Alicia Morgans: Hi, this is Alicia Morgans, Associate Professor of Medicine at Northwestern University and a GU medical oncologist. I am so excited to have here with me today, Dr. Phuoc Tran, who is a Professor of Radiation Oncology and Molecular Radiation Sciences at the Johns Hopkins University where he has just concluded the ORIOLE trial. And I'd love to hear you tell us a little bit more about that. Thank you so much for being here, Phuoc.

Phuoc Tran: Oh, thank you so much, Alicia, for having me. I'm very happy to present on behalf of all the other, you know, study co-investigators, the results of our Phase II randomized trial of observation versus stereotactic ablative radiation for oligometastatic metastatic prostate cancer. That's a mouthful, so we shortened that up; just because we're in Baltimore, we shortened it up to the Baltimore ORIOLE study. And that study aimed to try to answer some questions regarding a space that's becoming increasingly more interesting to folks across all different types of cancer, but also particularly in prostate cancer.

This space, also known as the oligometastatic space, is first hypothesized by two investigators in the University of Chicago, Dr. Ralph Weichselbaum and Dr. Samuel Hellman, who posited that metastasis is not just a binary state of being localized and metastatic, but actually like many things in life represented a spectrum or shades of gray. And if you believe that, the spectrum theory of metastasis, there is a spot along that spectrum by which patients who have a sufficiently low enough level of metastatic burden could be impacted, not only obviously by systemic therapies such as chemotherapy, hormonal manipulation, and immunotherapy, but also local therapies in the form of surgery, radiation or some form of ablative therapy.

And so that was really the hypothesis that we set out to test, was could local therapies impact the natural history of metastatic disease. Now prior to the conclusion of the ORIOLE study, there had already been a number of other positive trials and other histologies, namely two positive studies in non-small cell lung cancer, both Phase II studies, adding on local therapy, either surgery or radiation to consolidate disease in patients who had metastatic low volume oligometastatic non-small cell lung cancer. And those studies were both positive for progression-free survival advantages. And then one of them actually had an overall survival advantage.

There is a couple of other Phase II randomized studies suggesting similar benefits. Those were obviously seminal trials. One of the issues we're trying to answer though, whether local therapies can impact further on the natural history of disease is that in those trials, patients had obviously systemic therapy.

There are really in the metastatic space, very few histologies that allow one to just look almost exclusively at local therapy and feel comfortable that you're not endangering your patients. And oligorecurrent hormone-sensitive prostate cancer, or castration sensitive prostate cancer, is I think one of those spaces. There's quite a lot of data suggesting that men that have become, you know, that have had their prostates either taken out or irradiated and then biochemically recur and develop low volume metastases are not adversely impacted if they're not immediately put on systemic therapy. In this case, the standard of care would be hormonal therapy or androgen deprivation therapy. So we felt that this was an ideal space to examine whether local therapies in this case highly focused radiation known as stereotactic body radiation, SBRT, or stereotactic ablative radiation, also known as SABR, could change that natural history, and again answer the question of you know, does an oligometastatic state really exist.

So we took patients who had oligorecurrent prostate cancer, castration-sensitive, with one to three metastases that can be in the nodes or the bone, just not visceral. And we randomized them in a one to two fashion, one to a short observation of six months for upfront consolidation of all of their metastatic lesions with SABR. It was a 54 patient trial, again randomized one to two 18 observations over no more than six months, and then 34 patients to SABR.

The primary endpoint for the trial was essentially a composite progression endpoint of PSA failure and imaging at six months. And then we had a number of secondary endpoints that involved lesion control, metastasis-free survival, and then some exploratory endpoints involving the next generation imaging with PSMA PET/CT, as well as circulating tumor DNA, and also looking at the immune system, the rather novel technique at the time and still, known as T cell receptor sequencing.

So the trial, which was just recently reported out in JAMA Oncology last week was positive for its primary endpoint, showing an improvement in progression between gentlemen on the SABR arm versus observation. So in the observation arm, 11 out of 18 of the participants progressed at that six-month time point, which was 61%. As opposed to the SABR arm, which was only seven out of 36 which was 19%. And that was highly statistically significant.

