New Research in Genitourinary Cancers from ESMO Virtual Congress 2020, with Neeraj Agarwal, MD

ASCO: You’re listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world’s leading professional organization for doctors who care for people with cancer. 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. Cancer research discussed in this podcast is ongoing, so the data described here may change as research progresses. In this podcast, Dr. Neeraj Agarwal discusses new research in kidney, prostate, and bladder cancer presented at the European Society for Medical Oncology Virtual Congress 2020. This meeting was held virtually September 19-21. Dr. Agarwal directs the Genitourinary Oncology Program at the Huntsman Cancer Institute at the University of Utah. He is also a Specialty Editor for Cancer.Net. View Dr. Agarwal’s disclosures at Cancer.Net. ASCO would like to thank Dr. Agarwal for discussing this topic. Dr. Agarwal: Hi, my name is Dr. Neeraj Agarwal. I'm a professor of medicine and the director of genitourinary oncology program at the Huntsman Cancer Institute, Salt Lake City, University of Utah. Today, I'm going to talk about 3 major clinical trials which were presented during the 2020 annual meeting of European Society for Medical Oncology. All these 3 trials are practice-changing trials. And they have huge impact on how we treat patients with bladder cancer, prostate cancer, and advanced kidney cancer. Before I proceed further, I want to disclose that I have consulted and received honorarium to the sponsors of all these 3 trials, which include Exelixis, Galentic, AstraZeneca, Pfizer, and EMD Serono. I was also involved in the conduct of the PROfound clinical trial, the trial in prostate cancer which I am going to discuss about, as a steering committee member. Let's start with the trial in advanced kidney cancer. So this trial was a large phase III trial. It was named as 9ER trial and used a novel combination of cabozantinib plus nivolumab versus sunitinib. Hundreds of patients were randomized to treatment with cabozantinib plus nivolumab versus sunitinib. What we saw was really remarkable. The progression-free survival, which is defined as how long these drugs were able to control the disease from progressing, was remarkably improved with the combination of cabozantinib plus nivolumab versus or over sunitinib. In fact, the progression-free survival was double with the novel combination of cabozantinib with nivolumab versus sunitinib. So if you look at the absolute months, how long the disease was controlled or was contained from progressing, it was 16.6 months with the novel therapy with cabozantinib and nivolumab versus 8 months with sunitinib. In fact, if you look at the progression-free survival estimate as assessed by the treating clinicians who were treating these patients, it was even higher at 19 month versus 9 month. Overall survival was also improved. We do not have data in absolute months in overall survival, but if you look at the hazard ratios, basically that means that there was a 40% reduction in risk of death on treatment with cabozantinib and nivolumab. Even response rates were twice as high with cabozantinib and nivolumab. The most important aspect I would like to highlight of this trial was the quality of life as reported by the patients. The health-related quality of life in patients who received cabozantinib with nivolumab was consistently better throughout the duration of trial treatment over those patients who received sunitinib. And this speaks of the overall tolerability and safety of the agent. To summarize, the combination of cabozantinib and nivolumab is one of the new standard of care options for our patients and improves survival and quality of life in a very meaningful fashion. Thank you very much for listening to the data of the 9ER trial. Now I will move on to the prostate cancer trial. The name of the trial in prostate cancer was the PROfound trial. I'd like to bring to your attention that this is the first-ever phase III or large randomized trial which was successful, which was positive, in the realm of metastatic or advanced prostate cancer, where patients were selected based on a biomarker. The biomarker in this context was mutation in the DNA repair gene inside the cancer cells. So truly, it was a very novel trial, with a novel design, and a really new idea in the field of prostate cancer. So in this trial, around 400 prostate cancer patients or patients with advanced prostate cancer, who were experiencing disease progression on novel hormonal therapy such as abiraterone or enzalutamide, and they could have received chemotherapy as well, were randomized to treatment with olaparib, a PARP inhibitor which targets those cells which harbor the DNA repair mutations or DNA repair gene mutations. So patients were randomized to treatment with either olaparib or the other novel hormonal therapy which they had not received before, which were enzalutamide or abiraterone. The patients were divided into 2 different cohorts. The first cohort had patients with BRCA1, BRCA2, and ATM gene mutations. The second cohort included patients with 12 other different types of mutations, also in the DNA repair gene. Again, what we saw was really striking. Treatment with olaparib resulted in delaying of disease progression as well as a significant increase in the overall survival. Overall survival was improved in these patients by almost 4 and half months on treatment with olaparib. If we look at the median overall survival in patients who did not get olaparib and who were on enzalutamide or abiraterone, the median overall survival was 14 and a half months. And that had improved by almost 5 months in patients who received olaparib. It basically translates into 30% reduction in risk of death. I would like to bring to your attention, is that almost two-thirds of patients on this