Feb 20, 2019
Dr. Benjamin Maughan who is the mentee of the GU Daily News Associate Editor, Dr. Neeraj Agarwal, discussed the presentations and research that stood out to him during the recent GU Cancer Symposium. Dr. Maughan is an Assistant Professor in the Division of Medical Oncology at Huntsman Cancer Institute.
Welcome to the ASCO Daily News podcast. I'm Lauren Davis, and
joining me today is Dr. Benjamin Maughan, who he was the mentee of
the GU Daily News Associate Editor, Dr. Neeraj Agarwal. Dr. Maughan
is an assistant professor in the Division of Medical Oncology at
Huntsman Cancer Institute. Dr. Maughan, welcome to the podcast.
Well, thank you. It's a pleasure to speak with you, Lauren. So
you've just returned from the GU Cancer Symposium. How was this
year's event compared with previous years?
It was fantastic. Lauren, I've been going to GU ASCO for a number
of years now since I was starting fellowship at Hopkins, and it
just keeps getting bigger and bigger. So it's a fabulous meeting.
One significant change, I will say, this year compared to the
previous year is, as the meeting is getting bigger and there's a
lot of research going on in the GU malignancies, we're starting to
see more and more practice-changing results and research being
presented at GU ASCO.
That's very exciting. What presentations stood out to you?
There, actually, were quite a few, as I was alluding to with your
previous question. But definitely the practice-changing data really
stands out the most. And we saw that both in the field of prostate
cancer and kidney cancer. I guess specifically in the prostate
cancer, we saw a number of trials that have been published to date
exploring in this M0CRPC space, or patients who have
castration-resistant prostate cancer but no identifiable metastases
on scans since M0CRPC.
We've seen a couple of these trials with PROSPER and SPARTAN
showing that apalutamide and enzalutamide respectively improved
metastasis-free survival in this setting. Now, at GU ASCO 2019, we
saw the third big trial presented, which was darolutamide with the
ARAMIS trial. This, again, was in an M0CRPC patient population, and
they were randomized 2-to-1 to darolutamide or a placebo. Of note,
the baseline characteristics were pretty similar to what we've seen
with the PROSPER and SPARTAN trial, in that the PSA doubling time
was pretty short, meaning these were fairly aggressive
patients.
That's an important point because some patients have a very
prolonged PSA doubling time, and those patients may not benefit
from any of these therapy. Those specific trials have not been
done. So it's unclear the value of these therapies in those better
prognostication patients. But regardless, in the ARAMIS trial, we
saw a significant improvement in the primary endpoint, which was
metastasis-free survival. It was 40 months with darolutamide versus
18 months with a placebo, and led to a significant improvement as
measured by the hazard ratio and it was statistically
significant.
Interestingly, all of the other specific subgroups appeared to
benefit-- age, prior [INAUDIBLE] therapy, radiation, or surgery. So
now we have a lot of data between all three of these trials showing
that novel hormonal therapies with either apalutamide,
enzalutamide, or now darolutamide significantly benefited these
patients. Now, because these patients have no metastases, we always
have to ask our question-- and therefore, they're not having any
symptoms from their disease-- we have to be very cognizant of any
specific side effects that we may cause or a worsening of their
quality of life by introducing therapy this early in their
treatment process. And that was really encouraging news with the
darolutamide.
The discontinuation rate of darolutamide was the same as the
placebo group, 8.9% and 8.7% respectively. Fatigue is a big issue
with this patient population because of their ADT therapy, which
causes a lot of fatigue. We've seen fatigue with apalutamide and
enzalutamide. And there was a slight increased rate of fatigue or
asthenia in the darolutamide compared to the placebo, but it was
small-- it was around 15% or 16% versus something like 11% with
placebo. So it appears that it's very well-tolerated. So that was
really encouraging news overall.
The other big news with prostate cancer was in a slightly different
space, it was in the metastatic hormone-sensitive prostate cancer
population. And this was the ARCHES trial, specifically with
enzalutamide versus placebo. So in this trial, patients were
randomized one-to-one to either ADT with placebo or ADT with
enzalutamide. Now, historically for these patients, the treatment--
we've seen a number of clinical trials looking at ADT plus
chemotherapy or ADT plus abiraterone, both showing improvement over
ADT plus placebo alone. And so this trial, we've been anticipating
for a while.
Again, it showed that patients regardless of high volume or low
volume disease, if they had de novo metastatic disease, so they
were presenting with metastatic disease at presentation of their
diagnosis of prostate cancer or if they had previously been treated
for localized disease and then progressed to metastatic disease,
all of those patients appeared to benefit with the addition of
enzalutamide over placebo. Very importantly, though, a number of
these patients, just because of the CHAARTED and the STAMPEDE data
that came out before, a number of these patients were allowed to
receive docetaxel before enrolling in this trial. Somewhere around
20% of the patients had received prior docetaxel, and those
patients also appeared to benefit from the enzalutamide.
And that's particularly important because now we're starting to ask
the question, since docetaxel and these novel hormonal therapies
have non-overlapping toxicities and distinct mechanisms of action,
what about trimodality therapy? So again, it's a relatively small
subset, only about 20% of the patients, but it's intriguing and
interesting to note that they also did benefit. So now in the
prostate cancer realm at GU ASCO 2019, we saw further evidence that
the M0CRPC population benefits from darolutamide. We saw that in
the ARCHES trial, enzalutamide is another therapy that appears to
be highly effective in these patients with metastatic
hormone-sensitive prostate cancer patients. And so all of that was
very encouraging news.
That's very exciting in the research front. What about the
education sessions? Were there any that caught your attention?
