Matthew Smith: It's good to be here. Thank you, Neeraj, for that nice introduction.
Neeraj Agarwal: Thank you for being here. Obviously, we are here to talk about your presentation at the 2026 APCCC meeting. As you know, Matthew, you have been a leader among several other things. One of the areas where you have produced seminal results is the use of bone-modifying agents or bone-strengthening agents, Denosumab, RANK-Ligand inhibitors, and bisphosphonates in patients with metastatic hormone-sensitive prostate cancer and metastatic castration-resistant prostate cancer. We also know that there is significant confusion in the field, because these agents are approved for patients with metastatic cancer and bone metastasis. But in prostate cancer, the indications, approvals, and evidence are different if you look at metastatic castrate-resistant prostate cancer versus metastatic hormone-sensitive prostate cancer. I'd like to get your insights on how you use them, what the data are with these agents, and what would you recommend. That's the core of the discussion today.
Matthew Smith: That's an absolutely perfect setup. I share your view. I'm really struck with the level of ongoing confusion in the field, despite now really a few decades of work. I think it'd be worth focusing on a couple of issues to start. And really, one is nomenclature, and then the second is therapeutic intention. This term skeletal-related events is often misunderstood. Similarly, and it really relates to disease related skeletal complications, meaning complications in bone due to bone metastases. That, in some definitions in clinical trials, includes fractures, even radiographically-assessed fractures, which there's some debate about the relevance of those endpoints. But I think this has led to a view that everything that happens in bone in a prostate cancer patient is a skeletal-related event, and it's really not the case. Patients with bone metastases may be at risk for disease-related skeletal complications, or so called skeletal-related events, but all patients are at risk for osteoporotic fractures and androgen deprivation therapy increases the risk for osteoporotic fractures. Other drugs, like androgen receptor pathway inhibitors, may further increase the risk, whether due to a direct effect on bone or greater risk for falls.
The way we address those problems are very, very different. The principles of preventing osteoporotic fractures are really the same principles as in the general population. Screening for patients at greater risk, recommendations of vitamin D supplementation, adequate dietary intake of calcium, and in patients who are at sufficient risk for an osteoporotic fracture to administer an FDA drug in the dose and schedule appropriate for osteoporosis. All right. Osteoporosis is really a disease where you have net bone loss and you have modestly increased levels of bone turnover, including osteoclast activation.
Disease-related skeletal complications are like the opposite end of the spectrum of bone disease, where you have very extraordinarily high levels of bone turnover, extremely high levels of osteoclast activation. The best way to prevent disease-related skeletal complications is to control the disease. First and foremost, our priority there in patients with progressive metastatic prostate cancer is to treat the underlying disease, and in selected patients, to use osteoclast-targeted therapy to prevent disease-related skeletal complications, including spinal cord compression, fractures within bone metastases, pain progression, other events of that sort.
There, though, you need a drug at a higher dose and schedule appropriate for SRE prevention. And the trouble is these two concepts are often intermingled and osteoporosis is referred to as an SRE and the other way around. You really have to consider the therapeutic intention, what are you trying to prevent? And then, what's the right drug dose and schedule? And unfortunately, the [inaudible 00:05:13] continues to confuse these issues, and it's rather surprising, I have to say.
Neeraj Agarwal: Are there different terminologies we should be using for using these bone-modifying agents when we use them in metastatic castration-resistant prostate cancer versus in metastatic hormone-sensitive prostate cancer?
Matthew Smith: Well, the whole issue is, and you raised a really good point. All men are at risk for fracture, and we can increase that risk by older age, risk for falls, low baseline bone mineral density. And then, many of the drugs we administer increase the risk of fractures. Androgen deprivation therapy, we and others published that data more than two decades ago. And then, other drugs we use to treat the disease, like androgen receptor pathway inhibitors, increase the risk for fracture. That's been beautifully demonstrated in the studies of non-metastatic CRPC, where we're sure the events occurring in bone are not due to the cancer. They don't have detectable metastases, and yet, those drugs further increase the risk for fractures. That should just be called osteoporosis and fractures. The principles of management are largely overlapping or almost perfectly overlapping with the general population.
I would say, in some ways, like having these cancer-specific guidelines for osteoporosis and fracture prevention, in my view, have done a disservice to the field. Years ago, there was this term that was popular, it's cancer therapy-induced bone loss, or CTIBL, as if it was some unique condition unrelated to osteoporosis in the general population. It's not, it's much the same. And then, on the other hand, SREs are sometimes used in the most general concept, like to include osteoporotic fractures. If you do that, then you can easily mix up what the right drug dose and schedule would be for managing that problem. The evidence for using drugs like Zoledronic acid and Denosumab on a frequent basis every three or four weeks at doses appropriate for SRE prevention comes from randomized phase-three trials done long time ago in mCRPC, and perhaps to align with the label in other cancer types, it doesn't specify mCRPC, even though the studies were done in mCRPC exclusively. Denosumab, for example, is approved for SRE prevention in metastatic prostate cancer, but the data from that trial is only in patients with mCRPC.
