[MUSIC]
Hello, my name is Tom Hope.
I'm one of the nuclear medicine physicians here at UCSF.
Today, I'm going to talk about
PSMA PET and its roles
functional imaging in prostate cancer.
I think we're all familiar with PSMA by now.
This stands for prostate specific membrane antigen as
a transmembrane protein overexpressed
on prostate cancer cells.
Now, interestingly enough, it's actually not
specific to prostate cancer,
it's overexpressed in some benign diseases
such as Paget's disease,
fibrous dysplasia, other osseous lesions,
but also in other cancers; lung cancer,
renal cell cancer, glioblastoma, etc.
But nonetheless, it's very useful for imaging and
treating patients with prostate cancer
as we'll talk about in the coming slides.
Now, with the advent of PSMA PET,
we have many stories like patients like this.
This is a 69-year-old man
who had a radical prostatectomy.
His PSA after surgery was 0.7.
You can see now,
we can see very easily and accurately
both osseous disease and soft tissue disease.
The goal here, and we're actually finally there,
is that PSMA PET has now replaced
the combination of CT and bone scan that used to be used.
Not only did it get rid of
two studies and turn it into one,
it is more accurate,
faster, and easier to interpret.
Now, there's a bunch of molecules
out there which are sometimes
confusing to patients and also to physicians.
I should note that all of the ones that are really
being evaluated to share the same urea motif,
and so these are very similar to one another.
In the bottom left there,
you have DCFPyL,
piflufolastat and PSMA-11,
which in my mind are equivalent and
interchangeable for the imaging
of patients with prostate cancer.
One of the biggest issues with
PSMA PET are some of these false positives.
There's a lot of lesions that will mimic
prostate cancer, particularly rib lesions,
unilateral or focal rib lesions in patients
with initial staging are almost universally benign,
and it took a while for us to really understand this.
But when you have a lesion like this
which has peripheral rim,
sclerosis, and focal uptake,
we know that this is not prostate cancer.
But there are other lesions such
as ganglia as in this case,
which can mimic pre-sacral lymph nodes and
other benign diseases such
as hemangiomas and Paget's disease,
which can also sometimes look like prostate cancer.
Other tumors such as HCC,
thyroid cancer, and in this case,
lung cancer can also have pretty high uptake on PSMA PET.
But I think with proper training,
we can hopefully convert these "False
positive interpretations" into true negatives.
With good training of nuclear medicine physicians,
we will hopefully be able to accurately interpret
these studies so this isn't a problem moving forward.
But with the recent introduction
of this imaging modality,
we're still in the learning curve for
most nuclear medicine physicians in the United States.
Now, in terms of the data,
there are some trials to talk about.
First are the initial staging studies.
There's two major studies done at initial staging.
One is a study that was performed at UCLA and
UCSF that we use to lead to the approval of PSMA-11,
and then there was
the Osprey trial which evaluated DCFPyL,
what became the piflufolastat.
Here are very similar studies.
You can see very similar number of patients
and nearly identical accuracy numbers.
This really shows us how well
we can actually see pelvic lymph nodes.
This is compared to surgery at
initial staging using PSMA PET.
That sensitivity number looks pretty
low, so it's surprising.
But that's because we're missing very small
sub centimeter lymph nodes with PSMA PET.
When you're comparing to surgery,
pathologists can pick out very,
very small nodal metastasis
which you might otherwise have missed.
This is in patients where in essence
the conventional imaging was negative.
Seeing anything is an improvement
upon the existing imaging modalities.
Now, this imaging in initial stage
really does change management.
For example, if you look at radiation therapy planning,
seeing these PSMA positive nodes actually change
the radiation therapy plans
in over 50 percents of patients.
That's actually pretty remarkable,
50 percent of patients with high-risk prostate cancer,
the radiation therapy plan was
changed based on the results of the PSMA PET.
But I think maybe more importantly,
are patients like this.
Here, the patient Gleason 4 plus 3 are high,
PSA was stage,
and you can see the mediastinal disease
as well as supraclavicular
on the left uptake that was
biopsied and came back prostate cancer.
This patient would have undergone a prostatectomy,
which would have been not clinical useful because
he had metastatic disease at the time and
undergone other morbid therapies without
actually knowing where his disease was if
we didn't have a PSMA PET to accurately
stage him at his initial presentation.