There were also a number of secondary endpoints, again on local control as expected for SABR was extremely good at 95-plus percent local control. We also saw a very interesting finding using PSMA PET/CT. So at Hopkins where the majority of the patients were enrolled, we had available to us one of the more novel radio PSMA ligand tracers know as DCFPyL. All the patients on the SABR arm were imaged with PSMA PET/CT prior to treatment, and then at six months. And then a number of the observation patients were also imaged subsequently later in the trial.

Something that I have to credit our IRB on is that they forced us to be blinded to results of the PSMA PET/CT, because, and is still the case, we really don't know the significance of lesions found on PSMA PET/CT in this patient population.

So with our results being blinded, what we found ourselves in the unique opportunity of doing is having a set of patients who were treated on the SABR arm, who had only a portion of their lesions, PSMA avid lesions treated with SABR, and then a portion of patients who actually had all of their lesions treated with SABR.

And what we found was that those patients that had all of their lesions consolidated by SABR did considerably better, not only for progression-free survival but also distant met-free survival. And when I say distant met-free survival, I'm not speaking of lesions that we treated that grew or did not grow, but actually new lesions that arose outside of the treated area. And the difference in distant met-free survival between patients who had their lesions totally consolidated, versus only you know, partially consolidated, so still some PSMA avid lesions present, excuse me, without being ablated with SABR, resulted in very robust result with regards to distant met-free survival. So a hazard ratio of 0.19, which was obviously very statistically significant between patients who had all of their lesions, all their PSMA avid lesions consolidated, versus not.

Some other interesting findings, exploratory findings were the following, which was we were able to examine the consequences of SABR on the immune system. And it has been a long-standing question whether radiation, SABR specifically, could be immunogenic, and result in a systemic immune response. By taking blood samples before treatment and after treatment in both the observation and the SABR arms we were able to use a technique known as T cell receptor sequencing, which is a very sensitive way to look at the changes in the dynamics of the T cells that are in the periphery.

And what we found was that patients who underwent SABR had statistically significant changes in the T cell, different abundance of certain T cells where certain T cells seem to become more abundant following SABR. And there was a trend towards what's called reductions or contractions of certain T cells, some types of clonotypes. And that was statistically different when compared to the observation cohort.

So again, longstanding question of whether radiation could potentially be immunogenic. And what we found was that in fact, again the nice thing about this ORIOLE cohort is that we don't have any confounding systemic therapy that would be on a board, as I mentioned, for those other trials in non-small cell lung cancer. And so I think this is the probably the most robust data that we have, that SABR can, in fact, induce a systemic immune response.

And taking it further, this is totally exploratory, but what we found was that when patients at baseline had more diverse T cell repertoires their called, so they're just the different abundance of all the different T cells that you have out there, they ... that correlated actually statistically in the SABR arm with patients who were less likely to fail at six months.

And then finally, you know, with all the data that's coming out with these Phase II trials, and maybe we can talk about some of them later, there seems to be a signal suggesting that one, oligometastatic state exists and that patients really can benefit from metastasis directed therapy in the form of surgery or radiation in improving progression-free survival, and in some cases maybe even overall survival. But just like any therapy, we realize that not all patients will benefit. So it'll be really important to identify the patients that benefit most.

By using circulating tumor DNA, which is a form of cell-free DNA, that all the cells of our body release and are floating around in circulation, using a method known as CAPP-Seq by one of our collaborators out of Stanford, Max Diehn, we were able to demonstrate that there's a certain mutation signature that is able to perhaps, if we validate this, perhaps predict patients who benefit the most from SABR.

Alicia Morgans: So really fascinating, both that we see a longer time to progression with this intervention. But then within those patients who received SABR, those patients who ended up having all lesions targeted with the SABR, rather than just a few that were identified really by conventional imaging, rather than this more intense molecular imaging. I mean that shows what I usually think about is like a dose-response curve, where essentially the intensity of your therapy is associated with the outcome. So really, really powerful.

