Good morning. My name is Thomas Hope and I'm
a radiologist and nuclear medicine physician at UCSF.
Today, I get the opportunity to talk to you about
functional imaging and the role of
PSMA PET in prostate cancer.
Now, there are a lot of radiotracers that are used
to image and stage patients with
prostate cancer and it can sometimes be confusing.
FDG, fluorodeoxyglucose is a sugar analog,
sometimes called a sugar PET,
which can be used particularly in patients
with later-stage disease and it can be prognostic,
but it's not very helpful in
localizing small volume disease.
On the other side here we have sodium fluoride,
which can be used to visualize
osseous metastatic disease and choline,
as well as another amino acid ratios of
fluciclovine is also used frequently in prostate cancer.
But the newer generation agents is PSMA,
which we will talk about here.
PSMA stands for prostate specific membrane antigen.
It is a protein that lives on
the membrane of prostate cancer cells and is
overexpressed in prostate cancer compared to
other tissues in the body and
so by targeting this protein,
we can actually see where proteins are that are in
prostate cancer membranes and
localized prostate cancer metastasis fairly accurately.
Now, UCSF, we've been using a molecule
called gallium 68 PSMA-11.
This is the diagram,
the molecular structure of that molecule.
On one-half of the molecule is
a key later and this is the part of the molecule that
binds to gallium 68 and on
the other side of the molecule is a urea motif.
This is a small motif that will bind to
PSMA and gives this molecule
the specificity for prostate cancer.
We then put gallium 68 into
this molecule and injected into patients.
We take this molecule,
we inject it into the arm of the patient.
That molecule then circulates throughout
the body of the patient and binds
to the PSMA molecule on the surface of
tumor cells and once it gets within the tumor cells,
the gallium will then decay,
giving off radioactivity that
can be imaged using a PET scanner,
positron emission tomography scanner.
That results in images like this,
which can localize prostate cancer in patients.
In patients, you can see the
salivary glands, which is normal.
There's liver uptake, the highest uptakes,
usually in the kidneys and the urine that comes
out in the bladder and a little bit of splenic uptake.
But in this case, you can see there's a small
sub centimeter, left para-aortic lymph node,
right here are retroperitoneal lymph node,
which has uptake,
which is clearly seen on the PSMA PET,
it would be very hard,
if not impossible to determine that was
metastatic disease without the PSMA PET to show you
that there's uptake consistent with
metastatic prostate cancer and this
is really where PSMA PET shines.
I'm hopeful that in a year or two we'll get
to a place where staging with prostate cancer
will be done primarily with
PSMA PET and no
longer will patients be getting a bone scan,
a CT scan, or an MRI.
You get a single imaging study
to stage the entirety of the patient,
both bone and soft tissue staging.
UCSF, over the last number of years,
as everyone in the audience probably knows,
we've done a lot of work with gallium PSMA-11,
and we were fortunate enough in December of last year to
obtain approval of gallium 68 PSMA-11 by the FDA.
This was done in a collaborative effort
with the University of California, Los Angeles,
known is the only current
PSMA radiotracers FDA approved.
What's interesting is we were able to
get it approved and both initial staging,
that first bullet point there as well as at the time
of biochemical recurrence when a PSA
starts to rise after definitive therapy and that's
in distinction to other drugs
such as fluciclovine or choline,
which are only FDA approved
in a setting of biochemical recurrence.
This is really bringing PET imaging
to the initial staging as well, which is wonderful.
Now, I do have to take a second to
compare PSMA to fluciclovine.
I should note that fluciclovine is
widely available in the United States,
is reimbursed by Medicare and is currently
the standard imaging modality
for prostate cancer patients.
Moving forward, we anticipate that obviously
PSMA PET will replace fluciclovine,
but it's not yet widely available
and so the majority of patients in the country
who have prostate cancer
will be undergoing a fluciclovine PET.
Now, in this case, you can clearly
see that there's focal uptake here,
this top row on the fluciclovine PET in
the right pelvic sidewall lymph node
and you can also see it on the PSMA PET.
But you can see the uptake in the tumor here on
the fluciclovine is 3.9
compared to the adjacent background,
which is about 1.2,
is about a three-to-one ratio
between tumor to background.
In the PSMA PET,
that tumor to background ratio is more
like 50 and that's what makes it much
easier to localize and see disease is how much more of
the ratio that goes into the tumor
and how much less there is in the background.
That contrast between tumor
and background allows people like me,
radiologists and nuclear medicine physicians
to localize disease.
In this case, both of
the imaging studies localizes disease.
In this study, in a different patient,
you can see in the right seminal vesicle there's
very subtle uptake and the fluciclovine PET.
Now, there is a higher uptake
in the tumor compared to background,
a little less than two to one ratio.
But the PSMA PET has much higher focal uptake,
which is much easier to visualize,
in spite of the fact that there's also
activity in the bladder at the same time,
you can clearly see this local recurrence
much better with PSMA PET.