Now, biochemical recurrence is
really a workhorse of PSMA PET.
Similarly, there's trials with gallium PSMA-11 and
DCFPyL in the biochemical recurrence setting.
These are pretty similar,
although the way it worked out
actually was slightly different,
but the positive predictive value of correct localization
between these two molecules is again nearly identical.
You can see the detection rates at
different PSA cutoff values are very, very similar.
Again, highlighting that PSMA-11 and
DCFPyL should be
considered equivalent and interchangeable.
This data was then used to gain
the FDA approval for both of
these agents in 2020 and 2021.
Similarly to initial staging,
PSMA PET is very helpful to localize
a disease which will impact radiation therapy planning.
This is a group of 125 patients from UCSF
who had a PSA less than two after radical prostatectomy,
over half of those patients had
PSMA positive disease on PSMA PET,
and 30 percent of the 125 patients had disease that was
missed by standard radiation fields that are performed.
This clearly highlights and we really need to see where
that disease is for
radiation oncologists to accurately treat it.
If they don't know where the disease is,
then they won't be knowing what they're treating,
and patients will biochemically
recure again after their therapy.
Now one note, and I was really happy
about this, the NCCN guidelines,
which are the major guidelines in the United States
that dictate how people practice,
stated that they do not feel that conventional imaging is
necessary prior to a PSMA PET.
For flu sickling,
many insurance company will
require patients to have a negative
CT and bone scan prior to approving a flu sickling PET.
NCCN took a much more aggressive approach
this time around and said, "Hey,
there's no role in getting
a CT scan because the sensitivity is basically so low,
why would you start with that imaging study?
Instead, we should start
staging patients with the PSMA PET."
I think this is really important in terms
of access and patients.
Here's an example of a patient biochemical recurrence.
Really just highlighting how different CT
and PSMA PET is.
This patient had no evidence of
disease on CT scan so it was M0,
bone scan is negative.
You can see on PSMA PET these very, very small nodes.
That's a 76 millimeter left
supraclavicular or less superior mediastinal lymph node,
which is markedly avid on a PSMA PET.
Clearly is metastatic prostate cancer completely
re-staging this patient who would
otherwise have been M0,
no evidence of metastasis when
he was being treated for his biochemical recurrence.
Now, in terms of how these results impact outcome,
this is a story that's still in progress.
But the first paper that
really came out was the EMPIRE-1 study,
and this actually evaluated
fluciclovine versus conventional imaging
using both for radiation therapy planning
and patients with biochemical recurrence.
In the EMPIRE-1 study,
patients did better at
four years if they were staged with fluciclovine compared
to conventional imaging with
the biochemical free survival rate
of 51 percent versus 76 percent,
then this is actually impressive with fluciclovine,
which we know performs less well than PSMA PET,
it actually also imparts
a benefit in terms of patient outcomes.
Now, we do know that PSMA PET
itself has major changes in
management in over 50 percent of
patients who are imaged with PSMA PET.
If you have no evidence of disease,
people tend towards receiving surveillance,
if they have nodal disease,
they tend towards getting
local therapy like radiation therapy,
and if they have metastatic disease,
they start to be treated with systemic therapy.
Now, the role of PSMA PET is currently being
evaluated in a trial
by Jeremie Calais that's completed enrollment,
which is similar to the EMPIRE-1 study,
which is comparing PSMA PET to
conventional imaging or radiation therapy planning.
Hopefully, soon we'll see the results
of this trial and see whether or not
PSMA PET did in fact improve
outcomes compared to conventional imaging.
Now, I want to take a little bit of a sidestep
here and talk about PSMA-negative tumors.
I think PSMA-negative tumors are a
little confusing to some people.
In the castration resistance
setting and stage after chemotherapy,
PSMA-negative disease is a really poor prognosis.
But in the initial staging, that's a different story.
Here you have a patient on MRI.
The MRI shows restricted diffusion in
the prostate with low signal in the ADC,
and there's really no uptake on
the PSMA PET associated with that tumor.
Now, if you look,
as I said in the mCRPC setting,
PSMA-negative disease patients do much worse.
Here, you can see the outcome of patients who have
a very low PSA
compared to the patients who have a higher PSA,
and those who had,
in essence, an FDG,
PSMA mismatch, i.e.,
they had FDG positive disease and PSMA-negative disease,
those patients did very
poorly compared to the overall population.
