Read the Full Video Transcript

Neal Shore: Hi everyone, and welcome to UroToday and our online medical education program entitled Beyond Androgen Blockade to New Pathways and Novel Treatments in mHSPC and mCRPC. I'm Neal Shore and I have the privilege and honor to moderate today's discussion following a presentation by my dear friend and colleague Dr. Fred Saad. His topic today is Bone Health Management for Advanced Prostate Cancer. Please proceed Fred.

Fred Saad: So thank you very much, Dr. Shore or Neal as we know each other. And it's a pleasure for me to talk about prostate cancer and bone health really and how this applies to 2023.

So these are my disclosures. I've worked with several companies, especially in research and all the funding goes to my institution.

We've known for a long time now that ADT or androgen deprivation therapy impacts bone health. Bone loss goes beyond early menopause. And we also have established that as patients stay on ADT for longer and longer, the risk of fracture goes up over time. What's interesting in the osteoporosis literature is that even these asymptomatic vertebral compression fractures that we can pick up on X-rays actually appear to increase the risk of mortality by twofold compared to age match controls over time. So these even asymptomatic, so-called vertebral fractures are of clinical significance. And we've also seen with other databases that the effect of fractures on survival also negatively impacts patients on ADT.

And there are well-established risk factors for osteoporosis and fractures. The history of previous fractures, fragility fractures, long-term use of glucocorticoid therapy that is now more and more common in prostate cancer, family history, age BMI, the use of tobacco, alcohol consumption and diseases like rheumatoid arthritis all play a role in increasing the risk of osteoporotic fractures. And there are tools that are country specific tools in trying to estimate the actual risk of the patient in front of us of having a fracture over time. And you can plug in a lot of data in here that you know or don't know. And what's interesting is you can figure out fracture risk even without knowing the bone marrow density of the patient. Obviously if you know the BMD, it actually helps to determine the risk and if the patients are at risk, then you can establish the need for treatment.

And there is good data and general guidelines and consensus on who should get a bone mineral density. And when you look at these consensus guidelines, you realize that you should get at least one bone marrow density in patients over 65, whether they are male or female. And these patients play a big part of who we actually treat with prostate cancer. For younger patients, you need to look at risk factors that accompany age and you see highlighted prolonged use of steroids or other high risk medications, which would include ADT as a risk factor that should encourage us to get at least one baseline BMD. And this goes beyond the recommendation of ensuring adequate calcium intake and vitamin D supplementation.

And then who to actually treat will depend on where the patient falls in terms of risk of getting a fracture over 10 years. And patients at low risk can easily be followed without any therapy and suggested repeat BMDs every one to three years depending on the risk of fractures. And then on the other extreme, the high risk patient should always be considered for pharmacotherapy and include the patient in terms of determining what they should actually get. And then the big bulk of our patients would fall in the moderate risk category. And here we're going to look at risk factors beyond the ones we calculate and that would include patients on long-term ADT. And it's highlighted here in these guidelines and the long-term use of drugs like steroids that could increase the risk of pathological fractures.

And how to actually treat I think is treat left up to the physician and the patient. And we have excellent data with IV bisphosphonates, oral bisphosphonates , so they can maintain bone mineral density. And denosumab has actually been studied in terms of bone mineral density preservation in a large randomized study, but is the only one that actually looked at the reduction in risk of fractures over time. And beyond pharmacotherapy, we really have to encourage our patients on ADT and with prostate cancer to exercise. This is well established that this can increase the chances of preserving the bone quality and also maintaining the muscle strength that would decrease the risk of falls and an eventual fractures that these patients are at risk of experiencing over time.

And then we go to the other extreme, bone targeted therapy in men with metastatic CRPC. And whether this is still relevant in 2023 I think is very important and it still is a little bit controversial, but absolutely the data would support that these patients are at risk of experiencing complications due to their bone metastases, obviously in combination with the reduction in bone health because of their long-term ADT use. And what we realize is that if you follow patients until death, almost every patient will experience one of these skeletal related events or what we call bone complications, whether it be palliative radiation therapy for bone pain, an actual fracture, and unfortunately a large proportion of men will experience a spinal cord compression. And all of these can be reduced in terms of frequency and delaying the time to these events.

