The first two cases are patients of Ivan's.
He's going to drive the presentation and discussion here,
but I'll advance for you.
Thank you, Rahul. I'll present a case.
This first one is a patient
with hormone-sensitive prostate cancer.
We'll talk a little bit about how we
start and select therapy for this patient.
This is a young patient
who until his diagnosis of prostate cancer,
was healthy had not a lot of
other medical conditions that he was seeing
a doctor for, but was diagnosed.
If you can see,
after having some rectal pain and
some changes in his urination,
had a PMSA level that was checked and
showed was elevated at a 340.
Then you've got staging with a bone scan
that actually didn't show any metastatic disease.
He had an MRI of the prostate that showed a large mass,
large tumor in the prostate and also
evidence of spread to lymph nodes in the pelvis.
Then you get a chest x-ray actually that
was done before seeing us that
showed possibly some spots in
the lungs that were concerning for spread to the lungs.
Then I think if you advance there maybe one more.
Then after that he had a biopsy of
his prostate tumor or the mass in the prostate,
and it showed prostatic adenocarcinoma,
so prostate cancer with
a relatively high Gleason score of eight.
Maybe before we talk about next steps,
I'll open it up to you,
Rahul and Eric, and if you want
to highlight any aspects of this case so
far and what you would be thinking
about doing next for the workup.
I think this is clearly someone that has
high risk prostate cancer and there is
concern for visceral organ metastasis,
so this is someone where we
definitely would want to make sure
our further staging is
really comprehensive and certainly
a CT scan of the chest,
abdomen, pelvis to really better
characterize the potential metastasis here.
I think it's going to be
a part of it because that's going to
really dictate a subsequent therapy.
I would agree. I would add to that that absence
of metastasis on bone scan doesn't mean much.
It just means that I can't see anything in the bone and
they could either be
bone scan lesions that are so-called lytic,
which don't show up on bone scan
or this is a cancer that doesn't involve bone.
I would also say
because I'm anticipating questions from the audience,
why not PSMA PET? Two reasons.
The practical reason is that it's not
really approved in this setting,
although that may change.
It's really improved only in climbing PSA,
for example after definitive local therapy.
But you could argue for local staging.
But the other reason is that we know
that patients with aggressive variance of cancer,
oftentimes will be PSMA negative.
Probably shown in some of those pictures.
It just wouldn't be that useful,
I agree with Rahul's plan to do a comprehensive imaging.
Then if you can advance to the next step, the next slide.
The first thing that he had,
I agree with everything that was said,
so he had genetic testing.
Any patient with metastatic disease
should get testing for inherited mutations.
In this case, it was negative,
which most of the time it is negative.
This patient had a PSMA PET scan,
which is not uncommon
for us to see it although we talked about
some of the limitations of the reason why
sometime it may not even be approved.
In this case so interestingly,
as Eric was mentioning,
so it showed the cancer in the prostate gland,
it showed some lymph nodes,
it also showed spots of cancer in
the lung and actually some spots of cancer in
the liver and these were mostly seen on
the CT scan of the CT component of the PSMA PET scan.
If you actually looked on the PSMA PET component,
these tumors didn't have a lot of PSMA uptake,
so they didn't really light up
extensively on the PET scan.
If you advance anything one or two,
you can see, so the tumors in the lung,
and then you can see they're a little more subtle,
but you can see also some tumors,
some metastasis in the liver.
Maybe we can talk at this point about,
with this information,
how to think about treatment
and what treatment Eric or Rahul,
you would think about starting in
a patient like this if you saw him in clinic.
This is a perfect example when you and Rahul,
were talking about doublet versus triplet therapy.
I think it's very easy to say that what we
wouldn't do is start Lupron alone, start ADT alone.
I think Dr. Aggarwal had in this slide.
I think it was you Rahul,
that we should be using
intensified therapy in virtually every patient.
It's very rare patient with
metastatic disease that
shouldn't get intensified therapy.
This patient appears to
have probably two types of cancer, at least.
One that is PSMA avid and is perhaps more likely to
respond to Abiraterone and Lupron.
But he also has these liver metastasis
that are very low in PSMA and
likely or are more likely to
be less responsive to straight up hormonal manipulations.
This might be a patient that I would actually
do triplet therapy and where I would use chemotherapy.
I don't think there's a role for chemo
and ADT alone ever.
If I'm going to use chemo,
I'm going to intensify with androgen signaling liver.
I would agree with that. I do use
triplet therapy maybe a little bit
more than some of my colleagues and particular,
those patients that have likely metastasis in the liver,
just because the studies with
the intensified ADT when
you give just the doublet without
chemotherapy don't suggest that
you get a huge benefit in patients with
liver metastasis just because these patients do have
more aggressive prostate cancer and that type of cancer,
it does seem to be predisposed to be
less responsive to hormone therapy.