Yes. So in terms of the educational sessions-- again, that's
one of the nice features about some of these disease specific
symposia, as opposed to the annual ASCO meeting, is there's a lot
of education, as well as just straight research. And so we get lots
of debates about controversial topics with a lot of thought leaders
in the field, et cetera. So that's another nice part of GU
ASCO.
One debate or educational session that I thought was very
interesting was this discussion between a radiation oncologist, [?
Jason ?] [INAUDIBLE], and a urologic oncologist, Michael Cookson,
about what's the ideal first line therapy for patients with
muscle-invasive localized bladder cancer. Is it trimodality therapy
or is it neoadjuvant chemotherapy followed by cystectomy? This is
something that's a growing debate in the field. Now historically,
it's always been viewed as the neoadjuvant chemotherapy followed by
cystectomy is the ideal treatment for these patients.
First line therapy and the trimodality therapy-- I guess I should
specifically mention-- so trimodality therapy is where patients
have optimal debulking with the TURBT, followed by concurrent
chemotherapy and radiation therapy, followed by surveillance. So
they felt that that trimodality therapy is best reserved for those
patients that are not cystectomy candidates for a variety of
reasons, comorbidities or other such problems.
There's some growing evidence to suggest that perhaps trimodality
therapy may be an equally effective way at achieving oncologic
outcomes, ie, cures, at the same time, though, preserving the
patient's native bladder, and therefore improving their overall
quality of life. So this debate was highly instructive and very
interesting. I will say, Dr. Cookson was pointing to the National
Cancer Database information comparing retrospective data, but
comparing the overall survival with radical cystectomy versus
trimodality therapy, suggesting that radical cystectomy is more
effective in achieving oncologic outcomes with cure.
But Dr. [INAUDIBLE] appropriately pointing out that these are
retrospective analysis and there's a lot of patient bias that goes
into this, because again, historically, trimodality therapy is
reserved for those patients that are not deemed surgical
candidates, oftentimes because of comorbidities. So their worst
prognosis patients, and you would predict that those patients have
inherently a worse overall survival anyway. So it was a very
instructive and intriguing debate, and I anticipate perhaps we
eventually will see the gold standard of a randomized controlled
trial performed, which will answer the debate. But very
instructive, very interesting, and a great component of these
meetings.
Are there any other takeaways that were important during the
symposium?
As I mentioned, prostate cancer isn't the only disease area where
there were some interesting and exciting clinical trials that came
out that are practice-changing. We also saw a number in kidney
cancer. The two highlights in this area were both asking the
question, does a tyrosine kinase inhibitor, a molecule targeted
therapy in combination with a checkpoint inhibitor improve cure
rates over tyrosine kinase inhibitor alone?
Currently, the standard of care for patients with metastatic kidney
cancer is either monotherapy with the tyrosine kinase inhibitor or
combination checkpoint inhibitor with ipilimumab and nivolumab. So
we've seen some data come out recently looking at these molecularly
targeted therapies plus checkpoint inhibitors. And so at GU ASCO
2019, we saw updated results on a number of things. One, on the
updated results from ipilimumab and nivolumab, demonstrating that
the complete response rate is somewhere around 10%, 11%. But then
we also saw some updated results of axitinib plus nivolumab versus
[INAUDIBLE].
In this trial, about 20% of patients had favorable risk disease,
65% or so had intermediate risk disease, and another 20ish percent
or so had poor risk disease, so about what we typically see in
clinic. And the response rates were high with the PD-L1-based
therapy. The complete response rate was around 4%. The trials that
we were really excited to see the results from was the KEYNOTE 426
study, which was axitinib plus pembrolizumab versus monotherapy
with sunitinib.
So again, this, similar to the others, w
as a first line therapy. Patients were started on a lower dose
of axitinib of 5 milligrams, and it could be dose escalated if it
was tolerated. And the enrollment across the trial based on the
risk categorization of INDC was similar to what we've seen in a lot
of these trials. Again, about 30% of favorable, a little less than
60% had intermediate risk diseases, something around 15% had poor
risk disease. So very similar to the other targeted therapy plus
checkpoint inhibitor trials that had just recently been
reported.
The results were pretty encouraging. The hazard ratio was 0.69 for
death or progression, favoring axitinib plus pembrolizumab. Around
90% of patients were alive at 12 months versus just under 80% for
sunitinib. The complete response rate was around 6%. So again, very
encouraging data. The one potential issue that we need to look to
is safety as we're comparing these strategies versus the current
gold standard immunotherapy approach, which is ipilimumab plus
nivolumab. So the proportion of patients discontinuing treatment on
this axitinib/pembrolizumab trial was 30% versus 14% for
[INAUDIBLE]. And that's approximately what we see with the
ipilimumab and nivolumab data.
Again, this appeared to be well-tolerated and safe, and it seems to
have advantages over ipilimumab and nivolumab in that regard in
terms of safety. The big question that everyone's asking is, which
strategy is more effective and [INAUDIBLE] a larger proportion of
patients that have durable responses? These may be cures. Again,
that number is around 11% based on the updated data that was
presented at GU ASCO for ipilimumab and nivolumab versus in the 5%
range that we're seeing so far with the axitinib-based combinations
with either pembrolizumab or atezolizumab.
So it's still fairly early with either of these trials. We need to
see if with time the complete response rate improves. But overall,
really exciting and really encouraging, because these combinations
appear to be active, well-tolerated, and are definitely leading to
durable responses in patients.
That's great. It sounds very promising. Again, today, my guest has
been Dr. Benjamin Maughan. Thank you for being on our podcast
today.
Thank you so much. I appreciate the time Lauren.
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