The first drug that was proven to be effective is zoledronic acid reported almost 20 years ago that can delay the time to these skeletal related events and at the time looked like it might actually play a certain amount of role in terms of survival. And then came denosumab, which did a head-to-head study that showed it was not only non-inferior to zoledronic acid but actually showed superiority in terms of delaying bone complications. And importantly, when you look at these results compared to patients not getting treated at all, and you see you almost double the time that patients will stay without experiencing a bone complication.
So the question remains, do these bone targeted therapies add to current treatment options that have multiplied over the last 20 years? And we actually reported data on the combination of bone targeted therapy and abiraterone in the chemo naive asymptomatic setting coming from Study 302 and patients were allowed to come in with or without a bone target therapy. It was left up to the investigator before coming into the study. And we saw that the use of bone target therapy looked like it might be improving overall survival, delaying time to pain that requires opiate use and maintaining quality of life for a longer amount of time.
And we looked at the combination of these therapies of bone targeted therapy to abiraterone compared to abiraterone alone and also the placebo groups. And we saw that the combination looked like it really seemed to delay the time to opiate use over abiraterone alone, maintaining quality of life with the combination over the other therapeutic options in that study or therapeutic stratifications. And even in terms of overall survival, they look like an advantage with the combination of a bone target therapy and abiraterone. Even studies with radium-223 looked like the use of a bisphosphonate in this study looked like it did much better when it was combined with radium over the control arm compared to patients who are getting radium compared to placebo without bisphosphonate use. So really looked like the combination of bisphosphonate and radium were what was driving the reduction of skeletal related events in the pivotal Alsympca trial that led to the approval of radium for metastatic CRPC. And a phase 3B study, international study, looking at the real world use of radium appeared to indicate that maybe the combination of radium and denosumab did better than radium alone in terms of even overall survival in this study that was reported a few years ago.

Now the question is what happens if we don't give bone protective agents today in a contemporary cohort of patients? And we can be informed on what happens by an ongoing phase three study that hasn't reported the efficacy results yet. But this study looked at the use of enzalutamide in first line mCRPC with or without radium-223. So obviously we're looking forward to seeing if the combination of radium and enzalutamide will be better than enzalutamide alone in first line mCRPC. But this study has informed us about the importance of bone protective agents in these patients.

And what you see here, these Kaplan-Meier curves of the blue one being radium in combination with enzalutamide without a bone protective agent. And you see the fracture risk over time in that blue line. Then the green line is enzalutamide without a bone protective agent, and you see the risk of fracture over three years that goes up significantly. And then the red and black lines at the bottom show what happens whether or not we're using the combination but with a bone protective agent and you see this significant decline in fracture rate.

And if we look at actual numbers, and this study had started without an obligation of bone protective agents. So we have a cohort of patients without a bone protective agent, and you see that as early as 12 months, you see this fracture rate that is quite impressive. And at 18 months, actually 45% of patients experienced a fracture that were getting the combination of enzalutamide or radium and as high as over 20% with enzalutamide alone without a bone protective agent as early as 18 months. So this has actually led to the obligation in the study to be using a bone protective agent as this data was maturing. And now with the obligation of a bone protective agent, you see that the risk of fractures plummeted by about 90%. And so this now I think adds to the importance of considering bone protective or bone supportive agents when we're treating patients with mCRPC.

And so based on multiple studies over the last 20 years, the use of bone protective agents for mCRPC are recommended by all guidelines to at least be considered in the management of our patients regardless of what they're actually getting as treatment. And this is available online, but the Canadian Urological Association, we try to put a treatment algorithm to try to avoid some of the confusion in terms of how to treat patients that are non-metastatic that are not castrate resistant and patients who are castrate resistant with bone metastases because the dosing of therapy is very, very different if you're treating a CRPC metastatic patient compared to osteoporosis fracture prevention. And so it's important to try to figure out who we need to treat and then how best to treat them with this kind of algorithm that is accessible and will be available.

