Feb 17, 2021
In today’s episode, Dr. Neeraj Agarwal, medical oncologist and director of the Genitourinary Oncology Program at the University of Utah’s Huntsman Cancer Institute, highlights recent advances in prostate cancer research.
Transcript
ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. My guest today is Dr. Neeraj Agarwal, who is a medical oncologist and director of the genitourinary oncology program at the University of Utah's Huntsman Cancer Institute. Dr. Agarwal joins me to discuss promising new therapies for patients with prostate cancer featured at the 2021 Genitourinary Cancer Symposium.
Dr. Agarwal has served in a consulting or advisory role for
AstraZeneca, Bristol-Myers Squibb, Exelixis, and Merck, among other
organizations. His full disclosures, and those relating to all of
our episodes, are available on our transcripts at
ASCO.org/podcasts.
Dr. Agarwal, the symposium featured some really promising advances
in the prostate cancer space. Can you highlight some of the key
studies for us?
Dr. Neeraj Agarwal: Yes. I would like to mention
the final analysis from the TITAN study, Abstract 11, which I had the privilege
of steering with Dr. Kim Chi and Dr. Simon Chowdhury, along with
other colleagues. As most listeners know, the TITAN study was a
phase III trial, which randomly assigned patients with newly
diagnosed metastatic castration-sensitive prostate cancer receiving
androgen deprivation therapy to either apalutamide or placebo.
So all patients were receiving androgen deprivation therapy, and
then patients received either apalutamide or placebo. The dual
primary endpoints of overall survival and radiographic
progression-free survival were reported at the first interim
analysis, with a median follow-up 22.7 months and significantly
favored apalutamide. These data were published in New England
Journal of Medicine and led to regulatory approval of
apalutamide for men with newly diagnosed metastatic prostate cancer
in the year 2019.
At the first analysis, the study was unblinded. So when the study
reported positive results, the study was unblinded, and patients
that had not progressed on the control arm were allowed to cross
over from the control arm to the apalutamide arm.
Now, at a median follow-up of 44 months, OS continued to
significantly favor apalutamide arm, including those patients who
crossed over. So these are the data, presented by Dr. Kim Chi in
the symposium. So what we saw was that all other endpoints also
significantly favor the apalutamide arm. The final analysis from
this trial confirmed that these patients treated with apalutamide
derive significant improvement in overall survival with a 35%
reduction in the risk of death.
I would like to bring your attention this important point that when
they adjust for the patients who crossed over from control to
apalutamide arm, hazard ratio for overall survival benefit with
apalutamide improved further to 0.42, which translates into a 48%
reduction in risk of death with apalutamide compared to the
control. Such magnitude of improvement in survival with apalutamide
is great news for our patients with newly diagnosed metastatic
prostate cancer. And these data have already positioned apalutamide
as one of the top choices when we discuss treatment options with
our patients with newly diagnosed metastatic prostate cancer.
ASCO Daily News: Dr. Agarwal, are there
any other clinical trials that really stood out for you this
year?
Dr. Neeraj Agarwal: Yes, I would like to mention
Abstract
13, presented by Dr. Johann de Bono, where he discussed
biomarker analysis from the phase III high-potential 150 trial of
ipatasertib plus abiraterone in metastatic castrate-resistant
prostate cancer. This trial randomly assigned patients to either
ipatasertib plus abiraterone or placebo plus abiraterone.
Importantly, patients in this study were stratified by PTEN loss,
which was evaluated pre-randomization using the VENTANA
immunohistochemistry assay.
All primary endpoints of radiographic progression-free survival in
the ITT and PTEN loss population were reported last year
by Dr. de Bono. Treatment with ipatasertib plus abiraterone
significantly reduced the risk of disease worsening or death in
patients with PTEN loss by tumor immunohistochemistry, but not in
the ITT population.
An exploratory analysis further refined the cut-off for
PTEN loss, which was originally predefined at more than
50% tumor cells lacking cytoplasmic PTEN staining by
immunohistochemistry. So their results indicate a consistent
benefit with the combination therapy, with a more stringent cutoff
for PTEN loss by IHC.
In contrast, no benefit was observed in patients harboring intact
PTEN by IHC. Furthermore, patients harboring genomic
alterations in PIK3CA, AKT1, or PTEN by
NGS testing also derived significantly greater radiographic
progression-free survival benefit with the combination therapy of
ipatasertib with abiraterone compared to those harboring new
alterations in these genes.
