Bone Metastases and Mortality: Can We Be Doing More?

You can see here that the cost is very, very significant for any skeletal-related event all the way across the spectrum to spinal cord compression and needing emergent surgery. So what I want to do is, I want to break the talk sort of into two halves. The first half is the much more common problem that we face, and that’s the use of ADT and osteoporosis. And the second part of the talk we’re going to specifically talk about morbidity and mortality of bone metastases in prostate cancer and exactly what we can do to help our patients in our 2017.

So, here’s the number of patients with fractures one to five years after the diagnosis of prostate cancer. This is all-comers, and it is broken down by patients who are on ADT or patients who did not receive ADT. And again, you can see that the ADT very significantly increases the risk of a fracture after the diagnosis of prostate cancer, regardless of the stage of the disease. And again, as you all, as you all got it very nicely in the ARS question, survival after hip fracture is much worse for men than it is for women.

So, osteoporosis does increase with ADT duration; although, you can have an initial hit on androgen deprivation and the impact on osteoporosis the first two years, the longer you’re on ADT it continues to increase, and at ten years almost 80% of men have some form of osteoporosis due to the androgen deprivation therapy.

So, how do we diagnose osteoporosis? Well, clinically bone density, we all know, remains the gold standard. And bone mineral density, whether it’s in men, women, children with corticosteroid-related disease, or whatever, remains the best determinant of our bone strength. And it highly correlates with the fracture risk. And it is as reliable as blood pressure is in predicting a stroke.

So this is the World Health Organization (WHO) criteria for osteoporosis by DEXA scanning. This is all age corrected and age adjusted. So when you get a report back on the DEXA, it should be for an age corrected individual. So a normal is a minus 1 and above. Osteoporosis is diagnosed with a T score of less than minus 2.5. Osteopenia is low-bone mass. It’s basically between minus 1 and minus 2.5.

This is a very useful tool if you want to get very serious about managing patients in your practice, whether it’s a men’s health clinic or relating to androgen deprivation therapy you can go to the WHO FRAX Risk Assessment, and you look at a variety of issues, whether someone has had a fracture, what their weight, what their height, what their age is, whether or not they’ve been treated with androgen deprivation therapy, and it gives you a very reliable risk score for the patient’s chance of having a fracture in the next ten years.

Now, if you have osteoporosis, and we’ll talk about bone metastasis a little bit later. But these are sort of kissing cousins in respect, because almost always patients who have osteoporosis and then develop bone metastases are managed in a similar fashion. So our mainstay for the management of osteoporosis is vitamin D supplementation. If you have vitamin D levels, if you’re really serious about this, checking vitamin D levels on patients is the best way to accurately assess, do they need vitamin D supplementation at all, are they getting enough in their diet, or does and endocrinologist really need give them supra supplementation for whatever metabolic reason that they’re not generating enough metabolically active 25 hydroxy D, which is the only accurate way to really determine a patient’s true vitamin D level.

So, if you look at calcium supplementation it’s a little bit crazy. If you look in the literature what’s out there, there’s some very recent data that came out about two or threes ago, as always happens, some papers have suggested that men who get too much calcium actually increase their cardiovascular mortality by greater than 20%. A lot of groups now recommend just getting most of your calcium through diet, and supplement if needed with only 600 mgs of calcium a day. What I tell all my patients who are androgen deprivation therapy, or anybody who is on steroids or any kind of risk of osteoporosis, I think the best thing to do is just send them to get Caltrate 600 Plus D3. It’s relatively inexpensive. You don’t need a prescription for it, it’s over-the-counter, and that has 800 international units of cholecalciferol. I think that’s the easiest way, and that abrogates most of the issues. And again, if you’re real serious about it you can send them off for a vitamin D level, but I think in most patients it’s probably unnecessary, that falls more into the area of endocrinologists.

