Bipolar Androgen Therapy (BAT)- Sam Denmeade MD, Prostate cancer treatment with testosterone bursts


G’day. This video is about a treatment for men
who already have prostate cancer. It is about adding an occasional testosterone
boost to regular hormone therapy to treat prostate
cancer. Doctor Sam Denmeade of Johns Hopkins Medicine
reports on encouraging trials of this approach. The small numbers in these trials
means your doctor will not be recommending this
as part of the standard treatment as yet, except possibly in a clinical trial. When this video was made in February 2017
clinical trial openings were limited to the USA. But if you wish to understand the treatment
which could become a game-changer in the future this is for you. This video is an extract from an Answer
Cancer Foundation online support group meeting, but all sessions started with an
introduction to the Foundation by its leader Rick Davis and then introduction to Dr. Denmeade
by member Professor Bill Byrne a prostate cancer
researcher. There will be a link to a full
session at the end of this video, which also includes a full hour of questions and answers. Thank you for the introduction. I’m really excited to be here. I’m sorry I don’t have a webcam
I’m not much to look at anyway but you staring at me for an hour is probably
not the best thing and Hopkins doesn’t pay us
enough to have webcams so I don’t have one. I certainly wish I could be in there with
you. So I’m going to talk, many of you are familiar
this minute you are about what we have called bipolar androgen therapy. It has nothing to do with bipolar disorder
although now I get a lot of emails from psychiatric meetings and things about my expertise
in bipolar disorder. So it’s a name we came up with, and so I’ll
sort of explain what it means in a moment. I just got a quick overview of what I’m going
to talk about. Since everybody has different backgrounds
I’ll just spend a little bit of time on the background about androgens, androgen signaling. A lot of you may know a lot about this already,
so you can have a cup of coffee or tune out for
a while. Kind of some rationale why we’re doing this
and then some results from a pilot study and then a study we’re doing called the
Restore Study. A little bit of information about the larger
study we’re doing called Transformer and some thoughts about future directions in men with,
using this approach in men who have castrate-resistant disease. And then I have a few slides at the end about
a trial we did where we try this as a kind of
a first-line therapy intermittent hormone therapy
and we just published a paper about that last year. So I guess what we’re not talking about today
are other things we used to start from for. So testosterone replacement as you’re all
aware is big business and a lot of debate, controversy
about who should do it, who should not. Tons of stuff out there,
we’re not talking about that today. We’re also not talking about testosterone
that’s used in another way which is that of a
steroid. I got a lot of interest from various groups
about this as well. It is amazing what you can buy on the internet
if you want. So we’re not talking about that either. We’re going to be talking about using testosterone,
high dose testosterone as treatment for prostate cancer and the bipolar story is what we’re
going to get to. So first just some simple stuff. What is an androgen. I think everyone needs to
understand it when I say testosterone. It’s referring to a family of chemicals. So testosterone, dihydrotestosterone, all
these things are what they call steroid hormones
which bind to a thing that inside cancer cells
called the androgen receptor. Talk a little about that a second. Androgens are very important primarily
for sexual differentiation. So as the fetus is
developing if there’s no androgens and you have an XY, a male, you end up with a
female. So the default shape of a human is a female
unless you have a little testosterone in there. Testosterone is also important for the primary
sex characteristics. So making sperm and making all and sort of,
maintaining the sex issues like the prostate, the penis. And then finally testosterone
is very important and a lot of other things, bone density, muscle, libido, hair growth,
haematopoiesis, which is making red blood cells in the brain, lots of important
things. We certainly have learned a lot about how
important testosterone is with our therapies that
take it away. So all the side effects we get of hormone
deprivation are related to the importance of
testosterone. Not just in the prostate but in the whole
body. So what is a steroid hormone? These are some chemical structures I don’t
expect you to understand what they are. Basically carbon oxygen and hydrogen, but
you can see that this shape is a very important shape
in nature. So all of these steroid hormones look the
same. They have the same shape with different things
hanging off the side and they’re interchangeable. Testosterone can be made into estrogen; it
can be made into dihydrotestosterone. Progesterone is a precursor for all these
different androgens. So again we’re talking about steroid hormones
this is what we mean, this shape of molecule. Then how do we make these things? So this is a very complicated thing in the
body that involves lots of different tissues and
organs. So it starts in the brain. A part of the brain
called the hypothalamus makes something called LHRH, which is a hormone that moves from the
hypothalamus part of the brain to a gland called
the pituitary gland that sits right under the
hypothalamus. It makes another hormone; it gets in the blood
and goes to the testicle and there the testicle makes testosterone out of, starting with
cholesterol, a bunch of chemical steps to get
to testosterone. We know that other things can make testosterone. The adrenal gland, the muscle makes some
testosterone and this testosterone gets into the
blood and goes all over the body and affects lots
of tissues. In the prostate, relatively specifically in
the prostate there’s an enzyme that converts
testosterone into something called dihydrotestosterone, which is a more potent
form of testosterone. It binds better, it’s a stronger form, and
then once it’s in the prostate bound up as it is,
it then does all the different things that testosterone does in the prostate to stimulate
