D. Mitteldorf              Hello.  Welcome, everyone.  I see over 140 of you already on the call, and I imagine a few more are going to be popping on, because I can see the numbers growing every second.  My name is Darryl Mitteldorf, and welcome to the first of a six-part series, Conversations About Treating Advanced Stage Prostate Cancer.


This series is being brought to you by Malecare.  Briefly, Malecare was founded in 1998; it’s our country’s largest all volunteer men’s cancer support and advocacy non-profit, and in fact we’re actually on three continents now, we have groups in Australia, Europe, and here in the States.  A couple of things you probably know, if not, we’re unique in our focus on gay men and prostate cancer and on our program for prostate cancer diagnosed under the age of 50.  Our online support groups and quite large and dynamic, and everyone here is invited to join them.  You could start off by visiting malecare.org and follow various links to our various Websites.


Tonight the program is brought to you by our Advanced Stage Prostate Cancer Program, which has been in effect for about three years now.  We’re going to have a conversation with Dr. James McKiernan and Mr. Joel Nowak.


Dr. McKiernan is Vice Chairman of the Department of Urological Oncology at New York Presbyterian Hospital, Columbia University Medical Center.  We’re pleased to have him here, because he treats many patients with high-risk cancer diagnoses, in particular around prostate cancer.  Dr. McKiernan is actively involved with ongoing research programs focused on improving patient outcomes.  He’s authored and co-authored more than 80 articles, book chapter, and abstracts in the field of urologic oncology.  His research and discoveries have been published in journals such as Urology, Journal of Urology, Journal of Clinical Oncology, Cancer, and Cancer Research.  In short, he knows what he’s talking about.


If any of you want to connect with him after this, and I would imagine sometime during the week for a private consult or just to follow-up, his phone number is 212-305-5526, and that will be repeated at the end of the broadcast.


The other conversant is Mr. Joel Nowak, who is Director of Advanced Disease and Advocacy at Malecare, and he himself is a four-cancer survivor; he’s diagnosed with melanoma, thyroid, kidney, and advanced stage prostate cancer.


This teleconference is being recorded, so if you miss your notes or want to hear it again you can hear it on our Website; it will probably be up in a week or two.  It will last approximately 60 minutes.  A large number of you sent in e-mailed questions.  There’s a slight chance we might have time for live questions from our live audience, which means you, the listener, but with all the questions that we have and the conversations that Joel and Dr. McKiernan are probably going to have I think we’re in for a stimulating hour.


So I turn it over to both of you gentlemen.


J. Nowak                     Thank you.  This is Joel Nowak, and first I’d like to welcome everybody to the teleconference, and especially I’d like to welcome and thank Dr. McKiernan for his participation.  In the interest of full disclosure, I want to also let everyone know that I am a very fortunate individual, because Dr. McKiernan is one of my own personal physicians.  He is the surgeon who, when I was diagnosed with renal cancer, that removed my kidney, and he continues to follow-up and head my care in the area of renal cancer.  I also have the added benefit of his expertise when it comes to figuring out and planning my next moves and what I should and shouldn’t do with the treatment of my advanced prostate cancer.  I am very appreciative of him, and I am thrilled that he’s able to join us.


Good evening, Dr. McKiernan.  How are you this evening?


Dr. McKiernan            Good evening.  I’m great, Joel.  Thank you.  Thanks for having me.  It’s my pleasure to have this opportunity to participate in the call and hopefully share some of my thoughts on what’s happening right now in advanced prostate cancer and to field any questions anybody may have.


J. Nowak                     Terrific.  First, I’m actually going to start off with some very basic issues, and that’s the PSA.  PSA is the most used, or one of the most used, biomarkers for diagnosing prostate cancer, but PSA also has a role in understanding advanced prostate cancer and understanding the significance in when a reoccurrence happens.  I would really appreciate, just to get started, if you could talk a little bit about how you use PSA for someone who has had primary treatment and what decisions are made using those numbers.


Dr. McKiernan            Sure.  So PSA I think no one today in the United States can wake up any given morning and not either hear something about PSA on the radio or read an article about PSA in the newspaper; it always seems to be in the focus of controversy and debate.  Most of the controversy surrounds use of PSA as a screening tool, which means testing patients who are asymptomatic in the general population to try to find someone who has prostate cancer, and that’s a very hotly debated topic.


But your question really was about post-diagnosis use of PSA where it actually functions a little bit more accurately, a little bit better.  In particular, the classic example would be post-surgically.  So if a patient has a radical prostatectomy, removal of the entire prostate gland, PSA becomes a fantastic biomarker to determine whether or not the patient is indeed in complete remission or has relapsed.  And it’s very simple, it’s very binary; it’s either undetectable or less than 0.1 or it’s detectable at some level, and if it’s detectable it means the cancer is back.


