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Rashid Sayyid: Hello everyone, and thank you for joining us today in this UroToday recording. I'm Rashid Sayyid, a urological oncology fellow at the University of Toronto, and I'm joined today by Zach Klaassen, associate professor and program director at Wellstar MCG Health, where we'll be going over the 2024 key updates to the NCCN prostate cancer guidelines. In this recording, we'll specifically address one of the new sections, which addresses the prevention of symptomatic skeletal-related events in patients with bone metastatic CRPC.

So we've seen a lot of changes in these recent NCCN guidelines that were published in March. And what's interesting from a survivorship standpoint, we've really had two new sections that were added that specifically address the principles of bone health in patients with prostate cancer. The first one is the treatment of related bone loss, which we'll be discussing and going over in a later recording. We'll also, in this session, be discussing the section that discusses the prevention of symptomatic skeletal-related events in patients with bone metastatic CRPC.

And we see here today an excellent table of the summary of the recommendations by the NCCN, which discusses the optimization of bone health in all patient prostate cancer, specifically those receiving ADT, and also stratified by their current bone mineral density. We'll be going over all the evidence as well as the recommendations by the NCCN, in order to optimize this aspect of survivorship for our prostate cancer patients.

And so in mCRPC patients with bone metastasis, currently two agents have been shown to prevent disease-related skeletal complications, namely denosumab and zoledronic acid. And they've been shown to either prevent or delay the occurrence of these events. Namely, it's a composite outcome of fracture, spinal cord compression, or need for surgery or radiotherapy to the bone. And so which one is better? We know we have two agents that have shown efficacy in this setting, and really, that gives us many options, which is great, but ultimately, we want to pick one versus the other, depending on the clinical scenario.

And so in 2011, we saw a seminal paper by Dr. Fizazi published in The Lancet. This was a non-inferiority phase three trial that included almost 2,000 patients, specifically with bone metastasis. And they were randomized with one of two arms, either denosumab, which is given subcutaneously with IV placebo, and these were administered every four weeks, and we'll talk about why this is relevant later on, versus zoledronic acid given at four milligrams intravenously with subcu placebo. So that way, there was an IV and a subcu injection given for all patients in order to enhance the blindness.

And at the same time, in addition to these agents, all patients were strongly recommended to receive daily supplemental calcium, at least 500 milligrams, and vitamin D, at least 400 international units. And the primary endpoint was time to the skeletal-related event. And not only was denosumab non-inferior to zoledronic acid, but it also, once it was proven to be non-inferior, was also shown to be superior, by improving the median time to the skeletal-related event by almost three months, from 17 months to 20.7 months, so a clinically meaningful difference when we compare the two agents.

Okay, we looked at the efficacy outcomes. What about the adverse event profile? So when we look at the serious adverse events, they're roughly the same, at about 60%, but there are two specific adverse events that were more common with denosumab that are worth highlighting. The first one is hypocalcemia, and that was almost double. So we see in denosumab it was 13%, whereas zoledronic acid, 6%. So probably should check a BMP with a calcium level more often in these patients. The second thing is osteonecrosis of the jaw. And so although this did not meet statistical significance, we see that, in absolute amounts, it was only a 1% increase higher in denosumab, but it was twofold higher in patients receiving denosumab.

So it's important in these patients, before you start them on these drugs, to maybe have them see their local dentist, to get a quick check, and make sure that there are no contraindications to receiving these drugs. Now, one point of contention is how often should we give these drugs? We saw in this earlier trial by Fizazi and the rest of the team that these drugs were given every four weeks. But also, we saw that the adverse events, the serious adverse events occurred at least 60% of the time, and we also saw the hypocalcemia and the osteonecrosis of the jaw.

So if by decreasing the frequency that we give it, going from every four weeks to every 12 weeks, can we maintain the same efficacy, while reducing the frequency of adverse events? And so in 2017, we saw a very important paper published in JAMA that was also a non-inferiority phase three trial, that compared two years of zoledronic acid given every four weeks, which was the standard of the time, versus every 12 weeks, in almost 2,000 patients who had either metastatic prostate cancer, breast cancer, or multiple myeloma.