And when I think about the exploratory information that you're giving us regarding the immunotherapy, or just the immune effects, not immunotherapy, but the immune effects of the treatment, are you talking specifically about, you know, T cells that have this, again, diverse repertoire or diverse ability to attack new antigens or neoantigens that are expressed by the cancer cells, versus lower levels of Tregs for example? And those are suppressive T cells that kind of turn off the immune response. Or do you have any more detail on the exploratory immune situation?

Phuoc Tran: Yeah, absolutely. So just to clarify further, I'm sorry I didn't explain it in quite the detail that you probably wanted. But so the assay is drawing some blood, some peripheral blood. We're not looking at the tissue, we're just looking at the blood, and the cellular components that are being circulated in the blood. So and then at the baseline and then three-month time point, we perform this again, T cell receptor sequencing. And some of your viewers may know all the T cells in our body have unique T cell receptors, which allow them to recognize various antigens, neoantigens, et cetera. And those T cell receptors are hard-wired during T cell development in the DNA at the T cell receptor locus.

A way I always describe this is that each T cell that binds to a particular antigen is barcoded by nature for us. So it's sort of like in the supermarket, you know, you can tell what item you have because you have that barcode. Well, each one of our T cells is actually barcoded in a way that makes it very easy for us in the lab to identify that particular T cell clone, and they're called T cell clonotypes.

So we can track the number of T cells from that clonotype very easily with this PCR sequencing approach. And so what we found was that of this particular T cell type, which is predominantly, you know, your CD4s and your CD8s, that there were certain T cell clonotypes that seemed to be expanded, meaning there were more numbers of them after the SABR manipulation, as compared to observation.

So you know, this isn't, you know, I don't have the data that we would want, but one suggested implication of that finding is that absolutely what you said. Is that after the SABR, certain T cells may have seen something that they didn't see before, were stimulated to divide and divide so much actually, that they were found to be overrepresented in the periphery, or in the circulation.

And we did do some other exploratory analyses of that data and found that there were certain similarities of the sequence of the T cell receptor across at least three individuals. And that, you know, those were all in the SABR arm, and that least two out of the three patients did not fail that had this kind of similar sequence. Maybe they were seeing the same antigen; that's one speculation.

So it is, it's very preliminary. I think the result is clear that SABR causes a systemic immune response. We don't know if it's technically an antitumor immune response, but it is certainly a systemic immune response. And again, it's early, there's not much more we can say at this point about that, other than that, you know, SABR causes a systemic immune response.

Alicia Morgans: So really interesting. And as you said, really the most definitive information so far, of course, exploratory, but the lack of systemic therapy plus the clear insult or SABR that we know the time point and everything else, that we can then look downstream and see that we have an immunologic change in our T cells.

So this is new. This is really important. And this is really, I would say, can stimulate further studies down the way. So as you think about this, the ORIOLE data, certainly in the context of the STOMP data that we know from Piet Ost from before, what are your thoughts in terms of how do we use this information? How do we treat patients on a day-to-day, knowing that we have this information that if we treat these oligometastatic sites, we actually may change the trajectory of disease for our patients?

Phuoc Tran: Yeah, that's excellent ... I mean I, you know, it definitely should be mentioned, and credit should be given to Piet. His STOMP study, which is very similar to the ORIOLE in that he took all oligorecurrent patients and randomized them one-to-one to a period of surveillance or observation, or metastasis-directed therapy. In the case of Piet's trial, he allowed patients to have surgery or SABR, and a few patients had surgery, but the majority had SABR.

And his trial was positive, based on a Phase II signal finding a design for his primary endpoint, which was ADT or androgen deprivation-free survival, median survival, where the experimental arm that the metastasis directed therapy arm was 21 months median ADT-free survival, versus the observation or surveillance arm, which was 13 months. I see the trials as being very complimentary, showing that there likely is a signal here that needs to be obviously validated in a more comprehensive Phase III trial format. And a number of those studies are underway right now.

