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Alicia Morgans: Hi. I'm so excited to be here today with Dr. Arnoud Templeton, who is joining me from Basel, Switzerland, where he is faculty of medicine at the University of Basel and St. Clara Hospital, Basel. Thank you so much for being here with me today to talk about your presentation at GU ASCO 2025 on the REDUSE trial, or SAC9612. Thank you.

Arnoud Templeton: Yes, hi, Alicia. Great to see you. Thanks a lot for this invitation.

Alicia Morgans: Well, great to see you too, and thank you. Can you tell us a little bit about this study, what this update is trying to share with us?

Arnoud Templeton: Yes. So the REDUSE study is actually comparing two doses of denosumab in men with castration-resistant prostate cancer and women with metastatic breast cancer. And the concept we compare is eventually denosumab every four weeks, as is registered and was studied in the pivotal studies, compared to administration every 12 weeks. And this is designed as a non-inferiority study to show that the rate of symptomatic skeletal events is just as good if you give denosumab less frequently.

And the study has fully recruited 12,380 men and women. And we're still waiting for the final readout. But what we have now and what we presented this year at ASCO GU is the rate of ONJ (osteonecrosis of the jaw) in this study, which is a relevant, potentially quite nasty adverse event from these bone agents.

Alicia Morgans: Well, great. Thank you for that. And can you just share, I think one of the things that's so important about this study is that it is a large phase III. It's a non-inferiority study. And so it has to be kind of larger when we're trying to make sure that something is not substantially worse than something else. But importantly, this study is run by, funded through your team and through all the efforts, but not funded through a pharmaceutical company. And I think that's important to acknowledge all that your team went through and how you sourced that funding.

Arnoud Templeton: So this academic study was entirely funded by non-pharmaceutical entities, which is an organization of Swiss health insurance companies who are not really interested in research, but they do understand that there might be some cost savings in this concept. So part of what they saved through the study they sort of invested in conducting the study. And also from the Swiss government, we received some funding for this. Yes. But it's a purely academic study.

Alicia Morgans: Yeah, very, very interesting and maybe an opportunity for us as investigators to think about ways to fund our trials from different areas, so very, very, very interesting. So let's get to this study. Tell us, what was that randomization pattern? What was the pattern of treatment? How long did patients get their treatment with their bone health agents? And what were your ultimate outcomes?

Arnoud Templeton: Yes. So for the part where men with metastatic castration-resistant prostate cancer, which is about 40% of the study population, had metastatic castration-resistant prostate cancer. And after an induction phase, where everyone got denosumab 120 milligrams every four weeks for three months, then there was a randomization 1 to 1, where half continued every four weeks and the other half was treated every 12 weeks.

And the primary outcome, as mentioned before, was symptomatic skeletal events. And primary key secondary endpoints were toxicity, with focus on ONJ and tooth abscess, tooth infections, and hypercalcemia.

Alicia Morgans: Wonderful. So you really reported on those oral-type outcomes, ONJ, the tooth abscesses. And what did you find between the two groups?

Arnoud Templeton: Yes. So as we might expect, those events were less frequent in those who got less frequent denosumab. And especially after two years, the curves sort of started to separate. And there was a continuation of seeing more and more difference with more time elapsed.

So the median follow up here was 2.4 years. And this was true for all-grade ONJ and also for high-grade ONJ, for tooth infections, and for the combination of both. Yes. And this was true for the absolute rates, and also for the time to occurrence of the first ONJ or tooth infection event. Although, at this point, this has not reached statistical significance.

Alicia Morgans: OK. Well, I think that this is so important and seems actually immediately clinically actionable. Of course, the efficacy data in terms of reducing skeletal related events is still maturing. So we'll get that in a little bit of time. But do you feel like this information actually affects what you do in clinic? Does this affect your dosing of these agents in patients with mCRPC at this point?

Arnoud Templeton: So actually, when we saw the registration study published by Karim Fizazi a couple of years ago, the rate of ONJ reported in that study was 2.3% for those who got denosumab. And we see that in daily practice, these rates appear to be quite a bit higher, where we're now up to 8.7% really in our study. And this sort of triggers me to lower the threshold of increasing the interval outside of this clinical study.

So what I do in clinical practice is pretty early on, after a year, or in some patients even earlier, increase the intervals from four to six to eight and then eventually to 12 weeks. And so far, I think this has worked quite well. And also, the rate of what I would call symptomatic skeletal events is not—so that I could say that this is a problem. But obviously, this is why we do the study. And we're waiting for the primary outcome to mature. And we hope to have data ready for ASCO '26.

Alicia Morgans: Well, that is definitely exciting. And it also makes sense. I think in clinical practice that's a very practical, pragmatic type of an approach and I think one that probably is mirrored in many practices around the world. But I do wonder, one other question, and we sort of alluded to this as we were leading into this interview.

Sometimes I worry that if we are dosing someone with denosumab and we let that interval go too long—so longer than, say, nine months or so if we're thinking about a six-month dosing or even 12 months. And I'm not really sure what that precise interval is because I don't think that that's necessarily been defined. But if we let it go too long, there is concern, there's literature in the general medical population from our endocrinology colleagues that we may see a decline in our bone mineral density, actually rapid reabsorption of bone and loss of the bone that was built in that earlier dosing before you stop.

So I wonder, does this affect the dosing, the duration of dosing in this trial? And how do you think about that in practice?

Arnoud Templeton: Well, to the latter part of your question, in this study, we have specified that this is sort of open end. So you would stop if there's an ONJ event, obviously, but otherwise it's without stopping rules. What I do in clinical practice when I feel that we should hold this treatment, and I'm also a little bit concerned about exactly what you mentioned, I tend to give one dose of zoledronic acid, which is being built into the bone, give that to the patient.

And then I think it's less of a concern really. Yes. But you obviously would not do that in patients where you stop treatment, for example, because of ONJ.

Alicia Morgans: Agreed. And actually, that's what our endocrinology colleagues, at least in my center, have recommended, that you can do this capping dose with zoledronic acid but would never do that in a patient with ONJ. But for others, it may be something to consider. Well, this is very, very interesting. I wonder if you have a take home message for viewers who are trying to learn all that they can from this presentation at GU ASCO?

Arnoud Templeton: OK, I think point one is make sure the patient takes vitamin D and calcium. I think that's critical. Point two, send them to the dentist before you start treatment. That's what I do in all patients. And what I also do, I look into their mouths every time before he gets denosumab. I think it's worth it and ask the patients whether he's had any tooth extraction in the meantime. And be aware of these issues. And then I think it's a good thing to do, knowing that it probably doesn't affect the course of the disease very much. But I think bone health is a very important issue.

Alicia Morgans: Absolutely. And we've certainly seen this in some of our prospective trials, that if we don't pay attention to bone health, men do develop fragility fractures and other skeletal-related events that happen in these settings with metastatic disease in bone. And this is certainly something that we can reduce if we use these types of approaches. So thank you so much for sharing this really, really helpful, clinically pertinent information. It's always a pleasure to talk about bone health. And I so appreciate your time and expertise today.

Arnoud Templeton: Thank you so much, Alicia. I really appreciate it.