[MUSIC] Now we're going to talk about
lutetium PSMA radio ligand therapy.
So first let's start off
talking about what is theranostics?
This is the idea of using a molecule for both imaging,
diagnostics, and therapy.
In this example, on the blue side here,
this is the binding portion of the molecule,
of the urea motif that binds to PSMA.
On the opposite side of the molecule
in red, this is the curator.
This is what carries the radio metal into the tumor.
You can either put gallium or copper for imaging in there
or for therapy you could put
lutetium or actinium to treat a patient.
We're using the same molecule for both imaging to select
the patients and then subsequently to
treat the patients with lutetium.
This approach was evaluated in the vision trial.
This was a randomized Phase 3 study in about 800 patients
comparing lutetium PSMA 617
plus standard of care versus standard of care alone.
Of note, there was no chemotherapy allowed in this trial,
but the results demonstrated an improvement in
progression-free survival
with a pretty good odds ratio of 0.4.
Then also you can see here an improvement in
the overall survival with an odds ratio of 0.6.
The use of PSMA radioligand therapy
increased patients lives
and there was no evidence of
a negative impact on the quality of life.
This is what led to the approval
of PSMA radioligand therapy.
Now that we've been using this,
we see evidence of this efficacy.
Here's a patient who had on the left there are
positive PSMA pet when both extensive
nodal or osseous disease and some lymph nodes as well.
The middle there, that's imaging after treatment 1.
We do treatment of the lutetium.
You can see where the radioactivity went in the patient.
Then subsequently after treatment 2,
you can see the intensity went down
dramatically with the first therapy.
That's borne out in a quote from this patient who said,
"Before the first treatment I had to be
carried off the property and into the car,
couldn't even sit up in bed on my own."
After the second treatment,
he said, "It's a godsent as they say.
I haven't felt better." He was
able to walk to the car on his
own and do what he was wanting to do with his life.
Now, this is, I would say,
an unusual response, very good response.
But this is the type of response that is
driving the interests in PSMA radioligand therapy.
In March of this year,
the FDA approved lutetium PSMA 617,
which is brand name PLUVICTO or
vipivotide as a therapy to treat patients with
metastatic castration-resistant prostate cancer who've
previously been treated with
Anderson receptor pathway inhibition or
androgen receptor target therapy and attacks into
these kit-based chemotherapy
like docetaxel or cabazitaxel.
The other trial I always like to talk
about is the TheraP trial.
This was an academic study.
The vision trial was company sponsored trial
that was done to gain approval of the agent.
The TheraP trial was an academic trial
out of the Peter McCallum Institute in Australia.
This was a randomized one-to-one 200 patient study,
which was comparing lutetium PSMA 617,
just like the vision trial to cabazitaxel.
Unlike the vision trial, this actually
had an active comparator arms.
The treatment arm was
lutetium PSMA 617 and cabazitaxel was on the TheraP arm.
Now on the left here the primary end point of
the study was a PSA50 response.
The PSA falling by at least 50 percent.
What's interesting is that actually the use of
lutetium PSMA 617 resulted in
nearly a doubling of the percent of patients
whose PSA fell by 50 percent.
But interestingly, there was no significant difference in
overall survival between both arms.
People actually didn't live longer even though
their PSA fell more with lutetium PSMA.
I think the other important point of this trial,
the PSMA radioligand therapy was
much better tolerated than chemotherapy.
Here you can see
the progression free survival on the left
showing that there's some benefit of
lutetium PSMA 617 particularly the tail.
Out here at the outer months,
you can see benefit of patients who
have prolonged progression free survival.
But in terms of overall survival,
there's actually no difference between the use of
cabazitaxel, lutetium PSMA 617.
To me what this means is that I would choose
lutetium PSMA 617 over cabazitaxel.
Not because it's more effective,
but rather because it's better tolerated.
Patients do better, no neuropathy, less lethargy,
and people just having better quality of life when
being treated with lutetium PSMA 617.
Now talking for a second about
use of PSMA PET for selection of patients,
because I think this is a really important topic here.
The vision trial and
the TheraP trial had
two very different selection criteria.
The vision trial require patients
to have uptake greater than the liver.
I have these numbers on the left side.
Those are SUV's. They're quantitative measures of uptake.
The higher the number, the more radioactivity
goes to that tissue.
An SUV of one would mean
the tissue doesn't concentrate the radiation at all,
two it double the concentration over even distribution.
In this case, this patient had
an SUV mean of four in the liver.
To meet criteria for the vision trial,
you'd probably have to have an SUV max in
your tumor above four.
The TheraP trial on the other hand,
it required patients do have an SUV max over 20,
a much higher uptake than with the vision trial.
