Alicia Morgans:  Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist and Associate Professor of Medicine at Northwestern University. Thank you so much for being here with me today, Dr. Pedro Barata, who is an Assistant Professor of Medicine at Tulane University, GU medical oncologist, who has recently published a really informative paper, looking at checkpoint inhibitors, microsatellite instability, but finding information from liquid biopsies. Thank you so much for being here. Tell us a little bit about this study, Pedro.

Pedro Barata:  Alicia, first of all, thank you so much for having me here. It is a pleasure to be chatting a little bit with you about the paper. It just came out about two months ago or so, and we were just talking off a little bit about it, how fun it is to work with colleagues and friends. So just to give a little bit of background, right? So when we got the approval for checkpoint inhibitors for microsatellite instable tumors, also known as MSI high, there was a lot of data that it was built on, but it wasn't based on prostate cancer for the most part, right? In that initial study that is published in New England, they got two patients who were diagnosed with prostate cancer.

And so afterward, we felt that it was important to build some data specifically in prostate cancer, knowing that for an unselected group of patients with advanced prostate cancer, the role of immune checkpoint inhibitors is not great, right? The activity is relatively limited. And so we set the stage for that, right? So at the same time, or more recently, we have a dataset from MSI high tumors in prostate based on tumor tissue. But as you and I know, one of the challenges for patients with advanced disease in the prostate, in particular, is the lack of tissue. A lot of times we have patients with bone mainly disease, where it's not easy to think of a biopsy, it's not easy to get a tissue to run the sequencing assay.

And so we put together... We thought to put together an experience of how about looking for liquid biopsies that are started to inform us of the microsatellite status of those tumors, right? And see how many patients we had within the US and how many with MSI prostate cancer tumors and how many of them were actually treated with immunotherapy.

So we ended up reaching out to a couple of institutions, we have 8 institutions in total. But we sequenced more than 400 patients and we found 14 who were MSI high. So that our inclusion criteria included all men with advanced CR, castration-resistant, prostate cancer, treated with checkpoint inhibitors during the course of the disease. So of those 14 men that we found within these 8 institutions, we ended up with nine patients who received pembrolizumab which happened to be the only immune checkpoint inhibitor available. And so we decided to basically report the dataset or the experience with pembrolizumab in that setting. So as I said as, I... will just go over the results. Basically of those nine patients, roughly we have five or so that had measurable disease. Of those five, three had actually objective response rates.

So the 60% objective response rate sounds high, higher than what we saw previously. Whereas also, perhaps due to small numbers, right? Five patients is not a lot. In regards to PSA responses defined by 50% decline or more, we had about 44% or so. And so, when we summarize these data, what was clear to us was that every time we saw a PS... Or every time we saw an objective response, we also saw a PSA response, meaning PSA goes down and we saw tumor shrinkage if you will. And, when we did not see a response because it is hard to describe, measurable disease based on PCW group three criteria, right? For bone, essentially, we did see PSA responses in a fairly good number of patients, definitely higher than a lot of therapies that are available out there for unselected patients with metastatic castration-resistant, prostate cancer.

So we think, these studies to some extent, novel or unique because it's one of the first to put together the real-world experience with pembrolizumab, for MSI tumors, that is based on the liquid biopsy. And this is for patients who are not enrolled in clinical trials. So it gives you an idea and a perception when it is actually happening in real life, when we have the patient in front of us, right? And we sequencing, hoping that we will find a target and hopefully the targeted therapy we use in this case, immunotherapy for MSI high, is going to be successful.

Alicia Morgans:  I just think this is so interesting and important for the field because as you said, pembrolizumab has been approved for all MSI high tumors. But what is frustrating is that we don't have an abundance of data for prostate-specific patients. And you are certainly providing that, but the uniqueness of having a liquid biopsy be able to predict this is so important for this group of patients in particular, given the bone predominant disease. Aside from this paper, how has your clinical experience been in terms of getting liquid biopsies? Are there challenges? Are there successes? What do you think?

Pedro Barata:  Great question. So, I mean, and I know you have a similar practice from ours here at Tulane. So when we think about genetic testing, we comprehensively do both germline and somatic, and we're really talking... Your question is great regarding somatic testing. And so we do germline on everybody that steps in the clinic with metastatic prostate cancer. In regards to sematic, we do consider liquid biopsy every time we can, we do it for two purposes. One for because he has therapeutic implications, the second reason is for research purposes. So I would argue that we probably use it a little bit too much in a good way because we do it every time you progress on therapy if you will. The other thing is, if you notice, I mean, we have 14 patients, but only nine got pembrolizumab.  One of the reasons for that was because a lot of the other five patients, most of them were hormone-sensitive, castration sensitive prostate cancer, for which immunotherapy is not approved because he required progression on at least one line of therapy.