So to conclude this very brief overview, ADT clearly increases the risk of bone loss and fractures. There are basic principles that at least vitamin D and encouraging exercise should be done in all patients. And after that, we need to identify patients at risk and intervene as needed. Not all patients need to be treated the same. New treatment opportunities for advanced prostate cancer are much more effective early, but the downside is that this may increase the risk of fractures due to longer time on therapy like ADT and others, and the longer time these patients will survive, bone targeted therapy is part of optimal management of mCRPC. And data would suggest that earlier more intense regimen appears to be better, but recommend that if patients are doing really well after two years to consider either stopping or reducing the intensity of treatment to reduce the risk of osteonecrosis of the jaw, which is a risk in all of these patients.

And bone targeted therapy with metastatic CRPC therapy is safe and may increase the effectiveness of our therapies that we give patients today. But due to its mechanism of action, if we're giving radium-223, there is an absolute requirement to be combining it with a bone targeted therapy. So I'd like to thank you very much for your attention and I look forward to the discussions with Neal.

Neal Shore: Thank you, Fred. That was wonderful as always. It's amazing to think that you published in JNCI in 2004, that was a seminal piece of work that you led. Interestingly for me as a uro-oncologist as yourself, it was really one of the first times we started to recognize that in addition to our medical oncology colleagues, your oncologists can give intravenous treatments. And it is amazing 20 years later how far the field has gone really thanks to your great leadership.

You make such a great presentation, it was a great overview. Bone health matters, fractures matter. We see the graying of the world, more elderly patients, more patients with prostate cancer, and so great strategies and great review of the literature. Fred, when you have a patient who comes into your clinic in Montreal and you are talking to them about of course, their therapies and their stage, whether it's sensitive or resistant disease. I guess I have sort of two overarching questions. Number one, do you have a dedicated bone health clinic? Maybe you have it in some of your hospital systems, maybe not in others. If you don't have a dedicated bone health clinic, which I think most of our colleagues probably are not that fortunate to have. But you did allude to the fact that the prostate cancer stage, regardless, it's getting so much more complicated. But if you don't have a bone health clinic with that level of multidisciplinary coordination, tell me how you address a patient early days in terms of not just their treatment specific therapy, but how do you speak to them in the 15 to 30 minutes that you have and say, "Fractures matter, bone health matters."

Fred Saad: Yeah, that's a great question. So actually it's very rare that in our center we're going to be having a dedicated bone health clinic. For me, it's part of the management of prostate cancer. I think all of us are used to giving ADT, but we have the obligation to realize that when we're introducing this therapy that is the basis of all our therapies for advanced prostate cancer, that there are consequences. And yeah, it is getting more complicated, but either we have to learn to do this alone. Ideally, having a nurse that helps makes a huge difference. And so I have a nurse that reminds me when I forget something and we use a checklist. So it's part of the overall management of these patients depending on where they are.

We have a checklist, did we forget to prescribe the calcium and vitamin D if they're not eating properly to get enough calcium? Did we talk about exercise? So the checklist makes a big difference and it is getting complicated. So all of us have to have it. And the bone health issue is there. And why it's part of the checklist is because like I said, after two years, the patients are doing very well. For mCRPC, we have to take a few minutes and think, is there more risk in continuing the high dose or is this patient is not doing well and we should continue because the risk is actually greater that they'll experience a bone complication and think about.

But there are centers, if you're not comfortable with this, then clearly family doctors, bone health specialists can be of a huge amount of help. But it's part of our obligation. If we're going to get into this business of treating these patients, I think we have a responsibility to either organize ourselves or get help to be able to do this properly. It's an obligation to our patients. And like I said, and I think you agree, maybe not everybody should be doing everything. I think we have to recognize when we've reached our limit and then get help or refer to people that are very comfortable or have a setup to do this properly. And this goes beyond bone health alone. It's really the overarching management of these complicated patients.