There's also the SABR-COMET trial, which you know the PI of that is David Palma. And that trial is a trial of SABR in patients who have oligorecurrent disease, but of you know, a mixed histology. So there were I believe about 15 to 20% prostate cancer patients in that trial. A lot of other histologies. And that again, Phase II randomized study again with a signal finding design, positive with an overall survival advantage benefit.

So I think, you know, you have two prostate focused oligorecurrent trials, another trial that involves some prostate cancer patients that is positive. You know, I'm not willing to say wholesale that we should consider the standard of care, but I think there's very good evidence that there's a signal here that needs to be validated with a larger trial.

Alicia Morgans: I totally agree. And I think that as we move forward, patients will do well to look for these trials and try to enroll on them if it's something of interest to them. And you know, certainly, clinicians will take this data and will probably do some treatments that ... or treatment approaches that may or may not be validated by Phase III studies. That happens all the time in clinical care.

And as they do, I certainly urge them to be cautious. And as patients are thinking about this, we strongly suggest that they enroll in Phase III trials that help to sort this out. So as you are thinking about this data and certainly the work that is to come, Phuoc, what are your closing thoughts to the audience as they think about this, and how to think about, you know, ensuring that their patients get the right treatments?

Phuoc Tran: Absolutely. I would say, and I think many of us in this field agree similarly, is that we really need to have that Level 1 data. So you know, try to find trials where you can contribute to trying to answer that question of whether a metastatic therapy has a role in patients who have oligometastatic prostate cancer.

But I think even more so, we already know based on the studies like STOMP and ORIOLE and SABR-COMET that you know, we have some patients that do really quite well. And we've kind of labeled these three modes of recurrence where class one are patients that have had very good responses. You know, they're 18 months plus out, with no PSA failure, and it looks like they're going to have you know, they have long term control.

There's a class two where the patients, they recur, but they recur in an oligoprogressive way where they have maybe, you know, one, two or three mets. And they can actually undergo subsequent rounds of therapy or metastatic-directed therapy. And then there's class three that unfortunately, those patients probably did not derive any benefit from the metastatic directed therapy, and they're progressing in multiple areas.

And it's really that, you know, the last two, the class two and class three where it's obvious we're going to need to incorporate rationally systemic therapies, whether that'd be hormonal therapy, chemotherapy, radiopharmaceuticals like Xofigo®, or obviously immunotherapy, given the results of the ORIOLE. It's important for, and I think researchers know this, but it's really important for the lay listeners out there that absolutely it's important to try to find these trials, but more so be advocates for researchers and funding.

The ORIOLE trial was almost exclusively funded by a grant we were awarded through, a competitive grant we were awarded through the Prostate Cancer Foundation, the Movember Foundation. And you know, when an idea is kind of on the fringes it's not easy to get federal funding for something like this. So I would be remiss not to mention their support, and also advocate the patients out there and the patient advocates out there to help those foundations. Because those are the ones that really help for these projects that seem a little bit risky at first as opposed to the federal government, which is more likely to fund something that's, you know, on its way to being a Phase III.

Alicia Morgans: I completely agree. And I think that we're all very appreciative of the Prostate Cancer Foundation's continued support of these high risk, high reward studies, just like the ORIOLE study. And this one certainly has been high reward. Published in JAMA Oncology, and we are excited to see it there. I encourage everyone to go look at that publication, review the details, think about it for your own practice. This is a Phase II trial, so something that we hope will lead to Phase III findings that will ultimately change the course of our treatment paradigm. But for now, it's really exciting, and a great ray of hope for patients with prostate cancer who have oligometastatic disease.

Thank you so much for your time today, Phuoc, and I congratulate you and encourage you to continue to bring us your work, whether it's positive or negative. It's very thoughtful and we sincerely appreciate it.

Phuoc Tran: Oh, thank you so much, Alicia. I really appreciate the opportunity to share this work.