Videos of "New Horizons" Session at the 2011 PCRP IMPaCT Meeting (Text Version) - Dr. Oliver Sartor

Title of Talk: Prostate Cancer: Recurrence, Failure, and Advanced Disease

Dr. Howard Soule
He is a native of Louisiana, a Medical Oncologist, who—whose career took a—took a left turn probably for the better for a while after the disaster of Hurricane Katrina and he went up to the Dana Farber Cancer Institute to practice his skills up there. But fortunate for the folks in Southern Louisiana he’s back at Tulane and he is—he’s running their Medical Oncology Program down there at Tulane University. As a Genitourinary Medical Oncologist, Oliver has led a number of—of large Phase 3 trials and is an expert clinical trialist. And it’s also interesting to note that—and I had to ask him again today—his son represents the fifth generation in his family to be a physician in—in Louisiana. So Oliver, we’ll look forward to your comments about the hot new drugs out there.

Oliver Sartor, M.D.; Laborde Professor of Cancer Research, Medical Director Tulane Medical Center, Departments of Medicine and Urology, Tulane Medical School
Thank you, Howard. It’s a real pleasure for me to be here today. You know I look out and I see many people who could be my patients or might be my patients and it’s a big humbling because you know we have such a huge job to do. And as a Medical Oncologist, I’m incredibly aware of the challenges we face in the field, and the fact is every day that I’m in clinic, I’m aware of our deficiencies.

I thought I would share just a few things with you today. So it’s a brief talk and I was assigned the discussion on recurrences failing advanced disease, where are we now, and where we do go from here? And when we look at curing prostate cancer I think we have to deal with both facts and fallacies and I think Joel did a beautiful job of introducing the topic by noting that only about 14% of people with prostate cancer will actually die today.

Now one of the things that I get asked is you know well how do we cure prostate cancer? And I will tell you that today there are only two ways to cure prostate cancer. It’s surgery and radiation; that’s it. If you want to be cured, surgery or radiation represents your only possibility. And if surgery fails, then radiation is the only possible cure, because I get looked at all the time. They say well how are we going to cure this disease? And I say well we can cure the disease, but we also know as Joel very clearly pointed out and it was interesting; I was about to put the Whitmore quote within my presentation as well but Joel set me up for it. But the question is—and this goes down to my second bullet, the necessity of cure is often overestimated. And even men with PSA recurrences may have a low risk of clinical impactful disease.

So what we need to do, even for those with recurrent disease, is to segregate those who require treatment from those that do not, and that is one of the many challenges that we face. Now it’s also interesting that he quoted from the Freedland paper in JCO and chose a different figure. This is from the Hopkins database and it shows you the wonderful ability for great databases to give insights into the disease. And what we see here is not the people with the rapid doubling time who represent the minority of the disease, but rather then men with the slow doubling time and I’ll try to point this out on both sides—what we have is all cause mortality here. And these are people who had a PSA recurrence after a radical prostatectomy, and after 15 years prostate cancer-specific mortality in the subset is less than 10%. So 90% of these men after—after 15 years of follow-up are not dead from their cancer. And by the way, these are men who received no additional treatment, okay—no treatment.

So you have to be aware that even in the PSA recurrent state after radical prostatectomy that there’s a substantial subset of men who may not even have a disease that is dangerous to their health. It’s a very important lesson because we have to know who to intervene with and who not to intervene with. As it turns out and I think you know this, our therapies are not optimal. Everything that we do has side effects and before we introduce a therapy that has the capacity to harm we have to feel confident that we have the opportunity to benefit. And that’s part of the ardent science of medicine that I think we can make many improvements in going forward, because a lot of these folks actually do get treated too aggressively.

Now salvage radiotherapy and I’m looking at the PSA recurrence after patients, who have had surgery, is also—and this is another Hopkins database study that—well look at the title up here, The Salvage Radio-Therapy Increases the Opportunity for Cure, but the benefit was restricted to PSA doubling times of less than 6 months. Why was that? Because treating people who didn't need to be cured with a slow PSA doubling time did not provide a benefit; only segregating those at risk for death and applying the treatment in that population was key for the benefit to the patient, okay. Now is there—is this theme emerging? Hopefully it is. You saw it in Joel and you saw it with me. We’ve got to be better at discriminating who needs to be treated and who doesn’t in order to be good.

