Matt Cooperberg:  Hi, I'm Matt Cooperberg from UCSF, Department of Urology at the UCSF Helen Diller Family Comprehensive Cancer Center. It's a pleasure to welcome you all to another in our series of conversations within the UroToday Center of Excellence focused on localized prostate cancer.

Today, it is a real pleasure to be joined by Brian Chapin, who is an associate professor and the program director at MD Anderson, and one of a very small, elite group of urologists who have actually managed to conceive and execute large Phase III trials focused on management decision-making for localized prostate cancer. We are going to have a conversation today about sort of what it takes to get one of these trials off the ground and what the future of trials looks like for men with localized disease. Brian, thanks very much for joining us.

Brian Chapin:  Yeah, thanks for having me. This is great. I wish we could be doing it in person, but it is what it is.

Matt Cooperberg:  As do I. This is our world in 2020, for better and worse. So, to kick things off, maybe just tell us a little bit about what set you down this path, how you got interested in taking on the challenge of the big trials.

Brian Chapin:  Yeah. I mean, so, to be honest, I really never knew that this was something that I would be doing. And when I went to MD Anderson as a fellow in 2010, I actually went there with the plan of working with Chris Wood on renal cell carcinoma. And I was a Urology Care Foundation recipient, and lucky enough to have that and have the support of Chris Wood, and worked with hypoxia and systemic therapies in renal cell carcinoma cell lines. And Chris's focus has always been on local events renal cancers and integrating systemic therapy with local treatments, which I think really had an impact on my decision to kind of do what I've done, which is... I mean, it was a great conference that was weekly at MD Anderson.

And during that weekly conference, any trials that were going to be presented to go forward in the institution had to be presented through that conference. And so, really, that was a great format to learn about clinical trials, clinical trial design, how to format a question and put together something that actually could be an answerable question. And so, in doing that, and then attending our multidisciplinary conference where there was constant discussion about whether or not patients with metastatic prostate cancer should be receiving treatment of their primary, I approached Ana Aparicio, who's one of the medical oncologists at MD Anderson. And with my co-fellow at the time, Scott Delacroix, we basically sat down and hashed out a design that we thought might be a reasonable approach and fairly pragmatic, which I think is an important part of clinical trial design, and then presented it to the group.

And ultimately, it's part of what got me recruited to MD Anderson, was to do this trial. And it has been eight years since the time it opened to complete it. And it was a trial that, as you know, I mean, we opened it at MD Anderson, largely through institutional support and some philanthropy that we had, and then we were able to expand it to your site and to the UBC in Vancouver and Fox Chase Cancer Center. And really, a lot of that work got some excitement in the SWOG group. And my mentors there were Dan Lin and David Quinn and Ian Thompson were able to kind of bring a lot of this forward into a Phase III.

But it's always interesting to me, and I always tell the fellows as they are coming through our program, that what you come in thinking you're going to do is not necessarily what you're going to end up doing. And so, part of it is just understanding the discipline, and understanding how it works, and understanding how translational science works and clinical trials works, and all that is important. And then you kind of have to develop your own path as you figure things out.

Matt Cooperberg:  Absolutely. And be ready to seize the opportunities when they present themselves. Do you want to tell us a little bit about the trial? I understand you have a brief summary slide for us.

Brian Chapin:  Yeah. So, let me share my screen here. So, basically, this is our Phase III randomized trial of standard systemic therapy or standard systemic therapy plus definitive treatment to the primary in metastatic prostate cancer. So, SWOG 1802, which is actively enrolling. This is a study looking at the role of local treatment in the setting of metastatic disease, treating the primary tumor. Patients that have castration-sensitive prostate cancer, newly diagnosed, so essentially de novo metastatic disease, are eligible.

Patients can receive any of the standard systemic therapy, as per NCCN guideline, which is basically, at this point, a whole host of systemic approaches. We did that largely because it allows for changes over time as new therapeutics become available and the paradigms change. Patients received that therapy for up to 22 to 28 weeks, at which time they are randomized to undergo continued systemic therapy, with or without definitive treatment of their prostate. And definitive treatment could be surgery or radiation. It's basically at the physician's discretion and the patient's choice, as long as it has been identified prior to the randomization time point. We had several various stratification factors to try to make sure the arms are balanced. And then patients continue on their systemic therapy approach until the time of progression, at which time they come off of the study and can go on to any of the standard approaches to treatment that would be available to them.

