Alicia Morgans:  Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist and Associate Professor of Medicine at Northwestern University. I am so excited to have here with me today a friend and colleague, Dr. Fred Saad, who's a professor and Chairman of Urology at the University of Montreal Hospital Center. Thank you so much for being here today to talk with us today Dr. Saad about bone health.

Fred Saad:  Thanks, Alicia. So it's my pleasure. Thank you very much for the opportunity to talk about the considerations of bone health in men treated for prostate cancer. So these are my disclosures. So really, we've known for a long time that ADT has a significant impact on bone. We've known for about 15 years that men exposed to ADT, as they are exposed for a longer and a longer amount of time, are at increased risk of fractures. And why those fractures are actually important is that we have data supporting the fact that fractures do have an impact, a negative impact, on survival.

And we are now able in a country-specific manner to estimate actually the fracture risk of men that are going on to ADT and the FRAX score is something truly useful and really simple and actually covers several elements that are easy to capture. Whether it's age, weight, the use of steroids which is now relevant in today's era of novel hormonal therapies, secondary osteoporosis, which would be the use of ADT, and we could include or not actual BMD rates or levels which are not absolutely essential to be able to calculate FRAX which allows us to estimate the risk of having a fracture as patients are exposed to ADT.

And there are some very basic principles, and I don't want to dwell on this because this, I assume is well known. The problem is not always applied. So, for patients who are going to be on long-term ADT, there are strong recommendations for these patients to get a BMD measurement before starting or at least during the time they are on ADT. Ensure adequate vitamin D intake of between 800 and 2,000 units per day. Ensuring adequate calcium intake, which should be about 1200 per day whether it's exclusively in diet or for many people requiring supplements. Encourage exercise that we know strongly impacts bone health but also strengthens bone that supports, and the muscles around the bones, to reduce the risk of falls. Encourage, as physicians to stop smoking which increases fracture risks. Limit alcohol intake. Any patients at high risk, use medication that is proven to be effective.

When we talk about exercise, very briefly there are many ways to encourage patients to exercise and we have to give them simple recommendations in what kind of exercise can be useful to reduce the risk of fractures and the risk of falls that can lead to fractures. And these are exercises that can be done at home, relatively simple, and are found on websites like Osteoporosis Canada, and several other websites around the world. So strongly encourage these simple techniques. And in this COVID era, it is very reassuring that none of these actually need a gym to be able to do this and reduce the risk of fractures and falls.

In terms of the impact of bone protective agents in recent studies, and this is relevant now because we've got better and better therapies that allow patients to live longer and do not reduce the risk of fractures but may actually increase. And one example that actually increased the awareness of the importance of bone health is the ERA 223 study that was published not long ago that looked at the concept of patients with metastatic castration-resistant disease being randomized to abiraterone and prednisone alone versus abiraterone, prednisone, and radium-223 introduced earlier in the disease setting.

And what happened in this study is that very early on it was recognized that there was an increase in fractures that was truly unexpected. And within 18 months we saw that overall there was almost a 30% fracture risk in patients that were taking the combination of abiraterone and radium-223 versus 11% in patients on abiraterone and prednisone alone. And even 11% in patients without radium was higher than what we would have expected within only 18 months. And strikingly, because patients weren't obliged to be on a bone health agent, it was recognized also that the risk of patients experiencing a fracture was more than twofold if they were not on a bone health agent compared to patients who were. And patients without a bone health agent, it went up 37% in the combination of abiraterone and radium-223. So, I think this was really sobering and also maybe a wake-up call that even though we have very effective agents that are doing a great job and prolong the survival, supporting the bone remains critically important.

And if we try to just take a minute or so to try to figure out why we saw this high fracture rate, obviously it became an afterthought, but if we just go back to basics. In the bone, we've got a balance between bone resorption and bone formation, the osteoclast activity in the osteoblast. And when we introduce ADT, and this is a concept that we've known for a long time, that when you introduce ADT, you actually encourage a shift towards more bone resorption because of the effects on testosterone and estrogens. And if there are bone metastases, this will actually increase bone formation, but this is an abnormal bone formation that does not help in terms of bone strength.

And then if you add to the ADT abiraterone and prednisone which further increases the risks in terms of increasing bone resorption and osteoclastic activity because abiraterone will further decline testosterone levels, prednisone is well known to have that kind of effect on the osteoclast, you further compound the effect leading to more bone resorption and higher increased risk of fracture. And then if you add radium-223, which is an extremely effective agent that prolongs survival, but its mechanism of action actually decreases osteoblastic activity. So a further shift towards bone resorption,  it effectively also controls the bone metastases through abnormal bone formation, but the overall impact is an increased risk of bone resorption, increased risk of fractures. And with a bone health agent, you try to re-establish, and very effectively, in fact, reestablish some balance between the bone resorption and the bone formation and therefore clearly reducing the risk of fractures as we saw in this study.

So, the question was, "is this unique to abiraterone and prednisone?" And the simple answer is no. If we look at other studies using even purely AR targeted therapies like apalutamide or enzalutamide, we see that these patients obviously were followed longer because they stayed on study longer, but they had a high risk of fractures within only 18 months being exposed to either apalutamide or enzalutamide. It was about a 10% to 12% risk of fracture.  But even in the placebo arm, only followed for about 11 months, it was about a 5% to 6% risk of fracture in a very short amount of time. And one of the explanations for this high fracture risk is that patients were exposed to bone health agents and only about 10% of these nonmetastatic CRPC studies, and in PREVAIL, where these are metastatic castration-resistant patients, again you see a doubling, even a triple risk of fractures, excluding pathological fractures, in a very short amount of time. So clearly there is an important role for bone supportive agents in patients living longer because of these effective therapies.