After primary radiation therapy it’s a little bit more difficult to interpret.  It’s still a very good test there, but in general patients will drop their PSA to a low level, less than 1, and hopefully stay in that range forever, but three consecutive rising PSAs are usually what we use to determine the potential for a biochemical or PSA based relapse.


J. Nowak                     Terrific.  Now I know, as you mentioned, that it’s harder to use the PSA number post-radiation.  I know that it takes a while, that PSA will bounce around.  How long does one have to normally wait before one starts panicking and saying, “Oh my gosh, I have a reoccurrence.”


Dr. McKiernan            Yes.  After radiation is probably the most anxiety provoking, because, first of all, in the first year following radiation you usually actually don’t see the PSA stop falling until about nine months, twelve months, sometimes even as long as eighteen months after external beam radiation, and that’s what we call the PSA nadir, or the low point of the PSA, but then after that it can bounce around.  There’s even a medical term for PSA bouncing around, it’s called a PSA bounce phenomenon, and that’s seen most commonly after brachytherapy or seed implantation, and usually it’s seen in younger men under the age of 60 who have a PSA that suddenly jumps up at about twelve months to eighteen months following the seed implantation and actually does not indicate a problem.  It’s hard to interpret that sometimes, it does prompt patients to go for biopsies of their prostate, but usually that kind of PSA will decline suddenly again and get back down to a low level.


So we really look for three consecutive rising PSAs over the baseline nadir, or the low point.  If you achieve that, if that happens, you really should be evaluated with either a prostate biopsy or some type of imaging or both.


J. Nowak                     Right.  I have to say that the last year and a half or so has been really exciting when it comes to the area of new drug development, and specifically FDA approval.  I actually think that the last year and a half has been fairly unprecedented.  We just had three different drug approvals, Jevtana, Degarelix, and Provenge.  Could you tell us a little bit about these drugs?


Dr. McKiernan            Sure.  Yes, you’re absolutely right.  If you take a few steps back, if you’re new to the prostate cancer world, there have been decades in which we haven’t seen a new FDA approval, literally decades, and so to see three new drugs approved, all for advanced prostate cancer, all within the same really almost six-month period, is totally unprecedented.  I hope it’s a sign of things to come and a combination of more progressive research and development, both in the pharma world, as well as in the private sector, and I hope it’s also potentially a sign of the FDA paying more attention to prostate cancer and trying to expedite some of the drugs that, of course, work and are effective.  We don’t want things approved that don’t work.


But those three drugs, Degarelix is actually new form or hormonal deprivation therapy, and it functions as what’s called a LHRH antagonist.  It’s in the same class of drugs as LHRH Agonists that manipulate the hypothalamus and pituitary glands in the brain, and these are the drugs that are more commonly recognized as Leuprolide or Lupron and Zolodex or Goserelin Acetate, Eligard is another brand name.  So a lot of patients may have heard of these drugs or have been on these drugs at one time or another.


Degarelix is designed, actually, to work as an inhibitor of this access.  So it’s a slightly complicated difference, but most of the commonly approved drugs in that category are actually stimulators of a receptor and work by over stimulating a receptor that then causes production of testosterone to decline.  So it’s actually coming from a reverse mechanism and is not associated with the commonly described PSA or testosterone flare phenomenon.  When you first start a patient on Lupron or Zoladex there’s actually a sudden rise in testosterone, which can sometimes result in a rise in PSA—transiently, but some people think that that could be significant.  So Degarelix does not do that.  It’s an antagonist, and therefore it could potentially lead to faster drops in testosterone for people starting hormone therapy.


The other two drugs that you mentioned, one Provenge, I think most people on the call have probably heard of in some way or another.  It was in the news quite a bit a few years back when the FDA decided not to approve its use after a smaller clinical trial was positive.  But the company now, Dendreon, went back and did a much larger clinical trial that actually was powered appropriately and did prove to be positive for a survival advantage.


It’s a drug that works as a vaccine of sorts against prostate cancer.  It uses a patient’s own immune system, or white blood cells, and the cells are taken out of a patient, stimulated in a laboratory environment with an antigen or protein from prostate cancer, and then retransfused back into the patient to fight their cancer.  And actually it marks the first ever prostate cancer, or, in fact, first ever cancer immunotherapy, which has ever been approved by the FDA, which is a milestone amongst milestones.  It’s really a major event that happened in the very end of April.  That was tested in patients who had hormone refractory metastatic prostate cancer and proved to be more beneficial than the standard of care in those patients.