Neal Shore: Yeah, it's so important, and again, kudos to you because you saw the importance of this. And the health economic impact, I mean a fracture and ending up in the emergency department or hospitalized requiring a hip replacement and all of the attendant orthopedic requirements and complications and even the increased mortality risk. If we are more proactive as your content describes, exercise. So important now, I think everybody for the longest time maybe gave that a little bit of lip service. But exercise oncology, in addition to our appreciation for cardio-oncology and neuro-oncology, the bone compartment so important first in just preventing fractures, but also for preserving the bone milieu for subsequent therapies, which isn't the topic we're going over now. I wanted to ask you, Fred, you mentioned it in one of your concluding points, this notion around de-intensification, whether it's using zoledronic acid in mCRPC, bone metastatic disease or denosumab. A lot of the trials were based on Q3 week zoledronic acid, Q1 month DMAB. Have you looked at some of the literature and hence started to de-intensify for complication and or cost concerns?

Fred Saad: Yeah, and I think that led to part of the confusion is can we de-intensify and give it every three months or something like that? We've looked at the data attentively and I don't believe for a metastatic CRPC patient that's a safe thing to do, at least upfront. So I strongly suggest that these patients be intensified upfront for at least one or ideally two years. And then de-intensify because when you look closely at the data, if you go to the three-month regimen, bone markers are going up. And the way those studies were reported is they gave it a time dependent and the complications aren't occurring early on in these patients, especially if you're using this in hormone sensitive disease. So I think the data is supportive to do it as we did in the studies. But clearly at the time of the studies, patients weren't living four or five years, like we're seeing more and more now. But I think we need to be able to de-intensify or at least reflect on whether or not we continue to use this therapy as intensely if patients are doing exceptionally well. Unfortunately, the majority of our mCRPC patients aren't living much beyond two years. That's a sad thing. So it's not an issue for many of our patients that actually need the full therapy for as long as they're going to be around.

Neal Shore: Yeah, really important point. But the individualization of these regimens for visits to clinic and of course the mitigating the concern around ONJ, small percentage, but of course it's real. Again, brings in another facet to the multidisciplinary team, our oral surgeons and dentists. So important. Final question. How do you use in your bone metastatic patients, alkaline phosphatase or any other bone markers and just a point to be made when we combine therapies now, it's really nice to know that you can combine a bone protective agent or a bone targeted therapy or an anti-resorptive, we have all these different ways of saying it. There's really no exclusion for the most part, which is a nice thing to note with our life prolonging prostate cancer therapies, but biomarkers and bone health.

Fred Saad: So obviously if you're using a bone supportive agent, PSA is not going to be vastly different if anything, but you're perfectly right. One of our best biomarkers is alkaline phosphatase, which is reflection of the importance of the bone metastatic milieu that is osteoblastic in prostate cancer. But it's actually a very important biomarker, even beyond the bone targeted therapy itself. When we look at alkaline phosphatase declines, we know patients are doing well regardless of what we're giving them. But clearly if we're getting a good response in the bone milieu, the alkaline phosphatase should go down. And that is reflective of longer time without complications, but even reflective of longer survivals. And so every one of our patients is getting regular PSAs, but always with alkaline phosphatase because if that's going up, that is a bad sign. And then we probably have to consider changing our therapies if we expect to improve their survivals. Alkaline phosphatase, hemoglobin PSA, LDH, which is often forgotten are all of these biomarkers. But clearly the alkaline phosphatase comes up even better than PSA in terms of prognostic value for our patients.

Neal Shore: Well, thank you very much, Dr. Saad. What a great presentation. It's always my pleasure to be involved with research and educational initiatives with you. Thank you.

Fred Saad: It's a pleasure, Neal.