The Role of the Urologist in the Current Management of Advanced Prostate Cancer: 2016

The Role of the Urologist in the Current Management of Advanced Prostate Cancer: 2016

So you know we we’ve heard about these trials. We know that all these new, many of the trials that have shown a survival benefit in metastatic castration resistant prostate cancer been single agent trials. Now we are forced with again trying to figure out as Neal was talking about you know, especially with again these different mechanistic actions, how to actually use these drugs in combination.

These are my disclosures. So everybody’s seen this slide. This is that roller coaster slide that we are all aware. And again, I think it’s important that the urologist be involved in this entire spectrum of disease because again I would like urologist to basically own this disease. I think we need to continue to own this and be involved in the research. Everybody’s has seen the sentinel paper this is the Huggins and Hodges model that was again they won the Nobel Prize posthumously in the 60s. Again even though they didn’t have this understanding at the molecular level of the androgen receptor, they basically discovered that prostate cancer is a hormonally driven disease. As I keep telling all my colleagues, I think it’s going to be critical that we understand at a cellular level the mechanisms why the androgen receptor continues to play an important role. Then again like Neal had mentioned in his talk this morning and Larry did mention that again we know that 95% of, of testosterone is made in the testicles. You get a small percentage that has this paracrine production outside primarily in the adrenal glands. And again due to these mutations, now we see this production at the tumor cells actually produce their own fuel.

I stole this from Dr. Crawford. Again these are the sorts of historic landmarks as we talk about the use of hormonal therapy. And again, these are our current treatment options whether that be androgen deprivation as monotherapy, estrogens. Many of us in the day remember the use of DES bilateral orchiectomy, LHRH agonist and antagonist, anti-androgens, complete androgen blockade, and now some of these newer hormonal agents. However, ADT is not without complications. It’s not without risk and again there are a number of them that we are all becoming more and more aware of, and again it is up to us as the urologist as usually the ones that are instituting therapy, that we have to be cognizant of all the side effect profile. And again most of you hopefully are actively managing this and keeping your patients well aware of some of the risks that we create with androgen deprivation therapy.

As we move forward, we all know a significant number of men do fine just with localized prostate cancer. But as that first slide basically recognizes, there is going to be a subset of the population that is going to progress. And like Dan had mentioned earlier in his talk that this is sort of the big trial that was announced last year and this is the U.S. trial, the CHAARTED trial. And again as he presented in these patients, especially patients with high-volume metastatic prostate cancer that are hormone naïve, that the addition of six cycles of docetaxel chemotherapy with androgen deprivation therapy has a significant survival benefit and the delay to metastatic castration resistant prostrate cancer.

The jury is still out obviously with the low-volume disease, but again it is clearly important that the urology community understand this particular trial. Now again I think what you’re going to find fun and I’m already seeing it in Nashville is that you have a lot of medical oncologists who are promoting the use of early chemotherapy in the metastatic castration resistant prostate cancer space. Remember the minute we start ADT we change the disease, so you can’t really extrapolate the CHAARTED trial into the NCRPC space. So again understand that this is all driven around the androgen receptor. And again this is a great slide. This is the typical canonical pathway, but you have all these adaptive mechanisms that the cells will undergo that will impart resistance. And again, I really want all the urologists, especially if you are going to manage these advanced prostate cancer patients, to understand this slide.

What becomes critically important is that as we talk about this early identification of prostate cancer patients who are metastatic, remember PSA production is an androgen driven event. So you don’t have to have high levels of PSA to have metastatic disease. And then again that is a point that I think is lost on many urologists. So we talk about castration resistant prostate cancer as many of you know we’ve changed that verbiage over the past few years we used to call that hormone resistant androgen and insensitive. And the definition is really pretty simple androgen deprivation therapy, rising PSA, serum testosterone less than 50. You heard some great presentations about you know going lower with testosterone, and I think most of us agree that lower is probably better. And then we have this designation of what we call M0 and M1 disease, and I think it is very important to understand that at least right now if you have M0 disease like Larry talked about in his breakfast talk this morning, is that we have none of these approve agents that we’ve talked about over the past two days are approved for M0 disease. So it’s observation and clinical trial when you have radiographic disease however then we get into this whole game.

So again this is a different way of looking at it, these are all the therapies that basically have been approved since 2010. These are sort of the clinical trials and we’ve gone over many of these. So this is abiraterone, this is enzalutamide, these are a number of negative trials but again understand that again what you have is that you have a number of different therapies that are all mechanistically different. They’re all mechanistically different, so it’s going to be very important as we move forward how to critically think about using these therapies in combination.

These are the summaries of all these clinical trials, this monotherapy approach, as all these trials are designed and as we know many of these have a significant survival benefit. We talk about the AUA guidelines. This is basically I think very important that we all start using guidelines to basically treat our patients. It’s no longer acceptable to basically say this is the way we’ve always done it. So these are the AUA guidelines and then obviously there’s an NCCN there’s a number of other guidelines especially the EU, but again all try to treat your patients in an evidence-based medicine fashion.

