Darryl Mitteldorf
Hello and welcome to Malecare’s Advanced Prostate Cancer Program Teleconference.  Founded in 1998, Malecare is America’s largest and leading men’s cancer survivor and advocacy national nonprofit.  Malecare’s goal is to improve communication between you and your doctor by giving you the same language and understanding of your disease.


Tonight I see that we have actually over—604 people are currently listening and we’re honored that you’re allowing us to participate in your care.  Tonight you will be hearing Joel Nowak, Malecare’s Director of Advanced Disease and Advocacy and Dr. Neal Shore discuss the groundbreaking prostate cancer treatment Provenge.  Tonight’s talk will last approximately 60 minutes and will be peppered with questions that you, the listener, emailed in earlier this evening and last week.


Tonight’s talk will also be recorded and available for listening at our website Malecare.org in our Advanced Prostate Cancer web section.  Also, everyone here is invited to sign up for more information about our programs and our email newsletter, also at Malecare.org.  Now, please give your attention to Joel Nowak and Neal Shore, as they talk about Provenge.


Joel                              Good afternoon or good evening, everyone, this is Joel Nowak.  Before I get started with the teleconference I want to welcome everyone and especially Dr. Shore, who has agreed to donate his time with us this evening.


Dr. Shore is the Medical Director of the Carolina Urological Research Center, as well being on staff at the Grand Strand Regional Medical Center.  Dr. Shore has conducted more than 100 clinical trials focusing mainly on prostate and bladder disease, including the trials of Provenge.  Dr. Shore is a board certified urologist who has numerous publications in peer review journals and has lectured extensively on the treatment of prostate cancer.


I want to say that we are very lucky and gifted, very fortunate to have him.  And I do also want to say that after listening to this conference, if you have any interest in making an appointment to see Dr. Shore, who is located in North Carolina in the Myrtle Beach area, you may call his office at 1-877-809-8714.


And now we’re on to the conference.  Good evening, Dr. Shore.


Dr. Shore                     Good evening and thank you for giving me the opportunity to address your audience.


Joel                              It’s our pleasure.  These last two years, as you know, have been really exciting for those of us with prostate cancer.  We have a lot of new drugs that have been approved by the FDA and since it’s been four or five years since we’ve had any other drugs, it’s really a different era we’re looking at.  We have Jevtana, degarelix, denosumab, abiraterone, and of course we now have Provenge, which is really the main topic of tonight’s conversation.


Perhaps if we have some time later on we can go back to these other drugs, but I don’t know if we will.  So let’s move directly on to Provenge or sipuleucel-T.  Could you please tell us what actually your involvement was in the development of this drug?


Dr. Shore                     We have our own separate clinical research program called Carolina Urological Research Center.  I started that about ten years ago.  I’ve been in practice in Myrtle Beach since 1997 in South Carolina and I have 14 partners, 14 single specialty urologists.


Having trained in a program at Cornell and at Sloan-Kettering in New York I was always very disturbed by the fact that we didn’t offer as many things to the patients with advanced prostate cancers as I saw in other solid tumor malignancies.  I had the great fortune to work with some of the best medical oncologists, as well as the best urologists there.


One thing that was said early on in the introduction of the program was that if I’m a patient with prostate cancer it’s so vitally important to have your urologist and medical oncologist talking to each other, as well as the radiation oncologist.  And I think programs like this are so important because they give the patient the ability to ask each one of their specialty treating physicians what options are available to them and are their various specialists communicating well with each other.


In a long-winded way, I started my own clinical trials program over ten years ago because a lot of the companies, biotechnology companies, pharmaceutical companies, were having a really difficult time enrolling patients and getting answers that we needed to have.


We’ve talked about this war on cancer.  You see it on the front of Time Magazine; why aren’t we winning the war or maybe we are winning the war?  And I think what you said, Joel, is we’re starting to see some major advances in the battlefront, as you listed five new therapies in the last year alone, which is truly amazing.


So my involvement with Provenge or what the FDA describes as sipuleucel-T, that’s sort of the generic name that they’ve given as a classification for this particular vaccine immunotherapy, we can talk more about that, began in 2003.  I was an early investigator in the Phase 3 registration trial, which led to FDA approval in April of 2010.  So it took a full seven years of that Phase 3 trial, not including the earlier trials that began even before 2000.  So it really took over a decade and over $1 billion to get Provenge approved and to the market.


I was the second or third leading, accruing urology site in the country.  There were 50 sites in North America and being in Myrtle Beach, South Carolina, I have a lot of retirees.  About 70% of my populous is over 65 so we see a lot of cancer.  As everybody knows who’s listening, as we get older our risk factors for cancer increase with age and various other factors, but it wasn’t hard where I am to find patients whom I thought would benefit from consideration of the trial.


So we were the third leading accruing site.  And since it’s been approved in April of 2010, I’ve actually infused somewhere around 30 additional patients with Provenge.


I’m proud to say I’m the third author on the New England Journal of Medicine article, which was published in July of 2010.  For any of the listeners who want to look at that article, you can get a lot of the really great specifics and details of what the trial was that led to approval.


Joel                              I know that Provenge is a brand new type of treatment.  It’s an immunological therapy.  Could you actually explain what that means and why this is different from the other treatments we have available?


Dr. Shore                     Traditionally when patients have an advanced disease categorization what does that mean?  For simplistic purposes or understanding, the disease has escaped outside of the primary organ of etiology, be it the breast or the colon or in our case, what we’re talking about, the prostate.