things like growth, make more PSA, makes fluid for the semen etcetera. So I use this analogy to talk about the story
with my patients a lot and so I’ve had to make
a slide out of it. So I talk about the androgen receptor and
I think of the androgen receptor like a baseball
glove and the androgen like a ball, and for this
to be active the ball has to be inside the glove
to form an active conflict. And as you’ll see later most of our therapies
really are about trying to disrupt the ball getting into the glove. So in a more complicated way the androgen
receptor is a protein and it has a couple different
parts. It has a part that’s a signaling part that
other proteins stick onto. It has a part that’s called the DNA binding
part, so this receptor has to stick on the DNA to
do things. And it has a part that androgen binds to. And you can see there to the right of the
slide, without androgen the androgen receptor’s in
a certain shape and then when the androgen,
in this case DHT, this the sort of reddish
purple diamond is [indecipherable], the receptor binds to it, changes its shape,
moves into the cell nucleus, sticks on the DNA and
then does and activates all the genes that either
prostate or prostate cancer use to grow to survive,
then to make things like PSA, acid phosphatase, other growth factors. So the goal of all the therapy is really disrupt
this process, at least the standeard therapies that we have. So turning to the prostate itself, I’m sure
all of you know where your prostate gland is,
but I once had a student who did not, at one of his exams which is shocking to me. So I always try to include a picture to show
where the prostate is. So it sits right underneath the bladder. As you know the urine flows through the urethra
from the bladder through the prostate through the penis but also through the prostate cups. The semen, and the prostate is responsible
for making a lot of the fluid of the semen. But we still don’t really exactly know
what the prostate does. In terms of its primary function we know that
it’s involved in fertility in some way, but you
can take out the semen and sperm from a man and
still fertilize an egg. So the prostate isn’t critical for that. But it causes a lot of problems, even though
we don’t know what it does and it’s really small
but it’s really one of the major problems of a man
of the ages. First most men get what’s called BPH. Almost all of us will get this by the age
of 80 and that gives us lots of issues with urinary
problems. We also know that a lot of men walk around
with prostate cancer. Startling enough up to forty percent of men
by the time they’re 40 have some microscopic prostate
cancer. Now fortunately, in most men, that doesn’t
progress to become clinically significant, but certainly
there’s a lot going on there that we don’t understand. And there’s about 220,000 cases a year now. The number of cases has ben declining as has
the death rate, thankfully. But still a good number of men unfortunately
die every year from prostate cancer. So the original therapy and thinking about
prostate cancer that had really started was way way
back in the nineteen forties, and the hero of this
story is really this guy, Dr. Charles Huggins. He was at the University of Chicago and he
was even there when I was a resident there although
he was about 85 then and no one really knew who
he was at that point. But he was a brilliant guy and you can see
the date on this study is 1941. And he was the first guy to show that you
can treat advanced prostate cancer by lowering
testosterone. He wrote these two papers in 1941 which really
changed really how we treat prostate cancer and at the time really almost a miracle. Offers a lot for men who have very advanced
cancer. We didn’t have PSA at that point. And so he made a huge impact and he won the
Nobel Prize for this story later in the sixties. He was able to show that in 1940 that you
could use a biomarker to really look to see if a
treatment was actually working. That kind of anticipated a lot of what we’re
doing today. So getting back to this glove and ball,
most of, or all of, our hormone therapies right now as I said this is how they work. We try to disrupt the ball getting into
the glove. So one way you can do that is just get rid
of testosterone. So you can cut off the testicle; you can give
Lupron to shut off the testicle; you can give drugs like Zytiga, Abiraterone which turns
off the enzyme that makes testosterone. And so you end up with an empty ball. Or you can give things that block testosterone
getting into the glove, into the receptor. Thinks like Casodex, Xtandi and these are
things that are kind of shaped like testosterone. But when they get into the glove, the glove
doesn’t work quite right because testosterone can’t get in there. It’s close to the shape, but not quite the
shape. And we’re very good at this making drugs that
block testosterone. These are all the drugs that we have since
the nineteen forties. You can see the forties mostly we focused
on was the surgery. So we cut off the testicle; we
cut out the adrenal gland; we even cut out the
pituitary gland. And then later we started to have all these
different drugs, which really all of them do the
same thing in some way or another, blocking that
interaction. And we’ve now, in 2016, reached this point. Many of you will recall probably some part
of this. And the arrows kind of go all over the place,
so the flow of this is variable, but for the most
part most men received primary hormone therapy. We’re using more chemotherapy now with primary
hormone therapy. Everybody reaches this unfortunately this
castrate-resistant phase and then we do lots of
things. We try more hormone therapy; we have non hormonal
therapies. There’s a lot of clinical trial interest right
now in lots of things. Some big themes are immunotherapy, PARP inhibitors,
some interesting PSMA targeting, things like that. But this is the current paradigm. So turning backwards to Dr. Huggins again,
kind of back to the future, Dr. Huggins, this is an
idea I’m working on, but he’s the guy who proposed
it 50 years ago and really thought of two different
ways you could do this. One is to deprive the hormones, and we’ve
seen 75 years of that, but then the other way he