Now as we move into this sort of next era of this non-metastatic but hormone-sensitive prostate cancer because remember; we’ve got some pretty blunt tools—we then begin to pull out our hormonal therapy, okay. And hormonal therapy has been around since 1941. Nobel-Prize winning work from Dr. Charles Huggins, but we’re only now beginning to understand these interactions between the PSA recurrences and the hormonal therapy. So there’s a beautiful article presented by Dr. Laurie Klotz from Canada and also you quoted Dr. Klotz in your presentation as well. It’s—it’s amazing how we look to leaders in the field to provide insights.

We looked at 1,300 patients in Dr. Klotz’s study and the survival for those on hormones either intermittent or continuous was about 9 years and one of the things that was interesting is that the intermittent arm had more disease-related deaths; 122 versus 97, slightly fewer disease-unrelated deaths but here are patients who have recurred. And all of these were actually after radiotherapy and we had 696—almost 700 patients and yet for prostate cancer deaths it was only about 100. So even those who were PSA recurrence getting treated, the likelihood of dying from something else is still pretty high. And hormones work for a long time.

And then we begin to move in what we call the castrate-resistant disease and this today in our PSA era is almost all the non-metastatic variety. The vast majority of patients I see are with PSA recurrence, treated with hormones and then have another recurrence, do not have metastatic disease. But we can begin to understand how these patients can be segregated. This one doesn’t project particularly well but both the PSA high and the PSA doubling time allow discrimination. Again it’s a risk stratification procedure. And these risk stratifications are key for clinical decision making to apply the morbid therapies that we use to the group of men that are most likely to benefit.

Now when you get metastatic and castrate-resistant disease, we’ve got some pretty big trouble. And at this point we know unfortunately that the vast majority of men with this disease state will actually die from their disease. It’s big trouble but we’re getting a little bit better. And what I thought is—I would put the history of regulatory approvals here, and I don’t expect you to memorize this but going back to 1981 we were using Estramustine and it really didn't do a lot and then we began to introduce these radioisotopes and Mitranzantrone and all of these were FDA-approved because they reduced pain. It wasn’t until 2004—wasn’t until 2004 that we actually had any therapy that would prolong survival at all. And between 2004 and 2010 there were no approvals. But in 2010 we have two approvals, a novel immunotherapy and a novel chemotherapy and Abiraterone which I believe will be FDA-approved quite soon—all of these 2010 FDA-approvals and the 2011 as well are because prolonged survival has been noted in the Phase 3 trials.

This is an advance. Now you—I’m going to show you the data and you’re going to say well I want more. Well so do I. Now this is the Abiraterone data and you can see in the post-Docetaxel, post-chemotherapy setting that there is a modest prolongation, medium from 14.1 to—from 10.9 but I promise you that when you take these very, very, very advanced patients and you get a survival signal, as we move it up a little bit I think we’re going to be doing even more. So now we have a novel hormonal agent and we’re going to have more to follow. There is a concept here that is very critical. And that is an androgen receptor remains a very valid important target. But unfortunately I have a love/hate sort of relationship with the androgen receptor. I love it because it is the validated target; you know Don Tindall and others in this room have helped us to understand how critical it is for ongoing signaling. But at the same time the harder we hit that androgen receptor the more side effects we incur. The sexual dysfunction, the fatigue, the emotional (ability), the loss of muscle, the bone; we know that there’s side effects to these agents and I really want to know when are we going to get beyond the androgen receptor. So I love it and I hate it. So I use it all the time because I have to but I really want to do better.

Now the non-androgen receptor targeted therapies under current consideration include chemotherapy and you know I don’t want to be a—a chemotherapy apologist but I’ll tell you that it’s an effective therapy for some patients—some patients have real benefit but the toxicities are more than we’d prefer. We have fatigue; we have increased risk of infections. We have problems with associated with lower blood counts, anemia(s), potentially thrombocytopenia; clearly we need to do better.

Now immunotherapy, it’s now a validated approach but as you probably are aware the prolongation survival is modest and now we need to do better. And I’m hopeful that we can; I think that there are a whole slew of novel immunotherapies now moving into the advanced trials that are going to potentially provide benefit for the patients of tomorrow. But what about the other targeted therapies. Well, we still need validation. They’re interesting; so here is the Sipuleucel T; that’s the Provenge you’ve heard so much about and here you’ve looked at the survival curves and it is 25.81 versus 21.7. These are patients with metastatic, asymptomatic, or minimally symptomatic castrate-resistant disease and it’s better but we want more.