Bisphosphonates have been with us for several years now. Very popular in women, not so popular in men, but it’s starting to get more and more traction in that area. Bisphosphonates inhibit osteoclast activity and reduce bone resorption. And they can increase bone mineral density in the hip by up to 6%, but it takes a few years for that to happen. They can reduce the incidence of vertebral fractures up to 70%. But remember, one of the things, and those of you who really want to do a deep-dive into the area of osteopenia and osteoporosis is the concept of morphometric fractures. They’re not clinically apparent fractures, but if you do a detailed spine films you can pick up these small linear fractures. They may cause a change in the vertebral body, but these are counted by some papers as a skeletal-related event.   We’ll talk about skeletal-related event a little bit later. The important thing is you have a low glomerular filtration rate (GFR). Bisphosphonates are contraindicated, and again of course, anybody that you’re putting on a bisphosphonates you seriously consider a dental exam before you actually start it, because of ONJ risk, and every six months during it. The main side effect of bisphosphonates, I think everybody is aware of that we worry about is certainly the osteonecrosis of the jaw. But a new thing is coming out in the literature that’s been added to label, and that’s atypical fractures of the femoral shaft, which is sort of illogical. You would think you’re strengthening the bones, but it’s now been added to all the package inserts of the bisphosphonates that you may increase the risk of a femoral shaft fracture.

The other drug that’s out there if you want to get really serious about treating osteoporosis is denosumab, which is a rank ligand inhibitor and reduces bone resorption as well through different mechanism. It increases bone density probably a little bit more than the bisphosphonates do, and it decreases the incidence of a true vertebral fractures at 68%. But much more than the bisphosphonates, it actually decreases hip fractures by up to 40%.

These are the common osteoporosis agents that are approved in men. The oral bisphosphonates, there’s parenteral bisphosphonates, we tend not to use too much in urology, but there are some practices that do intravenous administration of zoledronic acid. Prolia, denosumab, and Achieva are the probably the more common agents that a lot of urologists use. Everybody knows there’s two forms of denosumab, there’s the Prolia, which is basically meant for men with androgen deprivation therapy induced osteoporosis, or just out of the gate osteoporosis through smoking or chronic steroid use, or something else, and very different dosing. Achieva is the form of denosumab which is, of course, used much more aggressively. It’s not really meant for men with osteoporosis, or a lot of men who do have bone metastases have long-term osteoporosis from their androgen deprivation therapy. And that’s a much more aggressive regimen of 120 mg subQ on a monthly basis.

At the present time the National Osteoporosis Foundation has guidelines for fracture prevention in men. They don’t necessarily say you have to use FDA approved agents. Everyone is completely in favor of vitamin D and calcium supplementation, but the National Osteoporosis Foundation suggests that if men have a history of a vertebral fracture or hip fracture, if they have a bad T score putting them in the osteoporosis category of a T score of less than minus 2.5. Or you do a FRAX score on them and you consider all the other factors that the FRAX score looked at. If they have a greater than 3% risk of having a hip fracture at 10 years or a 10 probability of any other fracture greater than 20% you probably should go ahead and treat them with an FDA approved agent of bisphosphonates, or denosumab, or something like that.

Interesting program down at Duke that they developed called a Healthy Bone Program. And what this group down there was able to show, that using their regimen, which goes as follows; they get a DEXA scan, this is for every man, not just patients with prostate cancer or ADT osteoporosis. Every man gets a DEXA scan in this practice world, that men age 50 undergo screening. If they have additional risk factors, and in our world that androgen deprivation therapy. And basically they have a program that focuses on clear smoking cession, regular exercise, calcium and vitamin D intake. And if you have a really severe T score of less than minus 2.5 they recommend pharmaceutic intervention. And in this men’s health primary care practice setting the patients are referred to an endocrinologist for a more aggressive management.

Next, I just want to move to the other area, which creates a lot of problems for us in the field, and that’s bone health in patients with metastatic prostate cancer. We’re going to talk about these four major areas, and talk about can we really be doing more to help patients in 2017.

Skeletal-related event, depending on which paper you read, people will pull out different skeletal-related events. The ones that are most commonly agreed to in most papers are pathologic fractures, spinal cord compression, the need for radiation therapy to the bone, any type of surgery needed to stabilize a bone fracture are accepted as skeletal-related events in men with bone metastatic disease.

