Jun 10, 2019
Welcome to the ASCO Daily News podcast. I'm Lauren Davis. And
joining me today is Dr. Benjamin Maughan, 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 be on, Lauren. It's always
great to visit with you.
We're glad you're here. Today, we're talking about stand out poster
presentations from the ASCO annual meeting that concluded Tuesday
for oncologists who are interested in prostate cancer. What did you
find most interesting?
You know, Lauren, there were so many great things. For oncologists
interested in GU, this is such a great time. I mean, there's so
much research going on. There were some wonderful plenary sessions,
amazing oral abstracts and poster discussion sessions as well.
But it's always riveting for me to go through the posters
themselves that don't get the big splash news that a lot of those
late breaking abstracts do, because there's so much great research
happening that you just can't put it all in oral sessions. So
there's so much great research that you can gain by going through
the posters as well as well as being able to meet one on one with
the principal investigators of that research.
So there's quite a few things. I mean, just to start off with
thinking about prostate cancer, there's a lot going on in prostate
cancer research today. You know, one of the things that I found
most fascinating was actually way in the back towards the end of
the prostate cancer posters. Now forgive me. I wrote down the name
to try and not get it wrong, but I'll probably mispronounce it. So
apologies if you're listening. But Dr. Linda Huynh, I believe is
how you pronounce it. The abstract number is 5085 from UC Irvine I
believe is where this person works.
But they were evaluating this concept of giving testosterone
replacement therapy to patients with localized prostate cancer that
have had a prostatectomy. So they evaluated these patients
retrospectively. But they were treated, obviously, prospectively
and the data was collected prospectively.
But they identified 152 patients that had received a prostatectomy
for localized prostate cancer and then, shortly after that,
received testosterone replacement therapy to treat their
hypogonadal symptoms. So then they case controlled this against 419
patients that had a prostatectomy for localized disease and did not
receive testosterone replacement therapy. The primary endpoint that
they were evaluating in this retrospective study was the time to
PSA relapse.
So interestingly, seven of the patients that had testosterone
replacement therapy ultimately went on to experience biochemical
relapse, so about 4% or 5% of the patients. Of those that had a
prostatectomy and no testosterone replacement therapy, 39 of those
patients had a PSA relapse, so about 9% or 10%. So it's a
retrospective study. There's a lot of inherent biases in that.
But surprisingly, the trend favored testosterone replacement
therapy. Now I'm not here to say testosterone replacement therapy
will help as an adjuvant treatment to protect these patients from a
PSA relapse. But it's really striking and surprising. Because right
now, the dogma is if you've ever had prostate cancer, then you
should be very cautious or not at all ever receive testosterone
replacement therapy. And they're showing that it possibly could be
very safe and have a huge impact on these patients' quality of
life. So that was fascinating to me.
Along those lines with trying to find improvements in quality of
life, there is another really interesting study that's sort of
paving the way for a new paradigm of how we think about and treat
prostate cancer. So Dr. Emmanuel Antonarakis from Johns Hopkins,
many people may know his name as someone along with Dr. Jun Liu
that helped bring to the forefront this whole new science of
antigen receptor spliced variants. It sort of went off on a whole
new vein of research here. I'm sorry. His abstract number is 5045,
and he was evaluating in a pilot phase II study an androgen
deprivation therapy sparing approach.
So for the most part, as we all know, as soon as patients have
relapse disease and they start systemic therapy, the bedrock or
foundation of that treatment is testosterone suppression with
androgen deprivation therapy. There's all kinds of side effects
that are attended with that, both things that just are bothersome
to the patient but significantly impacting their quality of life
with hot flashes and fatigue and mental impairment and cloudiness,
all the way to those asymptomatic problems that are very real and
problematic, worsening of osteopenia and osteoporosis, worsening of
cardiovascular disease, maybe causing dementia. Although, that is
still debatable. So in this trial, he was looking at patients that
had a biochemical recurrence, a PSA relapse, and was evaluating
monotherapy with olaparib, a PARP inhibitor.
Now interestingly, in this study, patients were not mandated to
have DNA repair defects to enroll in the trial. So it was open to
everybody. They were required to have a PSA doubling time that was
less than six months. It turns out their PSA doubling time was, I
forget the exact number, but something around the three month
range. So very similar to all of these M0 CRPC studies that have
come through recently, SPARTAN, et cetera. So these patients had
pretty aggressive disease as defined by their PSA doubling
time.