It wasn’t until 2004 that we saw the approval of docetaxel, also known as Taxotere, which was a big deal because prior to 2004 we didn’t have any systemic therapy to treat men with cancer that had progressed outside the prostate, that had also progressed despite suppression of the testosterone level.  That therapy, docetaxel, also known as Taxotere, is a chemotherapy.


Simplistically put, virtually all the chemotherapeutic agents, whether they’re for prostate cancer, breast, colon, lung, pancreas, etc., they’re geared towards stopping cellular machinery in a way that we describe as being—we use the word cytotoxic.  So the challenge with the chemotherapy or cytotoxic is it slows down or damages or destroys rapidly dividing cells, which neoplastic or tumor cells tend to be.  The challenge is trying to avoid the normal rapidly dividing cells, such as the cells that line that gastrointestinal track or the cells within the bone marrow, from being damaged as well.


Immunological therapy, to answer your question, is designed to stimulate the patient’s own natural defenses, specifically the patient’s white blood cells.  And the case of Provenge, or sipuleucel-T, it’s to stimulate the T-cells, or what we call the natural killer cells, which can directly attack the tumor antigen, proteins on the surface of the tumor, to slow down the tumor and impact the patient’s overall survival.


So this immunotherapy is sort of what one might think of as being a smart bomb to destroy or impact the tumor cell without impacting or affecting other healthy cells within the body.


Joel                              Sometimes Provenge is called a vaccine.  I guess the real question is why don’t we go around giving Provenge to everyone so that they don’t develop prostate cancer?


Dr. Shore                     That’s a good question and it’s a source of frequent confusion for not just patients but also for other physicians who are not normally following immunobioligics.  We tend to classify vaccine therapies as either a therapeutic vaccine or a prophylactic or preventative vaccine.


So the typical vaccine one might get for measles, mumps, rubella, in childhood or the childhood vaccines, those are designed to prevent a disease from ever happening.  Provenge is not a preventative or prophylactic vaccine.  It’s a therapeutic vaccine, which means it’s designed to help treat the disease, not prevent it but treat it, and help impact on survival.


Joel                              How does a man qualify or what does he need in order to get Provenge?


Dr. Shore                     The Phase 3 trial, known as the 9902B or the IMPACT Trial—a lot of these trials always have numbers.  They also have names that are typically acronyms for the overall title of the trial so 9902B means it was actually literally brainstormed back in 1999.


But having said that, in order to qualify for Provenge today, I think it’s fair to say that virtually all insurance carriers, third-party payers and most importantly CMS or the Medicare Network of Payers, are requesting that the inclusion and exclusion criteria of the Phase 3 trial that the FDA approved is followed.  So what that means is the patients who were able to receive Provenge in the trial—there also was an arm that didn’t get it in the very beginning, which is typical of all Phase 3 trials.  They’re blinded and randomized and there’s always a placebo arm to make sure that indeed the drug therapy has real statistical validity.


But the inclusion criteria to be a candidate for the study was you had to have had a diagnosis of prostate cancer, had been on some form of testosterone suppression, typical drugs like Leuprolide and whether it’s a one-month, three, six or twelve-month formulation, or have had surgical orchiectomy, enough to show that the testosterone level had to be very, very low.  And not only in addition to that, the PSA, the prostate specific antigen blood test, had to be showing three consecutive rises despite being on androgen deprivation therapy.


So this describes a typical verbiage that we used to call hormone refractory prostate cancer and then we started calling it androgen independent prostate cancer and now we refer to this disease state in our nomenclature and in our clinical trials as castrate-resistant prostate cancer or the acronym CRPC, which means on hormone suppression, diagnosis of prostate cancer and at least three consecutive rises in the PSA level from the absolute bottom or what we call the nadir.  Those levels are typically taken at least two weeks apart.


One additional very important caveat is radiological evidence of disease.  So what does that mean?  It means the patients had to have had positive findings of lesions on bone scans or CAT scans, but yet still be asymptomatic or really minimally symptomatic.  In other words, we didn’t want to have patients in this study that clearly would benefit going right to chemotherapy.


So in summary, what I just said, was patients with a rising PSA on hormone suppressive therapy and a positive bone or CAT scan who were overall still feeling quite well with not much discomfort, certainly not on any kind of narcotic analgesics.


Joel                              Now, for a man in today’s situation who has a lot pain, based on what you said, they would not qualify, they would not be able to get Provenge and have it reimbursed.  Is that still the case or is there more flexibility these days?


Dr. Shore                     I think overall, Joel, that is still the case.  Number one, I think that for a patient who is having cancer-related pain they really would be better off receiving a cytotoxic therapy or a chemotherapeutic.  The reason being is that it has a much more initial rapid onset of action.


What we saw in the Provenge Phase 3 trail was that the patients were asymptomatic and the survival benefit started to be seen about six months after the infusion.  Unlike a chemotherapeutic, you start to see the effect, in terms of its impact on cells, very, very quickly.  You see that because people also get impact on their normal cells.  They get hair loss, diarrhea and things of that nature.  Then once you stop using the chemotherapy, its effect is essentially over in a relatively quick period of time.


This is a very, very important distinction because with an immunotherapy like Provenge it’s only given in three infusions over the period of about 30 to 40 days and that’s it.  It’s effect can theoretically last for the entire patient’s lifetime.  So it takes a little bit of a slower onset to have its impact but yet it’s good and remains within the patient’s immune system in perpetuity.  It’s very, very different from a classic chemotherapeutic cytotoxic effect.


