#ASCO21: Advancing Treatment For Genitourinary Cancers With Dr. Neeraj Agarwal

Dr. Neeraj Agarwal, director of the Genitourinary Oncology Program at the University of Utah Huntsman Cancer Institute and incoming editor-in-chief of ASCO Daily News, highlights key abstracts in GU oncology featured at the 2021 ASCO Annual Meeting.   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, a medical oncologist and director of the Genitourinary Oncology Program at the University of Utah Huntsman Cancer Institute. He joins me to discuss key abstracts in the GU field featured at the 2021 ASCO Annual Meeting.   Dr. Agarwal has served in a consulting or advisory role for AstraZeneca, Bristol Myers Squibb, Exelixis, and Merck, among other organizations. He is a co-author of a study, Abstract 5073, that will be discussed in this episode. Dr. Agarwal's full disclosures and those relating to all episodes of the podcast are available on our transcripts at asco.org/podcasts.   Dr. Agarwal, it's great to have you on the podcast again.   Dr. Neeraj Agarwal: It's my pleasure, and an honor. Thank you very much for having me.   ASCO Daily News: Dr. Agarwal, let's start with some exciting news in the field of kidney cancer. LBA5 addressed the Keynote 564 trial, which evaluated pembrolizumab versus placebo as adjuvant therapy for patients with renal cell carcinoma. This study reported stunning results. What can you tell us about this trial?   Dr. Neeraj Agarwal: These are very important results from the Abstract LBA5, which is being presented by Dr. Toni Choueiri, from Dana Farber Cancer Institute, and colleagues on interim results from the KEYNOTE-564 trial, which showed that adjuvant therapy with pembrolizumab after complete resection of intermediate high, high-risk, localized or oligometastatic renal cell carcinoma improves survival outcomes.   So, let me give you a background first. Partial and radical nephrectomy is considered standard of care for treatment of men or women with localized renal cell carcinoma. However, approximately half of these patients eventually recur. In addition, many patients with limited metastatic disease undergo surgical resection.   Currently, there is no standard of care systemic therapy available for these patients. So, the KEYNOTE-564 study is a phase III trial evaluating pembrolizumab versus placebo--which is a standard of care, by the way, for these patients as adjuvant therapy for patients with clear cell renal cell carcinoma with intermediate high risk, high-risk, or those with metastatic disease who have undergone complete resection of metastatic disease.   Primary endpoint was disease-free survival for investigator assessment, in intent-to-treat population. Overall survival was a key secondary endpoint. In this study, a total of 994 patients were randomized, one to one, to pembrolizumab or placebo. At the time of data cutoff, median follow up was 2 years. There were no patients remaining on the study treatment.   If you look at the baseline characteristics, they were evenly balanced between the two arms. At the first, prespecified interim analysis, the primary endpoint of disease-free survival was met, though the median values were not reached for both arms. Pembrolizumab was associated with a significantly longer disease-free survival than placebo, with a hazard ratio of 0.68 and a one-sided p-value of 0.001, which translates into 32% reduction in risk of recurrence of disease or death with adjuvant pembrolizumab.   The 2- year rate of disease-free survival was 77.3% with pembrolizumab, as compared to 68% of the placebo. Overall, disease-free survival benefit was consistent across subgroups. Median overall survival was not reached for either groups, and the estimated 24 months survival rate was high in both groups at 96% and 93.5% with pembrolizumab and placebo, respectively. And really, there were no new safety signals seen with pembrolizumab.   So, I'd like to summarize these important results by saying that KEYNOTE-564 is the first positive, phase III study with a checkpoint inhibitor for patients with renal cell carcinoma, which has been surgically resected completely. And for them, right now, there is no real standard of care after the surgical resection. So, in my view, these results support pembrolizumab as a potential new standard of care for these patients who present to us after a complete surgical resection of their renal cell carcinoma.   ASCO Daily News: Excellent. Thank you for sharing those practice-changing results. There's another late-breaking abstract that people are excited about. That's LBA4 and the VISION phase III study, which used a novel PSMA-targeting agent for patients with metastatic, castration-resistant prostate cancer. What can you tell us about the VISION trial?   