Now again as we talked about, as we progress what happens is that yes, these patients are progressive yes, they have castration levels of testosterone. But they will progress, they will develop these resistance mechanisms and this is a slide Neal lent me and again this is your castration resistant prostate cancer. So not only do you  still have AR dependent mechanisms, but you have also AR independent mechanisms. And again this is where as these patients continue to progress, it’s going to be the challenge to understand all these different therapies.

So this is a set of slides Phil Cantoff lent me. So when you look at these pathways, you have basically circulating testosterone gonadal pathways. You have this adrenal intra clinical pathway, and you have all these agents that are targeting. You have pathways that include AR degradation, androgen receptor blockade, AR nuclear translocation, AR androgen, AR enablers, and then downstream you have AR DNA co-activator interactions. So again these are all the pathways that continue to allow these cells to survive and these patients to progress. And again this is what it looks like in a sort of block form and again you can have all these different pathways. The result is the cells will continue to find a way to grow. They will invade apoptosis and our patients will progress.

So again we have to go beyond this concept of just blocking AR. As Neal mentioned again, this M0 space. We’ve got three big global trials including Prosper, Spartan and Aramis. This is an unmet clinical need. And again I think all of us want these agents to be used more proximate. We understand these patients are at risk. So again when we talk about sequencing trials, so you know here’s a few trials of basically Dendreon. Now Valley has put together looking at the use of Sypoacell-T in combination with and enzalutamide or abiraterone. Again these trials were not designed to show whether or not patients live longer, they were designed to just to basically demonstrate that the immunotherapy response from Sypoacell-T remained intact. These are small trials, they’re going to continue to follow them.

But again you have a number of trials that are concurrently ongoing looking at combinations of different therapies. So this is actually a trial looking at whether or not docetaxel or cabazataxel should be used first. This is a post Abi/Enza trial, which is PRIMCAB. This is targeting the AR using Abi plus or minus ARN 509, which is the next generation AR signaling inhibitor. We have targeting AR production again with Enza versus Abi and Enza. We have again use of radium 223, which Neal talked to, and again you have a whole cup, a whole listing of novel therapies including the Galeterone, Tasquinimod, and again Neal gave a great talk the other day, basically on all the immunotherapy’s. Again the point here is that lots of drugs, lots of trials.

So this is the paper that Dr. Myers talked about in his talk last evening and this is a very good paper. This is basically a paper that came out in Cell last year. This is Charles Sawyers and Arul Chinnaiyan, it was eight academic centers. And what they did was that they basically did biopsy and their whole sequencing on metastatic sites of  I believe it was about 189 patients. And as Dr. Myers alluded to yesterday, t 23% of these CRPC harbor DNA repair pathway alterations, they have all these genomic alterations, 90% harbor clinically actionable molecular alterations.

So again this is a very good paper and I would suggest all of you read it. This is an article that was published by Arul Chinnaiyan and the folks up at Michigan. Then again this is a very nice summary. It’s a very nice overview about again trying to think about advancing precision medicine through genomic sequencing. And again this is the future. This is the prostate cancer cell and again you have mechanistically all these different drugs. It’s very, very daunting. Can urologists do it? Absolutely we can.

Again we have to have better surrogate markers to predict therapy. Again there is a lot of talk using CTCs, but again we’re talking about circulating DNA cell free DNA. And again I think this is going to be the next hurdle, is for us to basically have these liquid biopsies that will help us guide therapy. So in terms of medical management, where we’ve been – one modern chemotherapeutic drug. Where we are – five new agents. Where we are going – optimal timing and use of combination.

So I’m going to leave you with this, does anybody know who this gentleman is right here? Anybody know? So this is a graduating picture. This is a gentleman named John Sawyers. Dr. Sawyers was my chairman of general surgery at Vanderbilt. So this is his son Charles Sawyers. Sir Charles as many of you know is probably one of the world’s foremost thought leaders. And so why do you say to yourself is Concepion bringing this up? So this is again, this is Dr. Sawyers, this is Charles’ dad. This is Charles’ extended family. This is his dad, these are two of his uncles. They’re both general surgeons in Nashville. They both are all at Vanderbilt. Actually Charles’ grandfather was a general surgeon in Nashville. Charles was kind of the black sheep, his mother was actually an anesthesiologist. But the reason I’m telling you this story is because who in the room during their surgical residencies days ever did a vagotomy-antrectomy for peptic ulcer disease?

Yeah very few. Okay so back in the 70s through Vanderbilt, Charles Sawyers extended family, his father, his uncles through Dr. Scot, who was the chairman before Dr. Sawyers, gave a 25 year experience with vagotomy-antrectomy for peptic ulcer disease. And basically it is an operation now that is for historical purposes only. One pill put them out of business, one pill put that operation and obsolescence and that pill is call Tagamet. So the point of this story, and actually I’ve known Charles for close to 30 years, is that one pill potentially could put us out of business for prostate cancer. So again I want us to continue to be involved in the management and the research and understanding of the disease.