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Charles Ryan: Hello. 2021 marks the fifth year since the Memorandum of Understanding was written between the Veterans Administration and the Prostate Cancer Foundation. This memorandum established a series of Centers of Excellence around the country to disseminate and produce clinical research and basic research for veterans in the area of prostate cancer. I'm delighted today that two of the leaders of this program have joined me. One of them is Dr. Matthew Rettig. Professor Matthew Rettig is a professor at UCLA and Chief of Hematology-Oncology at the Greater Los Angeles Veterans Administration Hospital.

Matt is a medical oncologist and a colleague, and one of the co-directors of the VA program. And Dr. Isla Garraway is a urologist and Associate Professor of Urology at UCLA and Program Director for research at the Greater Los Angeles Veterans Administration Hospital. I'm really glad you both could be with me today to talk about this important program for the PCF.

Matthew Rettig: Thanks for having us.

Charles Ryan: So, Matt, I'll start with you. Tell us about this Memorandum of Understanding. It's been five years, and the funding has been a little less than five years. What did it spell out, and what are the goals of the program?

Matthew Rettig: Right. So this was an interesting series of events that led up to the signing of the Memorandum of Understanding. It was actually signed by Secretary McDonald in November of 2016. He was the Secretary of the VA under President Obama. There had been a lot of discussion about a program at the VA, and a PCF-supported one. In fact, I had been involved in discussions prior to the signing of the Memorandum of Understanding. I was always a little suspect as to whether or not it would really happen. And then it really happened. As part of that memorandum, the VA committed to $50 million of support for the Centers of Excellence to execute precision oncology within the VA. There are a number of other features of the memorandum related to the VA's responsibilities, career development, young investigators, further support of the program, etc. But the key piece, the key element of it, was the financial support that was committed by the PCF to the VA.

Charles Ryan: And what is a Center of Excellence?

Matthew Rettig: A Center of Excellence represents a VA medical center that has typically an established record in research, clinical research, basic research that is affiliated or ideally affiliated with an NCI cancer center. When this first started, there were six centers, and now that has expanded to 13, and many more are coming on board, some with PCF funding, and actually now some with VA funding. The Prostate Cancer Foundation and this program called POPCaP have been quite successful and have led to the VA supporting a separate program in lung cancer precision oncology, which is called LPOP. In addition, the federal budget now has a line item for this precision oncology. In the 2021 budget, it was $75 million, and that is actually going to increase to close to $100 million. For the current fiscal year, of course, that budget has not yet been approved as of today, October 19th.

Charles Ryan: As of this recording.

Matthew Rettig: Yes.

Charles Ryan: Well, we will talk about three components. First, we'll talk about the clinical trials and what you've learned, and what barriers you are facing. Then we'll talk about specimen procurement and biological data and outcomes data that the VA program may provide. And then we'll talk about how the VA program is really a model for addressing disparities in healthcare. So I'm going to stick with you, Matt, for the piece on the clinical trial. Tell us about the breadth of the clinical trials program so far in the VA and some of the opportunities you see and some of the barriers you've confronted.

Matthew Rettig: Sure. So ultimately what we are trying to do is deliver precision oncology. What is that? It's basically using the right drug for the right patient at the right time. And that is largely driven by the analysis of a biomarker, typically genetic sequencing, next-generation sequencing. So the VA has a program where the VA's central office will cover the cost of sequencing for any veteran with an advanced solid tumor or liquid tumor for that matter. And that is being done.

We can tell you, and Isla can tell you probably better than I can, that close to 2,000 veterans with prostate cancer have already been sequenced. And those data are available to us and other clinicians and investigators. So the clinical trials program aims to leverage these data to develop clinical trials that enroll patients based on a specific biomarker, specific genetic result. For example, mutations that result in homologous recombination deficiency, like the BRCA genes, along with some studies with mutations in other genes. And we enroll patients at these Centers of Excellence, as well as patients that live in proximity to the Centers of Excellence in that region of the VAs, which we call VISNs, or Veterans Integrated Service Networks. And they are-


Charles Ryan: So these can be non-veterans who are receiving their care, or they have to be veterans, but they do not need to be receiving their care at the VA?

Matthew Rettig: The latter.

Charles Ryan: Okay.

Matthew Rettig: Yes. So it's a veteran, has to be a veteran, but the patient does not have to be at the Center of Excellence to receive care.