Dr. Neeraj Agarwal: The VISION trial was reported by Dr. Mike Morris, from Memorial Sloan Kettering Hospital, and colleagues from across the planet. And this trial investigated the use of the Lutetium PSMA-617 in patients with metastatic, castration-resistant prostate cancer. As a background, Lutetium PSMA 617 is a targeted, radioligand therapy which delivers beta particle radiation to PSMA-expressing prostate cancer cells and surrounding microenvironment.   So, VISION was a randomized, open-label, phase III study, which evaluated Lutetium PSMA-617 in men with PSMA-positive, metastatic, castration-resistant prostate cancer, who had received prior treatment with the next generation androgen signaling inhibitors, such as enzalutamide and one or two taxane therapy regimens. Primary endpoint was radiographic progression-free survival, as well as there was another primary endpoint.   So, there were two primary endpoints--radiographic progression free survival, and overall survival. A total of 831 patients--so this is a large study--where 831 patients were randomly assigned in 2 to 1 fashion to receive Lutetium PSMA-617, plus standard of care, or standard of care therapy alone. I would like to point this out, that standard of care therapy was to be determined by the investigator, but excluded cytotoxic chemotherapy and radium 223.   The median study follow up was 20.9 months at the time of data cutoff. The baseline characteristics were well balanced between treatment arms. Lutetium PSMA-617 plus standard of care therapy significantly improved radiographic progression free survival and overall survival, versus standard of care therapy alone. The median radiographic progression free survival with lutetium PSMA-617 plus standard of care was 8.7 months, as compared to 3.4 months with standard of care alone, with a hazard ratio of 0.40, favoring the lutetium PSMA- 617.   The median overall survival with lutetium PSMA-617 plus standard of care was 15.3 months, as compared to 11.3 months with standard of care, with a hazard ratio of 0.62. These results basically translate into an absolute 4-month improvement in median overall survival, and a 38% reduction in risk of death, with PSMA-617 plus standard of care over the standard of care. I would like to point out that key secondary endpoints of objective response rates, disease control rate, and time to subsequent or first symptomatic skeletal event were statistically significant, and favored lutetium PSMA 617.   Overall, if you look at the treatment emergent adverse events, they were higher in the lutetium PSMA arm, at 52.7%, compared to those on the standard of care arm, which was 38%. And these were high grade treatment emergent adverse events. So, I'd like to conclude by saying that lutetium PSMA-617 plus standard of care treatment was a well-tolerated regimen that improved radiographic progression-free survival, and overall survival, as compared with standard of care therapy alone, in men with PSMA-positive, metastatic, castration-resistant prostate cancer, after prior treatment with novel hormonal receptor signaling inhibitors, such as enzalutamide or abiraterone and taxane chemotherapy.   Once approved by regulatory bodies, I am looking forward to using this agent in my clinic for our patients with metastatic, castration-resistant prostate cancer who have had disease progression on prior therapy with normal hormonal therapy and taxane chemotherapy. So, this is indeed a great news for our patients.   ASCO Daily News: Absolutely. Well, I'd like to ask you about adolescents and young adults with cancer. As you know, AYA patients navigate a lot of challenges in their cancer experience. Can you tell us about any studies that address this patient population?   Dr. Neeraj Agarwal: Indeed. There was an abstract--Abstract 5006, which is being presented by Dr. Hellesnes and colleagues from University Hospital of North Norway. The study team investigated non-testicular cancer mortality in relation to testicular cancer treatment in a large population-based cohort. Overall, 5,700 men, diagnosed with testicular cancer from 1980 to 2009, were included and identified from the cancer registry of Norway.   Clinical parameters and treatment data were abstracted from the medical records and linked with the Norwegian cause of death registry. During a median follow up of 18.7 years--it is a long follow up, by the way--in total, 665--or 12% of men--were registered with non-testicular cancer deaths. The overall excess non-testicular cancer mortality was 23% in men with a history of testicular cancer, as compared with the general population.   So, I'd like to repeat. There was an overall excessive non-testicular cancer mortality in men with a history of testicular cancer compared to the general population--by 23%. That's the first message I'm giving here. Second, there was an increased risk observed with platinum-based chemotherapy and radiation therapy, but not after surgery. So, I thought it was very interesting that there was an increased risk of non-testicular cancer mortality seen after platinum-based chemotherapy and/or radiation therapy, but not after surgery given the context of testicular cancer.   