Joel                              That’s interesting and I’m actually going to skip ahead of where I’m going to go and follow up on this.  You said that the positive results of Provenge would last for the rest of that person’s life.  So is there a need for boosters and so forth or is it just going to be there forever?


Dr. Shore                     In the study, the patients received only three infusions and it was stopped.  That was based on some earlier preclinical or some animal experimentation models.  So it was approved on the basis of just three infusions.


I can tell you they’re very simple to give.  They’re extremely well tolerated.  There’s no impact on the gastrointestinal track per say like one would expect in a cytotoxic.  Patients maintained their energy levels.  There’s no requirement to be on steroids.  The premedication for receiving an infusion is Tylenol and Benadryl, simple over the counter therapies.  And in over the 50 patients I’ve treated with Provenge I’ve never hospitalized anybody.  So the patient’s quality of life is very well maintained.


Having said that, your question is a key one and it gets brought up a lot.  If they’re doing well with just those simple three cycles given over a 30 to 40 period, what ways can we measure the patient’s cancer response or their immunological response three months, six months, a year, possibly two years later and would they benefit from any boost or additional maintenance therapy?


The very honest answer to that question is we don’t know.  Those studies need to be accomplished.


Joel                              I get a lot of questions and I’m sure you do to from men who have advanced disease but they are in an earlier stage.  Their logic says, “Well, if it’ll work at one stage, if I get it earlier won’t it work even better?”


Dr. Shore                     The stage that’s most close in clinical proximity to what I described, the guy’s got to have a positive bone scan or CAT scan, which means a positive enlarged lymph node or a positive lesion in the bone, and be asymptomatic and have this rising PSA despite being on hormone therapy/lower testosterone—there’s a whole group of patients who just start to have a rising PSA on that hormone-lowering therapy of the testosterone level, but yet their CAT scan and their bone scans are still negative.


I’ve always felt, and this is of course just Neal Shore speaking, I’m not speaking on behalf of Dendreon, that that would be the ideal time to get the immunotherapy.  Why wait to see radiological evidence when the patient’s could benefit even at that earlier point of the disease?


Your question, which is an excellent question too, is what about treating patients before they get to that androgen independent portion of the disease or the castrate-resistant portion of the disease where the PSA is going up?  Why not treat these patients when they still are “hormone sensitive?”


Then you could even argue why not even consider treating them if they’ve just had surgery, prostatectomy, or radiation and all they have is PSA relapse?


These are great questions and these are great studies to do.  This is important that the listeners on the program tonight get the word out for not only studies that involved Provenge but all other aspects of prostate cancer.  That we accrue patients to these trials because it’s only then that the FDA, as well as Medicare, will broaden the label, as well as all other third-party payers, and say, “Oh, okay, we see the data.  Now we’ll approve it and we’ll let patients benefit from it.”


Joel                              I want to say that if there are any people that are from Dendreon on this call, and I suspect there probably are, I want you to listen to what Dr. Shore said and please take this into consideration.


Anyway, I know Provenge is administered in a way that’s different than most other cancer treatments.  Could you give some idea or describe what the treatment process is like and what it is?


Dr. Shore                     What we have to do is begin while making sure they meet this appropriate inclusion and exclusion criteria, basically its kind of healthy-appearing men that have just sort of moved along this natural progression of the disease state.  So what we do is once we’ve shown that they’ve met that criteria in a very simple checklist in the office the patients will then receive what’s known as a leukapheresis or some people call it an apheresis.  This long Greek derived word, but it’s not very complicated.


All they do is go to a center.  There are many of these throughout the country.  Every state has multiple ones.  It’s oftentimes places where people might go for a dialysis treatment or for other types of blood filtration for other types of therapies, some with other cancers and sometimes with just hematological processes that don’t even involve cancer.


But really all apheresis is, is a piece of IV tubing, one in each arm, on the right side and the left side, and there’s a machine that’s able to filter out certain subpopulations of the white blood cells, which are then specially collected under sterile technique and then shipped off to the treatment plant where Dendreon has its manufacturing facility.


The actually apheresis process requires a patient just sitting in a reclining chair, reading a book and it takes place over about a three-hour period.  There’s no medication to take before or afterwards.  I just encourage my patients to stay well hydrated.  Drink a lot of fluids before and afterwards and that’s pretty much it.  There are some admonitions about avoiding certain types of citric juices or caffeine for a 24-hour period but it’s really quite simple.  There’s no anesthesia involved.  There are no antibiotics required.


So the process takes three hours.  The patient’s own personalized cells, no one else’s but that patient’s own personalized white blood cells, are then shipped, flown, however the quickest route is to the Dendreon manufacturing process where his specific cells are combined with the vaccine therapy, which creates the drug therapy known as Provenge.


This takes place over a 48-hour period or so.  The patient’s at home; not hospitalized.  He went and got the apheresis, went home after three hours and then comes back to my clinic where his specific Provenge therapy is now available.  It’s shipped back to my office.


The patient comes in and with another small angiocath, which we put in the arm or the hand, and the patient undergoes an infusion of now the Provenge vaccine therapy.  It takes place over 60 minutes.  The only medication that patient takes prior to receiving the infusion is a Benadryl and a Tylenol and that’s it.


That same process is repeated two weeks later and one more time two weeks after that.  So you can sort of do the math and the calendar estimate and realize that if everything goes pretty much to clockwork it’s about a 30 to 40 day overall timeframe from start to beginning, but it’s only really six days, three hours on one of the days and one hour on the other three days, of actually patient time commitment.