That's like priming the pump,
selecting our patients who are more likely to
respond more uptake on a PSMA PET,
more radiation dose goes to the tumor,
more injury to the tumor cells from
the radiation and more response.
Now that's shown by a couple of things.
First of all, the vision trial had
a much lower screen fail rate,
because they allow patients in with lower uptake.
They only had 13 percent rate of screen failure whereas
the TheraP trial had
over 30 percent of patients didn't qualify for the study.
Now that also resulted in a higher PSA50.
So patients PSA fell by 50 percent and
only about 45 percent of patients on revision trial,
but 65 percent of patients in the TheraP trials.
So by removing the patients who aren't good responders,
they actually had higher response rates
in the remaining patients.
Higher uptake, more likely to have a response.
Now, one thing I like to point out is
that patient's disease is very variable.
We use a PSMA PET to select patients,
but not all patients are created equal.
On the left side, here you have
someone who has localized disease,
only a couple of sites of tumor.
In the middle right you have a patient who has
very low uptake extensive disease
but not very avid disease.
Then the other two images show
pretty extensive but different size lesions
that are added on PSMA PET.
Now, although we consider this therapy personalized,
we use the PSMA PET to select patients
and give them a therapeutic targets that target.
It's not really because we're given all of
these patients the same amount of radioactivity.
So there's still a lot of work to do to really adjust
the administered activity to optimize
the treatment for each of these individual patients.
Now in terms of how your baseline PSMA uptake
relates to response,
there are some good of post-hoc analysis of the therapy.
Actually not post-hoc, prospectively defined endpoints.
They took an SUV mean uptake
measured on the baseline PSMA PET.
If you had an SUV mean over 10,
then you had a 91 percent chance of a PSA50 response.
Ninety-one percent chance.
If your SUV mean was less than 10,
you fell by nearly 50 percent.
You only had a 52 percent chance of a PSA50 response.
That uptake is very predictive of
how you're going to do in response to this therapy.
Now this was also done for the vision trial.
You can see here they did differently.
They looked at SUV core tiles.
They took them lower quartile,
upper quartile, and middle quartiles,
and then plotted radiographic progression,
free survival on the left
and overall survival on the right.
You can see as you get higher uptake,
you have more prolongation of
the radiographic progression free survival.
I think what's interesting in overall survival,
you can see that there's a batching
of the lower three quartiles.
The main benefit is that actually in
the patients who have high uptake
in terms of overall survival.
Here I pasted in the line for the control arm.
These are patients who receive
just lutetium or
just standard of care in essence, nothing.
Remember there's no cabazitaxel allowed in this arm.
The main benefit overall was driven
by patients with an SUV mean over 10,
similar to what was seen in the TheraP trial.
Now that being said, here's
a patient who has relatively low uptake.
His SUV max this disease is 11. So that's pretty low.
His SUV mean probably measures five or six,
is in the one of the lower quartiles of those trials.
Now after cycle one,
he has a PSA of 304 at baseline,
but then after cycle two his disease
in essence completely melts away.
His PSA goes down to 0.4.
I personally can't explain this.
Some patients are just more sensitive to
radioactivity and we don't
fully understand that sensitivity,
but we're trying to understand that by
biopsying patients prior to treatment
and Felix Stein is working on
a correlative study to understand
how we measure the sensitivity to
radiation in these patients prior to therapy.
Because you wouldn't not want
to give this patient therapy,
because he benefited greatly with it.
So oftentimes with patients with low uptake,
I will say, hey, let's go for it.
Let's try a couple of cycles,
see how you tolerate it,
see how your disease response,
and then we can decide if we want to
keep moving forward with the therapy.
On the other hand, here's a patient who has
an SUV max at 25 in his tumor.
Okay, pretty good uptake.
His PSA baseline was 289.
The SUV mean here is probably
12 or 13. Pretty good uptake.
But as subsequent treatments happen,
we can see some of the bone disease, for example,
in his pelvis actually is getting better,
but the liver disease is just not responding as
well and his PSA is already starting to rise.
So patients are very individual and
respond differently to the same therapy.
We can actually track that through
imaging after each individual cycle.
Now there are also patients who just
have PSMA negative disease.
So here the patient who,
if you can look on the MRI here,
there are these large metastases in the liver,
and you can see those correlate with
these like bright spots in the liver. No uptake.
No PSMA uptake in the tumor.
If you look in the therapy trial,
that red arm there is the outcome of
patients who have PSMA negative disease.
Comparing that to both the cabazitaxel and
the lutetium PSMA arm
patients who have PSMA negative disease or
fail screening on their PSMA pet do much
more poorly than patients with PSMA positive disease.
