Charles Ryan: Hello from PCF 2019. I'm delighted to be joined by Dr. Christopher Logothetis, who is Professor and Chair of the Department of Genitourinary Medical Oncology at the MD Anderson Cancer Center in Houston, Texas. Dr. Logothetis has been one of the pioneers in prostate cancer clinical research and is really one of the few individuals who was with the PCF from day one. I think we're now in our 26th year here meeting as a retreat and as an organization, and I'd love to get your perspective on the long view of the PCF and what it's meant to you, and what it's meant to our field.

Chris Logothetis: PCF is an interesting organization driven by personalities, inspired by the desire to make a difference, and frustrated by the regulatory administrative structures that didn't reward the best science. One of the biggest lessons that I learned from them is the evolution from rewarding senior leaderships to maintain their leaderships, in hopes of creating loyalty, was replaced by an approach of rewarding young investigators to create, ferment, and new ideas that challenge the field. In many ways, it's a lesson for many of our academic centers and many of our organizations that they should take a page from. I think actually that's been their major organizational achievement. The general creativity and the enthusiasm of the organization and constant evolution in response to opportunities has also characterized them. Obviously, desire to make a difference is at the core of what's happening.

Charles Ryan: Absolutely. What's interesting to me is PCF, and previously CaP CURE, have been at the heart and soul of my whole career from day one when I was a resident working on a CaP CURE funded project. It's interesting what you say that the organization stresses the cultivation of junior people, young minds, over the reward of the senior people. That is just taken for granted in this institution and it is something that as I step out of the prostate cancer world, I realize it's not that way everywhere, and I've been really the beneficiary of that culture. Of that culture of grooming people from day one and deferring to the younger people when opportunity comes along. It's really been great for my own career.

So you must've seen this organization grow from... I think it was a handful of you at Mike Milken's House at Lake Tahoe in the early 1990s to, I think we have 690 scientists here today in a convention center in Southern California. So it's really grown to be quite a significant operation. During the course of the arc of your career and this quarter-century with the PCF, you've been involved in the development of many new treatments, many new therapies. You and I have had an opportunity to talk about the differences between drugs and therapies, and the developments of treatments and platforms. I want to get a sense of where you think we are with these concepts. First of all, the concept of delivering therapy is more important than delivering drugs.

Chris Logothetis: Yeah. Thanks for the opportunity to point that out. When we started at the beginning, we didn't have any arrows in our quiver to deal with, so we had to focus on drug development. That is the strategy of identifying a drug, identifying a target, and giving the drug to patients and seeking benefit beyond the toxicity. That's drug development. In the years that have done that, our quiver is now filled with multiple drugs, and the environment is complex, so to stay focused on developing drugs, which remains essential, but exclusive to developing integrated strategies that take the complex therapeutic environment into account, is going to greatly limit us. The strategy of developing a large Phase III trial, though necessary to prove the efficacy and toxicity of a single drug, has to now be recognized is a very limited benefit for patients with prostate cancer. Because how one takes that and integrates it into complex therapeutic environments is where we believe the major therapeutic advances will come even as we fill this.

And that requires a couple of dimensions to achieve that goal. First is you can't go to associations only. You can't look at a set of genes, or a set of proteins, or imaging markers alone. You actually have to understand mechanism because the mechanism is what provides the rationale for combination. So all the associations that we develop have to be functionalized. That's one basic principle. The second issue is we have to deal with the dimension of time and trial design. Some of these that have been championed by Ana, who spoke earlier, are the trials that allow you to prompt the tumor with a specific powerful biological stimulus, screen for changes, and use that change or the response of the tumor to define your next therapy. These are critical. It turns out that it's very difficult to achieve because serially sampling tissues is very difficult to do in prostate cancer. That's why for a while we've now invested in liquid biopsies and I think they're coming to four.

So the concept of drug development is now a limited concept in prostate cancer, because major advances were curved between interaction between platforms, the concept of associations in the clinic to determine future outs without functionalizing it limits your ability to reason new combinations as well as they should be. All those parameters need to be accounted for. To achieve that goal, you need an infrastructure to integrate data. You need each platform, the functionalizing platform, the marker associations, the clinical trial platform to function equally at a very high level, and you have to be driven by a community spirit that willingly integrates all these to make a difference. It's not an easy goal to achieve, but whoever achieves that at the highest level is going to have the biggest impact.

Charles Ryan: Well, let's tie this back to our conversation about the PCF, because you may have the bioinformatics person in California, you may have the patients in Texas, and you may have the assay development going on in New York or somewhere like that. So this institution, this institution of the PCF and the culture of collaboration that it has created, allows us to bring those pieces together, I think even if we don't have them in our own individual institution or a university, and that's very exciting to me.

Chris Logothetis: Agree entirely. Couldn't agree more that that's one of the critical roles they've done is they've allowed many investigators to replace loyalty to their institution, and balance it better with loyalty to the science and their patients.

Charles Ryan: Yeah. Right, and my own personal story. I've been in a few institutions, all have been PCF institutions and I feel like I've never left the family, so to speak, because it's one group really tied together now globally around these issues. It's an exciting time in prostate cancer. I want to get back to a point you made earlier, which is the element of time, the rational biology question behind the combination. I see that and I think about that. I think that we have a lot of studies that are happening now that are combination studies, that are actually diving into the clinic with a relatively small amount of mechanistic information. But we don't have the time to spend five years doing all that mechanistic work, when we can combine a checkpoint inhibitor and a PARP inhibitor in the clinic now, and get that answer while we're working on those mechanistic questions. It's a little bit of criticism also, right? Because we have some combination studies that are starting where we haven't quite worked out what's going on or what's the potential there.

Chris Logothetis: I think my age is going to differ with you, all right? Then there's the reality is sometimes the best way to be spendthrift with everybody's time is to be too rushed. We have opened too many trials with too little thought, with too little design, without at least establishing possibilities, so we could work out the mechanism in parallel, and it's caused us great, sort of, delays in developing therapies. So you're right, it's a balance, and ultimately the experiment that really defines whether we go forward or not is a clinical one, and those observations that come from there. But co-clinical trials and doing things functionalizing them in parallel becomes a critical aspect to gaining sufficient confidence to go forward.

Charles Ryan: Yeah. Well, it's always a pleasure to talk to you, and I wish I could keep going, but we're going to run out of internet space, so we'll have to continue-

Chris Logothetis: Well it's a privilege.

Charles Ryan: ... continue this conversation elsewhere. But thank you so much for your mentorship and your years of guidance to the PCF. It's always a pleasure to talk to you, Chris.

Chris Logothetis: Thank you.

Charles Ryan: All right.