proposed was you give a lot of hormones to interfere with the hormone receptor. Unfortunately no one really listened to that
part of the story and so we haven’t seen a lot
of research in that area. Dr. Huggins went on to do this approach even
though he was a urologist. He went on to do this with breast cancer with
estrogen, not really focused on prostate cancer at that point in his career. So this is one of the credos I’ve lived
by about this idea which is by Albert Einstein for an idea that does not first seem insane,
there is no hope. So at first when you think about this idea,
many of you out there, your doctors have worked with you and you
feel almost a pavlovian kind of reflex that you
can’t have any testosterone; it’s the devil. And so, when we first proposed this idea,
most of the people thought we were pretty crazy
and we probably were. And so maybe that’s why it works. So what we’ll talk a little bit about that
road. But I have this over my desk at work so I
thought I’d share it with you. So why would this work and why do this? And so I’ve been using this slide in a lot
of the presentations I do, and it’s a slide that
has really nothing to do with prostate cancer. It’s about shrimp. So these are shrimp that live in the great
salt lake at Utah. They are called brine shrimp. It used to be you all probably remember in
every comic book there used to be an ad for
sea monkeys that you would buy dried and you could throw and you could get these animals. This is what they were. And these are harvested and they’re used as
fish feed a lot around aquariums. But these are incredible animals, so they
can can live in the extreme conditions of
saltwater that’s ten times more salty than the sea. They live in crazy temperature ranges
but, if the snow melts too fast in the mountains in Utah and it floods the lake all of them
die. So they basically get killed by water,
even though they can tolerate all kinds of different conditions, because they can
adapt to the change. They die by sort of shock. So I kind of think about hormone therapy like
that. It’s kind of a shock. So the cancer is living in this nice testosterone
stable environment and then we give a therapy that takes the testosterone to zero
and that’s an incredible shock. It’s the major growth factor for the cancer
and it’s gone. And so we know that very rapidly people respond. And so most of the response we see in patients
is within the first few months. PSA plummets, tumours shrink, pain gets better,
and so we go through this shock phase and then
we reach a phase that PSA is undetectable maybe, or
low. That stage can last month’s too many years
and the tumour is still there. It kind of goes dormant. You don’t really know exactly what’s happening
at this stage. Hard to study because it’s not much to biopsy. There’s not much to do. But we know the cancers there, kind of, sort
of in my mind, sort of rolling the dice trying
to figure out how can I grow again in this
low testosterone environment. Eventually it figures it out and it becomes,
we call that resistance, starts to grow again in
this new environment we placed it in. It adapts to it. So, my analogy is there’s sort of a sweet
spot where the cancer likes to live, and when we
perturb it, it does not necessarily die. It can take a little bit of change but not
a lot. So when we give it anti-androgens to block
the androgens we shocked it and we drop the growth
but it suggests this model that we can go the other way and give it a lot of androgens
but shock it too. You can basically move it out of its comfort
zone. And for that reason, to get these kind of
results, this is what got me started; these kind of
weird results. This is cells in a dish and you can see that
the growth’s fine, but if you give them an androgen
called R-1881 they stop growing. And if you give it an anti-androgen they can
actually stop growing. So they respond to shocking them in either
direction and that was always intriguing to me
why that could be. One of the reasons we think these cells get
resistance, one of the main reasons is, they still want that androgen receptor. They’re still kind of addicted to it,
and they just titrate, they make more and more
and more of it until they get a new level that
is that works for them. And so what we see in the cancer is the cancer
cells start to make a ton more of this receptor, maybe a hundred times more than they start
with. And they make more copies of the gene and
they mutate the thing and they make variants of
the thing that don’t need the ball anymore. But it still seems like it’s a critical thing. So there’s a lot of evidence in the lab
and a lot of it was led by this guy who was a
colleague of Dr. Huggins, who showed early on
that if you took cells that had been adapted to
live in low testosterone and you suddenly gave them
high testosterone, they would stop growing. This is a graph in an animal showing that
you go from point number two to point number three. Now over time the cancer readapts, starts
to grow again, and they showed later that you could
then drop the testosterone and the tumours would
shrink again. And the other part of this picture shows at
the beginning the little dark lines you can see
is androgen receptors sort of light gray. When they’ve been adapted the line gets darker,
suggesting there’s more androgen receptor, and
then when they get exposed to testosterone for a
while they readapt to kind of go back to baseline again. So they’re able to change depending on the
environment. So we found in our lab and others, you know,
this seems to work. You know the cancer cells stop growing when
you give them what we thought was their growth
factor. It’s kind of a paradox. Hard to understand really,
and why does it exactly happen we don’t really know. There’s lots of different reasons that we
see. In the lab people have shown, this is maybe
more detailed you need, but just the point here
is that it does a lot of things. We’re not sure which one of these is the critical
thing, or if all of these things are the critical thing. But certainly giving high-dose testosterone
has a profound effect on the cell. Some cells don’t care, some cells grow a little
better, and then some cells, about a third of
prostate cells in the lab stop growing when we give testosterone. We also know that the dose is important. So when you give a little bit, either nothing
