Fred Saad: Thank you very much and thank you again to Silke and Aurelius for the invitation, and this has been another excellent meeting and I’m sure the one coming up is going to be again to meet our expectations. So I was given the task to talk about a subject that I thought was no longer controversial, but I realize when I was reviewing the most updated data that there are still issues related to bone health and prostate cancer and I put underneath what more do we need to know? So these are my disclosures and as others have said, probably I’m giving this lecture because of some of these companies that are developing therapies that are extremely effective to help our patients live longer but are causing other problems. So what we’re trying to prevent and treat, I mean, you see the normal bone and what we’re trying to prevent is the osteoporotic bone or the weak bone that can lead to consequences.
So the first question is why screen and treat patients? This is very basic and I won’t go into a lot of detail about this. This is not why we’re here, but really just to remind that this is general knowledge in terms of osteoporosis. That it does happen in both men and females regardless of the use of ADT, and the lifetime risk of fractures in the hip for men is only about 5% but that has a much higher mortality rate even than in women. And we talk about vertebral fracture prevalence being around 20 to 23%, and what is the importance of those vertebral compression fractures, which we find anecdotally on x-rays that are done for other reasons and we find, “Oh, there’s a little compression fracture and maybe the patient, when you questioned, has a little bit of discomfort or pain, but are they consequential to the patients?”.
And this is probably the reason why we try to prevent these vertebral compression fractures as the primary endpoint for most benign osteoporosis studies is that over time, and probably there are multiple reasons for this, mortality is twice as high for age match controls without these vertebral compression fractures, whether you’re a male or a female. We actually have some prostate cancer data and this comes from the study that Matthew Smith had led and that we had worked on in terms of patients. About 20% of patients who came onto the Prolia® study in preventing osteoporosis and osteoporotic fractures in men that are non-metastatic hormone-sensitive. We did have about 20% of patients who came in with a vertebral fracture coming into the study as long as they weren’t osteoporotic they were eligible. And you see right off the bat that in terms of all patients, this is non-cancer related death.
There was a higher risk of dying from all-cause mortality in patients with these vertebral fractures as you see in yellow, and when you look at patients on the placebo arm it was almost a double in risk of death of all-cause within only three years. This was an eye-opener for myself as to the importance of these vertebral fractures, and this is really just a hypothesis-generating, but patients who actually got treatment, you saw this mortality difference disappear when they were treated for osteoporosis prevention with the denosumab.
So what is the impact of ADT? I won’t spend much time on this because everybody knows this data. That you do lose bone as you are exposed to ADT at a much higher rate than what you see normally with men that are aging. It’s more profound than menopausal women and it’s in the range of bone marrow transplants and also in terms of ovarian failure in patients on chemotherapy. And why that is important is this was probably the most eye-opening study that was presented with about 50,000 men with prostate cancer, comparing men on ADT for variable length of time compared to men that were not on ADT. And the fracture risk was increased by 50% going from 12 to 19% at the four year period. These are fractures that were not looked for in an aggressive fashion. These were reported in the SEER database either for symptomatic or captured on x-ray. So this was really revealing and published in the New England journal already more than 10 years ago. So the question is what more do we need? Then there were subsequent studies, again, with the SEER database on ADT and fracture on survival. So the impact of fractures on survival, and you see that men that had fractures at 48 months compared to men without fractures had significantly worst survivals.
So now that we know this, obviously, I won’t stand here and say that every man needs to have preventative therapy and there are ways of calculating fracture risk. The most robust is from the actual osteoporosis foundations and this is … I’m sharing here the Canadian Association of Radiologists and Osteoporosis that will classify according to BMD and according to age. So obviously if you have an osteoporotic patient that’s only 50 and healthy the risk of fracture would still be in the low risk, but as they get older, to be at a higher risk you don’t need to have as low of BMD to be at an increased risk of fractures. If you are having a fragility fracture or on prolonged steroids, you automatically increase your risk category by one.
But I think probably the easiest way for all of us is to use the FRAX assessment tool, which is country-specific. Almost every country has a FRAX specific for their country with their realities, with their sun exposure, their dietary habits, all the rest. And you can plug in the age, sex, weight, all the other parameters that help you to determine fracture risk, and you can do this with or without a BMD analysis. So if you have the BMD that’s an added value, but you don’t need a BMD to figure out whether the patient is at low, moderate, or high-risk of fractures. Matthew’s group had actually done this plugging in patients in the FRAX score and figuring out their 10-year risk of hip fracture by age in men going onto ADT, and what you see is as age increases men being put on ADT reached the threshold of fracture risk that should be considered for preventative therapy.
So the general guidelines. Who should we do a bone mineral density in? So these are available on the web, easily available and they’re repeated. So I’m sharing with you the Canadian guidelines I think are very well done, but if you go to all the guidelines this is repeated over and over again. So you encourage basic bone health for all individuals over 50. You increase, as you’ve heard repeatedly, exercise, calcium, and vitamin D, supplementation. And for patients that are between 50 and 64 if they’re going to be on prolonged steroids or high-risk medication, which would include ADT, and men that are … Sorry. And men that are over 65 all of these patients should be considered for BMD when you’re seeing them. And then who should we treat? Again here very simplistically if they are at a moderate risk, so their 10 year fracture risk, 10 to 20% and you’re on an ADT and this is specifically mentioned even though these are general guidelines for osteoporosis or long-term steroids that we just had excellent discussions around the use of long-term steroids that are coming into our pathway earlier and earlier. These men should be considered for therapy, and obviously, if you’re already in a higher risk category then there is good evidence for the benefit of pharmacotherapy over and above the calcium and vitamin D recommendations.
