Neeraj Agarwal: My name is Dr. Neeraj Agarwal. I'm a professor of medicine and a GU medical oncologist at the University of Utah Huntsman Cancer Institute. I'm honored to have two guests today on the UroToday, at the time of 2025, United States Prostate Cancer Consensus Conference, USPCC. Dr. Evan Yu, Professor of Medicine and Oncology at the Fred Hutch and University of Washington, and Dr. Tian Zhang, Associate Professor of Medicine and Oncology at the University of Texas Southwestern. You do a lot of other things at your cancer centers and I'm not going to elaborate all of them, but thank you for being here today.

Evan Yu: Thanks for having us.

Tian Zhang: Great to be here.

Neeraj Agarwal: One of the very interesting topics we discussed at the USPCC was the bone modifying agents. We know from the PEACE-3 trial of ENZA plus radium how important these agents are. Let's start with Evan first. For clarity, what types of dosing we are looking at as far as bone modifying agents are used in patients with metastatic prostate cancer?

Evan Yu: Right. It's a good question because there's really two different ways to approach this. The question is, are you trying to prevent skeletal-related events, which is something that occurs at the sites of bone metastases, like fractures, need for radiation, need for surgery, et cetera, et cetera. That generally is used at a higher dosing of either zoledronic acid or Denosumab and more frequent usage and higher dosing levels, or is your goal to prevent osteoporotic fractures, whereas it's usually it's a lower dosing dose less frequently.

For instance, zoledronic acid for skeletal events, people used to give it four milligrams every three or four weeks. I think more often now, people give it quarterly and there's data to show that that's not inferior. For osteoporotic dosing you can give that annually, even just once a year, either four or five milligram dosing. Similarly, for Denosumab RANKL inhibitor, it is 120 milligrams every four weeks to prevent skeletal-related events, but for the osteoporosis osteopenia dosing, it's dosed at 60 milligrams every six months. Big difference and so we've got to keep it clear in your head what your goal is. Are you trying to prevent fractures from bone metastases or events from the bone metastases or is it more a osteoporosis event, which we know that androgen deprivation therapy induces osteoporosis. They're both things to constantly think about.

Neeraj Agarwal: Thank you very much for explaining it so nicely. Tian, I know there is no ambiguity about using bone modifying agents to prevent osteopenia or osteoporosis in our patients with metastatic prostate cancer who are on long-term androgen deprivation therapy living with very low testosterone and they're very susceptible to have osteopenia and osteoporosis. What is your practice in your clinic from this perspective first?

Tian Zhang: Sure. I think it's really important that as we have patients on long-term androgen suppression, that we're monitoring their bone health. And so my practice is that we obtain bone density scans, we call them DEXA scans, and we watch them, usually yearly. If they have osteopenia, osteoporosis, we're often phasing in that osteoporotic bone modifying agent dose, usually of every six-month dose or a yearly dose at this point of either the RANK ligand inhibitor denosumab or the bisphosphonate, so zoledronic acid. I think we have seen in carefully done studies that people do keep up their bone health in terms of their lumbar and femoral bone density on those bone density scans. These agents are effective in helping preserve bone density in those situations.

Neeraj Agarwal: In addition to calcium and vitamin D supplementation.

Tian Zhang: Absolutely, yes.

Neeraj Agarwal: Which is great. Let's keep it very straight. Everyone should have DEXA scan. Everyone should be getting these medicines to prevent osteoporosis or worsening of osteoporosis if they have osteopenia or if they have osteoporosis, yes, for sure, to prevent osteoporotic fractures. Now, coming to the higher doses of these bone modifying agents, which we use in castration-resistant prostate cancer to prevent skeletal-related events at the site of bone metastasis. What is your practice, Evan, in patients with metastatic castration-resistant prostate cancer?

Evan Yu: Yeah, I do use them for metastatic castration-resistant prostate cancer. I think the challenge is that the studies that were done don't definitively tell us how long we should be going. Most studies give two years of the therapy and patients with metastatic castration-resistant prostate cancer, it's clear this can prevent skeletal-related events, but what's the optimal timing to give it? When should you introduce it? How long should you give it for?

