[MUSIC]
Good morning. Thanks again for joining.
Over the next few minutes,
I will give a brief overview of the current state of
the art treatment for metastatic prostate cancer in 2021.
Approximately 5-10 percent of all men diagnosed with
prostate cancer will have
distant metastases detected at the time of diagnosis.
These spots are usually first
seen on conventional imaging,
by which I mean a CT scan and bone scan.
However, as we increasingly
utilize PET imaging for newly diagnosed patients,
either in a PSMA or an [inaudible] in PET,
we're seeing more patients diagnosed with
distant metastases at the time of diagnosis.
This does not reflect a higher degree of risk,
but rather just a more sensitive imaging technique
that we are increasingly utilizing.
It's important to keep in mind that
unlike many other cancers,
metastatic prostate cancer can be
suppressed and treated for many years.
In fact, the average survival of five plus years for
metastatic prostate cancer is far
longer than that seen with other stage 4 cancers.
Our goal of treatment is to suppress the cancer as
durably and as potently as we
can with up-front hormonal therapy.
Many of our treatment decisions and
patients in metastatic prostate cancer are
guided by the assessment of volume of
metastatic disease at the time of diagnosis.
This definition is based on conventional imaging with
CT and bone scan and not by PET scan.
High-volume disease is defined as either
the presence of visceral organ metastasis,
such as spots of cancer in your lung or
liver or the presence of
four or more cancer metastases in the bone with
at least one falling outside the spine or pelvis.
The survival curves on
the right illustrate the difference in
average survival for men with
low versus high volume disease.
If you focus only on the green lines,
the top plot shows the survival
in those with high-volume disease,
whereas the bottom plot shows
a survival for low-volume disease.
Comparing these two green lines,
you see that the average survival is much
longer for those with low-volume disease on scan.
For patients with metastatic prostate cancer,
the standard of care has changed.
We used to treat such patients with
Lupron with or without bicalutamide.
Now, in 2021,
in almost all cases,
treatment should be intensified with a combination of
Lupron plus either abiraterone,
enzalutamide, apalutamide, or docetaxel chemotherapy.
All four studies have demonstrated
a long-term survival benefit
added to Lupron as
compared to patients treated with Lupron alone.
In the case of docetaxel,
is important to note that
this long-term survival benefit was primarily restricted
to those with high-volume disease
as per the definition we discussed on the previous slide.
Shown here are the long-term survival results
of all four of the treatments.
Docetaxel in high-volume metastatic prostate cancer,
abiraterone, enzalutamide, and apalutamide.
What is remarkable about
all four of these studies is despite
the slightly different patient populations and
different groups of patients enrolled in each study,
you see nearly identical hazard ratios
for improved survival with
combination treatment versus
standard androgen deprivation therapy alone.
When picking one particular treatment,
given these similar long-term survival
that [inaudible] across the therapies, how do we choose?
Well, this depends on a number of factors and that really
requires a detailed discussion with [inaudible].
Number one, the side effects
and impact on quality of life is critical.
For example, docetaxel may cause neuropathy,
hair loss, and a rare risk of
lung inflammation that can be quite serious.
On the other hand, docetaxel is given for
a finite treatment period of six cycles or 18 weeks,
as opposed to continuous combined hormone therapy
until resistance.
Other medical factors may factor in,
for example, a patient with out of control diabetes,
may not want to take or be given pramasone
concurrently with abiraterone because of
elevations in blood sugar levels.
For that patient, it may be more appropriate to
treat with apalutamide or enzalutamide.
Drug-drug interactions may factor in.
We particularly see this in
patients who are on chronic anticoagulation,
some of which may
interact with apalutamide and enzalutamide.
Drug costs are a huge factor and I think play
a big role in our treatment
decision-making, like it or not.
Abiraterone is available in
generic form and also has the advantage of
an alternative dosing schema in which patients can take
one tablet with a light fat meal as
opposed to four tablets on an empty stomach,
which can substantially reduce the cost of medication.