This was studied prospectively.
The UCLA group did a wonderful job doing
a head-to-head comparison of fluciclovine,
which is also called FACBC or an orange in this chart,
and PSMA in patients after radical prostatectomy and they
showed that fluciclovine have
about half of the detection rate of PSMA,
and maybe more importantly,
PSMA PET saw disease and
metastasis and knows it a
much higher rate than fluciclovine.
While fluciclovine primarily saw
disease in the prostate bed.
This is in the prostate bed here
where the primary tumor was.
The other thing to note is that it's not very easy
to interpret a fluciclovine PET
and there's a statistic called Cohen's Kappa.
If you have perfect agreement,
you would get a one,
if you have no agreement
between multiple readers, you have a zero.
The closer to zero the number is,
the more disagreement there is between readers,
the closer to one you are,
the more agreement there is between readers
and in this study in Lancet Oncology,
they're shown to be a lot
higher agreement when interpreting
a PSMA PET compared to a fluciclovine PET.
It should also be noted
the PSMA-11 is not the only radio tracer out there.
There's actually more than just these six.
There's a whole family of
these PSMA target radiotracers that
bind PSMA and it's really important to note that there's,
for example, DCFPyL down here,
which will hopefully become FDA-approved soon.
They all share the same motif, that's urea motif,
which gives them a very similar specificity and
sensitivity for detecting prostate cancer.
I consider these more like
a class and it's important that we get these
FDA-approved so that we can get
more of these radiotracers available to patients.
The difference is in these radio tracers
results really primarily in
a difference in bio-distribution.
PSMA-11 here, the one we use at UCSF and DCFPyL,
while the third one over here are very similar.
But this one, PSMA-1007,
which is currently in phase 3 clinical trials,
has a very different bio-distribution.
You can see there's much more activity in
the liver and much less activity in
the urine and this allows
potentially for better detection of local disease.
But overall, they all have
very similar sensitivity and
actually, and head-to-head studies,
PSMA-1007 haven't been shown to be better than
PSMA-11 or DCFPyL and
they all seem to function nearly identically.
It should be noted, PSMA-11,
we obtain FDA approval in
December last year and there's
actually a kit that should be
approved later this month to help get
PSMA-11 more widely available and
DCFPyL they submitted their application to the FDA in
September of last year and we're very hopeful that
this drug will get FDA-approved at the end of this month.
It could be actually approved very soon and
DCFPyL will be much more
widely available because it's fluorinated,
it can be distributed and made a much larger quantity.
This will hopefully be the drug that
most people are imaged with in the United States.
It should be noted that the results of
PSMA PET really changes the management of disease.
If you think about where disease is,
patients can have a negative PSMA PET,
and that's this left column here
and you can see the majority of those patients
actually had their management change towards
surveillance instead of doing active treatment.
Or patients can have nodal disease
in the pelvis or in the prostate bed and the majority of
those patients who were getting
local therapy or radiation therapy to the pelvic nodes or
the oligometastatic disease that were visualized on
the PSMA PET and then also you can have
metastatic disease and in these patients,
instead of getting targeted treatment or access valence,
these patients have change in management towards
systemic therapy and PSMA PET based on
the distribution disease has a huge impact
and then therapies of the patients
are getting in prostate cancer.
In particular, I want to focus on
biochemical recurrence after
radical prostatectomy briefly,
we did a study here at UCSF
looking at patients who had a low PSA after
radical prostatectomy and did
PSMA and 125 patients who had
a PSA less than two and about half of
those patients had PSMA positive disease.
But of those, 125 patients,
30 percent of them had disease.
They will be missed by standard radiation therapy fields.
You can see in this patient the green outline
here is the standard radiation therapy fields
and here's a no just
posterior to those fields that we
treat it with external beam radiation and this wouldn't
have been treated if we hadn't used
PSMA PET to localize that disease prior to
radiation therapy and so if you look at the rates
of recurrence after salvage radiotherapy,
it's about 30 percent and most likely that's
because radiation therapy missed the sites of disease.
Radio therapy actually works very well as
long as the radiation oncologist knows where to aim
the external beam and so this is where
we're really hopeful the PSMA PET can really
improve the outcome of patients and
prevent biochemical persistence and recurrence after
therapy and there's actually
now starting to be literature that really
suggests that molecular imaging like
this guiding radiation therapy
can really improve outcomes.
In summary, overall PSMA PET is really
the best imaging study to stage
patients and detect metastatic prostate cancer.
I think really importantly,
PSMA PET has a large impact
on clinical care and in particular,
as I pointed out in that last slide,
with radiation therapy planning and excitingly,
we got get gallium PSMA-11
approved at UCSF and there's one more
NDA pending for gallium PSMA-11
for a kit to make it more widely available.
But really, it's
DCFPyL that will become much more widely available
and hopefully provide access to
this really wonderful imaging study to more patients.
Thank you very much for listening.