My patients really find that extremely appealing because, let’s face it, most my patients are retired and they want to have time to do the things they like to do, whether it’s golfing or hunting or visiting family or traveling.  So one of the things when I first got involved in 2003 was thinking, “Wow, this is a particularly appealing therapy,” not only just for a urologist and medical oncologists, but more importantly very appealing to the patient that their quality of life is not impacted and hopefully, when we were doing the study, this would really have an impact on survival.


I’m very proud and honored to have been involved in this therapy.  Again, this is the only solid tumor therapeutic vaccine approved by the FDA period.  So it’s really a tremendous breakthrough in how we treat patients with not only advanced prostate cancer but hopefully how we might be able to move that into other areas.


Really the folks at Dendreon, the CEO of the company, Mitch Gold and the Chief Scientific Officer, Dave Urdal, and their team that they’ve had over the years, is to really be commended.  To get anything like this through trials and through FDA approval and Medicare negotiation and approval is a huge, huge effort, as anyone who understands the battle of getting access to therapy and reimbursement understands.


Joel                              One of the debates that often comes up on one of our Advanced Prostate Cancer support lines is whether they have a port installed prior to the apheresis.  Could you describe what a port is and do you recommend them?  What are your thoughts on that?


Dr. Shore                     Sometimes patients—I’ve used central ports or central line catheters.  I use them for my patients who just really don’t have good veins.  The veins are typically what we describe in the antecubital fossa, which is if you bend your elbow, you straighten it out and bend it, it’s that little nook in between your upper and lower arm just opposite your elbow.  That’s the antecubital fossa.


Of course some people are blessed with great big, ropey veins and it’s not an issue.  If a patients has poor venous access, then a very simple thing to do is get a central line catheter inserted by their local interventional radiologist or their vascular surgeon.


That’s typically done on an outpatient basis.  It doesn’t require any kind of general anesthetic.  It’s done with a local analgesic with a simple injection.  I’ve had probably somewhere around 10% to maybe 15% of my patients who have required that.  We arrange for visiting nurse services to come to their home and inspect their little bandage that’s on there.


The catheter can be left in for 30 to 40 days, as long as there’s normal good care of it and there are no signs or problems.  I’ve had some colleagues of mine who’ve had them put in, taken out, and then replaced two weeks later.  So it really just becomes whatever the patient and physician’s preference is.  The main reason for doing it is simply to get access to do the apheresis and then do the ultimate infusion.


Joel                              We know that no matter what drugs or treatment we take we’re going to have side effects.  We learned that very early in the prostate cancer treatment area.  So what are the side effects of Provenge?


Dr. Shore                     The side effects of Provenge that are really most commonly reported are what are described as the infusion type of reactions and I think it was reported somewhere between 60% to 70% of patients in the trial.  One must remember in trials that we report everything.  We’re very, very careful.  Every single statement or complain made by anyone is reported, as it should be.  In my own personal experience, I probably see these infusion reactions in about 33% of 25% of my patients.


So what’s an infusion reaction?  It basically is some mild flu-like symptoms, a little bit of the chills, some muscle ache, low-grade temperature.  It lasts for about 24 hours.  It’s very rare that it would last longer than that.  I’ve had an occasional patient, probably about one in eight or ten who when they’re actually getting the infusion will get some shaking chills, which is very easily treated with medication.


In my own personal experience, I’ve never had to stop an infusion.  I’ve never admitted a patient to the hospital for an infusion.  I’ve never had one go to the emergency room afterwards.  So I think what that really speaks to is the tolerability.


In the Phase 3 trail that led to approval, the IMPACT trial, 93% of the patients completed all three infusions, which encompasses a course of Provenge.  What that should tell you is how well tolerated the therapy actually is, as opposed to traditional chemotherapies, which have many, many more side effects and toxicities.


Joel                              One of the other really big things that comes up again and again and again is basically how do I know Provenge is working?  Many men report that despite receiving or even in between infusions their PSA continues to go up.  They have scans that show progression.  This becomes very frustrating and frightening to many of us.


Dr. Shore                     That is an emotional challenge and in some ways it’s an intellectual challenge.  It’s a challenge depending upon your perspective, if you’re the patient, if you’re the caregiver or if you’re the clinician.  It’s a very complicated issue.  I’ll try to make it understandable or interpretable for my own personal experience.


Many patients, regardless of therapy that’s available, whether it’s Provenge or even chemotherapeutics that are approved, such as docetaxel, we will often times—we can see the PSA go up, the prostate-specific antigen blood test go up and actually the patients are not progressing clinically or radiologically.  We can also see the opposite of that.  So what does that tell us?


It tells us that sometimes not everything is completely true to form and that the change in the rate of PSA is not always a perfect correlation to the clinical disease state.  We also know that there have been many other studies along the way, other drugs, other therapies that have had impact on the PSA.  The PSA went down in early stage trials, Phase 1, Phase 2, and then they did the big Phase 3 trials, the PSA came down.  They may have seen some changes in bone scan and CAT scan, but at the end of the day survival was not improved.


In fact, in some studies, I’m not talking about Provenge now; I’m talking about other therapeutics that we got our hopes up on where survival was not impacted.  When it comes to the end of the day and when it comes to the FDA deciding upon what drugs to approve, especially and specifically in prostate cancer, overall survival is the gold standard.


So as you brought up with our trial, the Phase 3 trial, the IMPACT trial, we didn’t see a significant change in lowering the PSA.  We didn’t see a significant change in the regression of radiological lesions on bone and CT scans.  But what we clearly saw was a statistically significant improvement on survival.


