William Oh: Thank you, this is an interesting talk. I didn't really realize that I was supposed to do two years only. I'm going to do a more conceptual talk because I think we've heard in this meeting that it's really the biology that's probably more important than the number of metastasis per se. Although, we don't fully understand what the most important factors are. I thought I would start with some historical context, which is the past. When I was a fellow many years ago, this is me starting out in this career 22 years ago. This was a slide that some of us have used, which shows a few things. One is that with androgen deprivation therapy, that's about a 5, 6%, 10-year survival, and the use of an antiandrogen had very little impact.

Actually, it gave me a chance to go back and look at this very classic paper. Many of you saw this, I used to quote this, this is Maha Hussain and Cathy Tangen from SWOG. They looked at 8894 which was the flutamide study, and about 7% of the patients lived 10 years with just androgen deprivation alone. As we think of the biology, there were clearly, even 20 years ago, there were patients who lived for a long time and we didn't understand why. There was an interesting comment here that they tried to model this and found that they could predict 98% of the patients who would die within five years. But they were very bad at predicting who would actually live for a very long time. I'm not sure we're actually that much better now.

This is a more recent study from the Scandinavian prostate cancer group of about 915 patients and a slightly lower percentage, 4.4%, survived greater than 10 years. Which is surprising given all of the new therapies we have during this era, but a lot of the same independent predictors of survival. The real issue now in the present, and you can see I've aged, I have the gray hairs and I'm not... I think I've been fortunate as everyone in this room has been to watch the last decade be an era of tremendous progress. I'm going to use the trials (TROPIC, COU-AA-301, AFFIRM, COU-AA-302, ALSYMPCA, PREVAIL, CHAARTED, STAMPEDE, LATITUDE) on the left side of the slide as the context of that we've all been hearing about for a case I'm going to talk about in a minute. But, unfortunately, the present standard of care here is that systemic serial therapy is what we do for patients with polymetastatic disease, ADT, ART, chemo, bone-targeted therapies such as radium, maybe Sipuleucel-T in the United States.

I think we all understand that local and/or metastasis directed therapy is still investigational and we're not really considering this for high volume or polymetastatic disease. Although, the question should be whether that's correct or not. I don't know that we understand the biology of why five metastasis should benefit from local therapy, but six might not. Then the other question really is we've learned that earlier intervention clearly seems to improve outcome. If you use the same therapy, whether it's docetaxel or abiraterone in the HSBC setting, we seem to get a larger benefit. This is what we know now.

This is a nice abstract that came from the GU group at Dana-Farber of Chris and Mary-Ellen oversaw a review of two cohorts from the 2004 to 2007, and subsequently from 2010 to 2013 in the era of these newer therapies. I'll just point out that the number of patients who lived five years in this institutional cohort went up from about 10% to about 26%. I think we would all argue that good systemic therapy has clearly changed the present state for these patients. Now the future, I couldn't find a picture of me in the future so I had to pick this person. He's about 10 years older than I am. The question really is where are we going with polymetastatic disease? Okay, and as many of you know, this is, of course, Jimmy Carter and his metastatic melanoma, which I think he's become the poster child of immunotherapy. I think this is still an area. This concept of cure is still an area that our patients, Mr. Millman I think would agree that we're looking for changing the future. Maybe not in two years, but in the next five, 10, 15 years, we clearly want to change the outcome for these patients with metastatic cancer.

In fact, I did a search for the word cure in PubMed with cancer, and we're not supposed to use this word. There's a lot of confusion about what cure even means, and yet look at the number of times these two words are actually quoted together in academic papers. Of course, we understand that there's a paradigm for cure, which is childhood leukemia. You can see on the graph on the left that with effective chemotherapy, and I could have used testicular cancer as well, that clearly with effective chemotherapy and subsequent eras, we were curing more and more patients. And now it's in the 70, 80% range are cured. Prostate cancer, we understand is a much more complicated disease given the long natural history, and this is the bill access in paper but going out 23 years, we still sometimes see that. Not only are these patients dying of comorbid illness, but they also may be having very late recurrences of their cancer. 

The question is what is a cure? What does it mean for a patient to be cured? Because we also know that this issue is true, right? This is a graphic from a colleague at Mount Sinai, Julio Aguirre-Ghiso. There's a whole science behind tumor dormancy, which I think we've underdeveloped and we have a clinical trial seeing if we can actually induce dormancy using five days of sanidine and all-trans retinoic acid based on his preclinical work in mend with a rising PSA with prostate cancer.

I think somebody showed this earlier in the meeting. This is a paper, a small paper from Memorial led... I think the senior author was Howard around this concept of a cure paradigm and early-stage metastatic prostate cancer. This is not necessarily all-ago metastatic, but the argument here was that with a series of additional treatments, ADT, ADT plus surgery in the middle, and then ADT plus surgery and radiation, you're getting greater chances of getting complete radiographic and clinical responses. If you looked at the patients who were off of their ADT and had a PSA that was undetectable with a recovered testosterone, about 20% achieved this in this very small pilot study. In fact, the concept is, is this a cure paradigm? Can we start to use this as a way to define what we're trying to achieve with multimodal therapy?

Let me just give you a quick example of a patient of mine who's a urologist at Mount Sinai, a voluntary urologist. In fact, he wrote up his case so the reference is on the slide. He presented in 2013 with a PSA of about 80 and multiple bone mets. You can see a quite significant disease, he was symptomatic. He started zoledronic acid and developed ONJ. He, subsequently, asked for and received a RALP, a robotic surgery. He had six cycles of docetaxel. He was actually about a year out from when CHAARTED was first presented, but asked for and we discussed it and thought it was very reasonable for him. He subsequently received three months of enzalutamide and six treatments of Radium 223. He's now seven and a half, about seven years out and his bone scan is completely negative. He actually had a Gallium PSMA that's also completely negative.

Now the question is obviously he's an anecdote, he was a patient who was a physician and understood the consequences of his situation. We did design a trial to try to see if we could mimic what happened for this particular man and we called it PRINT, Prostate Cancer Intensive, Non-Cross Reactive Therapy. We did not do it for hormone-sensitive disease, we weren't that brave. We thought we would try the same model for a CRPC to do a rapid cycling of different therapies. This is what we did, three months of abi plus radium, followed by three months of cabazi plus carbo, followed by three months of enza plus radium. This was one of my fellows who's now in attending. It took about two years to get funding. So thank you to a Sanofi and Bayer for funding this study.

In the middle of the study, as everyone knows, ERA 223 came out so we did have to remove the radium from this module. We are going to present this data at GU ASCO, but what is my prediction for the future? I think we've all heard during this meeting, molecular characterization of these tumors will be increasingly relevant. Immunotherapy, I think is going to be increasingly important, and combinations, including local and systemic treatments. I think the question of cure really is a functional cure. I think if these patients are living for long periods of time, is cure possible? Even in polymetastatic prostate cancer? I think the answer is yes if we are flexible about our definition. This is my patient, he gave me permission both to share his story and to show his photo. I think Joseph Conrad said, "The question is not how to get cured, but how to live." Thank you very much.