that subgroup. Because I’m not sure what the evidence of harm was in the subgroup, getting bone protection seems sufficient. If you look at some of the cancer-related outcomes like spinal cord protection, it’s reduced in the combination therapy. The data could have been ameliorated by running the study longer, instead of stopping the dangerous bit of it rather than stopping all of it. It kind of muddied the waters, and we’ve ended up not learning what we might have learned from the combination therapy. It was not clear to me that the combination may not in the long run turn out to be better if you ameliorated the early issues.

Noel Clarke, MBBS, FRCS, ChM: The baby is being thrown out in the bath water right now. It’s like the 70’s bio-study with estrogens. When you look at the data, that study was 1700 patients and was quite fascinating because the prostate-cancer specific survival was much better with estrogens than it was. But you may lose it on the cardiovascular events. What we’re re-examining with the estrogen trial and STAMPEDE trial is whether the estrogen is using patches as a primary androgen deprivation, and whether metabolically it is less harmful, and lowering cholesterol, blood pressure, and raising bone preservation. What we don’t know is whether there’s a cancer benefit from that end. We’ve had an interval from 1976 to the PATCH trial report. That’s largely from the same phenomenon, which is a positive anti-cancer effect being ignored because of the toxicity issue, which is probably avoidable.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Which could have been covered.

Nicholas James, MD: You’re involved with both the PATCH trial and of course the STAMPEDE trial. I think it’s going to be very interesting to see how that pans out. There’s obviously no pharmaceutical support for estrogen patches.

Transcript Edited for Clarity 
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