So the impact of bone metastasis on survival is very significant, and again, if you look at the patients, the time after initial prostate cancer diagnosis in years, a little more than 50% are alive at five years without bone metastasis, but those with bone metastasis, according to this 2010 paper in the Journal of Urology, very few are alive after five years. The site of prostate cancer metastasis on survival, if you look at the curves here you’ll see that the lymph nodes only disease tend to do the best. And as you get bone lesions your survival goes down. And once you begin having both bone and visceral metastases, those patients have the worse prognosis and the lowest survival. So the site of metastasis can have an impact on survival, and certainly in this category, disease to the bone gives you the biggest hit on your chance for survival.

So, over 90% of patients with metastatic castration-resistant prostate cancer ultimately will experience a skeletal-related event. And again as we mentioned, the skeletal-related events are not good. They include spinal cord compression, fractures, need for surgery or radiation therapy. And they are really the major cause of death and disability, and of course, quality of life of a lot of our patients. The antiresorptive bone targeted therapies are top line here. We’re not talking about using the standard oral bisphosphonates in this setting. If you want to be serious about helping stabilize men’s bones with metastatic prostate cancer you’ve got to get into the systemic administration, either their zoledronic acid or denosumab.

Now, the good news, bad news is that really these agents do not necessarily extend survival if you’re using them for specifically skeletal-related events. They do, the denosumab has been shown better to extend survival. I’ll show you the data in a minute. They don’t delay metastasis and some studies they delay or prevent skeletal-related events, but again, the papers are all over the place.

About 50% of men with castration-resistant prostate cancer will develop metastasis within two years of the CRPC diagnosis. And again, the literature is very, very evolutionary at this point. Traditionally the median survival has been with metastatic castration-resistant prostate cancer is reported to be less than 30 months. But we know with advantages in our various treatments that that is extending. More than 30% of men with simply a rising PSA and no evidence of obvious metastatic disease actually harbor mets based on how aggressively you image these patients. And Dave has alluded to this several times, the famous RADAR study. The goal if you have patients who are M0 and you want to offer them advanced castration-resistant, metastatic castration-resistant prostate cancer therapy they’re only approved in the setting of radiographic metastasis, so these men probably need to be imaged a little bit more than we are currently doing it. And in particular that panel on the right, the first scan with the PSA level is greater than 2 nanograms per mL for the M0 CRPC patient, the more you look for it, the more you’re going to find it in the appropriate patient. And again, I think this paper is getting a lot of traction, and a lot of people are recognizing that patients need to be imaged a little bit sooner to look for metastatic bone disease.

Alkaline phosphatase is, we’ll talk about the latest data out there with radium-223, but alkaline phosphatase, an oldie but goodie actually predicts the risk of bone metastasis in asymptomatic patients who are treatment naïve. And the data here is even getting more pronounced with radium-223, that we’ll talk about in a couple of minutes.

So NCCN guidelines to talk about patients with M1 disease, frank metastatic disease, and they talk about bone resorptive therapy with either denosumab or zoledronic acid. And they both consider these to be category 1 if bone metastases are present. So that’s gets a pretty high level of endorsement from the NCCN.

A phase 3 study of zoledronic acid versus denosumab in identifying the time of the skeletal-related event suggests that there was a slight advantage to the use of denosumab in patients in delaying the first skeletal-related events. So if you look at the adverse events, if you’re going to choose to use zoledronic acid or denosumab they have a lot of common side effects. One of the very interesting things is that you have to be aware of number one, if you use these agents you much absolutely, positively make sure patients have adequate calcium and vitamin D supplementation. One of the side effects of both of these antiresorptive agents can be hypocalcemia from inadequate intake of calcium. So these patients really need to be monitored very closely for their calcium and vitamin D intake. And I’ll note, early on ONJ, the jaw, was thought to be isolated to the bisphosphonates, but the more and more that denosumab, the rank ligand inhibitor was used we also now see an increased incidence osteonecrosis of the jaw. Acute phase reactions, again, tend to be a little bit more acute infusion. I have a very—the first time I ever used, the first time I gave an IV denosumab was the last time I gave it, because the patient ended up in renal failure. So I now let the medical oncologists give the systemic therapy. But you can—

Excuse me, I meant zoledronic acid, Zometa. ID, zoledronic acid. The man ended up in acute renal failure in the hospital for two or three weeks, so I now let the medical oncologist, like Dr. Petrylak and everything manage that. But again remember, ONJ can be seen with both denosumab and zoledronic acid.

