Evan Yu: Good day. We're here at UroToday at ASCO 2025 in Chicago. And I have the pleasure today of chatting with Dr. Lisa Horvath, a good friend that we've known each other for many years. She's a professor at the Chris O'Brien Lifehouse University in Sydney and also a professor at the University of Sydney in Australia. So Dr. Horvath, Lisa, thanks so much for joining us today.

I was reading through the abstracts, and I saw that you've done some great work here on some prognostic factors in metastatic hormone-sensitive prostate cancer from the ENZAMET study. And in particular, I have an interest in the insulin-like growth factor receptor pathway. And it looks like some of those markers have prognostic implications. So mind sharing with us a little bit of your thoughts on the biology, potential crosstalk with the androgen receptor pathway? And then I'll ask you what you actually did and looked at.

Lisa Horvath: So you've asked me about the bit I know, probably least biologically about just to make it difficult. So the study that we did was taking over 800 baseline samples, from the patients on the ENZAMET study. So there were more than 400 in the ENZAMET arm, a little over 400 in the ADT, plus nonsteroidal antiandrogen arm. So we had really good numbers.

What you are referring to is the IGF-1 and IGF binding protein-1 analysis that we did that was based pretty much on the charted work that Chris Sweeney and his group had done, where they'd shown that an increase in the ratio between IGF-1 and IGFBP-1 actually predicted for a better prognosis, when you were looking at ADT plus or minus docetaxel. So we really did this as a validation.

And we found exactly the same thing, that the increased ratio predicted for a better prognosis, although IGF-1 itself predicted for a worse prognosis. So it may be related to what's bound and what's unbound and what's biologically getting in. What is happening with this at a biological level, I confess, is not massively my area, although the IGF-1 growth pathway is clearly a growth pathway for prostate cancer and a number of other cancers. So I guess the real question is, will we be able to look more closely at the biology of HSPC to see whether this downstream could end up being an area to reinvigorate the idea of modulating the IGF-1 growth pathway?

Evan Yu: Right, right. Well, to my chagrin, some early attempts to inhibit that pathway using some monoclonal antibodies that target IGF-1R haven't really worked out, but it's a different time. Maybe some new biologic understandings, newer drugs. There's always hope and promise there, so—

Lisa Horvath: I think I would also say because I was involved in some of those more in colorectal cancer than in prostate cancer, we also didn't do any sort of biomarker prediction. We didn't do any sort of predictive work around it. So I'm a biomarker researcher. I'm very passionate about the fact that we can lose the ability to show efficacy in small groups by just treating everybody. So maybe this is a way of starting to think more selectively around who we treat.

Segueing across, of course, we also did a panel of cytokines, and again in charted. Chris Sweeney's group had shown that increased IL-8 was a poor prognostic factor, and we validated that. We also did a panel of exploratory cytokines, including IL-6, YKL-40, MIC-1, and found that elevations of pro-inflammatory cytokines really did predict for a poor prognosis. And that's also extremely interesting with the hypothesis that if your tumor is more inflammatory, it may not respond as well to the doublet treatments.

Furthermore, we've shown associations in the past in castration-resistant disease between the pro-inflammatory type and elevations of sphingolipids in the circulation, which is an area that we have particular interest in. Elevations of sphingolipids and a liquid biopsy biomarker called PCPro, which we've developed, is a poor prognostic factor and predictive of RP resistance in CRPC. And we've just published in Annals of Oncology the same results in metastatic HSPC in the ENZAMET cohort.

Evan Yu: Interesting.

Lisa Horvath: And what we see is a very strong association in those patients that are PCPro positive with elevated sphingolipids in the circulation are also correlate with high pro-inflammatory cytokines. And I think this is a new area where we might start to look at precision metabolic therapy. We can predict the patients who are going to die in two years. And they have these elevated sphingolipids and pro-inflammatory cytokines up.

Evan Yu: Do you believe that there's a cause and effect relationship between those elevated cytokines and pro-inflammatory environment with the sphingolipids? Or do you think—

Lisa Horvath: Yes, there is a established biological relationship between the elevated sphingolipids and the elevated cytokines. In fact, if you look in mouse models, if you need to use immunocompetent mouse models, if you get elevated sphingolipids, you simply won't see any effect of those elevated sphingolipids if you don't have an intact immune system. And there are receptors on immune cells that are switched on by ceramides, which are the major class of the sphingolipids.

So this is an area of great research in my lab in terms of, we've now got a clear compliant biomarker. How can we start looking at this as a way to target these very poor prognosis patients and take these signatures, not just as epiphenomenon but as actionable metabolic signatures that we could target with drugs. A lot of these drugs are actually sitting in endocrinology sections of the pharmaceutical companies, and we're busily pulling them out and looking at them in the lab and bringing them to clinical trials.

Evan Yu: Interesting. So do you mind mentioning some of those drugs that you're looking at?

Lisa Horvath: Yes, so one of the drugs we're looking at is opaganib, which is a sphingosine kinase-2 inhibitor. And in fact, with ANZUP, we're opening a clinical trial in the next month. And that clinical trial is called DARO-LIPID. And patients with metastatic CRPC will be screened for presence of the PCPro biomarker in their plasma samples. And if they're PCPro positive, for first-line CRPC, they'll get darolutamide plus or minus opaganib placebo controlled. And that will be really the first study of a precision metabolic therapy. And I should say, opaganib is owned by RedHill Biopharma, and we're doing this with RedHill and Bayer and ANZUP, which is the Australian prostate cancer collaborative group.

Evan Yu: That's very exciting. I mean, I like prognostic markers as much as anyone else. But what's better than prognostic are predictive biomarkers. And what's even better than that is when the biologic ties so tight that actually you have a therapy that targets the biology and that actually has antineoplastic effects. So it sounds like you're working on that and going in that direction there. So trying to take it to the next level.

Lisa Horvath: I agree with you. Nobody needs to tell their patient, hey, you've got a biomarker. It says you're going to do really badly. How about we do something about it? And I guess what we're really trying to focus on is how to make standard of care drugs work better if we can modulate the right metabolic environment for them.

Evan Yu: Are there imaging opportunities too with the sphingolipids? I mean, we used to think about imaging lipid metabolism in prostate cancer. We totally got involved in PSMA PET imaging. But if you're thinking about a therapeutic, could something like acetate or choline or something like that, be a better potential treatment response biomarker? I'm just making stuff up here, but what do you think?

Lisa Horvath: Look, this is a discussion that I've been having with my PET colleagues, especially around choline, which, of course, as you say, is very much involved in lipid metabolism. We haven't really explored it very well yet. It's been sitting in the edges of my mind. But I think it could be quite interesting.

The other factor, though, is we've got this very reliable biomarker. And what we're also hoping is that it may down the track be a therapeutic response marker. If you flip back to a more normal metabolism, we know that there are some patients that will do that spontaneously and they subsequently do much better. If we have drugs that can flip it, we may be able to tell the patients, we've flipped your signature, and now we think that's going to show that your prognosis improves over time.

Evan Yu: Excellent. Wonderful work, Dr. Horvath. Really, really appreciate you taking the time today to chat with me and with UroToday. So have a wonderful ASCO.

Lisa Horvath: You, too. Thank you so much for the opportunity.