The standardized mortality ratios increased significantly, with increasing follow up time of 10 or more years. The most important cause of death wasn't second cancer. Treatment with platinum-based chemotherapy was associated with a significant 1.69 to 6.78-fold increased standardized mortality ratio for cancers of the oral cavity, pharynx, esophagus, lungs, bladder, and leukemia. After radiation therapy given for testicular cancer, there was an increased--significantly increased--and we are talking about 3.02 to 4.91-fold increase--the standardized mortality ratio for cancers of oral cavity, pharynx, stomach, liver, pancreas, and bladder. Even non-cancer mortality was also increased by 15% after both platinum-based chemotherapy and radiation therapy.   I would like to highlight that there was an excess in suicides after platinum-based chemotherapy with a standardized mortality ratio of 1.65. So long term, overall cardiovascular mortality--and I found it interesting, because it is going against the dogma here--that long term, overall cardiovascular mortality was not increased with either chemotherapy or radiation therapy. So, I'd like to conclude--regarding this abstract--by saying that testicular cancer treatment with platinum-based chemotherapy or radiation therapy was associated with significantly increased long term, non-testicular cancer mortality, with non-testicular second cancer being the most important cause of death in these patients.   So, in my view, these results have important implications on patient counseling, selection of treatment for testicular cancer, and, very importantly, long term follow up of our young patients with testicular cancer after they are apparently cured of testicular cancer with platinum-based chemotherapy and/or radiation therapy. And usually we stop following them, in most cases, after 5 years. And how these results are going to impact the decision making regarding their long-term follow up. So, I think this study brings up a very important issue from those perspectives.   ASCO Daily News: Absolutely. Dr. Agarwal, I'd like to get your thoughts on Abstract 5004. That addresses PSA screening for African American men. What can you tell us about this study?   Dr. Neeraj Agarwal: So, this abstract, which is Abstract 5004, presented by Dr. Edmund Qiao and colleagues, examined the association of intensity of PSA screening with the disease severity of prostate cancer at the time of diagnosis, as well as prostate cancer-specific mortality in African American men younger than 55 years of age. So, I'd like to highlight two things, which this study is presenting.   Number one, the screening intensity in African American men, and second, how it is affecting the time of diagnosis, the type of diagnosis--meaning is it a high grade or metastatic prostate cancer--and most importantly, is it affecting prostate cancer-specific mortality in African American men? So, this was a retrospective review of Veterans Health Administration records of African American men, aged 40 to 55 years, who were diagnosed with prostate cancer between the years of 2004 to 2017.   The screening intensity was defined as percentage of years screened within the pre-diagnostic observation period. The cohort included 4,654 African American men, with a mean age of 51.8 years--so quite a younger population. A median pre-diagnostic observation period of 5 years, and a median follow up of 7 years. And these are pretty decent, long median follow ups of 7 years.   So, in this large national cohort, African American men aged 40 to 55 years, increased intensity of PSA screening was significantly associated with decreased risk of metastatic prostate cancer, or high Gleason Score localized prostate cancer, and more importantly, prostate cancer-specific mortality. So, in my view, these results have important implications on how to screen African American men in the age group of 40- to 55-year-olds.   Obviously, we don't screen for prostate cancer. And please note that these are the men who are more likely than others to present and die of aggressive prostate cancer. And even more importantly, these men are underrepresented in PSA screening studies. So, I think a lot of good lessons coming from this study.   ASCO Daily News: Indeed. Well, racial disparities are also addressed in a Medicare database study captured in Abstract 5073. The study set out to evaluate the real-world utilization of advanced therapies over time, and to provide data on utilization patterns among racial minorities that are often underrepresented in clinical trials. Can you tell us more about this study?   