I think one of the most exciting findings recently is that we can make a difference. And so looking at another study, very similar to ERA 223 is the study being run out of Europe, an international study including Canada, looking at enzalutamide versus enzalutamide plus radium-223.

And here, very interesting at the beginning of the study, there was no clear indication or obligation to use a bone protective agent. And within one year, only one year, patients obviously were on long-term ADT before coming into this study, but within one year on the enzalutamide alone arm, it was a 12% risk of fracture. In the combination of enzalutamide plus radium, that went up to 37% within only one year patients without a bone protective agent. And I think the good news is when you do introduce a bone protective agent, which is now an obligation in this study, it goes down to a 0% rate of fracture in 12 months. So I think we have an issue that we can at least address and treat appropriately and effectively.

And so a very simplistic approach in terms of men that are going on to long-term ADT, you need to be able to figure out whether they are at high risk, intermediate-risk, or low risk, taking into consideration T scores and other risk factors that are clearly important and listed here in terms of age, steroid use, fragility fractures in the past, smokers, et cetera. And the recommendation in the high-risk group is that these patients being encouraged to exercise, take vitamin D, calcium, plus bone health agents, like denosumab or bisphosphonates, and to repeat BMD in two years.

Whereas on the other extreme, patients at low risk will suffice with exercise, vitamin D, calcium, and you can simply repeat the BMD in one to two years and not treat these patients. So really, a risk adopted approach to bone health.

Now, if we go on to bone-targeted therapy in men with metastatic castration-resistant prostate cancer, and whether this is still relevant in today's era. So just to highlight the importance of bone metastases in terms of patients with mCRPC, and this is work from Susan Halabi and several other studies have confirmed the prognostic importance of alkaline phosphatase reflecting bone metastatic burden. And if you look at the weight of alkaline phosphatase alone, a very simple, cheap biomarker, this is actually more informative in terms of the risk of death in patients that surpasses PSA significantly. So just being above the upper limit of normal increases your risk of mortality. And the good thing is if you can reduce alkaline phosphatase, these patients will do much better. Whether you reduce it with a bone-targeted therapy, with other therapies that are now approved, whatever way you get the alkaline phosphatase down, leads to better outcomes in these patients.

And these patients that have metastatic CRPC, we've looked at data here in Canada and elsewhere. If you follow patients till death, almost every man will experience some form of skeletal-related event. They still happen. They just happen later than in the past because they don't happen while patients are responding to therapy, but they are still critically important to try to prevent in a patient's lifetime. And we do have effective agents for patients with mCRPC with bone metastases. Zoledronic acid was the first to show a significant reduction and delay in skeletal-related events. And then denosumab showed it was actually superior to zoledronic acid in these men with metastatic CRPC.

Radium-223, purely bone-targeted agent, but the first to show that we're actually able to both delay significantly the time to first symptomatic skeletal event but also clearly improve overall survival by effectively targeting the bone.

So the question is, "do bone protective agents or bone targeting therapies add to life-prolonging agents?" And one of the first studies to look at this was within the group of patients on the abiraterone\prednisone study in the chemo naive patients. And we looked at patients that had a bone-targeted therapy compared to patients who did not. And the combination of bone-targeted therapy and abiraterone led to better pain control, a longer time to pain progression, a maintenance of performance status for a longer amount of time, and even in terms of overall survival, this group of combined therapy looked to be doing better.

The U.K. group actually looked at a study of docetaxel with or without zoledronic acid, and also confirmed that you significantly delay the time to symptomatic skeletal events when the patients are taking the combination of chemo and a bone-targeted therapy. And even within the bone-targeted therapy era with radium-223, you see that with radium-223, if you combine it to a bisphosphonate, this is where we had the biggest impact in terms of delaying symptomatic skeletal events with over nine months time to the first event in patients on the combination therapy compared to placebo, whereas radium alone didn't have as much effect in terms of delaying skeletal-related events.

And intriguingly and obviously this is not a randomized study, but when we looked at a large international early access program, looking at the use of radium with other agents to our surprise, and also maybe now in retrospect to be expected, the combination of radium with denosumab actually led to improved overall survival compared to the patients who received radium alone in this analysis.

So to conclude, guidelines all over the world now because of the high level of evidence will recommend bone protective agents in patients with metastatic CRPC. Whether we're talking about Europe, the States, or Canada in the presence of bone metastasis and castration-resistant disease, a high level of evidence to support the use of bone-targeted therapy.

So this was a whirlwind tour of something that remains relevant and important, but ADT increases bone loss and increases the risk of fractures. Basic principles would suggest that we need to give at least vitamin D and encourage exercise and identify patients at risk and intervene accordingly. New treatment options for advanced prostate cancer are much more effective when we start early. But because we start early and patients live longer and live well, we actually might see an increased risk of fractures due to longer time of exposure on therapy and longer survivals, which is good for the patients, but means we still have to worry about the bone. Bone targeted therapy is part of the optimal management of metastatic CRPC. Earlier therapy, more intense regimens, clearly appear to be more effective and better, but on the flip side, if these drugs are used too late, they're almost useless in terms of improving outcomes.

The combinations with metastatic CRPC therapies are safe and may actually increase effectiveness. And due to the mechanism of action of radium-223, bone-targeted therapy is absolutely essential to ensure safety, but also probably to improve on efficacy.

So thank you very much for your time, and I look forward to seeing you all soon outside of this virtual concept.