Alicia Morgans: Hi. I'm delighted to have here with me today, Dr. Fred Saad, who is Professor and Chairman of Urology at the University of Montreal. We are going to talk about bone health today. So exciting.

Fred Saad: Yeah, it is exciting. It's something that we've been talking about for a long time, but unfortunately, there's still a lot of men that go untreated regarding their bones.

Alicia Morgans: Absolutely. And you know, I think it's important, actually, across the spectrum from the hormone-sensitive setting where we think more about fragility fractures, through the metastatic castration-resistant setting where we think more about either skeletal-related events, if we want to use the old term, or symptomatic skeletal events, if we're thinking in more clinically-relevant situations. But we saw in ERA 223 and then in PEACE as well, PEACE III, that this is an issue for men with advanced prostate cancer and something that we need to tackle.

Fred Saad: Yeah, absolutely. I mean, I think we got really excited with all these new therapies that came along after ADT with chemotherapy and then, after that, all the AR-targeted therapies and then Radium-223. This was really an exciting era and then, we forgot about something that might not be as exciting because it doesn't prolong life, but bone health in these men, it remains important. Even though they're living longer, these events are happening in men and we did an analysis in Canada that, before dying, 85% of men do have a symptomatic skeletal event that causes morbidity and cost to the healthcare system.

Alicia Morgans: Absolutely. And it can increase mortality and really impair a person's independence as well and ability to get around. So, how do you approach this in your patients, and why don't we start really in a metastatic castration-resistant setting because I think we have pretty clear guidance in that setting. How do you think about that?

Fred Saad: Right, and every guideline around the world suggests that men be offered bone-supportive agents when they become castration-resistant and have metastases to the bone. Obviously, patients, we're not aiming at preventing metastasis, even though we thought we might have an option for that. There's no real good evidence to prevent, but in patients with metastatic disease, they're at very high risk of fractures, needing palliative radiation therapy, having even spinal cord compressions. In fact, prostate cancer is the highest frequency of spinal cord compression of any solid tumor. So, when patients get to that stage, I think we need to treat them and we have excellent therapies with denosumab, with zoledronic acid. Those are the only two that have shown significant improvements over not treating those patients. But it's also important the intensity of treatment.

Alicia Morgans: Yes.

Fred Saad: And you and I have heard many people say, "Well, maybe we don't need to treat them that intensely. We can maybe spread out the number of doses." And we actually did it in several analyses, and when you dose de-intensify, the risk of these events increases significantly and so, I think in that state, every four weeks remains important. The question is how long? And, obviously, people are worried with long exposures of osteonecrosis of the jaw, among other issues, and so personally, after two years, we take a step backwards.

Alicia Morgans: Okay.

Fred Saad: And I saw you have a great Nurse Practitioner and we have the same thing, and these are checklists that we have. So, we take a look and we say, "The risk-benefit of continuing." So, that's where I would say if patients are responding really well to therapy, look like they're going to be living several more years, which is the exception still in castration resistance-

Alicia Morgans: True, true.

Fred Saad: ... then we either lower the frequency, or we stop altogether for a while and when they start to progress again, we would reintroduce.

Alicia Morgans: Okay.

Fred Saad: And that's been my approach to treat early, rather than wait until I've exhausted all the therapies and then introduce the bone health agents, which I think is too little too late at that stage.

Alicia Morgans: Okay. So, I think that's a fascinating approach and I think that a lot of us think about decreasing a little bit from the four-week schedule. And I know you actually spoke about this at APCCC a couple of years ago and about how denosumab, in particular, is not really maintained in the bone between doses and I'd love to hear your thoughts on why is it so important in the metastatic CRPC setting to continue with that monthly dosing? And tell me a little bit about the data you mentioned where, if you dose de-intensify, or de-intensify the frequency at least, there's this increase in events?