So there was a consensus panel know at the St. Gallen consensus that happens in Europe every couple of years. And this is basically a group of medical oncologists, urologists, radiation oncologists, and others that address a series of issues. And they get together and they work their way down to recommendations on how patients should be treated. And basically if you look at vitamin D and calcium supplementation as a baseline for patients with newly diagnosed castration naïve prostate cancer they agree with vitamin D, calcium supplementation, but they don’t necessarily recommend zoledronic acid or denosumab. For M0 CRPC, this consensus group actually did not recommend the use of osteoclast-targeted therapies in the M0 setting; however, once you got to frank bone metastasis everybody was basically on board with the use of either denosumab or zoledronic acid. They did not really come up with a strong recommendation of one over the other. But in the setting, again, to remind everybody, once you have documented M1 CRPC that the standard of care should be some type of antiresorptive therapy, either denosumab or zoledronic acid.

But what’s new in the area, everything which is old is new again, and of course, the Curies discovered something known as radium two centuries ago now. It’s hard to believe. They got the Nobel Prize, with Henry Becquerel for this discovery. They noted basically around 1900 that radium could be a cure for cancer. And a lot of work was done with radium, unfortunately, in the early part of the 20^th century it probably caused more cancers than it cured, because people didn’t exactly know what they were doing, or had no understanding about how radium actually worked.

So always like this because this reminds why we study chemistry in high school and college, because the Periodic Table comes back to haunt us here. And if you look at the reason that radium is used to treat advanced prostate cancer now, that it targets osteoblastic bone metastasis by acting as a calcium mimetic, and if you look at strontium, which we’ll talk just briefly about, all of these are calcium mimetics are very useful in the treatment of advanced prostate cancer.

So as a calcium mimetic it is bone seeking and it binds to hydroxyapatite. And again, the problem with prostate cancer, as you know, there is both bone creation and bone resorption. The bone that gets created is bad bone. It’s not necessarily very stable bone. So although you have an osteoblastic metastasis is not a stable growth of new bone, it’s actually very bad bone.

So we’re all familiar historically with strontium and samarium. They were kind of the go-to radiopharmaceuticals in the 80s and in the 90s, and they’re actually still around, but really not used that much. They’re primarily beta emitters that were used for palliation. The new kid on the block over the last ten years has been radium rediscovered over 100 years after its initial discovery as an alpha emitter. And the clinical benefit of it has been shown in clinical trials to reduce skeletal-related events and to improve survival. Remember, strontium and samarium were strictly for palliation, but did a big number on the bone marrow for reasons that we’ll talk about.

Very critical to understand the difference between alpha and beta emitters. Alpha particles are very large and don’t travel very far, and you can basically stop them with a piece of paper. Whereas, beta emitters, very small and have a very long-distance of travel because they’re very—they don’t get stopped very easily. But if you look at the bottom, the DNA hits the kill cells. Alpha is very big and very deadly. It takes very few relative hits of the DNA to kill a cell; whereas, beta you need to keep hitting the cells, for reasons that we’ll talk about. The reasons are that if you have beta and gamma radiation they tend to only induce single-strand breaks in the DNA which the body can repair more easily. Once you get double-stranded breaks in the DNA, and that’s where the alpha radiation really shines, but more lethal to the cancer cell and much more difficult to repair. So the bottom line is that our new compound that we have, the radium-223, Alpharadin is very, very short range, but has a very deadly kill. And the benefit that we have here if you look it is that it minimizes the damage to the bone marrow. Strontium and samarium were notorious at knocking out the bone marrow. They gave patients some palliation, but usually you can only give the medication once and sometimes twice before you really wiped out the bone marrow, particularly the platelets were very sensitive to the beta emitters; whereas, the radium-223 you can here is pretty kind to the bone marrow.