Now, one comment about patient selection
again and with PLUVICTO in the package insert,
it says the patients should be selected using
LOCAMETZ or an approved PSMA-11 imaging agent.
So it actually states, you should use PSMA-11 and
DCFPYL should not be used, which is odd.
Now, do you have to use
PSMA 11 for selection of patients?
I believe not.
I think it's important because it's
important in terms of patient access.
Not every patient has access to PSMA 11.
We need to allow patients to be able to
be imaged with DCFPYL,
or pig flu flow stat so that they have access
to mutation-based PSMA radio ligand therapy.
This is supported by data like this.
So you can see the liver uptake here is nearly
identical between PSMA 11 and DCFPYL.
So they should function nearly identically for
patient selection for PSMA radio ligand therapy.
Now at the end here let's talk a little
bit about some clinical trials.
In general, most of these trials are moving
lutetium PSMA 617 earlier in
the course of disease in patients with prostate cancer.
So the first trial here is the PSMA 4 trial.
This trial is taking patients who have
metastatic castration resistant cancer and
then who are progressing on
Abiraterone and Enzalutamide Darolutmide
or Apalutamide first-line androgen receptor
targeted therapy and randomizing them to
getting a second antigen receptor target therapy
or lutetium PSMA 617.
So moving pre chemo and the MCR HPC setting.
This has completed enrollment and we look
forward to seeing the results of this next year.
There's also two other registrational trials
evaluating exactly the same trial design,
the splash and the eclipse trial using lutetium PSMA INT.
So there'll be a lot of drugs
available in the space soon.
Then there's the PSMA addition trial,
which is taking patients who have
metastatic castration
sensitive cancer at presentation and
randomized to receive either ADT and
Abiraterone or ADT and
Abiraterone plus lutetium PSMA 617.
So this is moving it up into
upfront setting in the castration sensitive space.
There are also a number of combinations studies,
DNA repair pathway inhibition, for example,
PARP inhibitors like the loop
harp trial immunotherapy trials
combining pembrolizumab or
Ipi/Nivo with PSMA 617 chemotherapy trials
with docetaxel plus PSMA 617.
Then maybe at the most interesting trial
is the ENZA-p trial,
trial combining enzalutamide and PSMA 617.
This one interesting to me because there's a lot of
great PSMA PET CT realism study.
One trial I want to highlight is a trial out of
UCSF combining
PSMA radio ligand therapy with immunotherapy,
which Rahul Aggarwal is
a principal investigator along with Larry Fong.
This is looking at if we take
a single dose of PSMA radio ligand therapy,
and then use immunotherapy pembrolizumab
along with it can this prolong the response of patients.
Now, we're just evaluating the results of this.
But here's an example.
A patient on the trial low-volume disease but
very PSMA avid patient then gets treated with one cycle.
Only one dose of PSMA radio ligand therapy.
His PSA was 13.9.
This was his PSA over the two years after treatment.
So single-dose had a near complete response in his PSA,
and it's just starting to creep
back up earlier this year.
His post imaging two years out on treatment
his PSA was 0.5 and there's
no evidence of PSMA positive disease.
This is obviously not normal.
We don't see this very often.
So we're obviously very optimistic and
hopeful at something like
this could be beneficial to patients.
We're looking forward to our follow-on trial with
Rahul is leading here at UCSF in the near future.
The last thing I want to note is that
really a multi-disciplinary team is key.
Now, obviously I think nuclear medicine,
medicology are particularly important,
but it actually involves a lot of
other people, nurse navigators,
palliative care and nutrition,
urology, genetics, radiation, oncology,
a huge team together to treat for
these patients and really provide the most optimal care.
We're lucky here at UCSF to have
such wonderful people and all of these different areas,
the work would help really provide
the best care to the individual patients.
So in summary, first,
PSMA radio ligand therapy is
FDA approved and is now standard of care in
patients who have metastatic castration resistant
prostate cancer after chemotherapy
and antigen receptor targeted therapy.
Two PSMA PET correlates with response to higher uptake.
The better on average patients they're going to do.
But patients should still be selected
based on the vision criteria updake greater in
liver because even patients who have lower uptake
can have remarkable responses as Aisha.
Lastly, there are a number of clinical trials evaluating
treatment earlier in the course of
disease and combination therapy.
Really participation in these trials is key,
absolutely key for us to move
the field forward so that we can learn how to use
PSMA PET more effectively
in the future and really provide patients
with specific and beneficial care that
will prolong their life
and improve their quality of life.
So thank you very much.
[MUSIC]