It's also worth noting that the evidence there might, in some ways, be like a better or best case scenario for the value of those drugs, because they were done at a time when we had very little else to control the underlying malignancy. The best way to prevent an SRE is to control the cancer. And you won't be surprised to know, and you know this literature, that ARPIs, for example, reduce the incidence of SREs. Why is that? Because they control the cancer. It's not a surprise at all. That's the best way to prevent SREs. In appropriate patients, particularly those with progression despite your best therapies or extensive bone metastases even if their cancer is thought to be well controlled, there is a rationale and a good, and certainly motivation to use osteoclast-targeted therapies, specifically Zoledronic acid or Denosumab, to prevent disease-related skeletal complications or SREs.
The evidence in mCSPC is lacking. We and others did study, there was a CALGB study, there was a STAMPEDE trial that looked at that with Zoledronic acid, and there appeared to be no benefit for adding the drugs earlier. If you think about it, it may stand to reason. If you start a drug when you're introducing effective anti-cancer therapy in the old days, ADT alone, you're probably not going to have a benefit to adding an osteoclast-targeted therapy, because you've already done the most important thing, which is to control the malignancy with systemic therapy.
Neeraj Agarwal: So it all comes down to whether they have osteopenia or osteoporosis or not in metastatic hormone-sensitive prostate cancer.
Matthew Smith: Well, here's the rub. I'd say no. I wish I had an easy answer for you, but actually, assessment of fracture risk, most patients who fracture have a normal BMD. Why is that? Because most people have a normal BMD. The population with a normal BMD is greater than those with osteoporosis, for example. That said, a low BMD is a predictor of fracture risk, but it only explains like a modest amount of the entire individual's fracture risk, because other factors come into play, age, body mass index, it's the rare situation where being thin is a disadvantage. And that's because if you're very thin and you fall on your hip, you don't have any built-in hip protectors. If you're heavier and you land on your hip, you have built-in hip protectors. That's thought to be the explanation for BMI. A low BMI may also be a marker of frailty and greater risk for falls.
There's a variety of things. My recommendation for the osteoporosis or osteoporotic fracture prevention is to use National Osteoporosis Foundation guidelines. And that includes an estimate of the fracture risk based on clinical criteria using the FRAX online calculator, very straightforward, mostly driven by age. But it includes other things like BMI, smoking history, alcohol history, and family of parental history of hip fracture. You can get a pretty good prediction or estimate of the fracture risk based on those clinical criteria without a DEXA score without a BMD measurement. And if you have the BMD measurement, you can also include that to assess the fracture risk. But it's really not binary, just DEXA scan, drug, yes, no, because many patients will meet criteria for drug therapy despite a normal BMD.
And in my practice, for example, if an older man who's been on long-term ADT and on an ARPI and I'm meeting him for the first time and he comes in with a cane, I'm like, "I know he's at high fracture risk, so I don't need a BMD to decide whether he should be on a drug to prevent fractures in that scenario." You might still choose to do it. I use BMD to tease out the individuals who maybe wouldn't otherwise meet clinical criteria, or who I know will be on very long-term ADT, where if they don't need a drug now, they're likely to need it years in the future.
Neeraj Agarwal: I deliberately brought this up, because that's a whole point of focus. When you talk to many of our colleagues out there, presence of osteopenia and osteoporosis seems to be the guidance for using a bone-protecting agents or bone-modifying agents and not the FRAX score, which is you are saying we should be just using the national guidelines and the FRAX scores, which can easily be calculated in the clinic using the clinical criteria can pretty much guide us on who needs these bone-modifying agents in metastatic hormone-sensitive prostate cancer. Is that correct?
Matthew Smith: Absolutely. The whole point here is that if you're only using BMD, then you're missing the opportunity to treat a lot of other patients. The other part we should all know is that this gets to be a little bit wonky. BMD measurement in older men is very problematic. For example, spinal BMD, you look at hip and spine, spinal BMD is often overestimated by calcification of the posterior ligaments, osteoarthritis, vascular calcifications. It's very insensitive to measure, to predict fracture risk in older men, and you have that problem. And then, if the patient has bone metastases, because they're osteoblastic, you would overpredict the BMD, and so it's completely unreliable. I would never order a DEXA scan in someone with bone metastases, at least if they're known to be involving the pelvis. It's irrelevant. You're really missing the opportunity to intervene.
