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.
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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