And then, the endpoint. The primary endpoint is overall survival, but we are also looking at a number of things, including progression-free survival, quality of life, the need for intervention to the obstructive-type symptoms. And then obviously, like any of these SWOG-based studies, we have a biobanking plan. And that is going to allow for substantial translational research. Recently, Amir Goldkorn, who is kind of spearheading our translational SWOG program for prostate, he submitted an R01, and hopefully had a fundable score. So, it would be exciting if we are able to take samples from this study and kind of expand our knowledge of prostate cancer.

Just to give you an idea of the enrollment. So, I put this together. As of today, basically, we are looking at 1,273 patients in total. We're at 242 currently. There are a number of sites that have recently opened the trial. Actually, it takes quite a while to get some of these places open and going. As you can see here, kind of the top recruiting sites that are listed. And a lot of the site PIs that have been involved with this project from the start, I mean, even back to when you and I were talking about this for the Phase II, many of these sites were interested and had been a part of the development and design of the study and have provided insight.

In the last couple of months, we've had a drop in enrollment, and I think largely in part due to COVID. From about March to May, we had a decline. And we started picking back up again in June. In June, we hit our expected enrollment to 20 patients. And I think this past month, we were somewhere in the mid-teens. So, things are starting to pick up again. And I'm hopeful that as the COVID crisis kind of becomes something more of a norm and we understand how to manage it, that we are able to get back to kind of status quo, as far as clinical trials are concerned.

Matt Cooperberg:  So, what strategies have you used to facilitate enrollment? As you know, UCSF is not the best-performing site in a Phase II, in part because, in large part actually, because our radiation oncologists' group was not willing to withhold radiation randomized to the control arm, or who would be randomized to the control arm. And this was before the STAMPEDE data came out. So, especially now that we have the STAMPEDE data out... And you mentioned Ana Aparicio. She had a great comment at ASCO GU when these data were being presented for the first time from STAMPEDE, that this is, despite it being a prespecified subset analysis, it is a subset analysis. If radiation were a drug, it would not be approved by the FDA based on the STAMPEDE data. But I think it has been somewhat broadly accepted as a valid subset. So, has that finding of benefit for radiation in a subset of an RCT, has that proved an additional barrier to accrual, or are you still finding you can convince [crosstalk]?

Brian Chapin:  Yes and no. I think what it has done is it got people excited about the possibility that these types of treatments are going to provide benefits to patients. I think that anytime there's a signal of benefit from the therapy we apply, we all get very excited about that. And, in a lot of ways, it biases what we do, which is part of the problem with trying to run clinical trials, is that there is physician bias in existence from the word, go.

But I do think that that came out, and it showed an overall no impact from radiation across the whole group. But in the subset analysis, the low volume had a benefit. And I do think that got some people excited about it. But I think it also raised the question of, is this question answered? Or is there still more data needed to support this? And so, I think it's actually got a lot of people interested in enrolling in the study because they want to basically determine if this is the right thing.

And I would say that there is probably less radiation or NRG involvement than I would have expected. And that maybe because of that reason, and it may not. I mean, who knows. But I think it's largely been more run by urologists as opposed to radiation oncologists, which we had kind of looked at this from the start as being more of a surgical-based trial, and then incorporated radiation and capped out the radiation so that we would have some surgical data. So, the number of radiation patients that can enroll is capped out at a third of the total. And that was before any of the STAMPEDE data or anything else was available. And I think that's because of the STAMPEDE data, because of the HORRAD data, because of the PEACE1 data, which should be coming out sometime in the near future. All of those are radiation-based data. And I think we wanted to have some surgical-based data to see if surgery's appropriate.

Now, what STAMPEDE doesn't do is it does not support the concept of surgery in the setting of metastatic disease. I mean, we can not assume that local therapies are the same. Now, they might be equivalent both when prostate cancer is localized, but I don't know that we can state that for metastatic patients.

And so, from my perspective, the sites that have been doing very well with enrollment are the sites that do not provide surgery to the primary in the setting of metastatic disease outside of a clinical trial. And you do have to have that discipline. And it took a lot of effort within our own group. And then I've had lots of conversations with site PIs from the other programs about that.

And essentially, if a patient is understanding that this trial is essentially the standard of care, with a 50% opportunity to have an additional therapy that you wouldn't be getting otherwise, then you get more buy-in. If the patient could decide that they want to do the therapy anyway just because, and because you have a physician who might believe that it's active and beneficial, then that's going to happen. And those patients are not going to go on the study anyway.