Then the final one was the most recent one to be approved, I want to say that was in mid-June, that was a drug called Jevtana, which the generic name which is cabazitaxel, which is in the family of docetaxel and paclitaxel, those are both chemotherapies that have been previously used in prostate cancer.  This is a new generation taxane that was tested in patients who had been treated with chemotherapy in the past and the chemotherapy didn’t work anymore, and it actually showed a significant benefit in that population of patients.  So that was approved just recently.


J. Nowak                     Terrific.  So it gives us an approved alternative once chemotherapy has stopped working.


There have been some questions raised on the advanced prostate cancer list serve about the possibility of Degarelix being used as a second line hormone therapy.  Have you any thoughts about that possibility, those using Lupron first and then when it fails to move on to Degarelix?


Dr. McKiernan            I’m sure it will be done.  Physiologically it does make some sense, although it was not studied or approved for that use.  In other words, there’s never been a study to show, at least to my knowledge, that it has a greater efficacy in that setting than any of the other drugs, but since it works by a different mechanism of action and potentially lowers testosterone without that surge phenomenon it could make sense.  I would liken that to switching a patient from an oral antiandrogen like Flutamide to an oral antiandrogen like Casodex; they both attempt to do the same thing, which is block the androgen receptor, but they do it in a slightly different manner.  So I’m sure it will be done.


J. Nowak                     Right.  Do you think that if when used Degarelix, obviously as a first line treatment, is there a need to combine it with a Casodex or an antiandrogen?


Dr. McKiernan            Well, that’s a great question.  There certainly won’t be a need for that in terms of blocking the flare phenomenon, because that does not occur.  But the age old question in hormone depravation therapy, which still remains quite controversial today, is in fact does combined androgen blockade, which means the use of an LHRH agonist and an antiandrogen, is that better than, equal to, or inferior to the simple use of monotherapy with an LHRH agonist.  This is a question that’s been studied extensively over the course of the past 20 years, and the vast majority of the evidence would suggest that combined androgen blockade is slightly more effective than the use of an LHRH agonist alone, and slightly being defined as a difference of very, very small measured amount of time over a very long period of time.


So there are believers that combined androgen blockade is the standard of care, and I think they probably will use Degarelix with an antiandrogen.  Then there are other people who feel that it’s powerful enough treatment on its own, and there’s no reason to expose a patient to the side effects and/or the cost of an oral antiandrogen.


J. Nowak                     I see.  Now, of course, one of the things that we hear so much about is the fact that the drugs that have been approved recently really have not in their clinical trials demonstrated a huge survival benefit.  We’re measuring survival in a matter of months.  I think for Provenge it was either 4.2 months or 4.5 months, and Provenge comes with a whopping price tag of $93,000.  So the question comes is it worth it?  How do we deal with that, how do we weigh the value of a drug for limited survival, and are those survival figures real figures?


Dr. McKiernan            Yes.  That’s a great question.  Very hot topic amongst people in both politics and medicine these days.  I’m not a politician, so thankfully I don’t necessarily have to be the one who decides how to spend our limited healthcare dollars right now.


But as a physician I always find it interesting when we turn the spotlight onto the issue of cost and what is worth X or Y number of dollars.  I think we need to do it across the board and start looking at the entire field of medicine, because when we zoom in on one small treatment for one very serious type of cancer, let’s say Provenge for advanced prostate cancer, and say, look, four months for $93,000, that’s a very stark example, but there are examples in prostate cancer in which patients undergo radiation therapy, which is approximately a $55,000 treatment, and gain no benefit, in fact gain side effects only.


So we could probably save more money by making better decisions in primary treatment in prostate cancer, who should be on surveillance, who should not have surgery, who should not have hormone therapy, than we could in trying to sort of pinch pennies, if you will, in patients who are clearly in need of help.  Patients with metastatic androgen independent prostate cancer there is no debate need help.  Patients with localized prostate cancer that are in their late 70s, early 80s with low risk disease probably don’t need our help, and yet we spend a lot more money there and probably don’t help anyone.  So I always have to caution people when they start focusing on the cost only of things like that.


But, having said that, the four month median survival in that trial, the 2.5 median survival in the docetaxel trial, all these numbers are summarized statistics over a very large population of patients, sometimes up to 600 patients, 800 patients in some of these clinical trials, and it’s a way to summarize what happened to all these people.  But there are people in the trial who got quite a bit more benefit than that and there are some people in the studies that got no benefit and, in fact, were harmed by the drug or by the treatment.  So you have to individualize that type of decision and try to identify the patient who is most likely to get a durable or excellent response out of the treatment, and realize that four months or five months over a span of twenty months of life expectancy is a potentially substantial improvement in the patient’s quantity and, by the way, quality of life.  In most of these studies pain scores were improved, quality of life is improved.