And the prostate cancer patients accounted for 700, so roughly just over a third of the cohort. And importantly, we saw no difference in the proportion of the skeletal-related events, irrespective of whether these were for every four weeks or every 12 weeks. And actually, if we just look at it in absolute amounts, it was actually slightly lower in the every 12 week group. What's important is that the trend was consistent across all three tumor types, including prostate cancer. We also saw no difference in the secondary outcomes of pain scores, performance status scores, the incidence of jaw osteonecrosis, kidney dysfunction, and skeletal morbidity rates. And so, based on these results, the NCCN and many other guidelines currently recommend that every 12 week dosing for zoledronic acid is recommended when indicated for symptomatic skeletal-related event reduction.

And so what are some important considerations for the use of zoledronic acid, denosumab by the NCCN? So the NCCN really makes some important points about these drugs, namely that utilization of these two agents for symptomatic skeletal-related event reduction requires consideration of the degree of the benefit and the risk associated with therapy to optimize use dose and schedule. So basically, if you think that the upside or the benefit of these drugs outweighs the risk, then you should definitely use them in this setting where warranted. But it's also important to recognize that these two drugs were used or tested in an era where the only treatment option for mCRPC patients was really docetaxel.
And we know that we've had a plethora of agents approved in the mCRPC space, namely the ARPS, such as abi and enzalutamide. We have other chemotherapy drugs, such as cabazi, radium 223, lutetium, in terms of radioligand therapy. And so all of these have been independently shown to improve the skeletal events on their own. And so you would think that by combining these agents with zoledronic acid and denosumab that you would further improve the bone health, and there may be some evidence to warrant that. But also, it's important to keep in mind that they don't always act synergistically.

And there's evidence that combining radium 223 and abiraterone, both agents which have been shown to improve bone health, actually increases the frequency of bone fractures. So for the time being, given the evidence that we have, the NCCN and many other platforms do endorse zoledronic acid, with the caveat that as these agents get tested in more contemporary trials, we may notice changes and these recommendations may accordingly be affected.

And so based on the current evidence, the NCCN says that there's strong evidence to support the use of zoledronic acid every 12 weeks, for the prevention of these skeletal-related events in mCRPC patients specifically with bone meds. So these aren't mCRPC patients with nodal disease only or visceral disease, but bone meds specifically. On the other hand, denosumab, for the time being, is still recommended every four weeks, but there is ongoing research evaluating an every 12-week dosing at the current time. And so for the time being, those are the frequencies.

And it's also important to keep in mind that we just can't rely on drug therapy. But as we'll discuss in a later recording, lifestyle modifications are critical in these patients, namely weight-bearing exercise, about 30 minutes at a time, balance training, smoking cessation, and limiting alcohol intake. It's also important to keep in mind that, in addition to these drugs, calcium and vitamin D supplementation are critical. So when we talk about calcium supplementation, it's about 1,000 to 1,200 milligrams daily, and this can be from food alone and/or supplements, as well as vitamin D supplementation when needed, for a target serum level of 30 to 50 nanograms per ml.

But again, as we've gone over, it's important to note that a lot of the evidence in this space comes from older trials in this space. So really, there's been a lot of new evidence that has emerged and has really shed light on these recommendations. And at this point, I'll turn it over to Zach to discuss some of the more contemporary nuances, and how these can be framed in the context of bone health survivorship for these patients.

Zach Klaassen: Rashid, thanks so much for that great overview of the NCCN guidelines. So what I want to do over the last couple of slides is really dig into some of the new data, and really, these recommendations from the NCCN that Rashid just went through are all based on old data, and really, as he mentioned as well, old prostate cancer treatment regimens and really poor utilization of docetaxel. So what about more contemporary treatment regimens? How does this reflect our utilization of bone protective agents? And what's the data show us?

So let's look at the ERA 223 story. This was a trial published in 2019 by Dr. Matt Smith and colleagues in The Lancet Oncology. This was 806 patients that were randomized, one-to-one to radium 223 plus abiraterone versus abiraterone plus placebo. What's important about this study, and keep these dates in mind, because we'll have a couple of dates coming up that we'll refer back to, in November of 2017, the study was unblinded, as there were more fractures and deaths in the radium plus abiraterone group compared to the abiraterone plus placebo group. And we can see here these differences in median symptomatic skeletal event-free survival, as well as fractures, for symptomatic skeletal-free survival radium 223 plus abiraterone, 22.3 months, and longer in the abiraterone plus placebo group at 26 months. Fracture rates, radium 223 plus abiraterone, 29% compared to abiraterone plus placebo. So this is what led to a study being unblinded.