Charles Ryan: But the specimen will go there, and the sequencing and all of that.

Matthew Rettig: Correct. And the patient will generally come to that Center of Excellence for care. Although, we do have a virtual clinical trials program that is in a nascent form where we are trying to do clinical trials remotely. So patients who are not in geographic proximity to a Center of Excellence do not even have to travel, and we can offer precision oncology to such patients.

Charles Ryan: Yes, a big potential advance there, maybe benefited perhaps by the COVID pandemic where we have learned a lot about telehealth. So are you doing clinical trials right now where televisits and telehealth are an important part of the data collection?

Matthew Rettig: So not quite yet. We have remote consents, but the actual process is still being worked through, but I expect that in the year 2022, we will be able to initiate that process. And we've already selected two clinical trials as pilot examples for that virtual clinical trials program.

Charles Ryan: Great. Do you want to tell us about those trials?

Matthew Rettig: Sure. One of them has an acronym CHOMP, and it is a phase two study looking at a checkpoint inhibitor called pembrolizumab for patients who have either mismatch repair deficiency or inactivation of a gene called CDK12. And based upon the effect of these mutations on the genome, it's predicted that immunotherapy would be more effective. So we are studying this, and we're also studying the mechanisms of resistance to this therapy, both what we call primary resistance, as well as acquired or secondary resistance. And that is done through biopsies of metastatic tumors prior to treatment and at the time of progression. The other study that we are doing through this program is one that we are comparing olaparib, a PARP inhibitor, versus old chemotherapy called carboplatin for patients who have homologous recombination deficiencies, so these are the BRCA type mutations. And there is evidence that both drugs work well. Carboplatin at the VA costs about $5 per month, and olaparib, which is an oral agent relatively recently approved, is over $10,000. So there is a big cost difference. And it is not clear that there is much of a difference in either efficacy or toxicity.

Charles Ryan: So that is a really important study from multiple levels because carboplatin is easy to get, and inexpensive. And if it's equivalent to, or even non-inferior to a PARP inhibitor, it could really change the standard of care, obviously not only for veterans but for all patients.

Matthew Rettig: Exactly.

Charles Ryan: So. Excellent. So I'm going to switch, and we're going to talk about specimens and analysis. And tell us a little bit about what happens, what's the flow, Isla, of data and biological specimens from veterans.

Isla Garraway: Yeah. Sure. So, well, I mean, one of the main attributes of the VA is the data collection that the VA allows. And we are really trying to turn that into the ultimate win-win scenario so that we can elevate the care of our patients by using their data, as well as help researchers access that data so that they can perform studies that will eventually turn around and elevate the care of the patient even further. So one of the, I think, first feats that the POPCaP network was able to do is create a prostate cancer data core,

Charles Ryan: Okay.

Isla Garraway: Where they can leverage the existing electronic medical record system and the data warehouses where all of this veteran data has been stored for the past 20 years and identify all of the patients who have been treated, diagnosed, and treated for prostate cancer within the VA healthcare system. Not only can they do that, but they can identify patients who have metastatic disease so that we know the vital status of the patients who have metastatic disease. And so therefore, who may really be needed to access these clinical trials that Matt is referring to.

Charles Ryan: So there's an analysis team that gets access to this data, researchers from within the VA, perhaps even from outside of the VA at some point, come and say, I have this specific question. I want to know about CDK12 mutations in prostate cancer patients or something like that. And what is the process they have to go through to get access to that data, and tell us a little bit about the team that's.

Isla Garraway: Yeah. Absolutely.

Charles Ryan: On the job.

Isla Garraway: Well, we've assembled a really amazing multidisciplinary team. We've worked closely with some of the large data people at the VA, who, as you may have heard, have a Million Veteran Program, which is a really large research program to genotype and sequence veterans. And so all of that data is stored and coordinated by many individuals. And so by working with them, we've been able to kind of create our own kind of biorepository where we can house our data, where we can link that data, as Matt mentioned before, to archival pathological specimens. And then we can do a deeper dive into the medical record to really abstract key critical information regarding the patient's medical history, their treatment course so that we can understand kind of the clinical course of an individual level. And then since the VA is so large, at a population level, for people who have whatever you want, like a specific genetic mutation, a specific socioeconomic status, a specific race or ethnicity.