I'll tell you that in my practice it does require some thought because there is some data with some of the agents like Abiraterone or Enzalutamide, those agents that work very well, they can prevent skeletal-related events as well. It is true that if your cancer is well controlled, you are likely to have a major event at the site of bone metastasis. The time when I introduce these agents tend to be maybe at a point when a patient is progressing and I'm thinking about next line of therapy to introduce it there because I think when the patient is progressing, they're potentially at greater risk. I don't have wonderful data to support that. It's more anecdotal, but that's my practice.

Neeraj Agarwal: When do you typically start, Tian, the Zometa or XGEVA Denosumab or Zoledronic acid in patients with metastatic castrate-resistant prostate cancer who have bone metastasis?

Tian Zhang: That's a great question. We have many patients who go from the metastatic hormone sensitive space to castration resistance. As they're becoming castration-resistant and having progressive bone metastasis, I will start the process of getting insurance clearance and adding it to their plans. The easy option for practical purposes is to do an injection around the same time as their next Lupron injection because we're going to keep these patients on hormone suppression. From a logistics point of view, it's one appointment and they get both injections. That's when I generally add it in. If patients are coming from a more metachronous standpoint of developing metastatic disease after they've already had localized disease, biochemical recurrence, I think that's the harder part of defining when is the right moment to add.

Neeraj Agarwal: Then, you are starting them on ARPI, for example.

Tian Zhang: Yes.

Neeraj Agarwal: Maybe after ARPI.

Tian Zhang: Yes. We saw from PEACE-3, right, adding the bone strengthening agent for those patients made a difference in terms of their skeletal-related events. I think first line ARPI plus minus radium.

Neeraj Agarwal: Do you obtain dental clearance for everyone?

Tian Zhang: If patients have poor dental hygiene, I will send them for dental clearance. We talked a little bit about the 2% or so of osteonecrosis of the jaw. In patients who have difficulty with their teeth, I will. In people who have ongoing dental care, those are the patients I'm less worried about. Yeah. I certainly think adding their calcium, vitamin D, to your point, is the easy first thing and then add their bone modifying agent when we can.

Neeraj Agarwal: Yeah, dental clearance can be hard to schedule sometimes, many of them who do not have a dentist on board. Coming back to the dosing or timing, once you start them, you continue them for two years and then take a break or you continue them indefinitely?

Evan Yu: Yeah, it depends. I feel much more comfortable with stopping after two years of Zoledronic acid because that incorporates into the bone and it hangs out for who knows how long, for forever potentially. I feel a lot more comfortable with stopping after two years there. With Denosumab, I've done various things. I'm not 100% sure, but I tend to be willing to go longer as long as the patient's not having any major issues with hypocalcemia, they're taking their calcium vitamin D or they're not having any issues with osteonecrosis of the jaw.

I do get dental clearance for all my patients. It does take a little while longer, but it's rare where I feel like there's a massive sense of urgency that I have to start right away. If it takes three months to get dental clearance or even six months to get dental clearance, that's all right because like I said, the natural history of metastatic castration-resistant prostate cancer is long now, which is great. Patients are living a long time and we don't know exactly how long we should be giving these agents. If it takes three months to six months to get dental clearance, I'm okay with that.

Neeraj Agarwal: Thank you. Just to wrap up on the use of bone modifying agents in metastatic castration-resistant prostate cancer, we use them for preventing skeletal-related event at higher dose for zoledronic acid every three months, denosumab every four weeks, maybe space out a bit to meet patient's convenience, vitamin D, calcium. Getting a dental clearance to prevent osteonecrosis, as you pointed out, can be a big deal for many patients. There is no doubt everybody should be on it. The reality is, 50% of our patients with metastatic CRPC are not receiving bone modifying agents based on the Flatiron data presented at the ASCO-GU.