So to summarize my findings in a simpler wording, patients who are
harboring these mutations, such as PIK3CA, AKT1,
or PTEN by NGS testing, are a more stringent cutoff for
PTEN loss by immunohistochemistry at 50% or more, seem to
derive radiographic progression-free survival advantage with the
combination of ipatasertib with abiraterone. In my view, these data
are not ready to allow approval of ipatasertib for our patients
with metastatic castrate-resistant prostate cancer. However, these
data provide a strong rationale for continued development of
ipatasertib, and this class of drugs, actually, known as AKT
inhibitors, for men with metastatic prostate cancer, especially in
those whose tumors are deficient in PTEN.
ASCO Daily News: Well, staying in the
metastatic prostate cancer space, there have been some interesting
studies addressing the role of circulating tumor DNA. Would you
like to address some of these?
Dr. Neeraj Agarwal: I would like to highlight the
role of circulating tumor DNA in detecting DNA repair
mutations--or, as we call, homologous recombination mutations--in
men with metastatic prostate cancer. These data have been reported
in three abstracts, Abstract 25, 256, and 27. However, before I discuss the
significance of the findings from these abstracts, I would like to
provide our listeners with some background.
Obtaining and profiling the genomic landscape of tumor biopsies in
patients with prostate cancer is challenging. For example, in the
PROFOUND trial, which was the first positive randomized phase III
trial of a PARP inhibitor in prostate cancer overall, more than
4,400 patients--I want to repeat, 4,400 patients--were prescreened
at 206 sites across 20 countries. Of these 4,400 patients, more
than 4,000 patients had tumor biopsies available for testing.
However, only 2,792 patients--so basically, we lost 30% patients
out there--were successfully sequenced. Why we lost those 30%
patients? We lost them because of poor quality or quantity of the
tumor tissue.
So out of 4,400 patients, only 2,700-plus patients were allowed to
be screened genomically for the PROFOUND trial. These data indicate
that 30% of the patients may not be offered a life-prolonging
therapy with PARP inhibitors due to a lack in adequate quantity or
quality of the biopsied tumor tissue.
In addition, by the time of onset of castrate-resistant prostate
cancer patients, most primary prostate biopsies are often too old
for genomic profiling. And biopsying metastatic sites in prostate
cancer patients is challenging due to bone-predominant nature of
prostate cancer metastasis. Lastly, we have to remind ourselves
that obtaining tumor biopsies can be time consuming, invasive,
expensive, and may be associated with morbidity, such as bleeding,
infections, perforation, and more, especially in this elderly
patient population. Given all this, circulating cell-free DNA
genomic profiling offers a viable alternative for patients with
prostate cancer.
So the first two studies I would like to mention evaluated the
concordance between detection of BRCA1/2 alterations and
either tissue results in Abstract 25, or historic results reported
in the literature in Abstract 256. Overall, the findings from these
two abstracts indicate a high degree of concordance regarding the
detection of BRCA1 and 2 alterations, supporting
its utility in complementing genomic profiling in cases where tumor
tissue is unavailable or of low quality.
So to summarize these two abstracts, 25 and 256, what we see here
is that sequencing and detection of BRCA1 and
BRCA2 mutation is feasible in circulating tumor DNA and
matches--the results matches to what we see when we sequence tumor
tissue DNA. And this is great news because now we can delve into
circulating tumor DNA profiling when we do not have good quantity
or quality of tumor tissue available without having to worry about
repeat biopsies in these elderly patients.
So the last study in this context I would like to highlight is
Abstract 27 by Dr. Matsubara, reporting on the findings regarding
identification of patients with BRCA1 and 2
mutations by circulating tumor DNA or cell-free DNA in the context
of the PROFOUND study. Patients treated with olaparib who were
detected to have BRCA1, 2, and ATM
mutation by circulating tumor DNA had significantly improved
outcomes in radiographic progression-free survival compared to the
control population. So these data further support the use of
circulating tumor DNA testing for identification of patients
harboring BRCA1, BRCA2, and ATM
alteration who may benefit with PARP inhibitor therapy. And I think
personally, Geraldine, these data will definitely bring in
circulating tumor DNA testing to our clinic earlier than
expected.
ASCO Daily News: Well, thank you very
much, Dr. Agarwal, for highlighting some really promising
developments in the GU field.
Dr. Neeraj Agarwal: Thank you for inviting me,
Geraldine. It's always a pleasure.
ASCO Daily News: And thank you to our
listeners for joining us today. If you're enjoying the content on
the podcast, please take a moment to rate and review us wherever
you get your podcasts.
Disclosures: Dr. Neeraj Agarwal
Consulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Foundation One Inc, Pharmacyclics, Foundation Medicine, Astellas Pharma, Exelixis, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech
Research Funding (Institution): Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Takeda, Novartis, Pfizer, BN ImmunoTherapeutics, Exelixis, TRACON Pharma, Rexahn Pharmaceuticals, Amgen, AstraZeneca, Active Biotech, Bavarian Nordic, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Newlink Genetics, Prometheus, Sanofi
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