I do think we need better biomarkers
and I would probably encourage a biopsy of one
of the liver lesions and looking at
the genetics of that because that
might give some clues as to,
especially if you're on the fence about whether
you're going to add chemotherapy Nadph.
But in this context,
this is a patient I probably would give the triplet.
Then you really have two choices
there in terms of the two Phase 3 studies,
either ADT plus Abiraterone plus
docetaxel or ADT plus dura-glutamine
plus docetaxel and I think they're just comes down to
co-morbidities and what drug might have
less financial toxicity and so forth.
If they're clearly high-risk patient,
you want to try to maximally
suppress the cancer right off the bat.
I'm going to make one quick comment.
I was going to answer this question online,
but I'll just speak to it,
which is Dr. [inaudible] PSMA
nonavidity can be both a good and a bad sign.
Did I hear this correctly? Kind of.
In the setting of a climbing PSA after
[inaudible] and you're looking for
signs of recurrence and you can't find it,
so the scan is PSMA negative,
that's a very good sign.
It means that even using
this ultra-sensitive imaging modality,
you can't find stuff.
The piece that Tom references is,
if you can see a tumor on another imaging modality,
in this case that Dr. [inaudible] is showing,
known liver lesion and it happens to be PSMA nonavid,
that is a bad sign,
so two very different circumstances.
In this situation and
somebody else's work that Ivan has done,
PSMA being negative correlates with some of
these very aggressive variant cancers
that do require chemotherapy.
Totally agree with Dr. Aggarwal that a biopsy is
highly warranted the settings
so you know what you're working with.
Just to expand on that with the imaging piece
because I think this is something
we've actually talked about a lot is how
do we follow up patients on lutetium?
Should we really rely on just the PET scan uptake?
I think we pretty strongly argued,
and I think Dr. Hope in radiology
agrees that we really need
just the regular CT scans along the way as well.
Because you're really looking to make
sure you'll not see in the soft tissue spots
start to grow on the CT but really have
minimal or zero uptake on the PET scan.
Does that clearly as a high-risk situation
for which lutetium is not going to be beneficial.
Get them a PET alone without other imaging modalities.
This is why in the ADT resistance setting,
really probably need to use multiple types of
scan to optimally manage patient.
I think why don't we go on to case,
sorry. Go ahead Ivin.
No, no, exactly. I think the point
of this case just for the audience was just to
highlight some of the cases where we would
think about adding in chemotherapy.
But because of the trials we talked about,
now when we're using chemotherapy,
it's really part of the triplet combination.
What we wouldn't do is just ADT plus chemotherapy.
We typically add now a hormone pill in these cases.
Then the next case,
we're shifting gears a little bit.
This is going to focus really on the management of
the patient in castration resistance settings.
This is a older case.
Some of what was done is
not exactly what we would do now,
but basically a 70-year-old man who was first
diagnosed 12 years ago with localized prostate cancer,
but pretty high Gleason score was ten.
In the initial prostate biopsy and was
treated with radiation therapy and
two years of hormone therapy.
Unfortunately, very shortly
after stopping hormone therapy,
his PSA began to rise.
So he was restaged.
That showed a new bone metastases
in the lumbar spine and in by the right shoulder.
Then with that was started back
on hormone therapy with Lupron and bicalutamide,
which is an older, risks
that testosterone receptor blocker.
But unfortunately, six months after being put back on
hormone therapy his PSA has started to
rise again and he had worsening symptoms.
Then he was treated with PROVANGE and after that
was treated with Xofigo or radium-223.
Now, after six cycles of Xofigo,
he had repeat scans,
which unfortunately other words,
PSA had actually come down on treatment to
2.1 show progression of this disease.
Maybe before we talk about the next steps,
I'm just curious at this point.
Rahul or Eric, when you're seeing a patient,
the PSA is coming down,
but you're seeing on scans cancer that's getting
worse how would you think about doing a case like this.
I think that even before thinking about next steps,
it really highlights the need to
not just follow the PSA,
especially in the ADT resistant setting.
Unlike an earlier stage disease where PSA is a very
faithful to the indicator
of response than resistance ADT.
As we get further into the ADT resistance course,
there's less of that correlation there.
That's why we really tried to
emphasize getting scans at regular interval.
Had we not been getting scans
from this particular patient,
we wouldn't have detected this disease growth and lucky,
he was really quite symptomatic.
First highlight that needed to get that imaging can goes
back to what I was saying in my talk that we don't
want to rely on just the PSA alone.
In this case because it can't show growth or the low PSA.
This is a scenario where I do think
a biopsy is absolutely warranted.
We want to know what type of
prostate cancer we're treating.
At the ADT resistance stage, thumb,
prostate cancers undergo
what's called transdifferentiation.
They change into a type of cancer called neuroendocrine,
which just looks different under the microscope.
You see it in about maybe 15 percent of
patients with ADT resistant prostate cancer
that undergo metastatic biopsies treated differently,
the genetics are different,
the clinical trials that we have available are different.