Here is an example of a choline PET scan showing a very, very pronounce response to radium-223 in a patient with metastatic prostate cancer. An interesting little aside is the fact that initially radium-223 was developed as a palliative drug. And the development shifted quite dramatically because although it could palliate patients they suddenly recognized patients were living longer who were getting radium-223, so the whole work shifted towards now using it as a therapeutic agent, and that’s where the work started to change over six or seven years ago.

So the famous article that came out was the Alpharadin study, with Chris Parker as the first author now almost four years ago, showing that radium-223 in ALSYMPCA trial would extend survival. And basically these were patients with castration-resistant prostate cancer who either had docetaxel or were unfit for docetaxel. And they were randomized 2 to 1 to either get a placebo or get 6 monthly doses of radium-223. And the bottom line is that the radium-223 increased the overall survival by a little more than 3 months. And again, or mCRPC drugs, as you all know, were kind of locked in this 3 to 5 month survival advantage, but hopefully by layering these different drugs on top of each other in the coming years we’re going to be able to expand the survival.

Very pronounced improvement in time to first skeletal-related events in patients who got the placebo versus the radium-223, about a 6 month improvement. And the main things again you need to still worry about; although, the drug is friendly to the bone marrow, you can still see problems with anemia and thrombocytopenia, so you need to check cell counts before you start the patient and before each subsequent administration.

The other thing, since this drug is secreted through the GI tract, some patients actually can have some nausea associated with it. So basically, radium-223 can prolong overall survival and it also prolongs time to first skeletal-related event. And overall compared to other agents in this space it is well tolerated.

So an interesting paper was produced about a year and a half ago by Oliver Sartor where remember, it’s given monthly for up to 6 months and Oliver was able to show from an early access program that if patients got less than 4 injections they did not do as well if patients were able to complete the entire cycle of 6 monthly injections.

Papers have looked combining radium with bisphosphonates, and basically no extent in survival, but it did have a positive impact on symptomatic SREs. So again, since most of these patients are on some sort of antiresorptive therapy they get continued.

Our friend, alkaline phosphatase in a 3b study was really shown to be a very powerful marker. And in fact, more remarkably, or a more reliable marker than PSA. And again, we have the problem with the PSA not necessarily responding that vigorously with the radium-223, but alk phosphatase has proven to be a reliable marker. Radium-223 is only to be used without visceral disease, only in patients who have bone only disease. That’s the current label. If you look at it, it’s known as Xofigo, from a proprietary standpoint, for the treatment of patients with CRPC symptomatic bone metastasis, and no known visceral disease.

The little thing, those of you that follow this, there was a slight change in the label. The National Institute of Standard and Technology changed how they measure radium-223, from a practical standpoint there’s no difference in how the drug is administered, but if you look at the package label it changed from the original approval to the actual total dose of radiation that the patients were getting. We, our team at Jefferson, the Kimmel Cancer Center uses a lot of radium-223, and we wrote this practical paper on how do you administer radium-223, because it’s not simple. You’ve got to a lot of advance planning. At our shop it’s given by the radiation oncologist, in other shops it’s given by the nuclear medicine folks. But you’ve got to make sure that you have proper setups. In Canada and the United States, I know we have some Canadian colleagues here, they are slightly different in the label, and the paper goes over those differences. But the important thing is always check the laboratory parameters at the start of therapy, and during therapy. And if you don’t get a recovery of very low labs tests within four to six weeks you have to go and discontinue the use of the drug.

So the bottom line of bone health is patients on ADT, you should consider DEXA scanning and use basic management strategies before you get into drug therapy. Strongly consider antiresorptive therapy with M1 disease, and I think it’s generally considered standard of care to use denosumab or zoledronic acid for those patients. It’s radium-223 can help with symptoms and bone metastases, but also can extend survival. And you really have to have a good institutional program with support to use radium-223 in your clinic. You need a lot of coordination of the care.