If you haven't done it yet, I would encourage anyone listening to use the FRAX tool on the next 10 patients you see who you're considering this issue, and you'll quickly realize what drives the predictions. It's mostly age and a few other things, primarily age. You may not even, after a while, you don't need to necessarily get out the FRAX calculator and do the formal calculation. You'll know just by asking this ... If it's a 55-year-old non-smoker with no parental history of hip fracture, it's very unlikely that they're going to meet clinical criteria, unless they happen to have a low BMD. That's someone like if you know they're going to be on long-term ADT, you might say, "Let's get a baseline BMD," so that you can then compare it some years in the future.
Conversely, if you see the 89-year-old guy, who comes in with a cane and has been on ADT for the last 12 years and you're now assuming his care, you already know he's going to meet clinical criteria for drug therapy to prevent fractures. That's someone where the number needed to treat to prevent fractures is very, very low. Those are the patients that you really want to intervene.
Neeraj Agarwal: Now, coming to the metastatic castrate-resistant prostate cancer, Matthew, please tell us, based on many of our own trials, what is the evidence for use of Zoledronic acid versus RANK-Ligand inhibitor Denosumab in our patients with metastatic castration-resistant prostate cancer?
Matthew Smith: Yeah, it's a great question. These are old studies. They go back many, many years to a time before we had many of our current effective anticancer therapies, including none of the ARPIs were approved when both of those drugs were first evaluated. We don't know how they would perform in the contemporary landscape where we have much better anti-cancer therapy. It's a bit of a double-edged sword. We control the disease better, but then patients live longer, and then are going to, still at the end, be confronting similar issues to perhaps what was studied long ago. But patients are living much longer in the mCRPC disease state. They're living with large periods of that time with better cancer control. I don't know how they would hold up, honestly, if you were to attempt to repeat those pivotal trials in the contemporary era. I think if you included patients upon progression to mCRPC, you might not find much benefit, at least for the first few years.
And so, it raises lots of important issues, including like when to even start those drugs in mCRPC. I usually wait till patients progress, in the SRE dosing schedule, for patients who progress on their ARPI. Hopefully, they already got their ARPI for mCSPC. But usually, I'm thinking about it when they're like going on to either initiate chemotherapy or radioligand therapy as the moment where I'm going to do that. And then, the other question becomes, "Well, what's the right schedule?" When originally studied, Zoledronic acid was every three to four, these drugs were originally studied every three to four weeks, so you're looking at a very intense schedule. For patients who you project would live for many years, that's almost certainly overtreatment.
I also think about the extent of metastatic disease. if you're talking about all bone metastases are not the same, of course. All patients with bone metastases are not the same, particularly in an era where we now have PSMA PET CT, and we identify the disease much earlier. I'm usually thinking about when they're progressing on their ARPI, when they're on starting chemotherapy or radioligand therapy, if they have a substantial burden of bone metastases, that's when I'm thinking about escalating their bone-targeted treatment from the osteoporotic dosing schedule to an SRE prevention dosing schedule. I often, and I will be critical of the data that looked at alternative less frequent schedules. That said, I have generally adopted that as I think very acceptable alternative to monthly treatment. It's a rare patient that I would treat with one of these drugs monthly. More typically, would be doing it every three months, for example, or even six months in some cases.
Neeraj Agarwal: Yeah. You already addressed one of the very important questions I had in my mind, when to start bone-modifying agents in mCRPC setting given patients are living much longer. Many of the patients in the US are receiving ARPI in the metastatic CRPC, because the most common way for us to diagnose prostate cancer is localized prostate cancer. These patients get surgery, radiation, then they have biochemical recurrence, historically speaking, for over the last 10 years. They're often treated with single-agent ADT, intermittent or continuous, is rare to see EMBARK-style treatment being used widely yet in the community for biochemical recurrence, and then these patients develop mCRPC over time. In these patients, mCRPC phase can really last for four to five years.
Matthew Smith: Yes.
Neeraj Agarwal: Always worry about using Denosumab or Zoledronic acid, zoledronic acid for more than two years, because that's how they were tested in the trial. And again, the interval which you brought up every four weeks versus every three months, I will admit I often use them every three months rather than every month.
Matthew Smith: Yep. I have to say that the data supporting that is problematic. It was this non-inferiority trial. It was a non-inferiority trial done in CALGB, if I recall correctly. It included a host of other diseases, a lot of prostate cancer, including hormone ... Well, castration-sensitive disease, where two other studies that I alluded to earlier showed no benefit. So you had patients who couldn't benefit and they were randomized to two different schedules and you're like, "Well, if you see similarity, it doesn't mean anything." I don't think the study is very problematic and non-inferiority study designs also require an assumption of constancy, which doesn't exist in oncology. While I have many criticisms of that CALGB trial, I think the conclusion is probably right, which is that despite the problems, I think the conclusion's right, which is less frequent schedules are probably just fine for most patients.