So in some ways that tells us that we need to learn more about how to follow patients with improved blood work, improved blood tests, beyond PSA to let us know who are the patients that are responding well and who aren’t.  I think that is something that is going to require and is getting active clinical research.


Joel                              So the bottom line is I have to go by a wing and a prayer, so to speak, that I’m going to have a benefit.  Would that be a reasonable conclusion or not?


Dr. Shore                     Well, I don’t know that I would say a wing and a prayer.  There is some element of validity to that statement only in that if the PSA were just simply going up and the patient had had no change in clinical symptoms after Provenge I do not alter my therapy.  If the patient is getting a rising PSA and I get additional radiographic studies, such as a bond and CT and I see progression of disease, significant progression of disease based upon our agreed upon definitions, what are called in the prostate cancer working group, and I can confirm that then I might actually alter my therapy.


If I see significant radiological progression in conjunction with PSA elevation, certainly not just for PSA elevation alone, because this flare phenomenon of PSA, we even see that with chemotherapies and other therapies as well.  The most important thing, in addition to a progression radiologically, is if the patient is progressing clinically, a new onset of pain, loss of appetite, loss of weight and other clinical symptoms.


The wing and a prayer, I understand where you’re going with that.  It’s only because we’re limited by a lack of what we describe as valid dated, accepted blood work, specifically in the world of immunology to let us better guide our treatment decisions.  So we have to make our clinical decision to new therapy after Provenge based up what I just described.


Joel                              You also said that in certain circumstances you would consider changing therapy.  What exactly did you mean by that?


Dr. Shore                     Again, the patients who are ideally suited for Provenge are early one.  Their PSA is going up.  They’re on hormonal therapy.  They’ve now got radiological evidence of disease with a positive lesion on bone or CT scan that doesn’t include the liver, doesn’t include the brain or the lungs, but just as swollen lymph nodes.


If the patient, I felt, was clinically progressing, clear evidence of burgeoning disease radiologically and/or change in worsening of symptoms, in my patient population I would offer that patient either a clinical trial, and we have other clinical trials, or I would offer them the standard of care, which at that point for symptomatic patients that would be docetaxel, also known as Taxotere.


Joel                              Would you at the same time continue the Provenge treatment if they were, say, not completed with the three infusions?


Dr. Shore                     You probably haven’t selected your patient carefully enough if during the course of the 30 to 40 days that the patient was receiving his Provenge that they started to become symptomatic.  Ideally we want to identify patients who are far away from being symptomatic in that 30 to 40-day period.  Again, I really do think that patients are going to be best suited who are discovered earlier; which brings up a very, very important point.


It’s incumbent upon the listening audience, once they have that rising PSA, despite being on a hormone-lowering agent, just as Lupron or Eligard or degarelix, known as Firmagon, or Trelstar or Vantis, if your PSA is going up, you’ve got to talk to your urologist or your medical oncologist, more likely than not you’re still seeing the urologist.  You’ve got to talk to them and say, “Hey, how do we know where I am in terms of my overall disease state?”


Then if you haven’t had a bone scan in a reasonable period of time, in the last year or two, certainly a CAT scan, it may be a very good time to get one or both of those tests.  Then, based upon the rate of rise of the PSA or what we call the PSA velocity or the PSA doubling time or even an absolute level, certainly over eight or ten, it would be very reasonable to repeat those scans.


We want to find the patient who, again, is asymptomatic but now has a lower volume of disease before they start to become symptomatic.  I think that we want to avoid the steroids and the cytotoxic chemotherapeutics for as long as possible so as to not to have any risk of it impacting on the immunological benefit of Provenge.  Remember, Provenge is designed to reeducate or stimulate or better to potentiate the patient’s own native white blood cells, known as the T-cells.


Joel                              I’m going to move on to what’s probably a more inflamed area.  There’s been a lot of negative press and there’s been a lot of conversation about the significant cost of Provenge.  That gets for many people measured against the 4.1 months that it extends survival.  People are asking the question, “Is it worth it?”  I was wondering if you had a perspective on that.


Dr. Shore                     I do have a perspective for sure.  My perspective is that as somebody that’s been treating patients with advanced prostate cancer since I’ve gotten out of my residency now for a full 20 years.  I finished my residency at Sloan-Kettering and Cornell New York Hospital in 1990.


I can tell you that when you’ve been diagnosed and you’ve had your prostatectomy or your radiation and you’re unfortunately in the 20% to 30% of men who fail, you don’t fail and succumb to the disease in a matter of a couple of years.  It typically could be five to ten to twelve years.  So you can live with prostate cancer for a long period of time.  You’ve been on the hormone-ablative therapies and now you’re developing that resistant state.  The PSA is going up and you’ve got a positive lesion.


What I’ve been bothered by is watching too many men die of prostate cancer.  It’s a traditional race between the urologists and the medical oncologists against the cardiologists.  We don’t want our patients dying of cancer.  We want everybody to die of old age.  Old age is somewhat of a euphemism I think for cardiovascular disease.


But having said that, I think that when the patients can get a therapy that is extremely well tolerated, that doesn’t end up in the emergency room and that doesn’t end up in the hospital, that’s an interesting or additional correlation cost than what we might see with other therapies, the traditional chemotherapies where the patients can have lowering of their white blood cells.


They get prone to infections, other complications of diarrhea, etc.  When you factor in those issues the cost of care, hospitalization, emergency room visits, it can go up very significantly in addition to the ancillary drugs that we often times have to give patients on chemotherapy.  Suffices to say, Joel, these things cost money.