happens or they grow a little better. And then when you give a lot they’re blocked. And we see that if you look at it, so these
panels, “B” is what these cells look like under the
microscope. “D” is what they cells look like with a little
bit of testosterone, still looking healthy, and “F” is you can see lots of little dots,
big clumps, they self-destruct and fall apart under the high dose. So became evident to us that we’re going to
do a trial that we probably needed to use not regular
levels, at the time you could get things like hormonal replacement gels, but some kind of
shock level. And I’ll show you how we achieve that in a
second. So our hypotheses were one maybe we can take
men who were castrate resistant and give them
a shock of testosterone, high dose, and then drop
the level real fast. So kind of a high shock followed by a low
shock. This wouldn’t let the cancer cells adapt to
the environment very easily and we might be able
to catch them out of phase so to speak. If we could disrupt the regulation of the
receptor and we also thought that we might also
be able to resensitise, because if these cells adapted and droped the receptor they might
become sensitive again to things that lower hormone therapy. And we’ll talk about that a little bit. So this is what I mean by what we call bi-polar
androgen therapy. We’re basically taking men and giving them
an injection of testosterone, in the buttocks,
in the muscle. This dose of four hundred milligrams, it’s
FDA approved dose, so even though its high dose,
it’s not crazy high dose. So its and approved dose that used to be given
to men to kind of restore testosterone in older
men who have lost, their testosterone got low. And so there’s other ways to do that now,
the gels and creams and things you put under your tongue
and all kinds of things. But we’re using an FDA approved drug testosterone
Cypronate and we call it bipolar to reflect that
we’re moving quickly from really low to really high
so these two pair of polar extremes. The testosterone here when we injected, we
had a, our level here was 1500, the lab stoped measuring
it, but we know from other studies we probably get
two to three thousand. A level in a man who is about 70 years old
is probably two to three hundred, and then at
castrate level it is really zero. So this is a big change in the level that
happens really fast. So we started with a pilot study that, this
was funded by a, I had a patient of mine who had
prostate cancer, metastatic prostate cancer, and
amazingly while he was suffering from it, started
a small foundation and raised money. Had golf tournaments did all kinds of things
and helped support my lab and then later he supported
this small study with some seed funding and initially we did a combination of testosterone
and etoposide. Etoposide is chemotherapy that blocks DNA
repair. There was some evidence when we started that
maybe that’s how this works, that testosterone can
cause breaks in the DNA and if you block a pair
the two could work well together. What we found was a lot of the men kept responding
to this for three cycles and if they responded we kept him on it. Just testosterone alone and they kept responding. So we weren’t sure the Etoposide was helping
and we certainly thought it was making men sick. It made them lose their hair, a lot of nausea,
fatigue, anemia. Probably we had one man died on the study
from sepsis, from his blood counts getting too low. So, but we were really encouraged, might even
say shocked to see this kind of response. So some of the men, when we first gave the
testosterone, their PSA would jump up right away
and then to our surprise start to drop. And you can see this patient here, this is
an example, ends up getting this treatment for
18 cycles. This is an example of what his big lymph node
in his pelvis did. It had shrunk quite a bit
and then we also saw, when we stopped the testosterone, we had even a further response
once the man was castrate again. So we saw this in a good number of patients
and it was quite exciting to us. Over all about thirty percent of the guys
had what, we in our business, count as a response. Which is PSA went down by 50%. About about half
of the man had some shrinkage by fifty percent of
of their tumors. This was mostly in lymph nodes. The bone changes were a little bit harder
for us to see. Most of the men had stable bone disease,
not worsening disease. It was pretty safe, really nobody, nobody
started with pain and nobody developed pain. I’ll talk about pain a little bit later. And some of the men stayed on a long time,
in fact one man was on it for three years. And ah the men felt really good. A lot of the men who had lost their ability
to have sexual function we’re extremely happy when it came back, and a lot of them didn’t
want to stop the therapy even though their PSA
was going up because they felt so good. And to our surprise all of the men that we
put back on some kind of hormone lowering drug,
it worked again. And a couple of the guys, even a drug that
had been working, but they were failing, we put them
back on the same drug and it worked. So all of that was really interesting and
it allowed me to have this weird experience where
I live off of grants here at Johns Hopkins and I
often will send the same grant into more than one
place, because the chances of getting the grant
is very low, and with this approach I had a weird
experience of getting two grants at the same time,
which has never happened to me before. So that has allowed us now to do two different
studies. And I’m gonna tell you about what those
studies are along the way here. So the first study, I really like acronyms,
so you can see this is one of my first acronyms, which we call the Restore Study. This study is taking men who have progressed
on either Abiraterone or Enzalutamide or both,
and then giving them this treatment with testosterone
alone and then see what happens. So 30 men on the study will get either
Enzalutamide or Abiraterone-Enzalutamide, but whatever they got last, if it’s Enzalutamide,
they would get get re-exposed to that. Same is true for Abiraterone. They all stayed on continuous block of their
own testosterone production with Lupron or things
like Lupron, because you want to be able to control
the testosterone. And so we’ve now able to go finish the part