Fred Saad: Right. And this comes a lot from both real world evidence, but also even in bone markers, that when patients are metastatic castration-resistant, their bone resorption markers amazingly, even though they look osteoblastic, are as high if not higher than breast cancer patients, even multiple myeloma. So these patients are at risk of fracturing, of having events, and if you start spreading it out too early, these bone markers come back up and the event rates go up. And we did an analysis looking at different centers in Canada, some that give every three months and some that give every four weeks, and we saw that patients that were getting it every three months that needed it, were actually having almost the same event rate as patients not treated at all.

Fred Saad: So either you treat properly and ... You know, when you look at even the trial of zoledronic acid against denosumab, the reason there was the biggest difference between both is that the zolendronic acid patients often have to stop or lower the intensity of treatment. There was 18 less percent drug and with denosumab, I'm going to get 18% more therapy, they had an 18% superiority to zolendronic acid. It's amazing how the intensity seems to relate to the effectiveness of these agents.

Alicia Morgans: So, we'll try to put a link, I think, to that paper on the site because I think that's really important data, particularly as we still wait for Dr. Gillessen's data to come out on the Swiss experience about the frequency of dosing because this guidance is something exactly as you said, how frequently and for what duration do we need to proceed at that frequency, is really important. One other thing I want to ... Oh, please go ahead.

Fred Saad: Just one other thing that's always a little bit of a problem with clinical trials that are reporting, is that you're only getting events while the patients are on clinical trial.

Alicia Morgans: Yes.

Fred Saad: And these events usually happen in the last year of life. And so if you're only capturing for two years when men are doing well for the first two years that they're on therapy, you're not really seeing a big difference. It really does happen later. And so I would be cautious about reading too much into the event rates on trial and that's why we did the real world until death and we saw the event rates are really happening in the last year of life.

Alicia Morgans: So you make a great point and just to reemphasize that, we actually spoke just a few minutes ago about how, for example, the STAMPEDE study that included zolendronic acid and the zolendronic acid and docetaxel arm, actually stopped capturing information related to that therapy at the time of PSA progression. And so we might think that actually the skeletal-related events might happen after you stopped the therapy and those would not have been captured on that trial. So can you elaborate on that?

Fred Saad: Yeah, and I think we did make attempts in treating men with these therapies in the hormone-sensitive metastatic setting but, unfortunately, the trials for several reasons weren't done adequately to address the point because if you stop following them when they become castration-resistant is when the events actually happen, or when you stop drug, when they become castration-resistant, it's hard to see a difference. So for now, I think the evidence is not there to start in the hormone-sensitive setting, but clearly, in the castration-resistant metastatic setting, the evidence is there. And as you mentioned, the Radium-223 story just emphasizes that in these patients, and we're seeing it even with AR-targeted therapies, that as patients are living longer, we're capturing events that we didn't expect, like fractures.

Alicia Morgans: Absolutely. And so interesting too, I think, that if we use these bone-targeted agents, we can actually take that event level down substantially, which is what we saw in PEACE III.

Fred Saad: And PEACE III was amazing.

Alicia Morgans: Yes.

Fred Saad: It went from almost a 30% fracture incidence-

Alicia Morgans: Yes.

Fred Saad: ... within one year-

Alicia Morgans: Yes.

Fred Saad: ... down to zero-

Alicia Morgans: Zero.

Fred Saad: ... when you treat with the bone-targeted therapies.

Alicia Morgans: Very impressive. So before we move on to fragility fractures, one more question. I was speaking with Tia Hagano the other day and she mentioned some study that demonstrated that when you stop denosumab, there's actually potentially a reflex increase in the development of skeletal-related events. And I'd love to know if you have any comments on that or if you're concerned about that as you dose de-intensify after the two years?

Fred Saad: Yeah, so I think a lot of that data is from the osteoporosis setting, where it was already pretty infrequent and when you stopped, then the bone markers went back up. So this is in more in osteoporosis. I think in the metastatic setting, we definitely wouldn't stop in a patient who is progressing, but in a patient who is completely stable cancer-wise, bone-wise, I think it's an option to maybe spread it out, but this is after having had intensive therapy for a couple of years.

