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May 29, 2020

In today’s episode, we hear from Dr. Neeraj Agarwal, associate editor of the ASCO Daily News and director of the Genitourinary Oncology Program at the University of Utah’s Huntsman Cancer Institute, about key abstracts and remarkable new developments in the GU field featured during the #ASCO20 Virtual Scientific Program.



ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. I'm delighted to welcome Dr. Neeraj Agarwal to the podcast today. Dr. Agarwal is Associate Editor of the ASCO Daily News and directs the Genitourinary Oncology Program at the Huntsman Cancer Institute at the University of Utah where he also serves as Professor of Medicine.


Dr. Agarwal joins us to discuss abstracts and some remarkable new developments in the GU field featured during the ASCO20 Virtual Scientific Program. Dr. Agarwal reports paid consulting on the scientific advisory boards of AstraZeneca, EMD Serono, Pfizer, Janssen, Bayer, Exelixis, Genentech. And full disclosures relating to all Daily News podcasts can be found on the episode pages. Dr. Agarwal, welcome to the ASCO Daily News podcast.


Dr. Neeraj Agarwal: It's a pleasure. Thanks for having me.


ASCO Daily News: Dr. Agarwal, can you tell us about the abstracts in the GU field that you're really excited about this year?


Dr. Neeraj Agarwal: Of course. I would like to encourage the listeners to visit abstract LBA1 on the JAVELIN 100 trial, which was presented by Dr. Tom Powles on the efficacy of avelumab in patients with metastatic urothelial carcinoma as a front-line maintenance therapy. In this remarkable study, 700 patients were enrolled in a phase III randomized control trial after they had completed chemotherapy, the standard chemotherapy for a new diagnosis of metastatic urothelial carcinoma or metastatic bladder cancer.


So, just to take a step back, currently, the standard of care for patients who are diagnosed with metastatic urothelial carcinoma is chemotherapy with cisplatin or, those patients who are not eligible for cisplatin, chemotherapy with carboplatin-based regimens. The median survival is approximately 18 months with cisplatin-based chemotherapy regimens and lower with carboplatin-based regimens.


And, at this point of time, we wait for these patients to experience disease progression, which is universal, pretty much, in these patients. And, when they have disease progression, they are treated with immune checkpoint inhibitors. And five of them are currently approved in this setting.


So what was novel about this study presented by Dr. Tom Powles and senior co-authored by Dr. Petros Grivas is that they utilized ab immune checkpoint inhibitor, avelumab, which is already approved for patients who are experiencing disease progression. So, instead of waiting for disease progression, the patients were randomized to receive standard of care, which is observation, versus treatment with avelumab. So this entirely new concept is called as front-line maintenance therapy.


So 700 patients who had completed four to six cycles of chemotherapy for their metastatic urothelial carcinoma were randomized to standard of care, which is observation with scans every three months, versus treatment with avelumab right after completion of their chemotherapy. The primary endpoint was overall survival.


And it was striking to see the improvement in overall survival. The patients who received avelumab, the median overall survival was 21.4 month versus 14.3 months in patients who did not receive avelumab. The hazard ratio for overall survival benefit was 0.69, which basically translates into a 30% reduction in risk of death in patients who receive avelumab therapy.


It was remarkable to see that overall survival was significantly improved in patients who received treatment with avelumab. The median overall survival was 21.4 months versus 14.3 months with a 30% reduction in risk of death in patients who received avelumab therapy. Even progression-free survival was also improved in patients who were receiving avelumab with approximately 40% reduction in risk of progression or death.


The side effects were expected, as to what you would see with avelumab therapy. And avelumab, as you know, is immune checkpoint inhibitor already approved in patients with metastatic urothelial carcinoma. And side effects seen were expected, and there were not new signals as far as safety was concerned.


With these results, there is no doubt that avelumab will be approved for our patients who are completing chemotherapy with carboplatin and cisplatin for metastatic urothelial carcinoma. And they will have the chance to receive avelumab up front in a front-line maintenance setting. And this is very gratifying to see these kind of results for our patients.