of the of the study where the men who are Enzalutamide. We are still recruiting recruiting for the
Abiraterone arm. I’m going to show you some of the data we
have on this study. So some of the eligibility they have to stay
on hormones, they had to have a rising PSA, they
had to have some kind of disease we could measure,
And then we didn’t allow anybody anything worrysome,
like spinal cord issues, problems with the urinary
tract. And then the big one was pain. So, in the past people have tried to use this
approach to treat bone pain by combining it with
things like radioactive compounds, and what they
found, and this was back in the seventies, is that when you gave a man with bone pain
from prosecutor testosterone the bone pain got
very worse very fast. And so we have excluded in on our studies
anybody with symptoms. We’ve had a few men that we’ve missed, judged
the the symptoms thinking they had arthritis when
it was pain from prostate cancer. And just like back in the seventies we saw
the pain get very bad. Often before they even got home for the clinic. It’s interesting why it happened so fast. We’re not sure what’s going on. It’s definitely not making cancer cells grow. Its probably stimulating some kind of inflamation
in the cancer. Most of those men, the pain goes away within
about a week, and a bunch of the men, we only had
a handful, three or four of them, but I shouldn’t
say a bunch, in those men it seemed like the pain
didn’t come back. Well we’ve been really hesitant to, you know,
induce bad pain if we can avoid it. So this is the PSA response we saw, so you
don’t have to care about the color, this is something
we call a waterfall plot. Use it a lot in oncology. So the bars below the line are the people
that had a good response, the bars above are the guys
who didn’t. Of course again we get excited if it’s more
than a 50-percent drop. So you can see about half of the guys had
a drop in a PSA, and just like the earlier studies,
about a third had a big drop. Ah, the other piece of this is what are mechanisms
I mentioned earlier was we thought, from some studies in our labs of our colleagues here,
that testosterone might be able to break the DNA. So many chemotherapies cause a single break
in the DNA. Most chemotherapies do not cause a double
strand break. Often double-strand breaks can be lethal because
it’s really hard for the cancer to glue that back
together. So you can see here, this is just an image
of the cancer cells treated DHT. All those little pink dots are places where
the DNA is broken. You can see the controller didn’t get any
therapy on a few and the ones that got the DHT have
a lot. So with that in mind, we start to explore
why is this working in some of these guys and I’m
gonna show you response of one man. Others are best response. This is a man who got a lot of different treatments
as you can see, a lot of hormone treatments. Came on the study with a PSA of around 10. We started the testosterone, basically had
a complete response. So all of his PSA went to zero and all of
his disease disappeared. He was on the study for about two years like
that. Reasonably, unfortunately we, first we thought
we’d cured him because of this, but in the last
month his PSA has gone up to point two. So we probably didn’t cure him. But we had a really profound effect. So we started thinking we just figure out
this one guy maybe we can get on to something. So the first thing we did is some genetic
testing on him and to our surprise he had two mutations
and very key DNA repair enzymes BRCA2 and ATM. So we’re not going back in our study and starting
to look at you know the other guys that responded. Is this a feature of that and maybe that’s
a marker for who would respond. So just an overview of where we are and these
are the 30 or so 29 guys on the first part of
the study, again I mention about a third of them
had a good response. When we looked at their x-rays about 15 percent
had tumors that actually shrank and the rest of
them had the most part stable disease. A lot of that was in the bone. Then a few men actually showed progression
of their disease. In terms of safety it was really like
the first study, pretty safe. The biggest side effects we see are some
tenderness in the breast. Some men get ome swelling. We had a few men have very, some pain
develop, but very low-grade. Not always easy to know if it’s cancer pain
or not, but that was our score. A couple guys had some bad things happen and
we don’t know again if that’s related to testosterone
or, you know, things like a heart attack. These are older guys, so they’re at risk
of heart attack anyway. Pulmonary embolism again could be due to
testosterone but also is a risk for just from prostate cancer. So we’ve only seen these in individual people
so we’re not totally clear how it’s related. And then of course we saw very positive effects. Most of the men feel a lot more energy. You certainly see their blood counts go way
up, and those men who could have erections
get erections back. It certainly is a way to make your libido
go through the roof. And sometimes it’s frustrating for men
who can’t have erections because they have libido,
but they can’t do anything. And one of my patients complained that he
chances his wife around now, but when he catches her
he can’t do anything. So that’s been a good thing and a bad thing
I guess depending on how you look at it. The other part of the study was looking at
well what happens when we take the people off the
testosterone, can we resesitise them if we give
them Enzalutamide again. And so, or Xtandi. So here we found that most of the men the
PSA goes back down when we give them Xtandi. These are all men who had been on Xtandi
and the PSA was going up when we started. So we were pleased to see that in a lot of
the men it goes back down. Unfortunately most of those men that PSA response
is short lived, so it’s somewhere between three to six months. Again I like showing my extreme responders. We have had one or two patients have a
response like this though, where you have a
dramatic decline in their PSA. And again this man also had mutations in his
DNA repair, although these are mutations but we’re
not sure what their significance is, they have not
been described before. But it is intriguing that in both of these
extreme responders we did see something related to