Finally, as we've discussed for
those with low-volume disease,
there really was no proven
long-term survival advantage with docetaxel in
this setting and we would choose amongst
the hormonal agents for these particular patients.
Once a patient starts on treatment,
the nadir or low point in
PSA after six months of starting
treatment is a very good indicator for
how long the cancer will stay
sensitive to hormone therapy,
as well as a predictor for long-term survival outcomes.
In here in the Kaplan-Meier plot,
is the long-term survival dividing
patients by a nadir PSA above four,
which is represented by the bottom curve,
between 0.2 to four,
represented by the middle curve.
Those with an optimal PSA
less than 0.2 are shown in the top curve.
With the newer studies with
a combination treatments with abiraterone,
apalutamide, enzalutamide, and with docetaxel,
the same holds true.
A nadir PSA of less than
0.2 after 6-12 months of therapy is
a sign that the cancer has a
better than average responsiveness
to hormonal therapy and improve long-term outcomes.
In patients with metastatic cancer,
we still consider treating the primary tumor.
There are potential advantages to this approach,
including the prevention of new sites of cancer spread,
as well as control of the primary tumor,
which can otherwise lead to
problems such as urinary obstruction.
As shown in the survival curve on the left,
in patients with low volume metastatic disease,
there was a long-term survival advantage
achieved with the addition of radiation to
the prostate coupled with
hormonal therapy as compared to hormonal therapy alone.
A similar survival advantage could not be
demonstrated in those with
high volume disease as shown on the right.
This is another example where
the volume of disease at the time
of diagnosis impacts our treatment decisions.
Based on these results,
we do offer radiation to the prostate in
patients with low volume metastatic cancer.
We don't routinely do so for
those with higher volume disease.
However, it is worth noting that a patient who
has obstructive urinary symptoms related at
the primary tumor that does not readily
respond with the initiation and systemic therapy,
that patient should still be
considered for focal treatment of the prostate.
[NOISE]
Finally, it's worth noting that there are
a number of ongoing questions in
this clinical disease setting and it's one of
the most active areas in
prostate cancer research at the current time.
Amongst the pertinent questions are,
should we combine chemotherapy and hormonal therapy?
Right now, we do not recommend this approach as
there is no phase 3 clinical trial data to support.
There are multiple clinical trials underway.
In patients with only a few metastases detected
on a sensitive scan technique such as a PSMA PET,
should we be adding in
metastasis-directed radiation for such patients?
This is an ongoing question.
In selected patients,
should we think about addition of PARP inhibitors,
particularly those with
DNA repair pathway mutations such as BRCA2?
Should we think about the addition of lutetium-617,
which you'll hear more about?
Should we think about that as
a up-front treatment in
combination with hormonal therapy?
Finally, should we think about
revisiting the concept of intermittent therapy?
Earlier I talked about
this approach in the rising PSA setting.
In patients with metastatic cancer,
this is not standard of care.
However, in patients who are
on intensified hormonal therapy,
for example, Lupron plus abiraterone,
who achieve an optimal PSA nadir
of less than 0.2 after 12 months,
I think it's an open question as to whether we can
revisit intermittent therapy for such patients.
These treatments and these ideas should not be
considered standard of care at the current time,
but stay tuned for updates over
the next several years as we
get results from these studies.
To wrap up, here are the take home points.
The PSA nadir or low point after the start of treatment,
along with the volume of metastatic disease,
using the definition that we've defined,
are key prognostic factors in the set.
The standard of care for nearly all men with
metastatic hormone-sensitive prostate cancer
should be a combination treatment.
Lupron coupled with one of the following shown there,
abiraterone, enzalutamide,
apalutamide, or docetaxel,
with the latter being restricted
to those with higher volume disease.
Treatment of the primary tumor is
recommended for those with low volume disease on
baseline imaging or obstructive urinary symptoms
that don't readily improve the treatment.
Thank you very much for your attention.
I would have loved to join the live Q&A event,
but I'm celebrating my 10th wedding anniversary
with my wife this weekend.
I hope I can always see you live at our next event.
All right. Thank you, Rahul.
Let me ask one question, first of Mack.