Now that's very different from initial staging.
Here, this is data from the primary trial,
which was looking at the role of
PSMA PET in patients in active surveillance.
You can see here that
the SUVmax correlates with PI-RAD score,
so the higher the uptake,
the higher the PI-RAD score, also,
the higher the uptake,
the higher the Gleason score.
In essence, lower uptake is actually
better at time of initial staging.
This is also borne out in looking at
patients who receive salvage radiation therapy.
If you have biochemical recurrence after
definitive therapy and your PSA starts to rise,
then if you get a PSMA PET,
if you have a negative PSMA PET or local disease only,
you do much better than
patients who have distant metastases.
The point here is that actually having
a negative PSMA PET in
the setting is actually a good thing.
Those findings were independent
of the PSA time of imaging.
Whether or not your PSA was
below 0.5 or greater than 0.5,
you still had a market benefit over
patients who have disease outside of the prostate fossa.
PSMA PET is actually much more
prognostic than the PSA and having
no evidence of metastasis at time of
biochemical occurrence for tends
a much better outcome for the individual patient.
I think that's important as a lot of patients
fret that they don't have metastases,
they can't see something if they want to target it,
but you actually want a negative PSMA PET,
those patients would do better.
Now, one other thing I want to talk about is
we always talk about stage migration.
You do a PSMA PET, and you see more disease.
Patients are being migrated, as I showed you,
a couple of patients who were M0 disease
now have M1 or are metastatic.
This is an interesting observation.
For example, there was the STAMPEDE Trial.
This trial here looked at the role of
prostate bed radiotherapy in
patients who had metastatic disease.
What they showed is that if you have
low-burden metastatic disease,
radiation therapy to the prostate bed
was beneficial for patients,
so patients lived longer if you
had low-volume metastatic disease.
This was based on bone scan,
three or fewer bone metastasis.
Now, here's three patients with positive bones scans,
a rib lesion, a skull lesion,
and a spine lesion.
All of them negative on a PSMA PET.
Actually, PSMA PET particularly in
low-volume disease on bone scan,
will actually downstage many patients,
may be 20 percent of patients who
were previously thought to be metastatic.
The benefit probably in
salvage radiotherapy in that setting is actually
treating localized disease
misclassified as metastatic disease.
Just remember that it's not always
an upward stage migration,
but sometimes actually is a downstaging of
patients based on the results of a PSMA PET.
The last thing I want to talk about is
metastatic castration-resistant
or M0 castration-resistant prostate cancers.
These are patients who
have conventional imaging-negative disease,
but have a positive PSA
in the castration-resistance setting.
This was studied extensively.
Dr. Small, let a lot of the trials here,
the SPARTAN trial, evaluating apalutamide,
there's also enzalutamide and
darolutamide that were evaluated
in non-metastatic
castration-resistant prostate cancer setting.
If you do PSMA PETs in these patients,
in essence, all of them have disease.
They're obviously not surprising.
There is no such thing as M0 CRPC,
98 percent of patients who were
M0 CRPC had a positive PSMA PET.
I think what was interesting is 40 percent of
those patients had oligometastatic disease
or unifocal disease,
which might be able to be treated
with SBRT target radiation therapy,
which isn't commonly used in the CRPC setting.
This is being evaluated by the PILLAR trial,
which Rahul Aggarwal is the principal investigator on
comparing apalutamide to apalutamide plus SBRT.
In summary, there are now actually five
approved new drug application for PSMA PET.
Four of them are PSMA-11,
one at UCSF and UCLA.
The whole goal of us being
generic was that
other companies who get approvals, and actually,
since our approvals,
two different companies have created kits for
PSMA-11 and now it's more
widely available in the United States.
Then there's a new drug application for
DCFPyL or piflufolostat which is a fluorinated agent,
also used widely in the United States.
PSMA PET impacts the management of
50 percent of men imaged for biochemical recurrence,
it really changes the management of patients.
The most common change
is for planning for radiation therapy,
so really the radiation oncologists who are most
impacted by the results of the PSMA PET.
Then, lastly, remember,
a negative PSMA PET is not
actually a bad thing in a patient biochemical recurrence,
you want a negative PSMA PET
because those patients will do
better after treatment if
there is no evidence of metastatic disease.
Thanks. [MUSIC]