DNA repair. So the other part of the study that we looked
at is, you all may be familiar with the story or
not about the androgen receptor variant. This is a kind of thing that, hard to conceptualise,
but I’ll do the best that I can. So basically the way I explained it to patients
is the cancer can start making a variant of the
androgen receptor that basically is a glove that doesn’t need a ball. So it can still signal in the nucleus of the
cell without androgen. So here I showed in a cartoon, you can see
the same cartoon we used before, I just cut off the
part of the protein that testosterone sticks to. And so in studies done here at Johns Hopkins
we now have a test for this and I think there
will soon be a test that will become a standard
test around the country. But in this first study we looked at guys
who either didn’t have or did have this variant,
called variant 7. You can see the blue bars if you were variant
7 negative you had about a fifty percent response
to these drugs. But if you have the variant in your blood,
very positive, nobody responded to the drug. We’re going to follow a study in a larger
number to confirm that, although it looks like the
response is very low, not zero, but low. The other thing we started to see was if you
have that variant your disease was probably the
worst disease and probably grew and progressed faster
and we don’t have enough evidence, uh evidence yet,
but it’s looking like you might, patients like that
might die faster. So we’re starting to work think about other
treatments that we can do in this group. One of the interesting things about the androgen
for the testosterone is we’re looking at the men
in our study who have the variant and so we had
a cohort here of six of them out of a total of 17
men that we could sample. And so we have six men who were positive for
this variant and all six became negative when they
got on the testosterone. And some of those men actually responded to
testosterone well. That’s awesome. So we’re excited by that. We gotta sort of follow-up what that means
and whether by knocking down the variant you could
add another drug here in combination is what we
might want to explore. Unfortunately when we put the men back on
Abiraterone and Enzalytamide the variant comes back on, pretty quickly so the machinery kind
of stays there and we’re still working the details
out of how we might take advantage of this information. So the other thing is an ad. We’re about to open
a third arm of the Restore study and this is an arm
for men who are just newly castrate resistant. So their PSA has started to go up, they haven’t
had any other hormone treatment. We think this might be the best place to use
this therapy with testosterone because the cancer
cell has not adapted in other ways yet. So that arm is going to be 30 patients and
it’s going to be here at Johns Hopkins and it will
open probably next month. We’re doing a lot of additional correlative
things and we’re trying to to look at and do
genomic testing of all the patients also to try
to get more information about whether this DNA
repair goes along with responding to the treatment. So the other study were doing, which I don’t
have a lot of data to share with you, I will just
tell you a little bit about it, it’s called the
Transformer Trial and Transformer is this crazy
acronym that I made up that no one can remember, but that’s okay. It killed an hour of time for me. The grant that we got was from the Department
of Defence Prostate Cancer Research Program and
it was called a Transformative Grant. We decided to call the trial the Transformer
Trial. And this was a very good-sized grant which
is now allowing us to do a bigger trial to kind of
prove this concept. So this is a little bit different trial and
here these are men who have been on hormone therapy
and they have been given Abiraterone and are progressing. They didn’t get randomized to either receive
Enzalutamide and standard treatment or testosterone. And instead of PSA as the kind of endpoint
we’re looking at, we’re actually looking at how
long does it take their catscan bonescan to get worse. And one of the reason we did that is because
as you may be aware PSA is a gene that’s controlled
by testosterone. So you could have the scenario when you give
testosterone, even though the cancer doesn’t get
any worse, it can make more PSA, and it would fool
you in to how effective this could be. So those earlier studies, you know those results
we saw are great, it might even be better,
we just don’t know because we’re looking at PSA
as the endpoint. So this study is really a harder endpoint
of how long till we see the scans get worse. Just like the previous studies the men have
to stay on some type of hormone suppression,
Lupron, Zoladex whatever, and then when these men
progress on their scans they get the opportunity to
cross. So testosterone men can go on to Enzalutamide
and the Enzalutamide men can go on testosterone. And in this study were looking at
a number of things how we, androgen variant, it is is affected, some scans that we’re doing,
a couple other correlative studies. We’re trying to enroll 180 patients, we have
17 places in the US that are doing the study. We’ve enrolled about 143 patients, although
we only have about 120 that were eligible. So we’re still looking for 60 or so patients. And it’s a three-year grant, we’re in the
third year so we’re trying to enroll all those patients
this year so we can at least complete the enrollment and then we’ll start following
the patients for response. All these are patients that have to be in
pretty good shape they can’t have had Enzalutamide before. And the obvious answer to why we did it this
way at the time we wrote the grant Enzalutamide
wasn’t approved yet so we had to pick someplace to
start. I know a lot of them start with Enazlutamide
now and aren’t eligible for this and that’s just
unfortunately the way it rolled out. I tend to use more Abiraterone as my first
new drug anyway based on how I see the patients tolerate
it but each position is different. Patients have to have metastatic disease and
then they have to show some kind of progression
on Abiraterone. And again the key things we’re excluding is
anybody with pain, we’re excluding people who have
gone off chemotherapy for resistant disease because