So, I think the impact of the available data has people excited. I do think it warrants further evaluation. And I'm hopeful that we can continue with the accrual and keep the trial going and complete the planned 1,200 patients.

Matt Cooperberg:  I recall you talking to Jenny Donovan at some point about lessons learned from protecting their successes and enrollment there. Anything that you have found applicable from?

Brian Chapin:  Yeah. We did. And unfortunately, we couldn't financially bring on someone to do that role for us here in the US. But yeah, I mean, definitely some lessons learned. And I think part of it is really just you have to kind of educate the physicians taking care of the patients to try to make sure that they are not having their bias come across in the discussion.

And what we did for SWOG and for 1802 is we put together a video. And the video has a... there's a link that is available through the SWOG website, and through YouTube, and has been sent out to all the site PIs, and the patients can view that video in the clinic, in the waiting area or at home on their own. And basically, it's a five-minute video just describing the trial with some graphics to kind of make it very plain for people to understand what is going on, and also to take out some of that bias because it is really hard if you believe that it works or if you believe it doesn't work, it's hard not to get that across to a patient. As you know, with everything else we do, it's a challenge. And so, that is one thing we've done.

And the other is, I have a terrific research group here. And the research nurses really do all of our physical consenting. And so, they will sit down with the patient after we've gone through it with them and really go over the details to the finest point of exactly how often they need to be here, what they have to do, and really what the goal is of the study. And I think that has been very successful.

Matt Cooperberg:  Have things been changing with PET imaging now that we're finding more metastatic disease with lower volume? Is that changing the nature of accrual?

Brian Chapin:  I mean, yes and no. I mean, I think a lot of us are uncertain what to do with this PET imaging. I mean, we've had this conversation offline many times. We recently just submitted an editorial, going over kind of all of these issues that are coming up with clinical trials. In particular, with this study, what we are seeing is that there are more people getting PET scans in this setting. Whether or not it's approved to be in this setting, they are happening more frequently. Or patients are getting PSMA PET scans kind of outside of the US, or even in the United States, on some studies and whatnot.

And we anticipated that when we wrote the trial. And so, with the trial, it is written in that if a PET is positive, as long as it's biopsy-proven metastasis, then patients can still go on trial. If the PET is positive in a single spot and the biopsy is inconclusive, I personally think you got to give that patient the benefit of the doubt that it could be a false-positive, and you got to move on with your local treatment as you would in any other setting.

It has definitely muddied the waters a little bit. Our radiology colleagues and our nuclear medicine colleagues, they've created a lot of things that have really kind of outpaced our ability to test them. I mean, especially in prostate cancer, when you are looking at minimum 5, 7, some would say 10 years before you can even say if there's an impact of something that we are doing. And imaging is one of those.

Matt Cooperberg:  For sure. The last theme. The experience of getting this trial off the ground, obviously very high activation energy, and major kudos that you went over that peak. You mentioned mentorship from Dan Lin and others. What were the key factors that actually got this off the ground? And what was your experience working through SWOG? I mean, do you think it's a sufficiently effective process for surgical trials?

Brian Chapin:  I think mentorship is key for everything that we do. I mean, if I don't know how to do something, I'm going to ask somebody to show me how to. And that's part of being a mentee as well. I mean, you have to kind of know when to reach out and know when to kind of push things. But yeah, I mean, Dan was instrumental in getting this up in front of SWOG. I mean, we presented this first in front of SWOG in 2015. David Quinn and Dan Lin were the SWOG prostate leaders at the time, and still are, and were incredible with helping me to put together an approach that would be acceptable to the group.

My own internal institution. I mean, I have my chair, Colin Dinney, who basically has been supportive from day one and helped me to get the Phase II going, which then resulted in the Phase III. Ana Aparicio is the co-PI on Phase II. She is the medical PI on the Phase III. I mean, she has had a huge part of the role of putting this together.

But yeah, mentorship, I think is critical. And part of that is just trying to figure out how to manage the systems. I mean, a lot of us don't even know how the collaborative groups work. We put together a seminar series for the SUO, and one of the topics is talking about collaborative group trials and how the actual system is put together because I don't think people realize. And there is not just the group itself, but there's the actual steering committee within the group. There's the task force. There's the GU steering committee at the NIH level. I mean, there are a lot of levels of kind of oversight to get a trial to completion that takes a lot of politics and tact. And sometimes I don't have those, so I got to reach out to my mentors to help with that.