ASCO Daily News: Dr. Agarwal, there are several posters that show promising improvements in overall survival for patients with prostate cancer. Can you tell us about these studies?


Dr. Neeraj Agarwal: So there were three poster discussion sessions on patients with non-metastatic castrate-resistant prostate cancer. So, just to step it-- take a step back, about two years ago, three trials, PROSPER, SPARTAN, and ARAMIS, all phase III large randomized trials, which were conducted in patients with non-metastatic castrate-resistant prostate cancer, these trials utilized therapies with enzalutamide, apalutamide, and darolutamide respectively. These are potent direct androgen receptor inhibitors. And all these three trials met the primary endpoint of metastasis [INAUDIBLE].


So, just to take a step back, in patients with M0 CRPC or non-metastatic Castrate-Resistant Prostate Cancer, which is those patients with prostate cancer who are experiencing the rise in the PSA levels, but are not yet seeing metastasis on treatment with androgen deprivation therapy, and, until two or three years ago, we did not have any treatment options for these patients. And the standard paradigm was to wait for onset of metastasis before you can use-- or you can treat that with this novel androgen receptor inhibitors.


These trials used these agents early on and showed progression-free survival improvement. In this ASCO 2020, the updated results on overall survival were presented. Remarkably, all these three trials showed improved overall survival with enzalutamide, apalutamide, and darolutamide in patients with non-metastatic CRPC.


In my view, these results are very important because overall survival remains the gold standard in my mind and in several of my colleagues' minds to be the gold standard or to be the standard outcomes or the ultimate outcomes we like to see in our patients. Having overall survival be met by these trials, there's no doubt that the treatment of my patients or our patients with non-metastatic CRPC will further change with the utilization of enzalutamide, apalutamide, and darolutamide being options for these patients.


There were no new side effects reported. No new safety signals were reported. And I think-- I have no doubt that this is a welcome news for our patients, as well as providers who are treating these patients. I would like to encourage the listeners to visit the ASCO website and look at abstract number 5514, 5515, and 5516 to see further description on these three trials, which are PROSPER, SPARTAN, and the ARAMIS trial results on patients with non-metastatic castrate-resistant prostate cancer.


ASCO Daily News: Excellent. So are there other new agents that will likely move the field forward or have already done so?


Dr. Neeraj Agarwal: I would like to particularly highlight the combination of cabozantinib and atezolizumab in patients with metastatic castrate-resistant prostate cancer who are experiencing disease progression on the standard, novel, hormonal therapies, such as enzalutamide or abiraterone.


I would like to highlight the combination of cabozantinib, a multi-tyrosine kinase inhibitor, and atezolizumab, an immune checkpoint inhibitor, in patients with metastatic castrate-resistant prostate cancer who are experiencing disease progression on normal hormonal therapy, such as enzalutamide or abiraterone or both. I had the privilege of presenting these data in ASCO this year, and the abstract number is 5564.


So these are the results of a phase I trial where, originally, 30 patients were supposed to be recruited, and the cohort has since then-- since then, cohort has been expanded to 130 patients. These are the results from first 44 patients. All of these patients were experiencing disease progression on abiraterone or enzalutamide or both.


In fact, 50% patients had disease progression on both. One third of these patients had received chemotherapy with docetaxel in the castration-sensitive prostate cancers, and what we saw was remarkable. The combination of cabozantinib and atezolizumab resulted in objective responses in 32% patients and additional stability of disease in additional 48% patient. This translates into stable disease or responses, which we call as clinical benefit rate or disease control rate, in 80% of these patients.


I would like to point out that these patients had either visceral metastases or extrapelvic lymph node metastases, both of which are considered bad prognostic signs when we see these patients in our clinic. And they had to have disease progression in these sites radiographically before they could be recruited on this clinical trial.


The median duration of response was 8.3 months. And patients were able to receive this treatment for a median of six month. So duration of therapy was six months. Median duration of response was eight months. And the responses or, I would say, disease control was seen in 80% patients.


