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Bone Health in Prostate Cancer

Panelists: Joe OSullivan, MD, Queen's University; Nicholas James, MBBS, PhD University of Birmingham; Noel Clarke, MBBS, Christie Hospital
Published: Tuesday, Dec 11, 2018



Transcript: 

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Now we’re going to talk about bone health and treating metastatic castration-resistant prostate cancer [mCRPC]. Noel, I’m going to turn to you first. I know you have strong research interest in bone metastases in prostate cancer; tell me a bit about this.

Noel Clarke, MBBS, FRCS, ChM: Well, it’s not that well understood, and given the scale of the problem, not that well researched. We have patients who develop bone metastases, the majority of which are men who die from prostate cancer from bone metastases—at least 90%. If you looked hard you’d find it in most patients.

Some of those are highly asymptomatic, and some of those are associated with pathological fracture cord compression. What we know now is that the process of bone formation and bone destruction is very rapid in prostate cancer. People have looked over years at the radiological appearances and said, “Well, these are osteoblastic metastases aren’t they.” And, of course, when you look at the bone breakdown markers and how the skeleton is being broken up by prostate cancer, you see rather surprisingly that prostate cancer is a more lytic disease than breast cancer and lung cancer.

It’s important to understand that what you’re seeing is that the whole metabolism is booted up. Something that is important to recognize is that there are certain patients who are at high risk of developing skeletal-related events.

Now in the older classification, skeletal-related events [SRE], for example—in the old bisphosphonate studies—the SREs were radiological and people looking at little bits of radiological factors and so on. In the later studies—the ALSYMPCA study is a very good example of this—they were clinical events. SREs were either the pathological fracture, the core compression, radiotherapy to the bone, or treatment of bone pain; that’s the group to focus on.

What we’re really interested in doing in treating prostate cancer is to try to avoid an SRA [steroid receptor activator], which is in some cases a catastrophic event but in many cases predictable. There are certain critical markers that you can look at where the metastases are to show how heavy the skeletal load is, including alkaline phosphate and lactate dehydrogenase. If the alkaline phosphatase is about 150, and the LDH is up, you’ve got a heavy skeletal load—that’s the patient who is going to run into trouble.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Nick, in your practice you see a lot of patients with bone metastases obviously. Is there any characteristic that you warn patients to watch out for when they have bone metastases?

Nicholas James, MD: One of the things we have charted out on our electronic systems is alkaline phosphatase. I’ll sit and look at 2 graphs in these patients and see what the PSA is doing. I’m looking very closely at the alkaline phosphatase. If they are climbing, and if it’s above the normal range, that sets a loud bell ringing, particularly in patients with a large metastatic burden. One of the things we will do with these patients proactively is we have—and I’m sure a lot of other centers have this—spinal cord compression cards that say, “If you get these symptoms, phone this number. Don’t wait till the next appointment.” Because obviously it’s much easier to prevent these things or manage them early than when somebody is paraplegic, when it’s essentially too late.

I’m very keen on being proactive about radiating these patients. We’re having many debates with our purchasers at the moment about how we have to administer this, because a lot of the data around palliative radiotherapy is uncertain in an era in which patients are living a few months with multi-metastatic disease. It’s not the same treating 1 or 2 metastases in patients who are going to live for years. Durability of control is much more of an issue, and I think that the stereotactic literature is very much trending in favor of dose escalation if you’re treating relatively small numbers of metastases. Where we’re going to be in a few years’ time is that, if the patients have low metastatic burden, we’re going to try to radiate before they ever get a problem—so that’s palliative in a sense, but it’s a very different sort of palliation.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: A longer-term strategy. You’re trying to give the patient a longer period of time without symptoms of the bone metastases.

Nicholas James, MD: The second thing is that—and we see this very clearly from the abiraterone [Zytiga] trials, the enzalutamide [Xtandi] trials, and from the docetaxel [Docefrez] portion of STAMPEDE—that if you have an effective anticancer therapy, your rate of symptomatic skeletal events drops. Docetaxel upfront reduced by 40% your risk of SREs 8 years later. It was a profound and long-term effect. In general, the best way to palliate cancer is to treat the cancer, not to do something else.