Mack, can you just expand a little bit
on, and I know you will,
[LAUGHTER] the role of radiation therapy to
the prostate in men with
metastatic prostate cancer, which Rahul described?
Here's my specific question to you.
The sentinel study that everyone cites,
which is the STAMPEDE study,
used radiation to the prostate only,
and yet you've been telling
us there's a high risk of pelvic nodes.
How should we be treating patients?
Is there a limit to the extent
of metastatic disease beyond which you say,
you know what, probably radiation is not indicated?
That's a great question.
In my practice, first of all,
the fractionation that they used
in the STAMPEDE study is not
a fractionation that I would use to try to
get local control in the classic sense.
I don't actually use the fractionation,
although I use their data to
justify doing prostate radiation.
We talked yesterday about treatment of the primary.
I use SBRT to treat the primary in four fractions.
If I'm not going to treat the pelvis,
I just treat the prostate.
Then I use the justification
based on the OReO study which
deals with SBRT for
metastatic disease survivor patient
who has metastatic disease.
They don't have bulky adenopathy,
they just have a local primary which is untreated and
say an isolated bone met or isolated pelvic met.
I treat the prostate,
and I treat the metastasis with SBRT.
I don't typically treat the whole pelvis.
If they have nodal disease that's
obvious on PET scan or by CT or MRI,
I will treat the prostate and
the nodes and the metastasis.
That's how I'd look at it.
I think that pelvic radiation can be immunosuppressive,
and so if a patient has an isolated metastasis,
I treat the prostate and the isolated metastasis.
Got it. The second part
of that question that I had for you was,
if you're not going to be treating the metastasis,
let's say it's 10 spots or five spots,
the patient presents with metastatic disease,
at what point do you say, no,
there's no reason to treat the prostate itself?
When you talk about the STAMPEDE study,
the number of the high volume versus
low volume disease was based on conventional imaging.
If a patient has conventional imaging
that shows no evidence of metastatic disease,
but a PSMA PET shows several metastases,
I still treat those metastases [inaudible] [OVERLAPPING]
What if you have 20 metastases on PSMA PET?
Well, then you have systemic disease.
I've never treated 20 metastases,
but I've treated quite a few.
You have to really individualize it.
When you look at nodal disease,
I think that nodal disease,
there's a paper that you all,
I think you were involved with
Susan Halabi looking at
the prognosis of patients with metastatic disease.
I look at nodal metastasis
differently than bone metastasis.
If a patient has a lot of bone mets,
I think they need bone-targeted treatment and they
need chemotherapy and other treatment.
If they have a bunch of
lymph nodes involved that are in the pelvis,
they can have internal,
external iliac, [inaudible] common iliac.
I don't hesitate to treat
a whole lot of nodes that are in the pelvis.
I can treat all the way to the diaphragm,
and those patients can have
a very long and sustained benefit
of treatment with only nodal disease.
I think the biology of patients with
nodal disease only would support
more aggressive radiotherapy than
the patients with bone- dominant disease.
Understood. Hala, let me ask you before
we move on to the next talk.
In patients with known bone metastasis,
who of those patients will you send to
our radiation oncology colleagues to
consider radiation of the prostate?
That's a great question.
I think when we think about the STAMPEDE, Arm H data,
that is the main data that we're
thinking about when we're considering
the benefit of prostate-directed radiotherapy in
the context of metastatic disease.
When we think about that, we really
need to be convinced that this patient
has low volume metastatic disease, so less sites.
I think it's reasonable
to first evaluate how many sites are there.
If the patient has five or less,
perhaps that would be reasonable to discuss.
We know that from that data there seems to
be a real benefit to that population to consider.
I guess I would add to that,
the patients that we wouldn't
radiate as Mack was alluding to
high risk because of
metastases to liver or [inaudible]. [OVERLAPPING]
Absolutely.
Because those patients are not
likely to benefit from that.
But it is a mind shift.
It wasn't so long ago
that no matter what Mack and Matt were telling us,
we didn't believe in addressing
the prostate in the setting of metastatic disease.
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