I wish everybody could get these therapies for free, but as I’m fond of telling my son, there is no money tree in the backyard.  We have to pay for these therapies and the land of innovation, of research and development, is the United States.  I can only look at a company like Dendreon that took over a decade and over $1 billion to get a product to market.  It could’ve all failed.  So there is an issue of recuperation of that time and effort.


When it comes to the cost of therapies, I’ve read things on the cost of other—there are some other therapies out there for systemic disease that are much more costly and there are some that are less costly.  As a clinician and someone who’s seen men die of prostate cancer, if I can offer the patient a therapy that is not going to impact on their quality of life but extent the overall quantity of their life, I think it’s a great thing.


The bigger issue is about how our country and government is going to continue to pay for therapies.  It’s very controversial and I don’t think there are any easy answers to that.


Joel                              Just to share my stripes, I’m 100% in agreement with you.  As a matter of fact, I actually did an analysis of the cost of the extra survival time for Provenge versus the survival time for Taxotere.  I actually concluded that the cost per month of extra survival time on Taxotere, a drug that no one questions, is actually more expensive when you add in all the ancillary costs.  If anybody’s interested in reading that analysis, it is on the Advanced Prostate Cancer blog, which is at AdvancedCancer.net.


The other thing that I find that there’s a lot of confusion about is what is the 4.1 months survival, the median, actually mean?  I know you’re not a statistician, but I think that people get hung up on the statistics.  Would you be comfortable talking a little bit about what that actually means and what a median is and things in that order that could maybe help clarify some of that?  Are you able to do that?


Dr. Shore                     Sure.  What the median means is that at any point in time 50% of the patients—at the median, if you look at the graphs, you see the separation of the curves of the patients who received Provenge versus those who didn’t.


It’s a little more complicated than that because about 2/3 of the patients who originally got a placebo actually went on to get what was called a frozen product of Provenge not the actual product that one would get today.  So there was even 2/3, if not more, of the patients in the placebo arm that actually went on to get another version of Provenge, which some have argued is clearly not as potentially efficacious as what one can get today.


But having said that, there were, at the median, 50% of the patients had a 4.1-month survival advantage.  Well you say, “4.1 months,” but you have to remember, my dialogue in terms of months, I tend to think more in terms of percentages because what that means is just 50% of the group.  There could be patients above that who might’ve had an eight or ten month survival advantage.  And of course there may have been some who had such aggressive disease that they might’ve been less than four months.


Another way of thinking about this is if you talk to medical oncologists, there have probably been only two or three other drugs in all of medical oncology, all tumors, all malignancies that have had at least a four-month or more improvement.  We have to put this in the perspective that these are patients, and many of the listeners or a portion of the listeners, who have been battling this disease for a long period of time.


If we do nothing, the average life expectancy for someone who has asymptomatic, advanced or metastatic castrate-resistant prostate cancer, can be about 18 to 20 months.  Well, if I had 18 to 20 months and somebody looked at me and said, “I’ve got something that’s going to give you an extra four months on top of your 18 months,” that’s an enormous benefit.


It’s not about the four months of survival advantage for when you were newly diagnosed.  This is about a four-month advantage when the pace of the disease is really starting to take off.  And it’s a four-month median survival advantage with a very short duration of therapy, only 30 to 40 days, that’s extremely well tolerated.


So my hope is that not only will patients benefit from Provenge if given as early as possible, making sure their physicians are getting the scans, checking their PSA to make sure they meet enrollment criteria but that they can benefit at some point also from appropriate use of chemotherapy, absolutely.  As you mentioned there’s cabazitaxel or Jevtana, which is a second-line chemotherapy, which as been approved.


There are other oral drugs.  There’s the drug abiraterone, which is approved also after progression from taxotere.  And we’re working on so many other therapies, both oral and intravenous to give earlier on in the disease state.  So the big hope is that we make this truly a chronic disease, much like having high blood pressure or diabetes.


Joel                              Thank you so much.  Since you’ve been involved in the trials, Phase 3 trials early on, are you still seeing men who were in those trials who are still alive today?


Dr. Shore                     Yes.  I still have—again, the Phase 3 trial finished well over almost three years ago.  The answer is yes.  I have patients now who are receiving therapy, who have received their course of the three infusions, and not only look remarkably healthy but also are acting remarkably healthy.


I think that’s what so exciting about the drug and therapeutic developments now in prostate cancer.  Our challenge, as the clinician-treating community, is a better understanding how to sequence and how to combine all these new therapies.  Honestly, we don’t have all the answers.


As we started talking about earlier, we need to work collaboratively all the different specialties, the urologists, medical oncologists, radiation oncologists and collaboratively with industry.  Industry is anxious and willing to work collaboratively.  We need to work collaboratively with our government; the NIH and NCI funded grants.  We need to work collaboratively with the academic centers and the community centers where many of the patients are.


I think it’s advocacy groups like Malecare who really are the glue for all of these organizations that I just mentioned that helps bring everybody together and says, “Hey, wait a second.  Here’s an unanswered question.  Here’s an unmet need.  This is what needs to be addressed.”


Joel                              Do you see a difference in African American, Asian and Caucasian men that come to see you, as far as the nature of their cancer and how they respond to treatment, including Provenge?


Dr. Shore                     That is an excellent question.  There is, unfortunately in this country, a disparity amongst the African American population, in terms of their mortality rates, regarding specifically for prostate cancer.  It’s really unconscionable that in the Southeast, an area where I am, South Carolina in particular, as well as the District of Columbia and Washington D.C. and metropolitan areas in the north, the mortality rates of African Americans with prostate cancer is nearly doubled to all non-African American groups.