What has been debated over the last few years is, if you’re giving an anticancer agent, do you need bone protection as well? And I think back to the zoledronic acid trials when people were living a couple of years out—so probably, people simply weren’t living long enough, whereas now the survival times go up. Bone health is going to become increasingly important in metastatic disease. The ERA 223 trial, which I know we’ll discuss in a minute, shows very clearly that the patients receiving abiraterone have substantial rates of fractures and noncancer fractures as well. We need to think both about the cancer-related fractures but also the bone damage of all these other drugs we’re giving to treat the cancer.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Noel?

Noel Clarke, MBBS, FRCS, ChM: Well, I was just going to add that it has been a constant source of frustration in that there’s a lot of level-1 evidence about how to use these drugs. And there’s the issue of bone protection in relation to androgen deprivation, which we’re going to come to.

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

Noel Clarke, MBBS, FRCS, ChM: There’s the issue of preventing the pathological factor called compression associated with metastatic sights. What’s clear is that, on the level-1 evidence in relation to denosumab, you really have to target these therapies—and zoledronic acid, or any bisphosphonate, is very different from denosumab. If you give a bisphosphonate, the dose is cumulative; it gets into the bones—you don’t get it out of the bones; it’s very tightly dialed in. If you’re treating anybody who’s likely to survive longer than 2 years, you should give very careful thought as to whether you should be giving the drug early or whether you should delay it. And the same is true with denosumab.

So we come back to what Nick was saying a few minutes ago, which is, the rate of change of the alkaline phosphatase is critical because that group of patients in the LDH [lactate dehydrogenase] middle will not survive a long period of time; they’re likely to die within 12 to 24 months. That’s the group of men who will potentially benefit from a drug like bisphosphonate or denosumab. Don’t give it to somebody who’s got 1 to 3 metastases and have them on this drug for 4 years, because your rate of osteonecrosis of the jaw [ONJ] will go up.

Nicholas James, MD: There are 2 considerations here, aren’t there? What you’re talking about is reducing the rate of SSEs because of bone cancer. The STAMPEDE trial did test that to the ultimate limit. We put the zoledronic acid in at the beginning, and we saw no benefit on cancer-related SSEs, and what we saw, indeed, was ONJ. But there’s the second set of effects that I think we need to be worried about as well, which is the osteoporotic effects. You don’t need to give zoledronate once a year to stop osteoporosis—it’s twice a year; there are 2 separate indications for these. The osteoporotic indication, and that comes after the radium-223, is something we actually increasingly need to think about, which we never needed to think about in an era when patients weren’t living very long.

Transcript Edited for Clarity 

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Transcript: 

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Now we’re going to talk about bone health and treating metastatic castration-resistant prostate cancer [mCRPC]. Noel, I’m going to turn to you first. I know you have strong research interest in bone metastases in prostate cancer; tell me a bit about this.

Noel Clarke, MBBS, FRCS, ChM: Well, it’s not that well understood, and given the scale of the problem, not that well researched. We have patients who develop bone metastases, the majority of which are men who die from prostate cancer from bone metastases—at least 90%. If you looked hard you’d find it in most patients.

Some of those are highly asymptomatic, and some of those are associated with pathological fracture cord compression. What we know now is that the process of bone formation and bone destruction is very rapid in prostate cancer. People have looked over years at the radiological appearances and said, “Well, these are osteoblastic metastases aren’t they.” And, of course, when you look at the bone breakdown markers and how the skeleton is being broken up by prostate cancer, you see rather surprisingly that prostate cancer is a more lytic disease than breast cancer and lung cancer.

It’s important to understand that what you’re seeing is that the whole metabolism is booted up. Something that is important to recognize is that there are certain patients who are at high risk of developing skeletal-related events.

Now in the older classification, skeletal-related events [SRE], for example—in the old bisphosphonate studies—the SREs were radiological and people looking at little bits of radiological factors and so on. In the later studies—the ALSYMPCA study is a very good example of this—they were clinical events. SREs were either the pathological fracture, the core compression, radiotherapy to the bone, or treatment of bone pain; that’s the group to focus on.

What we’re really interested in doing in treating prostate cancer is to try to avoid an SRA [steroid receptor activator], which is in some cases a catastrophic event but in many cases predictable. There are certain critical markers that you can look at where the metastases are to show how heavy the skeletal load is, including alkaline phosphate and lactate dehydrogenase. If the alkaline phosphatase is about 150, and the LDH is up, you’ve got a heavy skeletal load—that’s the patient who is going to run into trouble.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Nick, in your practice you see a lot of patients with bone metastases obviously. Is there any characteristic that you warn patients to watch out for when they have bone metastases?