But let's dig a little bit further into what was utilization of bone protective agents in this trial. So this is a snapshot of table one from the intention to treat population baseline characteristics. We can see that in the abi plus radium group, only 39% of patients were on bone protective agents, and only 42% of patients in the abi plus placebo group were on bone protective agents, either denosumab or bisphosphonates. And when we dig into the supplemental tables, we see that this is really what leads to or doesn't lead to fractures.

And so in this first column here of two rows or two columns, we see the abi plus radium combinations, the patients that had fractures, 21% utilization of bone protective agents, and those that didn't have fractures, 48%. So clearly, we see here that utilization of bone protective agents makes a difference. And we also see this in the abiraterone plus placebo group, with fractures, utilizations are very low, at 24%, use of bone health agents, up to 45% of those without fracture. So there seems to be a signal here that, with both the intervention and the placebo group, utilization of bone protective agents does decrease the risk of fracture.

Also, digging a little bit further, let's look at symptomatic skeletal event-free survival with the use of bone protective agents and without the use of bone protective agents. When we see these two groups, abi plus radium in blue, abi plus placebo in red, when bone protective agents are used, essentially overlapping Kaplan-Meier curves here, hazard ratio 0.932. When we don't use bone protective agents, we do see worse symptomatic skeletal event-free survival for the abi plus radium group, hazard ratio here, 1.252, not statistically significant but close, and an increase in fracture rate of 25% for that abi plus radium group.

So clearly, the utilization of bone protective agents is key for both groups, but really importantly in this slide, the take-home message is it basically brings that risk to even between the two groups in this trial. So there were several ramifications from the ERA 223 trial. So in the discussion, the authors note, "The finding that the use of bone health agents was associated with the decreased fracture frequency in both groups in this study shows the importance of the use of these drugs to prevent skeletal morbidity in patients with metastatic castration-resistant prostate cancer." Clearly, in their supplemental, further digging into the reasoning, it shows that when these patients are on these agents for both groups, there's less bone morbidity.

Equally important, and really for the ramifications for future trials, is what happened to the PEACE-III trial. And this is the enzalutamide plus or minus radium 223 trial. And as I said before, in November of 2017, the ERA 223 trial was unblinded because of the fracture rate. This led to, in March of 2018, based on this ERA 223, the PEACE-III IMDC issued an urgent safety letter, and then subsequently, in April of 2018, there was a mandate for bone protective agents in the PEACE-III trial. And so it became very important in the medical community, the funders and the stakeholders in this trial were really concerned about the possibility of increased fractures in enza plus radium 223, based on what was seen in the ERA 223 trial.

And so Dr. Tombola and colleagues at ASCO 2019 did a safety analysis of the next 146 patients. And so this is after mandated, the bone protective agent use increased from 42.6%, about what was seen in the ERA 223 trial, up to 86.7% after the mandate was established in April of 2018. And what they found in this trial is that basically the use of bone protective agents completely abolishes the risk of bone fracture. And this is starting bone protective agent six weeks before the first injection of radium 223. We can see here in the box, only one fracture in the patients that received bone protective agents in either group out of 19 patients overall that did have a fracture.

A subsequent update was presented by Dr. Gillison and colleagues at ASCO 2021, so two years later. This is now 267 patients. We've seen tremendous uptake in the use of bone protective agents, 96.3% after the mandate was issued in 2018. Again, the fracture risk shows that, basically, it's ameliorating fractures in both groups, with a fracture rate of only 2.6% in the enzalutamide alone group and 2.7% in the enzalutamide plus radium 223 group.

So I know Rashid gave us some excellent NCCN guideline conclusions from what was included in the 2024 update. These are some additional thoughts and some important conclusions. It's important to point out that this is the first time in 2024 that the NCCN prostate cancer guidelines have included bone health and bone protective agents in their update. If we look at this figure on the right, this is Medicare data, there's been historically very poor utilization of bone protective agents in the real world, and as we've seen in these trials as well.

So in this Medicare study, if we look at 2016, the blue line is any bone protective agent, roughly around 60%. And so we've seen it in the update of the PEACE-III trial in 2021, this number was up to 96%. But certainly, at least from this older data, looking at the real world utilization, this is about what we would expect. Not very good utilization, roughly 60% of patients getting bone protective agents. And so the new inclusion of bone health in the guidelines is timely. It also is a call to action, and it also makes sense that this is included now, given the likely presentation of the PEACE-III data either in late 2024 or in early 2025. So we thank you very much for your attention. We hope you enjoyed this NCCN update for UroToday on the prostate cancer guidelines, looking at the prevention of skeletal-related events in mCRPC patients.