Our next topic is androgen deprivation therapy with
this the non-metastatic prostate cancer,
which will allow us to integrate a number of
the concepts that we've heard about
this morning and yesterday.
From this morning, recall that a PSA recurrence
happens after following definitive local therapy
with surgery or radiation in some patients.
The source of the PSA recurrence may not always be
apparent even when we use the PSMA PET scan,
and we've seen some lovely example this morning.
This scenario has been termed
non-metastatic or PSA only recurrent prostate cancer.
As we've heard, if
additional local therapy is not feasible.
For example, after surgery if
radiation has already been done or it can't be done,
in some of these non-metastatic
the current prostate cancer patient,
ADT, androgen deprivation therapy
is in fact an appropriate therapeutic option.
Now, as we learned
yesterday with regard to androgen deprivation therapy,
testosterone is fuel for growth of the prostate cancer.
There are two sources of testosterone
as we discussed yesterday,
the testicles and the adrenal glands.
Testosterone that comes from
the testicle can be eliminated by
androgen deprivation therapy and
here are the medicines that we discussed yesterday.
Historically, we would term elimination
of testosterone from the testicle ADT,
or the very first treatment
that we would use in this setting.
Now, unfortunately, eventually ADT resistance happens.
Prostate cancer cells develop a resistance to the ADT,
they learn how to grow in a low testosterone environment.
We turn this cancer a mouthful
ADT resistant prostate cancer or
androgen deprivation therapy resistance prostrate cancer.
Now, while that is
the appropriate term for this syndrome,
I do want people in the audience to know that there's
a very unfortunate term that is used as
an abbreviation out there which is CRPC,
which stands for castration resistant prostate cancer.
This really hearkens back to the days of
Charles Huggins that we talked about yesterday
where surgical orchiectomy was the way ADT was done.
Unfortunately, the name has stuck and so you,
your physicians, and you'll hear people
use CRPC as the term.
But it really refers to
ADT resistance in prostate cancer cells.
Really it's characterized by
prostate cancer cells that have developed
the ability to live on
the very small amount of
testosterone that's floating around,
that's produced by the adrenal glands
because the testicles
have been taken care of already by the ADT.
This has led to the development of
a number of androgen signaling inhibitors
or ASIs that eliminate the contribution of
adrenal androgens and that typically are used as
treatment number 2 following treatment number 1 with ADT.
Again, we talked about that a little bit yesterday.
Here is the diagram of
the medicines that are used, the ASIs,
that are used to block the uptake of
testosterone into the prostate cancer
either enzalutamide,
apalutamide, or darolutamide,
or that simply prevent the adrenal glands from making
the testosterone in the first place
and the medicine is called abiraterone.
Now, putting these two concepts together,
that of PSA recurrence that of
using ADT for these patients.
If patients with a PSA recurrence after
local therapy are treated with long term ADT,
very fair question to ask is,
can they develop resistance to the ADT?
The answer is yes, unfortunately.
We term this disease non-metastatic or nm for short,
non-metastatic ADT resistant prostate cancer.
Again, some people will term this non-metastatic
castration resistant prostate cancer or nmCRPC.
This is defined as patients who have a climbing PSA only.
No evidence of cancer on conventional PET scan or MRI of
the abdomen and pelvis or on
the bone scan and a low testosterone level.
You will note that
this definition is based on conventional imaging,
not push it within PET,
not PSMA PET,
it's really conventional imaging.
I want to convince you and show you that non-metastatic
androgen deprivation therapy resistant prostate cancer
is a very important clinical diagnosis to make.
We're starting with the first bullet here.
Because the only evidence of
prostate cancer is a detectable PSA,
non-metastatic ADT resistance prostate cancer
patients have no symptom.
They don't have any symptoms
because they don't have metastases so it's
really tempting to ignore the diagnosis.
However, if we were to take 100 patients with
non-metastatic ADT resistant prostate cancer,
within two years, nearly half,
45 percent would have
either develop bone metastases or have died.
This is obviously not
a benign disease that should be ignored.
As it turns out,
in those patients that have
a very rapid climb of their PSA,
which is called
a PSA doubling time which is very short,
the risk of developing metastasis and
death goes up very rapidly.
By contrast, patients with a very low rate of climb,
a long PSA doubling time,
have a very low risk of developing metastases.
I just want to provide
a caution that the PSA doubling time
isn't something that we eyeball.
Now that we look at PSA in
one month and look at it six months later,
and see if it's doubled it's called
a six-month doubling time.
It actually has to be calculated
using many PSA values and
there are a number of very
simple online calculators to do this.
I can certainly provide them
to people if they're interested.
Now, why is PSADT,
PSA doubling time important?
Well, I'd like to draw your attention to this graph.
I'll walk you through it.
The y-axis over here, going up,
indicates a relative risk for bone metastases or death,
just an increasing risk,
and 1.0 is standard risk no increase there.