Dr Neeraj Agarwal:  Yes. Indeed. These data, presented by Dr. Steve Freedland from Cedars-Sinai, and colleagues, which highlighted a critical issue of unacceptably high number of patients with metastatic castration-sensitive prostate cancer not receiving standard of care, life-prolonging therapy in the United States. In this study, which I also had the opportunity to co-author, the investigators evaluated real-world utilization of systemic therapies backed by level 1 evidence from large randomized phase III trials, which showed treatment intensification with docetaxel, or novel hormonal therapies, such as abiraterone, dramatically improved overall survival in men with metastatic castration-sensitive prostate cancer.   In addition, the study team also evaluated the receipt of these therapies by racial minorities who are usually underrepresented in these clinical trials. So, this was a retrospective study of a Medicare database, which covered the time period between January 2009 and December 2018. Adult men with new diagnosis of metastatic prostate cancer were included. The first line treatments were grouped by prostate cancer specific drugs prescribed within 30 days prior to, and 120 days after the index date, which was the date of diagnosis of metastatic disease.   Remarkably, a total of more than 35,000 patients with metastatic castration-sensitive prostate cancer were included in the study. These comprise 12% patients who are African American, 5.3% patients [who were] Hispanic men, and 78.5% men who were white. So, the study had a good representation of racial minorities.  The results were startling to me.   Starting in the year 2015 or ‘16, when docetaxel was already approved after showing dramatic improvement in overall survival, which was soon followed by similar results with abiraterone, within a couple of years showing similar overall survival benefit--less than one third patients with metastatic castration-sensitive prostate cancer received these therapies from 2015 until 2018. The treatment intensification, which is the terminology used for combination of androgen deprivation therapy with docetaxel or novel hormonal therapy such as abiraterone, enzalutamide, and apalutamide--so treatment intensification was even lower for Black patients than white patients.   So, to summarize, in this large and nationally representative patient population with diagnosis of metastatic castration-sensitive prostate cancer, less than one third patients received standard of care treatment intensification, even in the year 2018. More importantly, the data showed even less frequent use of treatment intensification in Black patients versus white patients. A similar study, by my colleague, Dr. Umang Swami from Huntsman Cancer Institute, in the Abstract 5072, also showed that despite level 1 evidence demonstrating improved survival with intensified regimens with ADT plus docetaxel or normal hormonal therapy, such as, as I said, abiraterone, enzalutamide, apalutamide--frequent intensification was underutilized in men with metastatic castration-sensitive prostate cancer, in more than 4,000 patients studied.   And importantly, these patients were included from the claims data from commercially insured--I want to repeat--commercial insured and Medicare Advantage populations. So, these patients you would expect to have good financial coverage for their treatment. And even then, less than one third patients were receiving this standard of care, intensified treatments backed by level one evidence from phase III trials. Less than one third patients were receiving this therapy.   Even in patients with visceral metastasis--which we know is the most aggressive form of prostate cancer--there was a similarly low level of treatment intensification. So, I think these data are very important for us to know. And there are important steps for us to take down the line. We do not know why this is happening.   Why are our patients are not being offered standard of care, life prolonging therapies for castration-sensitive disease? Is it an access problem? Is it a problem with education, awareness? We do not know. So, I think a lot of works needs to be done in this direction.   ASCO Daily News: Absolutely. These data are very, very concerning. Dr. Agarwal, thank you very much for sharing your incredible insight with us today, and highlighting these very impactful studies in the GU field.   Dr. Neeraj Agarwal: Thank you very much for having me.   ASCO Daily News: And thank you to our listeners for your time today. If you enjoyed this episode, please take a moment to rate, review, and subscribe, wherever you get your podcasts.     Disclosures: Dr. Neeraj Agarwal  Consulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Exelixis, Merck, Novartis, Eisai,   Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences  Research Funding (Inst.): Bayer Your Institution , Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen,   AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, crispr therapeutics, and Arvinas  Disclaimer:  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.