trial who received abiraterone or enzalutamide were allowed to cross over to novel therapy with olaparib during the conduct of the trial when they had disease progression on enzalutamide or abiraterone. So when you factor in this crossover— because whenever you see crossover, it always leads to attenuation or a decrease or apparent diminution of the survival benefit. If you account for the crossover of those two-thirds patients from control arm to the olaparib arm, the median overall survival was even further improved with almost a 60% reduction in risk of death. The side effects with olaparib—  there are 2 main side effects which I would like to mention. One is nausea, and 1 is anemia, which really differentiated olaparib from the alternative enzalutamide or abiraterone. And these 2 side effects are easily manageable in the clinic. So based on these data, olaparib was approved by FDA and now is available in the clinic. I think the biggest challenge for us is to identify those patients who are candidates for treatment with olaparib. So any time a patient sees a doctor, a patient with advanced prostate cancer sees a doctor, it is extremely important that the discussion about genomic testing is brought up. Genomic testing of the tumor, genomic testing of the tumor tissue, as well as the circulating tumor DNA coming from the tumor, which is floating in the bloodstream, and referral to a germline testing clinic. Because many of these mutations are heritable and they can result in familial predisposition of other cancers. So, to summarize, PROfound trial in advanced prostate cancer patients for the first time showed that patients can be selected for a targeted therapy based on underlying mutation in the DNA repair gene in their prostate cancer cells. And if they have these mutations, they are candidates for treatment with olaparib. There's another drug which also got approved in a very similar setting in patients who have already received chemotherapy, is rucaparib. So there are 2 drugs now which are approved in this setting for the patients who are harboring these DNA repair gene-related mutations. So the final message which comes from the PROfound trial is a very important one. Every patient with advanced prostate cancer has to be tested for the presence of these mutations in their DNA repair genes in their tumors. And this mutation testing can be done by testing of the tumor tissue or by a simple blood test which looks at the circulating tumor DNA coming from the tumor tissue which is floating in the bloodstream. And of course, all patients need referral to a high-risk genetics clinic to be assessed for the hereditary component of these mutations to make sure they're not carrying these mutations in their germline DNA, which may potentially result in hereditary or inheritable nature of this mutation. Now I'd like to talk about the main trial which has already changed practice in patients with advanced or metastatic bladder cancer. The name of the trial is JAVELIN Bladder 100 trial. The earlier data was presented in the 2020 Annual Meeting of American Society of Clinical Oncology. And more data was presented in 2020 Annual Meeting of European Society for Medical Oncology. In the JAVELIN Bladder 100 trial, hundreds of patients with advanced or metastatic bladder cancer, who were receiving treatment with first-line chemotherapy with cisplatin or carboplatin and had received at least 4 to 6 cycles of these chemotherapies and did not have any evidence of disease progression, so they could be responding or they could have had stable disease - they had to have stable or responding disease - were randomized to treatment with avelumab versus best supportive care, meaning they were just watched carefully by the doctors, which is the current standard of care. So these patients who have stable disease or responsive disease after 4 to 6 cycles of platinum-based chemotherapy, they're watched carefully. So this was done in this trial for those patients who were on the best supportive care arm. And half of the patients received--in addition to periodic scans, they received treatment with an immunotherapy known as avelumab. Again, what we saw was really striking. The overall survival was clinically and significantly improved in patients who received avelumab. The improvement in overall survival with avelumab was approximately 7 months. So 14 months in patients who did not receive avelumab and 21 months in patients who received avelumab. This translates into 30% reduction in risk of death in those patients who received avelumab. Please note that the benefit with avelumab was present in every subset of patients in this trial. It didn't really matter where the disease was present, whether it was present in the viscera versus only lymph nodes, whether tumors were expressing a certain biomarker known as PD-L. Every group of patients responded to avelumab. The side effects of avelumab are not new to the patient and physician community. This drug has been approved in the later lines of bladder cancer treatment for almost 2 years now. Most of the side effects which happen are really easily manageable. And in less than 3 to 4% of patients, side effects can be more severe. We call them grade 3 and 4 side effects. And basically, they manifest as diarrhea, skin rash, liver function abnormalities. And for these reasons, patients who are receiving avelumab, they need to be followed by their oncologist at least on a monthly basis. Having said that, I think these data are wonderful news to our patients. In fact, we have never seen such magnitude of overall survival improvement in patients with advanced or metastatic bladder cancer in this setting ever. Thank you very much for listening to me regarding the data of the JAVELIN Bladder 100 trial. ASCO: Thank you, Dr. Agarwal. 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