Charles Ryan: Hi, Chuck Ryan here, and I'm delighted to be joined by Dr. Matthew Deek and Phuoc Tran, both from Hopkins, where they work at the Department of Radiation Oncology and Molecular Radiation Sciences and are members of the Kimmel Comprehensive Cancer Center at Johns Hopkins University.

They published a paper that caught my eye, and I think the clinicians and researchers out there have a lot to learn from this paper. It's on "The Mutational Landscape of Metastatic Castration-Sensitive Prostate Cancer: The Spectrum Theory Revisited". It's published now and available on Pub Med, and it's published in European Urology. So Doctors Deek and Tran, welcome.

Matthew Deek: Thank you. Thanks for having us.

Phuoc Tran: Thank you very much.

Charles Ryan: Dr. Deek, if you could just walk us through sort of the thought process that went into the design of this paper and your key findings.

Matthew Deek: Yeah, absolutely. So this paper was essentially born out of the evolving view of metastasis. As many of you might know, for a very long time metastasis was viewed in a very binary state. Either yes or no, does the patient have metastatic disease? Also in terms of treatment options, mainly only having systemic therapies or just observation. Because of that, we were interested in interrogating the metastatic castration-sensitive prostate cancer space a little more. In light of some of the changing views of metastasis, especially the view of oligometastasis or the fact that metastasis instead represents a spectrum of disease ranging on one end from someone who might have just one or two lesions to on the other end someone who might have 35 or 40. These two individuals might have a very different disease course, and there might be benefits to managing them differently.

The study essentially took individuals with metastatic castration-sensitive prostate cancer who had, for the most part, 95% of the patients included had their primary prostate tissue genetically sequenced looking at the DNA mutations that were driving their cancer.

We binned these patients into four groups. One, being individuals who just had a PSA recurrence or a rising PSA following definitive therapy, but never developed metastatic disease, even with long follow-up on the order of six or seven years. The next group is individuals with what we call metachronous oligometastatic prostate cancer, which was individuals with a few number of metastatic lesions, five or less. And then we had metachronous polymetastatic patients, which were individuals who had greater than five metastatic lesions at first recurrence. Finally, we had our last group of individuals, which were the de novo or synchronous metastatic disease group, which are individuals who at the time of their initial prostate cancer diagnosis had metastatic disease.

We wanted to look at what were the biological differences within these four different cohorts to see if there were molecular differences amongst them. I think there were three main takeaway points from the study. One is that if you look at the underlying molecular alterations in these four groups, it varied across the spectrum, specifically individuals who had either some PSA recurrence or metachronous oligometastatic disease, had a lower frequency of mutations, and things like p53 or DNA double-strand break repair compared to an individual who had metachronous polymetastatic recurrence or de novo synchronous disease.

The second major takeaway point that we took from this study is that p53 appears to be strongly prognostic for outcomes in individuals who ended up developing metastatic castration-sensitive prostate cancer, including individuals who initially developed metastatic castration-sensitive oligometastatic prostate cancer.

Charles Ryan: I think that's a key point. The TP53 point, that really jumps off the page of your paper. That is a key point that's a driver of the biology of this disease sort of throughout the full spectrum. It's almost safe to say, based on your analysis, more disease, more likely TP53 alteration. As a medical oncologist, when I see patients who have castration-resistant metastatic disease and we look at their tumors, we see a very high rate of TP53 alteration. It's really striking in your paper. This may be, I think, one of the most important findings that we can use moving forward.

Matthew Deek: Yeah, definitely very important. Unfortunately, we don't have any targeted agents that can target p53 right now, unlike something like a PARP inhibitor. But I think one of the things that can come out of this paper is starting to think about biological definitions of something like oligometastasis, especially as we continue to try to integrate local therapies into that disease cohort. How can we complement numerical definitions, for example, someone who has less than three or less than five lesions with something biological in order to one, develop novel treatment paradigms, and two, maybe expand the group of patients that we're treating with some of these focal locally directed therapies.

