Joe O'Sullivan: Good morning, everybody. You're very welcome to the last morning of APCCC 2022. Great to see so many people here this morning after the night out last night, so that's good. We've got a really exciting session to finish the conference. It'll be in two parts, session seven, and it's about oligometastatic and oligoprogressive prostate cancer. These are topics we've touched as we've come through the meeting. I'm delighted and honored to be joined by my co-chair Mary Ellen Taplin here this morning, and we've got a fantastic lineup of speakers, so I hope you enjoy. I'm going to hand over to Mary Ellen to introduce the first speaker.

Mary-Ellen Taplin: Okay. It's my pleasure to introduce Dr. Daniel Spratt. Dan hails from Michigan Radiation Oncology, and he'll be talking to us, What is the evidence of MDT and synchronous versus metachronous metastatic hormone-sensitive prostate cancer? Thank you, Dan.

Daniel Spratt: Thank you. I think since the invite until now, I've moved very recently to my new home, Case Western, but very close. It's only a two hour drive.

Mary-Ellen Taplin: Sorry.

Daniel Spratt: No, no worries. Conflicts of interest, I don't think any relevant, other than some of the imaging companies that help us detect oligometastatic disease. For level setting now it's becoming, across all of cancer and as a radiation oncologist, every cancer type or subspecialty is focusing on synchronous versus metachronous versus oligorecurrent, oligoprogressive, and it's becoming very complex to talk about and very confusing because trials are in very specific settings. And so today from prostate cancer, I think often what we're focused on for most of the evidence is in de novo, upfront oligometastatic, or synchronous disease, versus recurrent or oligometastatic metachronous disease, although there is other settings where we're studying this in prostate cancer, more advanced stages in oligoprogressive disease.

So the question is, what's the evidence for this? I think we saw from the survey results the prior day, this is being used a lot. From probably the best vocalist in history of Whitney Houston, we have nothing pretty much for me to talk about, so I could end the talk very quickly. In metachronous, we do have evidence. It's not necessarily immense, but when you take it in totality from both prostate cancer, pan-cancer studies, as well as even other cancer types, I think we have a fair amount of evidence.

Again, the randomized evidence, we do have none in the synchronous setting. In metachronous, we've heard many of these studies, Dr. Ost led the STOMP trial, there's the ORIOLE trial that was led out of Johns Hopkins, and then SABR-COMET is a pan-cancer trial that prostate cancer was reasonably represented, but you can see the sample sizes is here. These are not your typical STAMPEDE style, multi-thousand person trials. These are small trials, but all of them, positive.

To not repeat this too much, but STOMP, to identify oligometastatic disease, again, this is in the metachronous setting, used PET choline, and it was mostly radiation therapy in terms of the metastasis-directed therapy versus nothing. So there's no backbone systemic therapy, and it's similar for the ORIOLE trial, and it improved. You can look at it in many ways, but effectively, anything that relates to biochemical progression or progression-free survival, effectively, is going to correlate closely with ADT-free survival, because that's going to be the trigger in ADT. And that's similar to what was seen in the ORIOLE trial, which is more so using PSMA PET for the majority of patients to detect oligometastatic disease. Toxicity was low, as expected with appropriate doses of radiation therapy.

SABR-COMET was a larger trial, but it's pan-cancer. So the question, and as I'll show you near the end, some of the larger phase III trials ongoing, do we need to study this in prostate specifically? And then that's a question for the group, that if you test this in multiple cancer types, you could almost go back in history. Do we have trials for the benefit of, let's say, surgery across the body for cancer? We really don't. But if you think of removing a tumor or cytoreducing disease, could there be benefit? And so this trial actually has showed a survival benefit in this pan-cancer trial of adding SBRT.

So there's a lot of non-randomized evidence that's growing, so there's too many to really highlight. Some of them are 5-patient series. Most of them are all fairly small. I list some here, and I made sure to put the Milan experience and also in the metachronous, I'll highlight just a couple because there's so many to go over. Some of the early data out of Sloan Kettering, you can see here that this was sort of comprehensive treatment. So this is in the synchronous setting, newly diagnosed oligometastatic disease. Had local therapy, hormone therapy, and SBRT to all sites of metastatic disease. And 20% of patients achieved an undetectable PSA after testosterone recovery. Time will tell, is this a cure? But this is impressive results, nonetheless, for a population you normally would just commit them to lifelong therapy.

Hopkins put out a very small series, but again, oligometastatic disease, again, in the de novo setting, less than five sites. Similar therapy, they added chemotherapy with the hormone therapy, and actually, two-thirds, they said, achieved an undetectable PSA after testosterone recovery at 3 years. So again, this is suggestive of benefit to these patients. Milan. Similarly, they've said at 4 years about half have recurred, about a quarter have developed new sites of mets, and about a third of developed castrate-resistant disease. This was in a highly-selected population, less than two oligo metastatic sites. And then one of the largest series I could find, but really the results are fairly premature to interpret much from Beijing, almost 200 patients, less than five sites, radiating everything with hormone therapy. And at 1 year, again, I don't know what to do with it, but 94% had not, basically, developed castrate-resistant disease.

In the metachronous setting, there's, I would say, stronger evidence and there's, again, too many series to highlight. I just chose these series. The one that I'd like to highlight on the right, this PSMA trial, is very interesting, because all of the metastasis were detected purely by PSMA PET. So unlike ORIOLE where there was some that were CT-detected, this is purely PSMA PET. They gave high dose SBRT to all the sites. And what's interesting is they give, to me, some of the better estimates of how many patients truly achieve as close to what we could call a cure. It's about 22% in this study. I know there's some that will say it's 50%, 60%. It's probably they say 60% had a biochemical response, meaning 40% didn't even have a biochemical response to radiating the mets. And it's about a quarter, do you actually achieve complete biochemical, no evidence of disease. So I think when speaking to patients, this is more so the types of estimates I use with them.

The future?

Well, we need trials to better quantify benefit in both settings. In the synchronous setting, and I don't know what the formal name will be, it's changing, it was going to be arm M, I think now it's rolled into a STAMPEDE version 2, it's going to be a very large trial, at least 1800 patients. We're opening it, actually, at the center I'm at is the national PI for North America to have this at five centers in the US, but it will be treatment of the primary with standard systemic treatment and will be randomizing to +/- metastasis-directed therapy.

The future, again, this is a question for the group, how we want to approach this, is that there's many trials ongoing. I list some here with the primary endpoint of overall survival, and all of them that are in the hundreds of patients, none are nearly as big as what the STAMPEDE trial will be. But you see some of them like the SABR-COMET trial 3, which is again, testing three or fewer metastasis, SABR-COMET-10, which is testing up to 10 metastasis, because now with modern radiation therapy, especially with artificial intelligence techniques, we're able to more rapidly contour, plan, and potentially even treat multiple sites of metastatic disease. Seeing the potential benefit here with low probability of toxicity with modern treatment planning, is there a limit, essentially, to how many sites you treat. And then some other pan-cancer trials at the end I showed.

I think, in summery here, we don't. So although I, and many people I know, use metastasis directed therapy, more so on oncologic principles that, really, you cannot tell a patient that we have level one evidence that this must be done. We have some phase two evidence, and especially if you look pan-cancer, some fairly good evidence with low side effect profile of doing this in the metachronous setting. And I think when trials are available, we really do need to try to keep that equi poise, or we won't ever have this data. It'll be just like the imaging. We'll just be doing it without evidence. So with that, thank you so much, and thank you so much for the invitation.