Nicholas James, MD: One of the things we have charted out on our electronic systems is alkaline phosphatase. I’ll sit and look at 2 graphs in these patients and see what the PSA is doing. I’m looking very closely at the alkaline phosphatase. If they are climbing, and if it’s above the normal range, that sets a loud bell ringing, particularly in patients with a large metastatic burden. One of the things we will do with these patients proactively is we have—and I’m sure a lot of other centers have this—spinal cord compression cards that say, “If you get these symptoms, phone this number. Don’t wait till the next appointment.” Because obviously it’s much easier to prevent these things or manage them early than when somebody is paraplegic, when it’s essentially too late.

I’m very keen on being proactive about radiating these patients. We’re having many debates with our purchasers at the moment about how we have to administer this, because a lot of the data around palliative radiotherapy is uncertain in an era in which patients are living a few months with multi-metastatic disease. It’s not the same treating 1 or 2 metastases in patients who are going to live for years. Durability of control is much more of an issue, and I think that the stereotactic literature is very much trending in favor of dose escalation if you’re treating relatively small numbers of metastases. Where we’re going to be in a few years’ time is that, if the patients have low metastatic burden, we’re going to try to radiate before they ever get a problem—so that’s palliative in a sense, but it’s a very different sort of palliation.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: A longer-term strategy. You’re trying to give the patient a longer period of time without symptoms of the bone metastases.

Nicholas James, MD: The second thing is that—and we see this very clearly from the abiraterone [Zytiga] trials, the enzalutamide [Xtandi] trials, and from the docetaxel [Docefrez] portion of STAMPEDE—that if you have an effective anticancer therapy, your rate of symptomatic skeletal events drops. Docetaxel upfront reduced by 40% your risk of SREs 8 years later. It was a profound and long-term effect. In general, the best way to palliate cancer is to treat the cancer, not to do something else.

What has been debated over the last few years is, if you’re giving an anticancer agent, do you need bone protection as well? And I think back to the zoledronic acid trials when people were living a couple of years out—so probably, people simply weren’t living long enough, whereas now the survival times go up. Bone health is going to become increasingly important in metastatic disease. The ERA 223 trial, which I know we’ll discuss in a minute, shows very clearly that the patients receiving abiraterone have substantial rates of fractures and noncancer fractures as well. We need to think both about the cancer-related fractures but also the bone damage of all these other drugs we’re giving to treat the cancer.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Noel?

Noel Clarke, MBBS, FRCS, ChM: Well, I was just going to add that it has been a constant source of frustration in that there’s a lot of level-1 evidence about how to use these drugs. And there’s the issue of bone protection in relation to androgen deprivation, which we’re going to come to.

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

Noel Clarke, MBBS, FRCS, ChM: There’s the issue of preventing the pathological factor called compression associated with metastatic sights. What’s clear is that, on the level-1 evidence in relation to denosumab, you really have to target these therapies—and zoledronic acid, or any bisphosphonate, is very different from denosumab. If you give a bisphosphonate, the dose is cumulative; it gets into the bones—you don’t get it out of the bones; it’s very tightly dialed in. If you’re treating anybody who’s likely to survive longer than 2 years, you should give very careful thought as to whether you should be giving the drug early or whether you should delay it. And the same is true with denosumab.

So we come back to what Nick was saying a few minutes ago, which is, the rate of change of the alkaline phosphatase is critical because that group of patients in the LDH [lactate dehydrogenase] middle will not survive a long period of time; they’re likely to die within 12 to 24 months. That’s the group of men who will potentially benefit from a drug like bisphosphonate or denosumab. Don’t give it to somebody who’s got 1 to 3 metastases and have them on this drug for 4 years, because your rate of osteonecrosis of the jaw [ONJ] will go up.

Nicholas James, MD: There are 2 considerations here, aren’t there? What you’re talking about is reducing the rate of SSEs because of bone cancer. The STAMPEDE trial did test that to the ultimate limit. We put the zoledronic acid in at the beginning, and we saw no benefit on cancer-related SSEs, and what we saw, indeed, was ONJ. But there’s the second set of effects that I think we need to be worried about as well, which is the osteoporotic effects. You don’t need to give zoledronate once a year to stop osteoporosis—it’s twice a year; there are 2 separate indications for these. The osteoporotic indication, and that comes after the radium-223, is something we actually increasingly need to think about, which we never needed to think about in an era when patients weren’t living very long.

Transcript Edited for Clarity 
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