we’re dead trying not to take patients who are too
far gone in the disease kind of progression because
we’re worried about the pain developing. We don’t want anybody who has blocking, who
has problems with their prostate blocking their
urine because with the testosterone it can make
the prostate get a little bit bigger. And then again nobody who has risky disease
that were worried about breaking a bone or spinal
cord or things like that. So these are the sites all around the country. These slides I think will be on your website
so you don’t have to try to look at all them. But it’s a pretty good distribution, we have
the sites in the midwest, sites in the south,
sites that I’ve got out west, Colorado, California. One place where we don’t have sites, New York,
Massachusetts these are you know where two of the big cancer centers are. Texas we don’t have a site. You know they have their own things going
on, so we don’t we don’t have sites there. One of the sites in Texas we closed because
they weren’t able to put anybody on the study. You had people travel from, you know, fair
distance. So far the farthest is Hawaii to come to
Baltimore to be on the study. And unfortunately although we’ve got a lot
of interest from around the planet we have not,
we don’t have anything going on anywhere else in the US. We have been in talks with an investigator
in Australia, who is a person we know very well,
he is very interested in opening some kind of
study in Australia, in Sydney, I think it’s in Sydeny. And we’re talking about what we might do that
would be different where we might learn something,
do some kind of combined study with the group
there. So there will be more to tell about that later. So, again, 16 sites and rolling. So far we’ve treated, well now I can say 122
patients. We’ve had a couple of safety meetings where
they were blinded to the results. But we do have some safety meeting along the
way to make sure we’re not doing anything bad
and those safety meetings have given us the go
ahead to keep going. When we get our first 70 guys who have progression
and need to cross we’re going to look at the data. If it looks really good the study will end
then we’ll declare a victory and if it looks really
bad this February well we’ll fal on our swords and
declar defeat. But, most likely what will happen is it won’t
be enough against to make a definitive conclusion
yet. I want to show you, this is the first guy
on the study and I just, I only show this as potential
to show you maybe the potential of this in my
fantasies. So this is the patient who was on two of my
studies, the first one he was on testosterone, I
showed you earlier for 18 cycles. We took him off of testosterone, he had a
nice response to being castrate again. Started to progress, put him back on testosterone
and then at that time a study became available of
Abiraterone, which we put him on. Unfortunately he didn’t respond at all to
Abiraterone, had progression, and so we challenged him for the third time with
testosterone and he’s had a third response. And now we’re going on our sixth year
together, we’re basically treating him with on and off with testosterone I guess. So it shows at least some potential. He’s also the first man that we treated with
a lot of liver metastases and to my great amazement,
he had a nice response with his liver lesions
disappearing on his first scan. So, there’s many questions to answer with
this approach in this captured resistant population, and I guess the first question we’re going
to learn is should we keep doing this. I hope we’ll get a good sign from this big
study we’re doing to say yes to that. The second question we’re faced with is can
we move how do we move forward with this idea. This is not a, this idea does not involve
a drug company. Testosterone is generic, so it’s really been
based on getting some funds. So we’re struggling with with really how to
go with the next step. Our thoughts on the next steps will be some
kind of, you know, intelligent combination therapy. So if anybody’s on the line that has a million
dollars they’re not needing, and want to cut a check, we’d love to share it. Or some one on the line knows a million people
who want to give us a dollar, we take that too. So we’re trying to find ways through philanthropy,
maybe other grant mechanisms. Typical once you get a bunch of grants trying
to go back to that, well, grant agencies often
will say, well this isn’t any, this isn’t novel
anymore. You know, what are you goin to do for me lately. So it’s a bit of a struggle and we’re still
trying to think about how to do that. Some questions are you know, what’s the best
way to do this. Should give this, is this shock
high-low the best way. Would it be better to give this as some kind
of new kind of cream or something four each,
you know, turn it off and on right away. One of the problems with the shock is the
testosterone goes very high, then the drop is
variable. Some men at the end of a month the tostesterone’s
very low, some men it’s kind of low. But we don’t really know what’s the best way. We’ve been doing it once a month mostly for
convenience, for men who you know want to be on a
kind of routine cycle approach. We’re looking at a lot of things we could
combine with it. Could we combine other things that block DNA
repair, based on maybe a mechanism of DNA damage. Is there an effective testosterone in the
immune sense system, we think there is. We’re studying that. We just opened a study at Hopkins, this is
really, goes back to the Einstein quote about insanity. So we’re doing a study where we’re actually
doing bone marrow transplant in men and our idea
here is taking men who are newly castrate resistant. We haven’t had a lot of therapy. Probably young men and these men have to have
a female donor and we think by using a female
who doesn’t have a prostate that the donor’s immune
system will see the prostate as a foreign thing
once it gets into the the new host. We also have a new way to do bone marrow
transplants where just about everybody has a donor now. It doesn’t have to be a perfect match. And as part of the bonemarrow transplant we’re
giving high-dose testosterone later on to try to
stimulate the cancer cells. These are men who are going to stay castrate. Try to stimulate the cancer cells to turn