So the primary endpoint was a PSA reduction of 50% or more. So this
is a pilot study. So there were only 20 patients enrolled. And only
three of the 20 patients met the primary endpoint, so about 15% of
the patients. However, another four out of the 20 had some
reduction in their PSA, anywhere from 1% to 49%. So in total, about
35% of men had a serological response of some degree.
So if you actually look at the poster, though, it's pretty
interesting and telling. So four out of four patients with a BRCA2
mutation responded. And of those three that I told you about that
met the primary endpoint, all three of those were these BRCA2
patients. One of four patients that had ATM mutations responded.
And only one of 12 patients that were biomarker negative
responded.
So it's really fascinating. It suggests, I mean, it clearly needs
to be validated in a larger study, but it suggests that there might
be a ADT sparing approach that you could do for a select group of
men, which is what I hear all the time from patient advocates
around prostate cancer. What do you have for me that doesn't
involve testosterone suppression? So really fascinating.
That sounds very promising for patients with prostate cancer. What
about some other cancer types, such as bladder cancer?
There was a lot of great research all the way through the GU space.
So for bladder cancer, there was really two that stood out to me.
They stood out to me in regards to immunotherapy. Dr. Padmanee
Sharma's group at the MD Anderson Center, the abstract number is
4511, so she was evaluating neoadjuvant durvalumab and
tremelimumab.
So durvalumab's a PD-L1 inhibitor. And tremelimumab's an
anti-CTLA-4 inhibitor. So she was evaluating this combination in a
pilot phase II study in patients with muscle invasive bladder
cancer but were ineligible for cisplatin.
Now, that's important because right now there's no FDA-approved
therapies that are proven to be effective for that group of
patients either in the neoadjuvant space or in the adjuvant space.
So the standard of care approach for these patients is to move
forward with cystectomy or radiation therapy alone, with the
majority of them getting cystectomies followed by surveillance.
So their relapse rate is very high. So trying to find some other
therapy that can be effective for them is a huge unmet need right
now. Now, there was a couple of posters at ESMO in 2018 that
suggested neoadjuvant immunotherapy can be useful for them.
Pembrolizumab was tested and atezolizumab also was tested. So this
was really an interesting validation to see in a separate cohort if
the same approach of a PD-1/PD-L1 inhibition approach can be useful
for these patients.
Because this is a neoadjuvant treatment only, their duration of
immune therapy was also very short. That's the other really
fascinating thing to take into consideration here. So weeks 1 and 5
is when they had their immune therapy. And the planned time to
surgery was somewhere between weeks 9 to 11. So far the trial isn't
complete.
Their planned enrollment is around 35 patients, I believe. And
they're just around 30 that have enrolled. So there was a 43%
complete response rate, pathologic complete response rate, at the
time of cystectomy.
I believe 21 patients have gone on to cystectomy in this trial, so
43%. It's really high, which is fabulous and great because the
pathologic complete response rate, it's not a perfect predictor of
long-term overall survival, but it's a reasonable surrogate. I
mean, it's not an FDA-approved or recognized surrogate endpoint,
but it correlates fairly well with overall survival for these
patients.
But the other reason that that number is fascinating is because if
you go back and look at the pembrolizumab and the atezolizumab
data, this is a fairly consistent number across all three of these
trials. Anytime you talk about immune therapies, there are side
effects. But it was right in line with what we see consistently
with immunotherapy.
So around 17% had grade 3 immune-mediated adverse events. Two
patients had a delay in surgery because of complications. The delay
in surgery, I should say, was reported as more than 30 days.
So it can cause problems. But it's helping to create this
foundation that, maybe in the future, when we get the results from
my phase 3 study, it will provide some additional neoadjuvant or
adjuvant therapy for these patients that are in great need.
And the other one very similar to this, just briefly, was by Ronald
Dewitt. And the abstract number was 4530. So this was looking at
somewhat of a similar population, patients that have non-muscle
invasive disease, but a refractory to BCG, which is the standard
therapy today.
So if you're refractory to BCG, there's some other intravesical
chemotherapy you can try. The response rates aren't particularly
high. Or the other option is the cystectomy.
This was a much larger trial, just over 100 patients were enrolled.
And they were given standard of care. Pembrolizumab was the
immunotherapy in this setting.
The three-month complete response rate was 40%. Of those patients
that were complete responders, the median duration was very long.
In fact, the median duration was around a year, I believe. And at
least half of those patients that were responders had a response of
over a year.
Wow, that's remarkable.
