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Neeraj Agarwal: Welcome to Dr. Nicolas Sayegh, a resident in internal medicine at UT Southwestern. Congratulations, Nicolas, for receiving the Conquer Cancer Foundation Merit Award for this ASCO GU 2025.

Nicolas Sayegh: Thank you so much, Dr. Agarwal, for having me here. It's my pleasure to be here talking to you.

Neeraj Agarwal: So, Nicolas, tell me or tell us about the result of your study, which was considered worthy of a Merit Award. You looked at a big phase III trial database, which included patients with metastatic hormone-sensitive prostate cancer. And you chose to ask a very interesting question, which was whether, from the time of surgery for localized prostate cancer to onset of metastatic prostate cancer, this time duration correlated with survival outcomes after the onset of metastatic prostate cancer.

And to our viewers, I must tell them that this factor already has implications in the context of metastatic renal cell carcinoma, for example. So time from surgery to time of onset of metastatic disease—or when patients need to start systemic therapy for metastatic disease—is one of the prognostic risk factors in metastatic renal cell carcinoma.

But we don't know if somebody had localized prostate cancer 10 years ago and then developed metastatic disease five years after, or if someone developed metastatic disease two years after, whether it has any implications on survival in those who now have metastatic disease and are starting treatment.

Nicolas Sayegh: Yes. Yes.

Neeraj Agarwal: So please tell us, what did you do, and what was the inclusion criteria, and what were the results?

Nicolas Sayegh: Yes. Thank you, Dr. Agarwal, for this little background. So like you said, I like to focus on the metachronous subset of patients with metastatic hormone-sensitive prostate cancer. With those patients, like you said, the time from definitive therapy—either surgery or radiation—has been correlated with a more indolent disease course in other cancers, like you said, RCC, also breast, CRC.

So for us, we try to explore this in metastatic hormone-sensitive prostate cancer. In terms of inclusion criteria, we included patients who received radical prostatectomy and who had metachronous prostate cancer. Some definitions actually that we used in this study: metachronous was defined as not having metastases within 90 days of the definitive therapy. And the time to metastasis has been defined as the interval between the time of surgery and the time of initial metastatic diagnosis. So out of the patients included in that big phase III trial, which is SWOG S1216, 301 actually met those criteria and were included in our study.

Neeraj Agarwal: So large number—300-plus patients were eligible for your study.

Nicolas Sayegh: Yes, 301 were eligible, and they were also equally divided between the two arms of the trial. So just a little bit about our objectives in this study: our main objective was to correlate time to metastasis with overall survival and progression-free survival, progression defined by PCWG2 criteria. Other secondary objectives were to categorize this time to metastasis and see if there are some subsets of patients that do better than others. And the third objective was to also see if there is any differential response between those two treatment arms—ADT plus bicalutamide or ADT plus an ARPI.

So our initial analysis aimed to see how DTM (duration to metastasis) would be when it's used as a continuous variable. And surprisingly, it was not associated with either OS or PFS in either of both arms—ADT or ADT plus ARPI. So for this reason, we tried to categorize it into thresholds of 1, 2, 3, or 4 years. And similarly, results also showed that in all those thresholds, the hazard ratio was negative and ranged between 0.9 and 1.8, all of the intervals crossing 1, so not significant in any of those subgroups.

So those results were a little bit intriguing for us because in clinic, sometimes when we see somebody that recurs a long time after prostatectomy, we tend to feel like they have a better prognosis in general, or we tend to sometimes be more lenient while treating that patient.

Neeraj Agarwal: I agree with you. By the way, very interesting findings. Let me, for our listeners and viewers, say that I was surprised to see the results. We would expect that patients who took much longer to develop metastatic disease from the original surgery would have a better prognosis—that's our dogmatic way, even I have looked at these patients. And during our conversation with a lot of colleagues out there in the community, we see a consistent theme that many of those patients may not have been started on intensified or combination ADT—ADT plus, for example, enzalutamide, apalutamide, darolutamide, or one of those intensified therapy regimens—just because there was a perception that, “Oh, it was a surgery done long ago, and it took five years to develop metastasis. Probably patient will do fine with ADT monotherapy alone.”

So I think this is one pretty good implication of your research: there is no correlation. We should not hold off on intensification therapy on any of these patients, because disease aggressiveness or prognosis is not really dependent upon a long time between surgery and onset of metastasis. That's number one. Number two, any other implications you can think of?

Nicolas Sayegh: Yeah. Like you said, Dr. Agarwal, in the clinic, in the decision-making process, I think that time to metastasis should not be a part of that. And we should focus more on other factors, like the disease burden, the genomic profiling—that would indicate which treatment to use or to give our patients a prognosis.

Another thing is that intensification should be considered for all patients, no matter how long they took to develop metastasis. Like you said, intensification is now standard of care. The question of how to intensify needs to be answered in further research, but intensification should be considered in everyone.

Neeraj Agarwal: Yeah. I agree. So if patients come to us with, say, metastatic hormone-sensitive prostate cancer and tell me, “Doc, I had localized prostate cancer 10 years ago or 5 years ago, and it looks like I will do just fine,” based on this data, I will tell the patient that it doesn't really matter when you had localized prostate cancer. The fact that you have metastatic disease now, we have to treat your cancer as aggressively as anybody else's metastatic prostate cancer. Is that correct?

Nicolas Sayegh: Yes. Exactly. That's right.

Neeraj Agarwal: OK. That's fantastic. Last question. Did you look at genomic biomarkers associated with these responses or these correlations? For example, is it possible that patients who had tumor suppressor gene loss, and they had a long time to metastasis from the time of surgery—did they just not do well because they had genomic markers associated with poor survival? You have published a paper in that context, too. So did you look at those genomic biomarkers in this data set?

Nicolas Sayegh: So we looked at those biomarkers in our own data set at the Huntsman Cancer Institute, and like you said, we showed that in patients with mHSPC, those tumor suppressor genes—RB1, TP53, PTEN—are associated with worse outcomes. But what is left for us is to actually explore that in a trial-based database. We did not do this in the SWOG S1216 database for the moment, but this is something that we are aiming to do in other subsets.

Neeraj Agarwal: Well, Nicolas, congratulations again. Ultimately, time from prostatectomy to onset of metastasis doesn't impact survival after onset of metastasis, and all these patients should be treated with the current standard of care, which is intensification therapy or combination therapy regimens with ADT plus an ARPI plus/minus docetaxel chemotherapy. So thank you very much for being here and for taking the time to join us.

Nicolas Sayegh: Thank you, Dr. Agarwal. I would also take the opportunity to thank the Conquer Cancer Foundation for their awards and their support of early career investigators always.

Neeraj Agarwal: Yeah. And this is your second Merit Award, I believe.

Nicolas Sayegh: Yes.

Neeraj Agarwal: OK. Congratulations.

Nicolas Sayegh: Thank you, Dr. Agarwal.

Neeraj Agarwal: Thank you.