And so, I'm really reserving more intense therapy for patients who have off the rails bone progression or whom have already experienced skeletal complications, where you really feel that there's a need to do that. I think we derive a lot, and if you think about the population-based view, you're really providing most of the benefit by intervening at all, even if it's at a less intense schedule. I think probably the incremental benefit of the very intense schedule is very low for the vast majority of patients and may even lean towards causing more harm than benefit.
Neeraj Agarwal: How long? What is the duration of these agents once you start them in mCRPC?
Matthew Smith: Yeah. I use them continuously once I start, and that's part of the appeal of using a less frequent schedule. I'll also say that, for that patient who have initiated osteoporosis dosing schedule therapy, I generally going to use a drug that I would also use for SREs, because I don't want to be switching from oral weekly Alendronate to Zoledronic acid or Denosumab when they progress to mCRPC, because like oral Alendronate is completely inappropriate for SRE prevention, for example. I don't like to give two different drugs because when you give two different bisphosphonates, for example, or other osteoclast-targeted therapies, you just increase the risk for side effects. I like to stick with the same drug and I'm just going to switch the dosing schedule as appropriate.
When I initiate therapy, I generally continue. One little caveat to be aware of is, Zoledronic acid is a very long biologic half-life, because it's basically taken up in the bone. And in contrast, Denosumab has a reversible effect, and so, there is this effect of rebound when you discontinue treatment. We know that from the osteoporosis literature best. And so, if you're treating patients, particularly if they have a lot of bone disease burden, it's something to keep in mind, because you don't want to really abruptly stop their treatment, unless you cover them with a bisphosphonate. That's something I sometimes struggle with when patients with very advanced disease, if they're on Denosumab at the SRE dose, where if they're now going on to hospice or transferring care elsewhere, not to keep them covered. If they're going to hospice, it's probably not an issue, particularly if their life expectancy is short. But I don't like to abruptly discontinue treatment for someone who's going to live a year or more longer, because you could actually have a rebound effect with increase in osteoclast activation and potentially greater risk for skeletal complications.
Neeraj Agarwal: With Denosumab?
Matthew Smith: Yes, with Denosumab specifically.
Neeraj Agarwal: Okay. This is great. Very good information so far. Lastly, what are the doses we should be using these agents in metastatic hormone-sensitive or castration-sensitive setting versus castration-resistant prostate cancer setting. We discussed about this, but just for clarity, for clear messaging for our colleagues out there all over the world.
Matthew Smith: Let me just object with the terminology for a moment. Again, it's osteoporosis versus SRE prevention. The reason is, you can have a patient who, they could have mCRPC and they're going to get osteoporosis prevention because they have nodes. There's no SRE risk. It's all osteoporotic risk. They started when they're mCSPC and now they progress. It's really osteoporosis drug dosing schedule, and then SRE. Everybody's at risk for osteoporosis and fractures, whether you have bone metastases or not, whether you're on ADT or not, whether you're castrate-sensitive or not. Bone disease-related skeletal complications, or SREs, are really primarily what we're talking about are progressive mCRPC. That's a special category. Everything else is osteoporosis. So then you got to decide, do they need that or not?
If you have mCRPC and bone metastases, maybe you don't need SRE prevention, but you still may need osteoporotic prevention. Obviously, the severity of the SREs is much greater than an osteoporotic fracture for the most part, but that's the way I think about it. I like to stick with the same drug. For osteoporosis prevention, it's Zoledronic acid, four or five milligrams IV once a year. It probably has a much longer effect than for a year, but once a year, it's the standard schedule. We studied it at four milligrams in a phase-two trial. In the larger osteoporosis prevention setting in women, it was studied as re-classed at five milligrams. So four or five, either one is fine with me once a year. Denosumab is 60 milligrams twice a year for osteoporosis prevention. It is 12 times that annual exposure for SRE prevention, 120 milligrams every four weeks. Vastly different intensity of therapy, and so this is why you really don't want to confuse your intentions.
Neeraj Agarwal: That's such great insights. Thank you, Matthew, for sharing your insights on how do we use bone-modifying agents or bone-protecting agents in metastatic castration-sensitive versus castration-resistant prostate cancer. And then another caveat, they have to have bone metastasis in metastatic castration-sensitive prostate cancer for these agents to be used for SRE prevention. Otherwise, all other patients should be getting the osteoporosis, osteopenia dosing, if you will. Is that correct?
Matthew Smith: That's fair. Yep. I agree.
Neeraj Agarwal: Well, any last words?
Matthew Smith: No, this was great. Really appreciate you taking the time. I enjoyed it. Thank you.
Neeraj Agarwal: Thank you.