The reason being, we are being very proactive in terms of sequencing those tumors. So that ahead of time, so that when we need to decide a therapy, we already have the genomic information to make those decisions. Now, in regards to liquid biopsy to your question, for tissue you can do that because you can recover tissue, send it out for sequencing, and you just go on with whatever combination regimen you want to use. And then when you progress for CRPC, you can think of what are you going to do. For liquid biopsies in our experiences, the timing is really critical because you need to find circulating tumor DNA. And so, if you start someone on systemic therapy, that's going to work, if you do the liquid biopsy three, four weeks later, you're more likely not to find anything, right? You get a white result out of it because you're not going to find circulating tumor DNA.

And so, we opted to start doing it more at the time of progression, or when you have more tumor burden, where the chances are, you're going to find circulating tumor DNA that ultimately going to lead to a result that's going to be meaningful. We still have challenges with liquid biopsy, right? One of them is obviously, if we have a patient with a bunch of disease and you have a liquid biopsy result, you don't know where they're really coming from right? Due to tumor, clonal evolution, and tumor heterogeneity. You don't know if it's coming from MET one or MET two or MET four. The other things are, there's a different frequency of a [inaudible] fraction is quite different, and I still don't know what it means to have a 0.5% of something, right? Especially when you have other life-prolonging therapies available. The question is, are you going to favor a liquid biopsy result? Or even the tumor tissue biopsy result, if you will, versus using a life-prolonging therapy and save their results for later?

The other thing is if we repeat a lot of liquid biopsies, as I said, at time of progression, and often they are not the same. So things change over time, as we know, as we expose them to many therapies. So which one of the results are you going to take as real, right? The more recent one? The older one? What if the older one has a targetable alteration and the new one doesn't? And does that represent that that is what is driving the tumor or not at that point in time? If I had to summarize, I would say, I think it's a great replacement for tissue.

The concordance seems to be there, but a lot of times there is a non-concordance, it's more a complementarity of liquid plus tissue. But there's just... I think there is still a lot we don't know, how to use these in clinical practice. Unless you clearly find something that is present, you can tell for sure. Even if it's not germline, but it's there, it's in a high, a little fraction. And you're pretty sure that if you are going to offer target therapy based on the liquid biopsy results, you are pretty confident you're going to be addressing most of the majority of the tumor burden of that patient.

Alicia Morgans:  Wow. There is definitely a lot to unpack there. It sounds like you have another paper in progress with your serial liquid biopsies. I think just even trying to understand that and the effect of different treatments on the shifts in mutations is fascinating. And so I really do hope to see you and the team, Dr. Sartor and all of the folks at Tulane, put that together and show us how are these changing over time? And as you said, one of the benefits of this approach is that you are potentially getting... You're reducing the risk that you are going to do a biopsy of an area that has whatever those specific mutations are and miss the mutations in another place.

Of course, it is still possible because perhaps, not all of these areas of metastatic disease are releasing circulating tumor DNA, but you may have a little bit of a lower risk of getting very... A narrower slice of what the mutation status might be than if you actually were doing these tissue biopsies. But I really do look forward to you and the team unraveling all of this and helping us understand this evolution and understand better the correlation between tissue, and what we are able to get from these liquid biopsies. But this is, this is all fascinating and I congratulate you and the team for being able to look at this. If you had to put together really, an overarching message or a summary from the work that you've just presented for the listeners to hear, what would that be?

Pedro Barata:  No, so thank you. And I'm just thinking, as we have collaborated so far, and to keep friends and colleagues and experts in the field as you, is how we can move the field forward and get these datasets together. This is an example of a successful collaboration. We have many others, some actually including you and your group. And I think that is one of the ways to move things forward and develop data so that we can use it in clinical practice, right? As take-home points I would say, I think precision oncology is becoming increasingly important not only in general, in solid tumors, but really, in prostate cancer as well.

I think in the absence of a tumor using liquid biopsies to make decisions, it is a very important point. I think we need to test to find out our biomarker positive patients, despite immunotherapy has been seen as a little bit of a disappointment in the last few years in prostate cancer. And despite MSI is actually low frequency in the 2, 3% when you test and you find them based on the data we provided, we can safely use the liquid biopsy results to make decisions and offer immunotherapy to a patient where there is a high chance of response. That's how I would summarize the dataset that came out in the Journal of Immunotherapy two months ago.

Alicia Morgans:  Wonderful. Well, I look forward to continuing to collaborate with you and the team, Dr. Barata. And I also commend you and the team at Tulane and at the other institutions for working together to really shed some light on how we can better take care of these patients and integrating these liquid biopsies into care. Thank you so much for your time today.

Pedro Barata:  Alicia, thank you so much. It's been a pleasure talking to you as always. And thank you for highlighting this study, and I'm looking forward to our future collaborations and to speak again soon.