So what are the treatment options? So I think everyone in this room knows how to treat these patients. The problem is deciding to screen and treat. It’s deciding to do something about it is the issue. And one of the things is does every man need to have supplemental calcium? The answer is no. This is, again, on the websites. You can actually different tools to estimate the calcium intake and what you’re aiming for is to make sure they’re getting at least 1200 milligrams, and if their diet is well enough, they don’t all need to have supplemental calcium. So there are ways of calculating whether they’re getting enough calcium, and it’s all nice to say, “do exercise.”, but are there actual tools? And there are tools that can help you to reduce your risk of fractures with exercise and this is, again, not prostate cancer-specific but obviously, our patients are at higher risk.
So there are actually simple exercises that men can be doing to reduce their risk of fractures and falls and these, again, are easily accessible and the website is below to be able to access this and print them out for patients or refer them to these sites. If we come to the bone health agents when we get to pharmacotherapy, basically they all work. That’s the bottom line. I think they’ve all shown effectiveness. Some studies have been more pronounced, larger than others, have more evidence to support them. But the very first study that really shed light to this was I think Matthew’s first New England paper and all of us dream of a New England paper with 47 patients which would be undoable today, and now it takes at least 1500 patients to get into the New England Journal. He actually showed that you lose bone quickly in the first year and that you are able to prevent this bone loss with pamidronate intravenously, and then zoledronic acid, again, the same thing. And the same thing with zoledronic acid with only once a year formulation seems to be very effective, and even alendronate oral bisphosphonates seem to work. Again, these are BMD driven analysis. So bottom line is to think about who’s at risk, think about the recommendations, think about pharmacotherapy and whichever one you use is better than doing nothing.
So basically for many countries, it’s what you have access to and probably the most well-done study is the study of almost 1500 patients looking at denosumab 60 milligrams every six months. So this is one 12th the dose, or it’s 60 milligrams every six months rather than 120 every four weeks that we use for metastatic disease showed a significant improvement in baseline BMD. Most patients coming into this study were around two years of ADT before coming on. So there was already a certain steady state. That’s why you don’t see the profound future bone loss and this was the only study to report a reduction in vertebral fractures at three years, which was significant. So basic principles, very simple. BMD for almost all patients, a long-term ADT, vitamin D, 800 to 2000 units per day. Calcium, diet, check on it, plus or minus supplements to be aiming for above 1200. Exercise, it’s extremely important, well documented, but will it get done? This is the challenge. If your patients smoke, stop smoking if possible. Alcohol intake limited to less than two drinks a day and medication if they’re high-risk.
Let me just end on a couple of minutes in terms of fractures and the impact of bone protective agents in the recent studies, because this is not sexy stuff. I mean PSMA is a lot sexier. A lot of these new agents, radium, lutetium but what could we learn from these studies? So this is the study that was just mentioned about ERA 223 that led us to rethink the importance of bone health. Radium and abiraterone versus abiraterone alone. This was very striking and put an end to the study early where you saw the fracture risk of 26% in the patients getting the combination of radium and abiraterone versus 10% for abiraterone and placebo. I would venture to say 10% is already quite a bit just with the abiraterone and prednisone. And when you look these events happen early. Within 18 months you had 37% of patients getting a fracture if you had the combination, but you still had 15% of patients that weren’t under bone-targeted therapy getting a fracture with ADT plus abiraterone and prednisone. So we need to think about this, and this happens really quite early and it’s not because of the drugs it’s because we’re keeping patients alive longer on ADT.
So why the high fracture rate? Let me just in 30 seconds summarize why this might’ve happened to increase the fracture risk. So balancing bone remodeling is, as I think everybody knows, is a combination of bone resorption and formation. If you give simply ADT what happens is you shift towards osteoclast increase. You start losing bone, you add to that abiraterone, prednisone you further shift towards bone loss, osteoclastic inhibition because you get more profound testosterone reduction and you add to that the prednisone, which in itself leads to bone loss. And then you add to the radium, the problem is you block the osteoblast and so that further shifts towards bone loss and no longer enough bone formation. You add the bone health agents and you reestablish some of this.
It’s not unique to abiraterone or prednisone. When you look at the different studies (SPARTAN, PROSPER, PREVAIL) you see that there’s increased risk of fracture with every study. Even apalutamide, enzalutamide, and enzalutamide in the chemo naïve setting and bone health use is only 10% in these studies and these are centers of excellence. So there are problems, but the biggest issue is even, forget about the drugs… Look at the rate of fractures within 11 months coming into those two non-metastatic studies. Piece three with radium and enzalutamide. What has been noted and presented at this year’s ASCO is that with enza and radium, it’s not unique to abiraterone, there was a 37% risk of fracture. Yes, I get the message it’s going to be finished, this is my second to last slide. But with enza alone is 12%. So enza alone without a bone-targeted therapy, but with a bone supportive agent you go down to 0% and I think that’s what’s most impressive. And I’ll leave you with the approach, a simplistic approach of patients on ADT if they have multiple risk factors to go on to pharmacotherapy. If they have no risk factors or only one risk factor to give them exercise, calcium, vitamin D and maybe re-image them for the risk of progression to high-risk features. And the risk features are all listed here and I think all of this will be available on the website.
So very quickly, bone health is not cool but is important. ADT increases the risk of bone loss and fracture risk. New treatment options keep patients alive, but the increased risk of therapy on survival increases the risk of these complications due to the mechanism of action of radium 223. I think it’s absolutely essential to have a bone health agent and basic principles need to be able to adhere to, and we still need to do a better job for bone health and prostate cancer. Thank you very much.