So it’s a lightening rod subject and very difficult to even have a non-emotional conversation about, I think, for most people, but it’s going to be a huge issue going forward, there’s no question.


J. Nowak                     Yes.  Absolutely.  Maybe it wasn’t fair to ask you as a physician such a philosophical and political question.  I apologize.


Dr. McKiernan            No, no, it’s a perfectly appropriate question.  I probably won’t get elected to office with any of my answers, though.


J. Nowak                     I would vote for you anyway.


I know that some men question how long ADT can be expected to last and when they try to decide should they go on ADT even though they’re asymptomatic, they don’t have symptoms.  I know that one person had sent in a question actually saying that their doctor had said although they had a reoccurrence, their PSA was actually up over 5, and the doctor had said that he would not put him on ADT because he was asymptomatic, that he should just anticipate 18 months from ADT, but I know a lot of us don’t buy that.  So I was wondering what your experience has been.


Dr. McKiernan            Yes.  So you’re striking on, yet again, one of probably the core controversies in our field, which is in a patient who’s relapsing, after almost anything, including prior surgery, radiation, or even prior hormone manipulations, you’ve identified the relapse by an unequivocal rising PSA, you have a patient who is asymptomatic, has normal scans, normal CAT scan, let’s say normal bone scan, doesn’t even know that their cancer is back, but yet you have a blood test, very powerful, accurate blood test, that says yes it’s back.  What to do?  And now you have a tool, the main tool in the toolbox there being hormone deprivation therapy, ADT, and when do you deploy it.


So, of course, we love to look to the clinical trial world to say okay, well there must be a study that would help answer that question, and in fact there aren’t.  The closest thing we have to a study that could answer those questions are actually fairly old studies, which look at starting hormone deprivation early versus very late, and very late in those studies was defined by when a patient became symptomatic, and there’s no question that there’s clear cut evidence to support the use of early versus very late hormone therapy, but there is no definition of in between.  So none of those studies actually use PSA as a cut point or a trigger point to begin Androgen Deprivation Therapy.


So we’re left with a gray zone between let’s say a PSA that’s 3 to 5 and symptoms, and of course symptoms we know to be too late.  If a patient complains of back pain, bone pain, weight loss, those types of things, those are ominous signs, and usually their PSA will be in a 30 to 40 range by that point.  But is 6 better than 7 or 9 better than 10?  We really don’t know.  Oftentimes I will look towards something called a PSA doubling time, which is actually looking at the rate of rise of the PSA and not so much focusing on the absolute value, and I oftentimes find that to be a better predictor of who should or should not begin Androgen Deprivation Therapy.


J. Nowak                     Terrific.  Once I start ADT how long will it last?


Dr. McKiernan            Yes.  So traditionally ADT was a lifelong commitment.  In other words, a doctor would start a patient on ADT, and, prior to 1990, the most common way to do that was an irreversible form of ADT, surgical castration.  Nowadays we do have the capacity to give medical ADT or medical castration, and that can be reversed, obviously, it can be started, it can be stopped, it can be turned on and turned off.  So what’s out there right now is either continue it for life or continue it for a certain period of time until you achieve a nadir PSA, less than 1, less than 0.1 possibly, and then stop, and we call it intermittent Androgen Deprivation Therapy.  It’s commonly talked about.  Most patients are interested in it, because it does give the opportunity for a patient to be off the drug or off the side effect profile.


But we still don’t know for sure whether that intermittent Androgen Deprivation is better than, equal to, or inferior to non-stop, continuous Androgen Deprivation Therapy.  My gut feeling is it probably is at least equal to, if not possibly even a little bit better than, continuous Androgen Deprivation Therapy in terms of the probability of surviving longer and, of course, the side effects being minimized.


J. Nowak                     Right.  Of course, some of those side effects include issues of heart and vascular disease, which by themselves can kill you.


Dr. McKiernan            That’s correct.  Yes, that is correct.  The more we study and learn about men on testosterone suppressing therapies the more we realize that the side effects are pervasive, and they’re not just the hot flashes that everyone potentially experiences or the weight gain or the decreased muscle mass or the potential change in cognition and mental function, which are all debilitating enough, but there’s even more pervasive ones, like, as you mentioned, alternations in the cardiovascular system that may involve cholesterol, may involve things like C-reactive protein or some other more difficult to monitor factors that could increase a risk for heart attack, stroke, cardiovascular problems.  And that’s come out of some clinical trials in which men have been randomized to receive either placebo or hormone deprivation therapy.