Obviously, this is data from a relatively small trial. However, based on these encouraging data, very exciting data I would say, a phase III trial has already started, which is going to start recruiting patients all over the world in different countries, including in the United States. So I'm really hoping that this combination will ultimately be proven to be efficacious and will be available to our patient.


But, for now, our patients will have the opportunity to enroll in this clinical trial, which will be open across the country and, as I mentioned, across the world in different countries. I would like to encourage the listeners to visit abstract number 5564 to look at further description of these data from the COSMIC-021 trial with the combination cabozantinib and atezolizumab in patients with metastatic castrate-resistant prostate cancer.


So next abstract I would like to highlight is the health-related quality of life data from PROfound trial, abstract number 5539. As we know from the recent presentations and publications in New England Journal of Medicine, a new class of drug for patients with prostate cancer or patients with metastatic castrate-resistant prostate cancer, PARP inhibitor or Poly ADP-Ribose Polymerase inhibitor olaparib, was presented.


Based on this report and in that trial, which was a phase III randomized trial, which included patients with metastatic castrate-resistant prostate cancer who were harboring homologous recombination repair defects in their tumors or, simply speaking, whose tumors has DNA repair-related defects, these patients were randomized to olaparib, a PARP inhibitor, versus enzalutamide or abiraterone. These patients were already experiencing disease progression on enzalutamide or abiraterone prior to enrollment on this trial.


The radiographic progression-free survival was the primary endpoint. There were two cohorts in this clinical trial. Cohort number one included patients with BRCA1, BRCA2, and ATM mutation. Cohort two included patients with 12 other mutations, which are also included in this class of mutation leading to DNA repair defects in patients with metastatic castrate-resistant prostate cancer. The radiographic progression was improved. And, per a recent press release, overall survival was also improved with olaparib.


In this abstract, number 5539, of the PROfound trial, authors presented the health-related quality of life data, as reported by the patients themselves. And, in my view, health-related quality of life data are very important because they are reported by patients themselves without any interference from the medical team or any biases introduced by the medical treatment providing team.


So very rigorous health-related quality of data were obtained during the conduct of the trial. They were obtained by using Functional Assessment of Cancer Therapy-Prostate, also commonly called as FACT-P questionnaire, which comprised five scales or five subscales, which included physical well-being, functional well-being, emotional well-being, social well-being, and prostate cancer subscale.


The results show that the baseline FACT-P total scores were similar for both treatment arms. However, during the entire course of treatment, there was a consistently high FACT-P score, total FACT-P score, as well as a subscale score for olaparib versus enzalutamide or abiraterone. And there was a clinically meaningful difference between the treatment arms.


So what we really get out of these data is that olaparib did not only improve survival in these patients with very limited options, but also delayed deterioration in health-related quality of life compared to enzalutamide and abiraterone, and was associated with improved quality of life in our patients who had this unusually aggressive type of castrate-resistant prostate cancer.


For a further description of these data, please visit the abstract number 5539 on the PROfound trial. And all I can say at this time is this is indeed a very encouraging news for our patients to have an oral pill being available for them when the other option is chemotherapy in this setting, which is not only improving survival, but also improving quality of life.


ASCO Daily News: Thank you very much, Dr. Agarwal, for sharing your insights on these very promising developments in the GU field.


Dr. Neeraj Agarwal: Thank you very much, Geraldine. It's a pleasure.


ASCO Daily News: And thank you to our listeners for joining us today on the ASCO Daily News podcast. If you're enjoying the content, please rate and review us on Apple podcasts.

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.

COI Disclosure: Dr. Neeraj Agarwal

Consulting/Advisory Role: Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektor, Lilly, Bayer, Foundation One Inc, Pharmacyclics, Foundation Medicin, Astellas Pharma, Exelisis, Janssen Oncology, Merck, Novartis, Eisai

Research Funding: Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Takeda, Novartis, Pfizer, BN Immunotherapeutics, Exelixis, TRACON Pharma, Rexahn Pharmaceuticals, Amgen, AstraZeneca, Active Biotech, Bavaria, Nordic, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Newlink Genetics, Prometheus, Sanofi