It’s a complex, multifactor issue.  Part of it has to do with not appropriate enough use of screening.  A bigger part of it and I think a less controversial part has to do with African Americans not getting access to clinical trials.  There are a whole bunch of reasons why that may have happened.  There are some historical problems about African Americans being abused in clinical trials and now there are some issues in terms of just getting out information to the African American community.


But regarding Provenge, we did an analysis after the conclusion of the Phase 3 trial.  We call this a post hoc or after the fact analysis, which is kind of looking at things in the retrospective scope, which one can argue is not as valid as if you destined a study to look at it prospectively.  But having said that, and with the small numbers of patients in the Provenge trial, there was an unbelievably positive response of African American men, in terms of an even wider improvement or separation of the curves impacting overall survival even more favorably in African American men.


That work is incredibly thought provoking and needs to be verified and validated with more studies.  There is clearly more we need to understand from genetics and other markers amongst African Americans, perhaps the Asian community, the Latin community, the traditional Caucasian communities and finding out what are the markets, what are the variances that can identify somebody who would be a great responder versus somebody who might not be.


Joel                              One of the exclusions on the Phase 3 trials was HIV/AIDS.  Someone was HIV/AIDS positive.  They were not allowed to enter into the trial.  Can you tell us why that was the case?


Dr. Shore                     That’s a good question.  One of the challenges right now, and boy, I hope someone from CMS is listening to this broadcast.  I suspect they’re not.  If I had somebody who was HIV positive and had had no clinical evidence of disease right now from HIV but was in complete remission, had been in that for a prolonged period of time, who unfortunately also happened to have a criteria to get Provenge, I might have a really hard time giving it to that person because the third-party payers or even CMS might say, “Well, we have no data on those patients.”


Patients tend to get excluded in trials because you’re just trying to get a specific population of patients to meet an accrual pool.  Often times some arbitrary decisions are made.  I think at the time HIV patients may have been felt to be immuno-compromised.  They may have been felt to have a less likelihood of a significant survival and that their prostate cancer wouldn’t cause them an untimely death in comparison to their HIV.  Similarly we had other criteria regarding elevated liver function tests.


I think, to be very candid and blunt about it, I think some of these exclusion criteria, these are the exclusion criteria as opposed to the inclusion, are arbitrary and don’t make a lot of clinical sense.  It’s just an unfortunate limitation that some patients who have these exclusion criteria based upon a trial might not be able to benefit in the real world, now, even despite FDA approval.


We either need to do those studies in those subpopulations of patients or perhaps there just needs to be more lobbying and advocacy on behalf of those patients.


Joel                              Obviously that’s a task for Malecare and it’s also a task, again, if anyone from Dendreon is listening; we need you to do that.


I was wondering, in your practice, have you ever had a patient identify himself as being gay or transgender?


Dr. Shore                     I have a reasonable amount of gay patients with prostate cancer.  It’s certainly not the majority, but I have had many patients who have identified themselves as gay with prostate cancer.  I have not had a transgender patient.


Joel                              When someone identifies himself as gay do you change your treatment plans?  What do you do to accommodate any differences there may be?


Dr. Shore                     I don’t do anything different other than encourage them to, if they have a partner, to make sure they bring in their partner, because partner support, whether it’s a female spouse or a male partner, is extremely important.


For the gay population, there’s reluctance to bring in their partners.  I encourage that very strongly.  But in terms of my clinical treatment options, in terms of my therapeutic options, there’s absolutely no difference.


Joel                              Since you do work with men who are in end stage that must be mighty difficult.  How do you deal with that?  How do you keep yourself grounded when you’re dealing with them?  What sorts of things can you do or do you try to do with them?


Dr. Shore                     That’s a double-edged sword in that these patients actually are some of the most—the patients who are really getting close towards further and further progression is some of the most absolutely rewarding and emotionally gratifying times of being a physician that one can imagine.


As we get closer and closer to the end of life—we take a lot of pride in my clinic, particularly my research nurses and my nurses who work with me and have known these men and their families for a long period of time.  It’s a remarkably rewarding and gratifying experience to work with patients, talk with patients, hold their hands, laugh with them and cry with them, as they get to a progression of their disease state.


It’s a remarkably gratifying experience to have and it’s truly an honor as a physician.  And at the same time, when you lose someone, as I’m sure many of the listeners have, whether it’s from cancer or from anything else, lose of a loved one is an agonizing experience.  It can be something that certainly one may never get fully over.  But it’s a real privilege, I think, to be involved with that.


I think, in terms of our philosophy and I think what we’re starting to do a better job of in U.S. health care overall is addressing the issues and not shunning the conversation and the discussion about fear of both the patient and the patient’s family, addressing the issues of pain, issues of possible death.  Many physicians are extremely uncomfortable in talking about it.


We’ve done a poor job in our medical education system of discussing death.  We don’t like to discuss it as a culture, but it is quite a natural process.  If you have always the opportunity to offer hope and encouragement, which we certainly try to do, as well as avoidance of toxicity of therapy, that’s I think about all you can do.  And just be there.  Sometimes just being there is equally important.


Joel                              That’s good.  Are you at all familiar with some of the other immunological therapies that are currently in trial for treating advanced prostate cancer?


Dr. Shore                     Yes.  It’s an incredibly exciting time.  It’s just a wonderful, wonderful time.  Like I said, in the last year we had four FDA approved therapies since 2010 of April.  You mentioned them earlier, Provenge, Jevtana, Xgeva, known as denosumab, and then Zytiga, abiraterone.