So all of those features of this patient population can be studied and analyzed. So the process by which VA researchers can access this data is pretty easy right now because we've been able to establish for research purposes a centralized IRB, which is kind of just centralized approval to join a research study to access data from our biorepository. And so essentially what will happen is that a researcher who has a particular research topic in mind will submit a concept sheet where we have a little central review committee who will make sure that the work is not being duplicated. And if it already is, then we can see if there's a collaboration that is possible. And then the research team can apply, any COE can apply to have access to the central IRB and then access the data.


Charles Ryan: So we really need to encourage investigators, young investigators, people looking to start a career in clinical outcomes research, survivorship, clinical trials, to think about the VA as a place where they want to do their work, because not only do you have this amazing biorepository, you also have a growing clinical trials infrastructure. And you also have the nation's largest healthcare system with unified informatics, and then the potential for even outside of the setting of clinical trials, kind of a uniform therapy protocol. Right. And it's been published and you can speak to this I hope, about disparities and healthcare outcomes and how in the VA a lot of the disparities that we see outside of the VA system and the country at large are not seen in the VA system. And that's presumably due to equal access to care within the system. Can you speak to that?

Isla Garraway: Yeah, absolutely. In the POPCaP network, we have an entire group devoted to research in health disparities and trying to understand, first of all, what health disparities are still visible within the VA system, and as you mentioned, some disparities that are notable throughout the country in non-VA healthcare kind of disappear in the VA system. And it has been discovered that the reason for that is because of equal access. So once a patient can enter and access VA healthcare, a lot of the disadvantages that they might have due to socioeconomic status, or whatever factors impact their ability to access health go away. And so for example, we've done several studies looking at prostate cancer patients of African American descent who have been treated with, for example, radiation therapy in the VA system and they actually have better outcomes.

Charles Ryan: I've read that. Yeah.

Isla Garraway: Than Caucasian patients, and so it's very interesting. So the question is, where exactly are the disparities, and can we understand better the etiology of these disparities so that we can address them outside the VA and apply some of these principles outside.

Charles Ryan: Right. And I think veterans who might be watching this today and following your work, can be assured that if they are in Seattle, or if they are in Madison, Wisconsin, or if they are in Houston, Texas, the care that they are getting at a VA most likely is fairly uniform based on the stage of the condition that they have. And it is not so much driven exactly by the personality and the knowledge base of the practitioner. And that is where I think you are identifying where this disparity can kind of go away. It speaks to the power of large systems and uniform data sets, et cetera, et cetera. And I think we at the PCF are very proud to be a part of that in playing a role and driving that forward. And of course, extremely proud to be able to offer support to investigators applying their energies, as both of you and others.

So I want to thank you on behalf of myself personally, but also the PCF to which I am a new member, so to speak, of the leadership and thinking about the future of the VA program. So as we wrap up and think about the future, what is your loftiest ambition, Matt, about the VA program? When you think about it functioning at the perfect ideal level, what do you see? And I'm going to ask you the same question.


Matthew Rettig: So it's a great question. And that is ultimately what the mission is, which is, let's get every veteran, irrespective of their geography, access to readily available precision oncology. So I always like to say whether the patient is in Biloxi, Mississippi, or in Los Angeles, or in Boston, they have equal access. And that access is not encumbered by any obstacles, such as getting a specimen sequenced. So it happens naturally, almost automatically. And the information is acted upon rapidly, and the best care, state-of-the-art precision oncology is delivered to every veteran everywhere, with no veteran left behind.

Charles Ryan: I think that's a very good goal. Isla, same.

Isla Garraway: Absolutely the same. And in addition, I think, really leveraging VA data so that we can improve the life and life expectancy for all men in this country.

Charles Ryan: Well, I'm going to take what you both said, and I'm going to add to it. And I'm going to say what you've both said is no veteran left behind, service the veteran, but I actually also see if this functions as we want it to, the veterans will continue to serve the country, right? Because they will serve as the model for how we practice health, how we analyze data, how we do clinical trials in prostate cancer. And it's an incredible way through you for veterans to serve their country again.

Matthew Rettig: Yes. Thanks.

Charles Ryan: So congratulations on your hard work. I look forward to working with you through PCF in the future.

Matthew Rettig: Thanks for the conversation.

Isla Garraway: Great, thank you.