So it’s a big decision to start on Androgen Deprivation Therapy, and I think throughout the 1990s and early part of 2000s we took that decision a little bit lightly.  We thought well, it’s relatively non-toxic compared to chemo, it’s just an injection, you only have to come in once every three months, why not just start it on everybody, and I think it was overused quite a bit.


J. Nowak                     Now I’m facing a time, fortunately I don’t think I am yet, but facing a time where I’m becoming hormone refractory.  What are you going to tell me to do, what’s my next best step?


Dr. McKiernan            Yes.  Well, the first thing is look at the calendar and see what year it is, and hope the calendar says 2015, because I really think that in the future we’re going to have even a lot more options than we have now.  Right now we have more options than we had six months ago.  So this is the kind of thing sometimes patients will come in and say, “Well it doesn’t look good for me, doc, right, but you could keep me going for a while?”


“Yes, definitely.”


“Are there new things on the horizon, so if I can get through this year maybe next year you’ll have something else for me?”


That’s a very powerful, hope-filled message, but oftentimes in cancer it’s just not true, because things don’t happen that fast.  But right now in prostate cancer there’s no question that’s true, and if you can keep things in a stalled situation long enough and keep your eyes on the news you will actually see newer things coming out.


So at the moment an asymptomatic hormone refractory patient who is non-metastatic it would be a clinical trial or observation with a secondary hormone manipulation.  Those would be the most common recommendations.  If they’re asymptomatic and show a metastasis Provenge would probably be the right thing to do right now; it’s FDA approved, it shows a big survival benefit in terms of relative survival advantage, and it’s relatively non-toxic.  So that’s where I’d be looking right now.


J. Nowak                     Do you see any role for drugs similar to estrogen, you know with DES, as a second line hormone manipulation, or ketoconazole?


Dr. McKiernan            No so much DES; I don’t have much experience with DES.  I know some people still do use it.


I think ketoconazole is a mainstay of secondary hormone manipulations, but I think what’s exciting there, and is what’s coming I hope very soon in the future, is a drug called Abiraterone.  Now just give a caveat to everybody on the line, this is not FDA approved, but it is a drug that’s in fairly advanced phase III clinical trials, which we’re hoping to hear some results on mid-fall, November ish maybe of this year.


It’s a testosterone-lowering agent, so technically it’s not a chemotherapy.  It is a hormonal therapy, but it functions by inhibiting an enzyme that’s critical in the synthesis pathway of testosterone directly in cells that are making testosterone wherever they are in the body, including the testicles, which are the mainstay, the adrenal gland, and even in the cancer cells.  Because there’s more and more evidence now that suggests that some of the most advanced prostate cancer cells have figured out how to make their own testosterone and perhaps feed themselves with the fuel despite us, the doctors, knocking out the production of testosterone in all the other organs.  So this drug could actually target synthesis of testosterone wherever it occurs.


As I said, it’s being tested in two large phase III trials now.  I’m not sure if I’d call that a secondary hormone manipulation, but that’s what I’m most excited about going forward in the hormone manipulation category.


J. Nowak                     Right.  And do you think that the second line androgen deprivation can extend life, or is that kind of an unknown yet?


Dr. McKiernan            It’s an unknown.  It’s an unknown.  There’s never been a clinical trial that has proven beyond a shadow of a doubt that the secondary hormone manipulations do extend life.  What we do know that they do is about 25% to 30% of the time they will cause a PSA response, which will usually be transient, will usually last six months to seven months, and then the PSA will go back up again.  But the fact that it’s never been proven to extend life doesn’t mean that it doesn’t, but it means that we haven’t done the right kind of study yet to prove that it does.  So it may or it may not, we’re not sure.  We’re pretty sure that something that’s non-toxic and lowers your PSA is not bad for you, so it’s at worst neutral and potentially beneficial.  So I think it’s commonly done.


J. Nowak                     Yes.  Right.  And one of the other big controversies within the survivor community is the use of Avodart or Proscar as part of the ADT regimen.  Can you tell us a little bit about the issue, and perhaps how you feel about it and why?


Dr. McKiernan            Yes.  I know about the issue, and basically what it stems from is the fact that Avodart and Proscar are enzyme inhibitors.  They’re obviously both not approved for cancer treatment, they’re approved for benign prostate hyperplasia, and what they do is they inhibit the conversion of testosterone to its metabolite, which is called dihydrotestosterone, which in a lot of cells is actually the more active form of the chemical or of the hormone,