But yeah, I mean, I think that SWOG has been incredible in the sense that once the SWOG buys into an idea and once SWOG wants to support a trial, I mean, it is basically, it's like a moving train, it just keeps going. And the SWOG ops people have been incredible with helping to put together the study. I mean, once we got approved, we were activated within like 10 months, which is almost unheard of. It was incredible.

I do think that the collaborative groups... Some of the struggles that collaborative groups have are that when you... And you probably have this at your institution, like I do, where if I enroll someone in a collaborative group study, my institution loses money each time I do it. And the reimbursement is just lower than what it costs to run the study. So, from the start, you have to have a good question that people are excited about, something they want to offer their patients, something that they are going to get behind. Otherwise, it's not going to make it. I mean, it's something that will fail. But I don't foresee a future where we are getting more money for these studies, so it's going to be what it is. So, I think having something that is a good question, a good hypothesis and a pragmatic design that is something that's reasonably doable, is a big starting point for SWOG.

I do think that there are some inefficiencies in SWOG. And it's true with a lot of the collaborative groups. And it's not the fault of the groups. It's just that is how the system works. And I would like to see a shortened timeframe from the idea of being put forward to the trials being activated. I mean, in our case, it was four years from the time it was presented to the time it was activated. So, in prostate cancer, that's not forever, but by the time some of these things get going they lose some of the enthusiasm behind them.

Matt Cooperberg:  That is my last question actually, is do you think we have the right structures in place, or do we need something more like NRG, specifically for surgical-oriented trials? Do we need more, new infrastructure? What else can we do to get more trials actually going and activated a little bit faster?

Brian Chapin:  I think that NRG's part of the cooperative groups. I mean, it's not necessarily separate. But what NRG has done super effectively is that they are able to efficiently come up with a trial, put forward a design, accrue to the study. Granted, many of their studies have radiation treatment in both treatment arms, so it's easy for centers and physicians to be excited about accruing to those studies. But even so, they still are able to accrue quickly, get their results, and then move on in the same space without having to compete or overlap with other trials. And so, I applaud them for that efficiency. I wish all the groups were able to do that.

But I think it's really challenging for radiation, for surgery. Anytime you're looking at an intervention that has a substantial cost to it, how to measure and how to compare on a trial is a challenge. And we do not have industry sponsorship that is going to pay for... There's not a scalpel company that is looking to give me money to do surgery or not to do surgery. And there's not an SBRT company that is looking to cover the cost of a $35,000 SBRT treatment. So, I mean, that's kind of where I think a lot of the hangup is for looking at some of these intervention studies, which is why you see trials that are... It's surgery with or without a therapy; it's not necessarily surgery with or without surgery.

So, I think that it is really hard to do a trial where you are just asking a surgical question about technique or approach. Our bladder cancer colleagues have been able to do it through an R01 with the robotic cystectomy trial with [inaudible 00:21:12]. But I think those are kind of one-offs, That's not a system that is in place that we can continue to take advantage of and move forward with.

And so, I think there's been a lot of work by many about trying to figure out better ways to do it, and more pragmatic ways to randomize patients and to do things that don't require so many resources. But I wouldn't say that I've seen that happen to an extent that I have been able to participate.

Matt Cooperberg:  Well, aspirational goals, I think, for all as we go forward. And yeah, there are probably opportunities to rethink things in the intra and post-COVID era too, to get better interactions and make plans for the future. Any final thoughts for us?

Brian Chapin:  I think the main point I'd want to get across to everyone that's listening is I think as urologists, it's not necessarily been our culture to put patients on trials. And I think that we always have the patients' best interests at heart. And I think that we always want to do the best for our patients. And unknowingly, sometimes I think that we have done that in the absence of data and in the absence of generating that... or the ability to even generate that data, we sometimes think we might be helping and benefiting people, but we might be unknowingly hurting them and affecting their quality of life. And I think if we can kind of start curving our culture to be more of one where there is a trial for every patient. And if we can actually identify physicians and sites that are going to be really motivated to do this, I think that's how we need to move forward and that is how we need to make sure that we are actually generating evidence to figure out how to treat patients best.

Matt Cooperberg:  Could not agree more. Thanks very much for your leadership in this area, Brian. And really great to talk to you.

Brian Chapin:  Yeah. Thanks for having me. This has been great.

Matt Cooperberg:  Thanks for your time. Hope to see you in person soon, sometime in early 2021.

Brian Chapin:  All right.