And here’s the Cabazitaxel; these are patients in the post-Docetaxel setting, and post-Taxotere setting and we did prolong survival modestly but again we want more. And there’s side effects from these therapies as well.

So I thought I would introduce very briefly in the final 3 minutes that I have, something called stromal-targeted therapy. And one of the tremendous challenges with prostate cancer, particularly metastatic prostate cancer, is that it’s a heterogeneous group of diseases. Even our best androgen receptor-targeted therapies like Abiraterone do fail; they’re not curative. And when we look and this is from the Michigan Autopsy Program, Ken Pienta and colleagues who have done such a magnificent job of—up in Michigan studying this disease, they found that the cancers were different from patient to patient and as Howard Soule knows there’s now a molecular characterization, also coming from Michigan, but we know that there are lots of different subtypes of this disease.

And the thing that has become really hard is that it turns out that there’s even heterogeneity within individual patients, so the right shoulder and the left hip may not necessarily be the same. This heterogeneity is a tremendous challenge for targeted therapies. In addition, I do believe that there’s something like a cancer stem cell. It still remains controversial; it is not so controversial in diseases like CML, Chronic Myelogenous Leukemia, and we know that there are differentiated cells that evolve from less differentiated cells. We know from a huge number of animal model experiments that a stem cell probably does not make [new] PSA and that it doesn’t have any differentiation and they can remain quiescent and we know that our hormonal therapies and our chemotherapies are not effective in eliminating the stem cells—except in a few select cancers like testicular, which Joel mentioned, where we might be able to eradicate that stem cell.

So when I look at what I call the dual challenge of advanced prostate cancer I think that we have to overcome both the heterogeneity and the stem cells. How do we target these cells that are heterogeneous in both genotype and phenotype in the same patient? Can we inhibit stem cell survival and growth in patients with widespread cancer? That’s where I think we need to go. And one of the ways to think about this is within the context of the environment.

So let’s look at this beautiful bird, the Ivory Bill Woodpecker. The Ivory Bill Woodpecker is probably extinct. It used to live in the Southern [Inaudible] Forest. They didn't shoot the bird; it didn't—you know it wasn’t an army of gunmen who went out and—and killed the bird. All they did was just cut down the trees that constituted its habitat. And after you removed the habitat, the bird went away. It’s an environmental approach, a microenvironmental approach that is translatable into the cancer arena. And I don’t expect you to memorize all the different stromal-targeted therapies that we have in concept today—angiogenesis inhibitors, bone stromal-targeted radio-pharmaceuticals, things that will take endothelial antagonism. Joel, thank you for your contributions in this field; we’re still waiting to put it—get it over the finish line, but it does have some activity. Joel was instrumental in the development of this class of compounds.

The dasatinib which are the SARC inhibitors, anti-ligands, the bisphosphonates, all of these things are potentially going to provide advances but we have to learn how to optimally give them and there’s more. There’s more coming. So one of the things that I think is interesting is this particular compound which seems to target both the tumor cell and an aspect of the stroma as well and on the left-hand side you see a bone scan that is rather remarkably positive; on the right-hand side right here, 12 weeks later you see a bone scan that is rather remarkably normal. And that’s with treatment with the new compound called XL-184. It is a dual-targeted agent to VEG-F Receptor Type 2 which is part of the stroma, which is an angiogenesis inhibitor but in addition of [CMET] which is another target on the cancer cell inhibitor. So now we’re combining these direct targeted therapies to the tumor and the environmental regions as well.

So where do we go from here? I’ll tell you that it takes four drugs to cure Hodgkin’s disease and that’s one of our most curable malignancies. And if we’re going to make progress, I really believe that it’s going to take multiple drugs for metastatic castrate prostate cancer as well. We really don’t know right now how to optimize our combinations and sequences. And that’s one of our immediate challenges. Now that we’re having these additional therapies, how do we put them together in the most optimal way? But we need to do more; we need more agents. We need more effective agents because even our incremental progress which I am impressed with by the way because it’s the product of so much hard work and smart people—we still need something more.

I keep hoping that maybe we can target one of these stem cells in a rather strategic way but I do know that—what I believe—if we’re going to cure this disease it’s going to take a multitargeted therapy. We’re going to have to probably include the microenvironmental sites that are critical for tumor growth and the tumor too; that’s my hope, that’s my wish, and I’ll be working for it during the years ahead. Thank you very much.