on all these new proteins that this new immune system
might recognize. So that’s just our plan. We have our first man, we haven’t treated
him yet, but hopefully we’ll have some good results
that I can share back with you down the road. So that’s where we are and I’m going to jump
to one last thing then we can take questions and
this is well some points to take home. Again this looks safe, it does look like some
men respond, it looks like we could resensitise. It certainly seems to improve the quality
of life in some men. So it’s promising, it’s still experimental,
definitely not a cure, ah and I think, you know,
we’re going to figure this out one way or another,
where this fits in the treatment. Then the last thing I wanted to share just
because I had a questions about this. A quick question that we addressed which is,
could we do this earlier. Could we give this as first-line therapy? So we did a study and we published it recently
in the Journal for The Prostate and the question
we asked was what if we did intermittent hormone therapy a different way instead of castrating
and then stopping and waiting, waiting, waiting
till that testosterone slowly recovered. If our goal was to recover the testosterone,
why not just give it, and maybe we could prolong
the sensitivity, maybe we could make men feel
better, maybe we could minimize some of the side effects,
some of the metabolic issues, and maybe we can
improve quality of life. So I’m sure many of you on the phone are dealing
with this with the hormone therapy, all the problems of hormone therapy. You all know how important testosterone is
when you take it away. So these are things that intermittent hormone
therapy was designed to maybe try to make better. Not clear how well we do there with that. And so if you look at this is how we usually
do interment therapy if anybody’s on that approach,
we, you know, give it for a while and then we stop it if you respond, we let you recover
your testosterone, which sometimes takes a long
time. When the PSA gets up to a certain level we
start it again and if you respond we repeat until you
have resistance, and then if you don’t respond
we just continue on regular hormone therapy and add
others. So the advantage of this approach may be that
we can improve your quality of life. In my opinion the disadvantage of this is
variable recovery is a slow recovery. It gets back to this idea of adaptation, so
we’re giving the cancer lots of time to readapt
to this slow recovery. So the other piece to share with you is some
prognastic information from one of these studies where it might be shown if you get your primary
hormone therapy, if your PSA goes down less than
four, truely less than point two, your survival is a lot better than if it doesn’t. So that was our endpoint of the study which
is giving hormonal therapy, and in man who got
below four, giving him testosterone, alternating
with hormone therapy to see how long we can maintain
the best, you know, not getting resistant. So you can see here this cartoon, we called
it the Batman Study, and the Batman Study was six
months of hormone therapy. Kept everybody on hormone therapy and then
after six months, if you responded, you go three
months of testosterone and then three months back
on hormone therapy, and then three months of
testosterone and back on hormone therapy. And then we looked at how everybody did. So the primary endpoint was how many men
would have PSA less than four after a year and a half. We estimated based on not a lot of good
information but we can see from the literature around about forty percent of the men would
be like that. We thought we’d be, we’d declare victory if
we had sixty percent of the men like that. And we were able to get a lot of men on the
study really fast so we put 33 men on in a year
and we completed the trial on it’s last day. What we found was four men didn’t hit the
goal of getting less than four so they didn’t go on
the therapy. Seventy-two percent of the men got below four
after 18 months, so ah, when they got back to
hormone therapy after a year-and-a-half they were
still sensitive. Again well-tolerated. The biggest side effect was
swelling in the lower legs. [noise] A pretty significant improvement in
these guys in the usual things, strength, energy,
and then sexual function. So ah, we saw the PSA, some of the men when
they got down on hormone they had androgen suppression
and we gave it testosterone. The PSAs went way up and then dropped back
down again when we stopped. In some men it actually didn’t go up at all
really. So it’s ok, we didn’t have enough guys to
figure out if that was a marker for anything. So, ah w’ere also, now at this point struggling
with should we do a bigger study with this approach
as intermittent therapy, ah and again that would
take some significant funding and significant interest and we’re still debating how to do
that. So that’s where I’m gonna stop. These are some names of our team. Again we got this great funding from the One-in-Six
Foundation there in Akron Ohio. Unfortunately the patient Mr Hunsicker passed
away about two years ago, and then really this is
given in his memory. Really taught me what, you know, one individual
can do with the will power and the sort of desire
to kind of get things done. So I’ll stop there. I thank you guys for your
attention and for, I know a lot of you out there
are advocates for prostate cancer research and
appreciate that. This slide deck will be on the website and
you’re welcome to, if anybody wants to email me with
a question, I’m not really good about answering
the phone but I’m good with email. And if you’re if you think you might be eligible
for one of these trials you can email me and if
you’re not all the more I could tell you, hook you up with the site and as you’re eligible
and then hopefully then there’ll be more to come
as we move forward. Thanks to Rick Davis of the Answer Cancer
Foundation for allowing us to post this video. Access to the whole presentation, including
questions and answers, is at ancan.org/bat-presentation. The questions and answers begin at about one
hour four minutes. If you want to see more videos on advanced
prostate cancer in the future, click on subscribe. If you like this video please give it a thumbs
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