Zachary Klaassen: Hi. My name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. We're at ASCO 2025 in Chicago. I'm delighted to be joined on UroToday by Dr Grace Lu-Yao, who is a professor at the Sidney Kimmel Cancer Institute in Philadelphia, Pennsylvania. Grace, thanks for joining us on today.

Grace Lu-Yao: Well, thank you for having me here today.

Zachary Klaassen: You have a very important topic, looking at the risk of fractures and ARPIs and certainly with doublet and triplet therapy in the metastatic hormone-sensitive setting and then in the mCRPC setting. This is always an important topic because we want to be safe with our patients. So maybe just talk before we get into your study a little bit about the risk of fracture for these advanced prostate cancer patients.

Grace Lu-Yao: Sure. So for patients with metastatic prostate cancer, their risk of fracture depends on their age and the duration of use ADT. So for people in the '70s I would say there is probably somewhere between 13 to 18% within three years of diagnosis or the use of ARPI.

Zachary Klaassen: And tell us a little bit about your study design and the importance with these population-level studies. Just the database and how you guys selected it for your study.

Grace Lu-Yao: Sure. Of course. So our study is a population-based cohort study. That is, we follow the patient, reside in a certain geographic area. And the two databases we use are the SEER cancer registry. SEER stands for Surveillance, Epidemiology, and End Results Program. That's a cancer registry sponsored by NCI and CDC. They are the gold standard. So they have ascertainment rate of 98% to track cancer incidence and mortality. So they are really providing the most accurate data in terms of cancer.

And we also use the data from Medicare. As you know, most individuals living in the United States, are covered by Medicare if they are aged over 65 and over. And the beauty of Medicare is we can track patients over time and throughout different areas.

So if someone moved from Florida to California and to Idaho, we can still track them over time. And we track them actually from the time they started using the ARPI through the end of study or the first event of the fracture. So the longest time, we actually have seven years of follow-up.

Zachary Klaassen: Excellent. And so you identified patients that had fractures, prostate cancer, and then the ARPI. Just tell us a little bit about the cohort and how you got the cohort.

Grace Lu-Yao: So this cohort we actually use the use of ARPI as index day. So that's the starting point, the index day. And we go back to look at whether they have a risk of prior fracture or comorbidity or osteoporosis, and then follow them over time to see what's their risk of fracture. And we use the time to the first fracture as a primary endpoint.

Zachary Klaassen: Tell us about some of the high-level results from your study.

Grace Lu-Yao: Sure. So this study, we found that the prior fracture really is the most potent predictor of the fracture risk among all the factors we have examined. So for patients without the prior fracture, their risk of having fracture after ARPI reached to 25% if they don't have prior fracture. But for those with prior fracture, they actually exceed 50%.

And we want to whether use of bone health agent helps them at all. So we examine whether they use. And in our study there are about 37% of patients have bone health agent use right before or around the time of ARPI. And for those patients, we do see the risk reduction.

However, for those with prior fracture, the reduction is not sufficient enough to be really comfortable using that agent. So for example, for people with prior fracture, their risk exceeds 50% within three years with the use of bone health agent is still above 45%.

Zachary Klaassen: So good take-home point, risk of fracture really is a predictor of a future fracture. And we should be using BPAs for all those patients. But even in those patients who have a history of it, it's still a little bit on the scary side that they could have another fracture.

Grace Lu-Yao: Exactly. And I think that would be important to really assess the bone health of any prostate cancer patient, even before they get to the point of using ARPI.

Zachary Klaassen: It's always a good opportunity to talk about BPAs, because I think we've had Fred Saad talk about it, he's been talking about it for 20 years about the importance of bone protective agents. But we know from the ERA-223 trial, the PEACE-3 trial, which was just published. Really this should be standard of care for these patients. Maybe just talk about that that is a take-home point for this study.

Grace Lu-Yao: Right. For the PEACE study and our study, we both show that the use of bone health agent early on or around the time of ARPI indeed reduces the risk of fracture. But I think there are other things maybe we want to consider as well is to really start thinking about maybe exercise or diet can also help the patient to maintain bone health because I think what we learn is by the time a patient has very poor bone quality. Having that agent may not be as helpful as we wish.

Zachary Klaassen: Yeah. Absolutely. Congratulations on a great study. Any take-home points for our listeners today.

Grace Lu-Yao: Sure. So I think there are two take home. One is the risk of fracture is very high after ARPI, so we have to start thinking about bone health even before we get to that point. And the second is the real-world data is very important as we actually demonstrate that our risk is a lot higher than what was observed in a randomized trial.

And I think the reason is randomized trial is more selective about patient population. So usually they are younger, they're healthier, they have better performance status. So if we really want to make sure the results can be applied to the general population, including those with comorbidity or poor performance, it will be important to really use the real-world data to do a good job of monitoring the event.

Zachary Klaassen: Great take-home points. Grace, awesome discussion on UroToday. Thanks for joining us.

Grace Lu-Yao: Oh, you're welcome. It's my pleasure. Thank you.