We really want to know
what type of prostate cancer we had.
Yeah, exactly. This is
exactly what happened in this case.
The patient had a biopsy of one of his lymph nodes.
As Rahul was mentioning,
we saw exactly that under
the microscope that we were no longer dealing at least
in that biopsy with your garden variety prostate cancer,
but the small cell neuroendocrine differentiated
prostate cancer that tends to
not secrete a lot of
PSA and not really respond to a lot of
the testosterone manipulation therapies that
we use like Abiraterone or Enzalutamide.
Based on that biopsy,
he was actually treated with chemotherapy.
This is a chemotherapy that is
little bit different from Docetaxel
or cabazitaxel the chemotherapy that we use
for your garden variety prostate cancer.
Then had a somewhat of a response with
that actually fairly good initial response.
But then after about a year-and-a-half
his cancer progressed again.
As you can see, even in the setting of progression
his PSA was still a
relatively low though a little bit higher than the 0.2
that he was at after chemotherapy.
This patient had another biopsy done which
again showed a small cell carcinoma.
Part of the reason why a biopsy was repeated in
this case is the PSA was a little bit higher.
It's always helpful to
check to make sure that we're still
dealing with the same cancer.
In this case because the biopsy showed the same thing,
it was again treated with the chemotherapy that's mostly
targeted at the small
cell neuroendocrine prostate cancer.
Actually was enrolled in a clinical trial after
chemotherapy of immunotherapy with pembrolizumab.
But unfortunately, his disease
progressed even through immunotherapy.
Now it's interesting in this case is
that after his cancer progressed,
he had a third biopsy that
was done of a metastatic tumor.
This time it showed prostate cancer,
garden variety or adenocarcinoma.
No longer showed small cell carcinoma
when a third biopsy was done.
I don't know if maybe before we were talk about
next steps if Eric or Rahul,
you can talk about just the difference in
these biopsies and how often you're thinking,
or when you're thinking about doing biopsies in
these patients and how to explain the differences here.
I'll jump in. I think
earlier we were talking about how once you do
the germline genetic testing, that doesn't change.
But this is a great example of how
things can change within the cancer.
While one of two things is happening here.
Either the cancer really has
had this plasticity where it goes back-and-forth,
became small cell and didn't become small cell,
which has been reported or it was a sampling error.
It's just where you happen to put your needle.
But the point is really important that not
only do you want to repeat biopsies,
not only to see what it looks like under the microscope,
which is what was being done here,
but to look for any genomic changes.
Because some of those variants that Dr.
Aggarwal described in his presentation can
pop up later in the game and could
offer a therapeutic avenue.
Typically, under normal circumstances,
we definitely will do
a biopsy at the time of disease growth.
Provided there is an area that you
can put a needle into and obtain a biopsy.
But if someone has
anti-deprivation therapy resistant prostate cancer,
the cancer grows.
We try to biopsy it and treat it,
it regresses, it grows again.
Biopsy again. As much
as possible we try to biopsy the same areas.
We're comparing apples to apples.
Definitely look to biopsy in an area that has grown,
that is changed so you can see what
is happening in that area.
We can advance to the next slide.
Based on that, biopsy really shows how
the biopsy inform treatment
because he was treated with more chemotherapy,
but this time chemotherapy
they don't recognize that we use
for most prostate cancer cases
with docetaxel and cabazitaxel.
It was actually on that for
very long periods of time with a good response.
Unfortunately, eventually, this patient did progress on
chemotherapy and we tried using Olaparib,
so a PARP inhibitor or
genetically targeted therapy based on
a mutation in a DNA damage repair gene
that was picked up in one of his biopsies.
I think Dr. Aggarwal, your briefly
alluded to the different genes
and bracket 2 and bracket 1 are the ones that
are most sensitive to something like Olaparib,
there is barred one mutation.
Probably we know now that
it may make the cancer
less susceptible to something like Olaparib.
But in this case, unfortunately,
the patient did not respond to
Olaparib and ultimately was
transitioned to hospice and passed away.
But I think what I wanted to highlight with this case
is some of the treatments that we
use in their castration resistance setting,
but also the heterogeneity of prostate cancer.
Then it can be a spectrum and
that biopsies in genetic testing,
that's where it becomes so important,
especially later on in
someone's disease course to
make sure that we know what we're
treating and potentially open up
additional treatment options based
on the genetics of the cancer.
I want to add something.
Because I don't want people to
feel depressed by this case.
That had we taken care of this patient 10 years ago,
five years ago even his survival
would have been a year or two.
Because we didn't have the wherewithal,
certainly 10 years ago to understand what was going on.
Here we're talking about seven years.
Seven years is not enough.
It tells us that we have a lot of work left to do.
But there's also been remarkable progress.
I'm very confident that
the progress that is being made now is not incremental,
it's big stamps as we learn how to biopsy these patients.
I view this as a positive story despite its outcome.
Because we are so much further along.
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