We have several other very interesting immunotherapies that are out there.  One is called ipilimumab.  It’s being trialed in prostate cancer.  It was just successfully trialed and approved for patients with metastatic melanoma.  I think its trade name is Yervoy.


We also have some other therapeutic vaccines that are being trialed.  One is also known as Prostvac.  Its years away from completing its trial let alone getting approved, but it works differently from Provenge, as does ipilimumab.  These are different mechanisms of action.


What I love about that is these different immunotherapeutics, they’re not going to me-too drugs.  It’s not Bayer versus Anacin aspirin.  These are immunotherapeutics that are designed to re-stimulate, better involve our native immune system by going at it at different pathways.  So isn’t that exciting if you have advanced disease that you could have not just one but two or possibly three other ways of stimulating one’s immune system to fight the cancer?


Joel                              So we need to have you keep us alive so we can have a chance to sample all these treatments.


Dr. Shore                     That’s it.  And it’s not just about staying alive.  It’s about staying alive with good quality of life and being able to do the things that one worked hard to do in one’s life.  It’s a great time.


To bring it back, it’s sort of a scary time in that here we are.  We’re not on the cusp.  We’re right in the thick of understanding the different molecular pathways that cause advanced cancer and progression of cancer, but yet we are hitting a point right now where we’re at this economic challenge aren’t we?


So we have all these new therapies that are getting approved and more to be approved and yet we’re suddenly backing up against how are we going to handle the compensation for all of these things?


We don’t want to be shortchanged on it.  We have to be out there fighting for patients with prostate cancer because all the other organizations, and they’re good and great and noble causes, whether its cardiovascular disease or HIV/AIDS or breast cancer or even non-malignant entities, organizations like Malecare and others and patient advocates have to be out there making sure that we continue to get the resources and the funding to do these studies.  Not only do the studies but also to pay for the therapies that ultimately get approved.


Joel                              And of course, based on the political times, this is more important than it’s ever been.  So I reiterate that.


It’s common practice when someone’s diagnosed with breast cancer to be referred for genetic counseling.  I have never, ever, met a man who’s been diagnosed with prostate cancer that’s ever been told to get genetic counseling.  Is there a reason?  Should a man with prostate cancer get genetic counseling and what would the benefits be for him?


Dr. Shore                     That’s a hot bed of research.  There are some companies out there that are looking into that genetic analysis.  There’s no doubt about it; there are multiple companies.  None that I’m aware of that have received an FDA approval or at least a Medicare, CMS, approval for compensation.  This testing tends to be very expensive.


What we do know is that men who have first degree relatives, a father, a brother, even potentially second degree, a grandfather, who had a diagnosis of prostate cancer that was clinically impactful are at higher risk and that there is a genetic predisposition for certain men with prostate cancer, especially if your father was diagnosed at an earlier age or you have brothers or multiple cousins or uncles.  There clearly appears to be a genetic predisposition.  We even know that in African American men there’s a potential predisposition for the development of the disease at a younger point in time.


But yet we also appreciate that there may be clearly dietary and nutritional factors that increase one’s risk for prostate cancer.  Japanese, of Asian descent and upbringing, have a very low risk of prostate cancer.  When they come over to Western culture, Japanese Americans, their prostate cancer incidence goes up significantly to suggest dietary and/or environmental factors.


But you’re right.  There is no reflex genetic testing in prostate cancer like we do for breast.  It still needs to be worked out a little bit more.  I think it will be something that we’ll be seeing in the future.


Joel                              Terrific.  Actually, I’m looking at my clock and we’re ten minutes over our hour already.  I actually have a bunch of questions that people have asked.  So if it would be okay with you, could I forward those questions to you by email and you could perhaps give an answer and then I could send them back to the people, since I really don’t want to spend more time answering these because we are so late?


Dr. Shore                     I’d be happy to.


Joel                              I appreciate that.  I guess the last final question I’d like to ask you is what do you see in the future for men who are diagnosed with prostate cancer?  Here’s a chance to give a good global summary.


Dr. Shore                     Newly diagnosed with prostate cancer, we need to do a much better job of recognizing and advising our patients on who has the more aggressive of the disease that would benefit from aggressive therapy versus the patients who have an unaggressive disease or a low-risk disease that don’t need to be overburdened with localized therapies, whether it’s surgical or radiation or freezing, and leave those patients alone.  Having said that, that would save a lot of morbidity in terms of impacting on patient’s quality of life to avoid unnecessary over treatment.


What I’ve been most interesting in are the patients who have the more aggressive disease who we fail to treat as successful locally.  It’s this population where Provenge and other novel therapeutics will allow these men to live into their late 70s, 80s and 90s as if they didn’t have prostate cancer.  I think we’re getting there.  Clearly Provenge is a huge step in that direction, newer chemotherapies, newer oral targeted agents.


I would love to be able to finish my career knowing that the risk of dying of advanced prostate cancer is very, very small and patients will ultimately succumb to the typical old age phenomenon or just your ticker just doesn’t have any more ticks to it and that’s okay.  As long as we can do it in such a way that patients continue to maintain good quality of life then I think we’ve done our job as a medical profession.


Joel                              Dr. Shore, I want to thank you for taking your personal time to share your knowledge with us this evening.  For those people that might be interested in making an appointment to see Dr. Shore, you can contact him at 1-877-809-8719.


Again, for those people who are listening, Malecare will continue to bring other teleconferences on the hot topics facing us.  Check in with the Malecare website and we will also send notices to people who have registered.


Again, thank you, Dr. Shore, and thank you everyone else for listening in.  Have a good evening.