Charles Ryan: That's right. That's right. And there are a number of studies ongoing that are looking at the range of treatments from focal metastasis-directed therapy to combination chemotherapy in patients with de novo metastatic disease. We're even going to probably see some trials looking at radioligands in this context and others. So I think it's an important biological set of observations.

I have a question for your mentor, Dr. Tran. This is a great dataset. It's really been nicely characterized. Are these all patients who came from Hopkins or what was the process and sort of the timeline of actually collecting the data? How sort of generalizable are these patients in this dataset?

Phuoc Tran: That's a great question. I just want to acknowledge the great job Dr. Deek just did, not only with presenting the work, but pulling this all together. He deserves really the lion's share credit for this study.

I credit our terrific medical oncologists at Hopkins, whom we work with very closely in their adoption of somatic sequencing panels. This was primarily using FoundationOne® Medicine Panel, and as I said, they were early adopters. So you can really think about this as a real-world cohort. I think the results can give us a peek into what's happening in your clinic.

Charles Ryan: Yeah. Yeah, totally agree. And Dr. Deek, question back to you then is, okay, your message to the clinician out there who's faced with prostate cancer patients in their clinic, whether it be patients coming through who have been treated, have received local therapy or not, how can they use these data and how should they think about integrating these data into their patient care? Maybe it's not with the selection of a therapy, but maybe it's with the determination of a prognosis for a patient. Should they be trying to get metastasis biopsies? Should they be getting prostate biopsies? What do you think the future holds?

Matthew Deek: Yeah, absolutely. I think one of the nice things about this study is that it was mostly sequencing the prostate cancer primary tumor. That allows for, I think, nice and easy translation into the clinic throughout the country and throughout the world, because that is a tissue that will be most available to everyone. At least here at Hopkins, we do strongly believe in sequencing as many people as we possibly can who have metastatic disease, because like you said, maybe there's not a therapy that can be used right now, but possibly in the future, there can be. And two, it does help with, at this point, prognostication in terms of giving us an idea of how will this patient do over the course of their disease.

The nice thing about this paper is that we had a very long follow-up on the order of seven years, which is something really important in a prostate cancer cohort given its more indolent nature. I think hopefully in the future what we'll be able to do with some of this work is create integral biomarker studies to prospectively test these biomarkers and try to come up with prognostic and predictive biomarkers in order to not only know how a patient will do but also use that information to make treatment decisions in the future.

Charles Ryan: Yeah. Yeah. Great. I think one of the other points here that I'm getting, one of the lessons I'm learning, is that if I'm faced with a patient with de novo metastatic disease ... I see a lot of them ... Getting a prostate biopsy is good enough. In other words, it can give me a good window into the biology of their tumor. This is a conversation that's been had in a lot of circles is whether we should be going after bony mets or lymph node mets to get a sense as to what is the genetic profile, genomic profile of the metastatic tumors. But I think your message is that the primary tumor is still going to tell us a good amount of biology that we can use to sort of think through the patient's situation.

Matthew Deek: Yeah, absolutely. So biopsying a metastatic site might give you a little bit more information in terms of, was there a new mutation that was picked up during the disease course, but I do think that we are picking up a lot of information from the primary tumor itself, which is easier to obtain and still gives us a lot of information.

Charles Ryan: Yeah. Very good. Well, congratulations. It's a great paper, and I didn't say it at the beginning, but you're a resident in radiation oncology. It's a tremendous amount of work to do during residency, and you should be very proud of that. I'll also add that you're going to be transitioning to a faculty position at Rutgers. We look forward to hearing more from you both in the setting of great clinical care for men with prostate cancer, but also for the research from that center. No pressure though. Anyway, thank you both for joining me today, and any final words on your work or where you want to go with this next?

Matthew Deek: Well, hopefully, as I said before, we're going to try to look at these mutations one, prospectively, and hopefully two, within patients who had metastasis-directed therapy. Obviously being radiation oncologists, we have a huge interest in that. Hopefully, we can sort of mainstream a lot of these ideas and integrate a lot of this genomic information into the clinic.

Charles Ryan: Excellent. Excellent. Thanks again and congratulations.

Matthew Deek: Thank you.

Phuoc Tran: Thank you.