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Oliver Sartor: Hi, I'm Dr. Oliver Sartor. I'm here with UroToday. Special guest, Dan Childs, who's at Mayo Clinic, as am I. And Dan is an assistant professor, and he has really been doing a great job in terms of looking at the PSMA-617 lutetium-treated patients over time, compiling a great database, using both imaging as well as some genomics. So welcome, Dan.

Dan Childs: Oliver, thank you for that introduction. I was very happy to be invited to present our data. Again, my name is Dan Childs. I'm a GU medical oncologist at Mayo Clinic in Rochester, Minnesota. Here I manage our radiopharmaceuticals registry, and I also study supportive care issues that are important for men with advanced prostate cancer.

So today we're going to be talking about outcomes for patients with metastatic castration-resistant prostate cancer and liver metastases who receive lutetium. Now the clinicians listening to this call will recognize that liver metastases pose a significant challenge for our patients. Commonly, liver metastases emerge later in the disease course, when patients have been exposed to multiple lines of treatment. And unfortunately, most of our systemic therapies have limited activity.

Chemotherapies might induce a response 20% or 30% of the time, but unfortunately, these responses seem to be quite transient. So when 177 lutetium PSMA-617 was approved, there was hope that this modality would have significant activity in this setting, which is a real unmet need. In VISION, we saw that lutetium extended median overall survival by about four months in a cohort of men who were highly treatment-refractory.

However, now that we're getting more experience, we recognize that certain subgroups of patients may benefit more or less from this treatment modality. So the aim of our study was to use real-world clinical data to provide more granular estimates of lutetium's efficacy in men with CRPC and liver metastases.

This is a registry study that included patients receiving lutetium at Mayo Clinic and started treatment within the first year after regulatory approval. We excluded patients who had no research authorization, which resulted in approximately 23 patients with PSMA-positive liver metastases and 213 patients without PSMA-positive liver metastases.

On this slide, I present selected baseline characteristics for both cohorts. You'll note that the median age at start of treatment was 70 years. Approximately 40% of patients presented with de novo or synchronous metastatic disease, while the rest had recurrent disease after prior local therapies. On average, patients had received four prior lines of treatment before starting lutetium. Now, the two cohorts were relatively well-balanced, with the exception that those with liver metastases had a numerically higher PSA when they were starting lutetium.

Our non-liver metastases cohort was comprised primarily of patients with bone metastases, though 15% had non-liver visceral metastatic disease. Now I'll draw your attention to the right side of the screen, where we present baseline imaging characteristics for just the subgroup of patients with liver metastases. Most had one to three sites of metastatic disease within the liver, while the rest had more than four lesions on their baseline pretreatment PSMA PET scan.

We also present the volume of liver metastatic disease along with SUV mean and SUV max in the liver. We'll move on to our results. Median follow-up at the time of this analysis was about 10 months. Those with liver metastases completed fewer cycles of lutetium as compared to the patients with no liver metastases. On average, those who had liver metastases finished three cycles of treatment before discontinuation, and those without liver metastases completed five cycles of treatment.

On the right side of your screen are some waterfall plots for PSA. You'll note that those with liver metastases are on the top of the screen. Those without liver metastases are on the bottom of the screen. Patients with liver metastases were less likely to achieve a PSA 30 response and less likely to achieve a PSA 50 response.

Moving on to survival. Median overall survival for the cohort of patients with liver metastases was 8.3 months, as compared to not reached for patients without liver metastases. And then we performed a multivariate Cox regression model, including other prognostic factors, and found that the presence of liver metastases is independently associated with poorer overall survival.

Now we've had the opportunity to present this data at ASCO GU, and it's now been published in the Journal of Nuclear Medicine. In the process, we got wonderful feedback from GU medical oncologists around the country who ask us about a couple of other analyses. One question we were commonly posed was, is there a difference in overall survival when patients are sorted by the baseline number of liver metastases? And the answer to that is no, not within our data set.

We also started looking at the imaging variables in greater depth, and found a numerically longer survival for patients who had higher liver SUV mean at 11 months as compared to seven months. And then finally, we explored differences in the ctDNA profiles for our two cohorts of patients, those with and without liver metastases, and found that alterations within ATM, PTEN, and ROS1 were enriched within the liver metastasis patients.

However, this analysis is really limited by a small sample size. So in summary, within our registry, we've assembled a cohort of patients with liver metastases that are nearly as large as the VISION trial. Though we observed responses, our data does indicate that there is a higher probability of treatment failure and an overall guarded prognosis for patients with liver metastases who are receiving lutetium.

Now, there are a number of multivariate prognostic models from Gafita and from the VISION investigators that are really useful clinical tools. But to the busy clinician, I think it's notable that the single factor, the presence of liver metastases, is incredibly prognostic. It is very useful in helping you refine your prognostic estimates as a patient is starting treatment.

There are many things that we need to study. We need to study what are these factors that lead to the more limited activity of lutetium in the setting of liver metastases. And hopefully at some point down the road, we'll be able to overcome the resistance to treatment. And so with that, I have a couple of thank-yous. In particular, I want to acknowledge Dr. Miguel Munoz, who helps me manage our registry here at Mayo Clinic and has put in hundreds of hours into curating this data. I also want to thank Matt Thorpe, who performed the large task of segmenting all these images and getting that data back to us. So thanks to you both. And with that, I'll pause and turn it over to you, Oliver.