Yeah. So if you compare the standard of care that they'd be getting
alternatively, it would be a cystectomy. So that's quite
impressive.
That's really exciting. How about kidney cancer? Did you see any
interesting presentations?
There was some great presentations on kidney cancer about clear
cell disease and biomarkers coming off of the recent JAVELIN study,
et cetera, that Toni Choueiri did. And other people can talk to you
about that, I suppose.
But in the posters, what I found particularly interesting was this
focus on non-clear cell kidney cancer. So clear cell makes up the
majority of kidney cancer, around 75%. But there's still this 25%
that we don't have a lot of great data for.
There's a couple of trials like ASPEN, et cetera, that have
established TKIs as the standard of care for them. But the response
duration is not great, so trying to find other therapies that have
a longer duration of response is important. And so if we look at
the current armamentarium of options, immunotherapy is what we look
to as far as possibly providing patients a long, robust
response.
So there was a couple of trials looking at immune therapies with
non-clear cell disease. So the first was by Michael Atkins, and the
abstract number was 4569. So this was a report on KEYNOTE-427
cohort B.
So KEYNOTE-427 is this two-arm trial with cohort A, or cohort one,
whatever you want to call it, and is single-agent pembrolizumab in
clear cell RCC. And cohort B is non-clear cell RCC. And this poster
was just reporting on cohort B, the non-clear cell portion.
So most of those patients-- and it was a fairly large cohort; 165
patients. Now, unfortunately, this somewhat suffers from all the
research that's done for the most part in non-clear cell disease
where they take all of these other histologies, they're somewhere
around 8 or so, and they just lump them all together and say, you
are non-clear cell disease. But we do know that they all have very
distinct biology.
So they fortunately did break them up at least into the top three
pathologies. So 70-some percent were papillary, which is what we
typically see. Of the non-clear cell histologies, that's the most
common.
Chromophobe was around 13%, and unclassified was around 15%. Oh,
and the other important thing is they did do central pathology
review, which is very important any time you're doing a non-clear
cell study because the misdiagnosis rate is fairly high in this
population.
So these patients with any of these non-clear histologies got
treated with pembrolizumab. And the overall response rate was quite
high, around 24%. They specifically broke it up into those top
three histologies.
And the papillary objective response rate was 25%, chromophobe was
around 10%, and the unclassified was over 35%. So it does show that
there's a good rationale for immunotherapy in the non-clear cell
histologies, at least, certainly, you could say for the
unclassified and the papillary. Some people would argue that a 10%
objective response rate in chromophobe isn't meaningful.
There was some toxicity, as well, seen. Around 10% of patients had
a grade 3-plus reaction. And this was a 165-patient trial. And six
patients died directly from toxicity related to immunotherapies. So
it really helps establish that immunotherapy can be useful in these
non-clear cells.
And that was recapitulated in a study by Dr. Rana McKay at
Dana-Farber in their group there with Toni Choueiri, et cetera. And
that abstract is 4583. And they looked at a similar idea with
bevacizumab and atezolizumab. And this included, sort of, two
cohorts, clear cell RCC with sarcomatoid features, or any non-clear
cell RCC.
They did not specifically break it up into the subtype of what the
specific histology was for the non-clear cell group. But if you
look at just that non-clear cell group of 39 patients, the
objective response rate was 26%, very similar to the overall
objective response rate in Dr. Atkins' study of 25%. So it's
providing this promising new avenue of immunotherapy, demonstrating
efficacy in this population.
That's fascinating. And it's always good to look at the toxicities
for sure. What else did you see this year? And did anything
surprise you?
As far as what surprised me or what other interesting things in the
posters-- that's probably the best place, I mean, not only to meet
people-- I love the posters for that-- but it's a great place to
see new and developing biology of disease or understanding new
technologies to monitor disease.
I can't remember the abstract number off the top of my head, I
apologize. But in the bladder cancer poster session, there was a
poster looking at cell-free DNA. And not just presence or absence
or quantity of it, but they were looking at the fraction of the
cell-free DNA as a marker of patients having muscle invasive or
non-muscle invasive bladder cancer.
So that's just one example of many of the new, emerging uses of
technology across these diseases. So it's really fascinating to see
how people are thinking and using or repurposing a lot of
technology for these cancers. It's a great place to go to generate
ideas, I suppose, is what I'm trying to say.
That's terrific. Again, today my guest has been Dr. Benjamin
Maughan. Thank you for coming back to our podcast.
Thank you so much. It's been a pleasure visiting with you,
Lauren.
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