A number of three is a threefold risk of metastases.
That's 10, 100, 1,000 risk.
It's a high, high risk.
On the x-axis is the PSA doubling time,
getting shorter and shorter,
which means that the PSA is going up faster and faster.
PSA doubling time of two months means that in
two months your PSA goes from 1-2,
a PSA doubling time of 20 months
means that it would take 20 months
to achieve the same thing.
What you can see from
this graphic is that
there's an inflection point at the red arrow.
At the PSADT of around eight months,
where there's a dramatic increase
in the risk of developing bone metastasis,
suddenly it starts going straight up.
Patients with the PSA doubling time
of less than eight months,
and we've said 10 month to provide a little cushioning,
are at the highest risk
of developing bone metastases or dying.
Those obviously are the patients
who you should be focusing on to treat.
Whereas the patient over here,
at this back-end of the curve,
the risk is not that much higher,
and so this is
1.6 to 60 percent higher than you would expect,
because of 3 times this one.
This allows us to
identify the patients who need treatment.
Now, to hearken back to the ASI discussion,
these drugs are ideal drugs to use.
We know that their work is treatment number 2 in
ADT resistant prostate cancer I've told you that,
and they have a very favorable side effect profile,
which is really important.
Because this is a group of men who as we've talked about,
are starting out with no symptoms.
It would be not great to have
therapy that makes men who feel fine feel terrible,
even if it was a benefit.
These are particularly attractive drugs in that regard.
What can I tell you about
these three drugs at the bottom xtandi,
erleada, nubeqa,
enzalutamide, apalutamide, and darolutamide.
These three have been tested in this group of patients,
these three have been approved by the FDA.
We've actually helped develop one of these here at UCSF.
They are appropriate in men with
a PSA doubling time that is shorter than 10 months.
If it's longer than that,
meaning that the PSA is climbing relatively slowly,
it's probably less indicated because there's
less of a risk of developing metastases.
The results from the clinical trials that tested these,
were really quite impressive.
All of them delayed the time to
metastasis by two years roughly.
They all prolonged life,
they all delayed the time to
symptom developing and symptomatic decline,
they all have acceptable side effects and none
of them resulted in worsening in
the patient-reported quality of life.
These drugs really did meet the bill in
terms of what we wanted them to accomplish.
Most importantly they delay
the time for metastases and death.
Now, the one last thing I want to talk about
in this section is,
we've defined these patients based on conventional scans.
Negative CAT scan or MRI and bone scan.
If they have those regular scans,
then they've got a short PSA doubling time
using one of these three agents,
makes a lot of sense.
But what about if we do a PSMA PET and here's
an example of one from
this morning you will now know how to read these,
and you can see here 1, 2,
3 spots which slide up 1, 2, 3.
This is a patient who had normal CAT scan,
normal bone scan,
and now on PSMA PET scan
has a small number of metastasis.
It turns out that a PSMA PET scan is almost always is
frequently positive in one location or another in
these patients that have
previously been called non-metastatic,
just based on conventional imaging.
The fact that the PSMA PET scan,
now it's picking up
the metastasis that were always there,
doesn't change the fact that the agent,
apalutamide, enzalutamide,
darolutamide, still help these patients.
That patient with non-metastatic androgen
deprivation therapy resistant prostate
cancer on conventional imaging,
but with detectable metastasis by PSMA PET are very
likely to benefit from systemic therapy with these drugs.
So a PSMA PET or a [inaudible] PET in
the setting should not deter us from using these agents.
It does, as we discussed this morning,
raise the question about whether we should be
going after these spot with,
for example, targeted radiation therapy.
That's actually the subject of the study ongoing at UCSF.
Targeted radiation has been shown to be useful in
men with a climbing PSA in hormone.
But in this setting, once they are ADC resistance,
we don't know for sure,
although it seems to be the case at the moment.
In summary, non-metastatic androgen
deprivation therapy resistant prostate cancer,
it is a very heterogeneous disease,
but high-risk patients can be readily
identified by a PSA doubling time.
Patients with a PSA doubling time of
less than 8-10 months more or less,
are at very high risk with metastases or death.
There's many compelling reasons to treat these patients.
We can delay metastasis,
we can prolong life,
we can delay the time, the symptoms,
and we can avoid declining quality of life.
It turns out that apalutamide, enzalutamide,
and darolutamide are all able to achieve these goals.
There are subtle differences between these drugs,
we have our preferences,
but the differences are subtle.
Lastly, the benefits of treating with
a next-generation ASI,
which are the ones I just mentioned,
likely doesn't change just
because PSMA PET has happened to
identify previous disease that
were silent that we couldn't see on conventional imaging.
Thank you very much for your attention.
I know that that's a fairly complex field or area,
and I trust that it has helped clarify most importantly
the need to treat these patients.