Oliver Sartor: Yeah, thank you, Dan. And I think this is an important study because it actually looks at the prognosis of these liver metastatic patients. And admittedly, they've gone through a lot of therapy. But regardless, when you start looking at overall survival, and you're talking just about eight months, that's really very sobering.

So first of all, let me ask you, a number of these patients, actually more than 50%, had only one to three liver metastases. Should we be using liver metastasis-directed therapy in combination with the PSMA lutetium, or what do you do in your practice?

Dan Childs: Oliver, that's a great question. I think you and others will recognize we don't know the right answer here. What's clear is that we need more effective therapies for patients with liver metastases. Perhaps using a combination approach with focal therapies to the liver and then the lutetium to control the remainder of the systemic disease will be effective. Perhaps it's using other systemic therapies in combination with lutetium that will lead to the best results. I think the answer is right now we just don't know, and we need to study this population.

Oliver Sartor: You talk about focal therapies to the liver. I wonder if you might help educate our listeners regarding what those options might be in your clinic.

Dan Childs: Absolutely. In my clinic, we consider a combination of things. Some patients have a small number of lesions that are amenable to ablation. Some patients have a couple of liver lesions that can be treated with focal radiotherapies. There's interest by some groups in looking at other treatments like Y-90 to treat liver lesions. All of this is a place with limited data, but I think a good rationale behind using focal therapies to control the most aggressive, the most concerning disease in the liver.

Oliver Sartor: Yeah, thank you. And just to drill down a little bit, you said focal therapies and ablation. Now is that radiofrequency ablation? Or when you say ablation, tell me what you mean.

Dan Childs: Yeah. This is where, Oliver, it's so important to get multidisciplinary input. When I see a patient like this, I have them meet with our interventional radiologist to talk with them about, with the distribution of the disease, with the location of the disease, what is the form of therapy that's most likely to be effective and can be tolerated. We really need a big team in deciding the best approach for these patients.

Oliver Sartor: Yeah, thank you, Dan. One thing that I wanted to point out and get your input a little bit—I don't think you did the analysis, but many patients with liver lesions actually have a very low SUV, have a tendency toward perhaps the neuroendocrine phenotype, which doesn't take up PSMA. Do you have an idea about how many patients were scanned that did not have PSMA PET uptake greater than liver?

Dan Childs: That's a very good observation, Oliver. A lot of these patients move toward having more neuroendocrine differentiation. They lose their PSMA expression. Those patients wouldn't be captured within our cohort or our registry, because this is only patients that went on to receive lutetium. And so if they had non-PSMA-expressing disease, then they wouldn't have been offered treatment with 177 lutetium PSMA-617 or Pluvicto.

Oliver Sartor: Yeah, thanks for the clarification. You gave a presentation of some of the circulating tumor DNA. Do you find utility in terms of doing a biopsy of these liver lesions? Is that something you routinely do, rarely do, or just consider and talk about it, but not really do at all?

Dan Childs: I do many biopsies in my clinic because we get a lot of valuable data from profiling these tumors through imaging with our PSMA PET scans. But I also think it's very important to look at these tumors under the microscope and then to use that tissue for additional molecular testing. So commonly when I see liver metastases emerge, I am going to biopsy those liver lesions to do some further studies.

Oliver Sartor: Terrific. We talk about neuroendocrine cancers. But just as a brief comment, there are other types—subtypes of prostate cancer we don't talk about quite as much. Some of these are anaplastic or double negative, things that are non-neuroendocrine, non-adeno. And we're still defining what those really are and how common they are. But I know this, at times they appear in the liver, and they're very refractory to our typical treatments.

Dan Childs: That's right. And I hope that we're going to be intentional about banking these tissues and forming registries and then going back and studying the tissue more to better define these clinical subgroups of patients and figure out what treatments they'll respond to best, because it's clear from our data and others that we don't yet have a good solution to this issue.

Oliver Sartor: Dan, I'm going to come up with a summary statement, but I want you to either confirm or deny and then say anything else that you want our listeners to hear before we wrap up. Number one is liver metastases are bad in prostate cancer, and they're bad for a variety of treatments, including PSMA-lutetium. Number two, I don't think we really know what to do with them yet, and we need to have urgently more data to address this important subset. Is that a fair summary?

Dan Childs: I think that's a fair summary, Oliver. I'll refine a little bit. I'll say that in general, lutetium seems to have less activity for many patients with liver metastases. However, even within our data set, we did have some patients with liver metastases who had PSA 90 responses. So I wouldn't necessarily use liver metastases as a reason to exclude patients for treatment.

But for patients with liver metastases who start on lutetium, I would monitor them closely. I would make sure to repeat imaging. In our practice, we do it at least every two cycles. That way, if their cancer starts progressing, we can transition them to an alternative therapy very quickly.

Oliver Sartor: Right. Thank you, Dan. Dan Childs from Mayo Clinic giving a very nice overview on liver metastasis and PSMA lutetium. Thank you very much, Dan.

Dan Childs: Thanks, Oliver.