Definitely, we can work harder as a group to disseminate the information and data regarding the acuteness of the problem and how important these agents are.
Now, coming to the metastatic hormone sensitive prostate cancer. The space has really expanded from 15 months 10 years ago to about 40 years. Many patients are in metastatic hormone sensitive prostate cancer setting for years. There's no clear guideline or clear evidence in the contemporary patients who are getting ADT plus ARPI plus minus docetaxel. Now, more drugs will be coming in, lutetium, PARP inhibitors, maybe other targeting drugs, and these patients are going to be living even longer. What is your practice, Tian, regarding bone modifying agent use in metastatic hormone-sensitive prostate cancer patients who do not have osteopenia or osteoporosis? You're talking about using these agents in the skeletal from the perspective of preventing skeletal-related events?

Tian Zhang: Sure. The registrational trials in metastatic hormone-sensitive prostate cancer really didn't see a lot of events of true skeletal-related events on the treatments that we have available in these settings. The only one that studied it very carefully was STAMPEDE and STAMPEDE had a whole cohort of hormone therapy-treated patients who also received zoledronic acid and then also another cohort that received androgen deprivation with docetaxel as well as zoledronic acid.

What STAMPEDE showed us was that there was no improvement in progression-free survival or overall survival, but we recently saw an update secondary analysis about fracture-related hospitalizations based on the STAMPEDE cohorts and there were some improvements in the patients who were treated with zoledronic acid in decreasing the percentage of patients who were hospitalized for fractures. However, there was also the balance of osteonecrosis and other side effects from these treatments. I think in my practice, I certainly add calcium and vitamin D for these folks. We'll still be doing the osteoporotic type of agents and dosing schedules. It is not my current practice to add the intensity and the frequency of these agents at the frequent doses that were studied in STAMPEDE.

Neeraj Agarwal: Thank you, Tian. That's a very nice summary of what we should be doing. Do you think, Evan, STAMPEDE trial changed our practice of using bone-modifying agents in higher dose to prevent skeletal-related events, not the osteopenia, osteoporotic doses, in metastatic hormone-sensitive prostate cancer?

Evan Yu: Well, that's a really excellent question, and I can tell you that prior to that STAMPEDE secondary analysis, that was claims-data-based, I'll just say, my practice was only to do the lower doses for osteopenia, osteoporosis, for osteoporotic fracture prevention. After seeing the STAMPEDE data set where they did use the more frequent dosing of zoledronic acid for two years, it's making me think about it. That paper was just published maybe what, two months ago and maybe I think it's still online only, maybe even less than two months ago, but that being said and done, it's making me think about, are there select patients I should really be thinking about using this earlier? It hasn't been my typical practice. There was the CALGB trial that was an older study that accrued about 95% of the way and did not show a benefit to including zoledronic acid to prevent skeletal-related events.

This looks at even a more impactful thing, which is fracture-related hospitalizations. I do want to point out that the data was really all probably English data from the UK because that's where STAMPEDE was mostly done and they only had the claims' data from that subset of patients. There may be differences in patient populations. What I don't know is if for metastatic castration-resistant prostate cancer, perhaps they don't use as much zoledronic acid or denosumab, and that might've affected the risk of fracture-related hospitalizations in the control arm leading to them having more of those fracture-related hospitalizations and that perhaps in the United States, well, you're saying 50% still don't get it-

Neeraj Agarwal: Even for CRPC.

Evan Yu: -in the United States, even for CRPC, but if you do get it for CRPC, is then that potential benefit of getting zoledronic acid upfront for hormone-sensitive disease, is that completely abrogated? I don't know.

Neeraj Agarwal: Answer is, not yet, but definitely intriguing data and we'll love to have more evidence to support use of bone-modifying agents in metastatic hormone-sensitive prostate cancer in the higher dose to prevent skeletal-related events. For now, we should try, I think, our best to get bone-modifying agents for all patients with metastatic castration-resistant prostate cancer. You think that would be a adequate appropriate summary?

Evan Yu: Yes.

Tian Zhang: That's our discussion.

Evan Yu: Yes, I think so.

Neeraj Agarwal: Well, thank you very much for sharing your expertise and highlighting such a important topic of bone-modifying agents in patients with metastatic prostate cancer.

Tian Zhang: Thanks, Neeraj.

Evan Yu: Thanks, Neeraj.