Alicia Morgans: Yes.

Fred Saad: So I think we've stabilized the situation and it's going to come to your point of fragility fractures. I mean, these men have been on ADT for several years, so yes, there's the skeletal-related events or the SSEs, but we've also got the fragility because of the ADT exposure, which usually went untreated for all the time they were on ADT.

Alicia Morgans: That's true. Well, just to stop for a moment on fragility fractures. So in the hormone sensitive setting, we have a whole population of patients who may have biochemical recurrence on long-term ADT, or they're on ADT with their external beam radiation for a number of years, or they have hormone-sensitive disease and they are metastatic and they are on ADT for a prolonged period of time, sometimes with abiraterone, so even further suppressing testosterone signaling. So what are your thoughts about each of these populations? Do you think of them as generally one population and fragility fracture management is pretty much the same or do you divvy them up and think about them a little differently? What do you think?

Fred Saad: I try to keep things simple.

Alicia Morgans: Yes.

Fred Saad: And I think saying that they're all pretty much the same is maybe the most simplistic approach. And I would live with that very easily, if people would at least consider managing these patients.

Alicia Morgans: Yes.

Fred Saad: I mean, just being on ADT is already, we know, a risk. The bone loss in the first year and consecutively after that, requires calcium, vitamin D, and then we have to stratify according to risk if they need more supportive bone agents. And so patients that are elderly, patients that are taking steroids, and the abiraterone example is an excellent one, that further increases the risk. And then we can include a bone mineral density that we probably don't do enough to try to judge the risk of that patient getting a fracture, which has a significant impact not only on their quality of life, but also on their overall survival and there's loads of literature outside of the prostate cancer world.

Alicia Morgans: Yes.

Fred Saad: Just having these fragility fractures cuts your survival almost in half in many of these studies. I mean, it's a signal that things are going to do less well. So, I think these patients we have to ... they're not all the same, but if they're at risk they need to be managed properly, and I would encourage at least thinking about it. And there are natural things, too.

Alicia Morgans: Yes.

Fred Saad: Exercise has been shown to be very effective. The reality is we have to tell our patients what to do-

Alicia Morgans: Yes.

Fred Saad: ... and we have to be convinced that they're going to do it.

Alicia Morgans: Yes.

Fred Saad: But it's usually not enough in a high-risk patient. And you know, what I encourage people to do is to look at just the FRAX score and they're country-specific and you can plug in the age, the other risk factors and then it gives you really a percentage of risk of a significant fracture over the next 10 years and that can help decide who needs to be treated.

Alicia Morgans: Absolutely. So the WHO FRAX score, there is a calculator so that people can actually get that, and what I love about that calculator is at the bottom it says, well here are your criteria for initiating and additional osteoclast-targeted therapy, and we will put that link on, if we can as well, to really make sure people have access to that. So I agree with you. I think of this hormone-sensitive population, whether it's metastatic or non-metastatic, is one that's at risk for fragility fractures in the setting of long-term ADT, and so I do calculate that and I think the FRAX score is really critical in that. And if you have a patient who meets other criteria, like you said, older age, on steroids certainly, or a long-term ADT, if they have alcohol abuse history, other issues, you could actually plug them into the FRAX without a DEXA scan-

Fred Saad: Exactly.

Alicia Morgans: ... if you don't have access to that DEXA result and get an answer regarding the fracture risk.

Fred Saad: And that's what's amazing. A lot of our patients, even without knowing the bone marrow density, put them at a high-risk category and you don't even have to go any further.

Alicia Morgans: That's true. That is true. Well, that was a wonderful review of how we should think about bone health from the fragility fracture hormone-sensitive state, all the way through the metastatic castration-resistant state. There are nuances to each and I so appreciate you giving us your guidance on those areas and I thank you for your time.

Fred Saad: It's always a pleasure. Thanks, Alicia.