2021 Research Round Up: Prostate, Bladder, Kidney, and Testicular Cancers

June 23, 2021
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In the Research Round Up series, members of the Cancer.Net Editorial Board discuss the most exciting and practice-changing research in their field and explain what it means for people with cancer. In today’s podcast, 4 Cancer.Net Specialty Editors discuss new research in prostate, bladder, kidney, and testicular cancers presented at the 2021 Genitourinary Cancers Symposium, and 2021 ASCO Annual Meeting.

This episode has been adapted from the recording of a live Cancer.Net webinar, held June 16th, 2021, and led by Dr. Neeraj Agarwal, Dr. Tian Zhang, Dr. Petros Grivas, and Dr. Timothy Gilligan.



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 the Research Round Up series, members of the Cancer.Net Editorial Board discuss the most exciting and practice-changing research in their field and explain what it means for people with cancer. In today’s podcast, 4 Cancer.Net Specialty Editors discuss new research in prostate, bladder, kidney, and testicular cancers presented at the 2021 Genitourinary Cancers Symposium, and 2021 ASCO Annual Meeting.

This episode has been adapted from the recording of a live Cancer.Net webinar, held June 16th, 2021, and led by Dr. Neeraj Agarwal, Dr. Tian Zhang, Dr. Petros Grivas, and Dr. Timothy Gilligan.

Dr. Agarwal directs the Genitourinary Oncology Program at the Huntsman Cancer Institute at the University of Utah.

Dr. Grivas is the clinical director of the Genitourinary Cancers Program at University of Washington Medicine. He is also an associate member of the clinical research division at the Fred Hutchinson Cancer Research Center.

Dr. Zhang is an associate professor of medicine at Duke University School of Medicine and is a medical oncologist at Duke Cancer Institute.

Dr. Gilligan is an Associate Professor and Medical Oncologist at the Cleveland Clinic Taussig Cancer Institute.

Full disclosures for Dr. Agarwal, Dr. Grivas, Dr. Zhang, and Dr. Gilligan are available at Cancer.Net.

Greg Guthrie: So today, let's introduce our participants. First we have Dr. Neeraj Agarwal of Huntsman Cancer Institute and University of Utah and the Cancer.Net Specialty Editor for Prostate Cancer. Next we have Dr. Petros Grivas from Fred Hutchinson Cancer Research Center and University of Washington. He is the Specialty Editor for Cancer.Net for Bladder Cancer.

Next we have Dr. Tian Zhang of Duke Cancer Institute. And she's our Cancer.Net Specialty Editor for Kidney Cancer. And last, we have Dr. Timothy Gilligan. He is with the Cleveland Clinical Taussig Cancer Institute and the Specialty Editor for Testicular Cancer. So to start off, we'll have Dr. Agarwal talking about prostate cancer.

Dr. Agarwal: Thank you, Greg. It's such a privilege and honor to be here discussing these studies. So I would like to start with the first study, which was led by Dr. Stephen Freedland, a urologist at the Cedars-Sinai Medical Center in Los Angeles and was co-authored by me, Dr. Dan George, and many others. And here in this study, we present the utilization of therapies, which are associated and known to be associated with very significant, in fact, I would say dramatic improvement in overall survival, as shown by multiple randomized control trials over the period of the last 5 to 6 years. Just to take a step back for the audience, until 2014, standard treatment for metastatic castration-sensitive prostate cancer or newly diagnosed metastatic castration-sensitive prostate cancer used to be androgen deprivation therapy. And combining androgen deprivation therapy with those medications which were approved in the castration-resistant metastatic prostate cancer setting. So basically, using those drugs upfront led to dramatic improvement in overall survival with 33% to 35% reduction in risk of death across those clinical trials. So we actually wanted to look at the real-world utilization, so look at the real-world users of these medications in these patients who are being diagnosed with -- newly diagnosed metastatic prostate cancer in the United States. We also wanted to see how patients who belong to minority populations or racial minority populations, how they are being treated with these medications, which are backed by level 1 evidence. So this was a retrospective analysis of a Medicare database, more than 35,000 patients were included from 2009 to 2018. And we can see here a very representative patient population, predominantly white patients, 11.8% were African American, and 5% were Hispanic.

And here are the results. From 2010 to 2014, the use of standard androgen deprivation therapy with bicalutamide, was used in 97% of patients. We did not have trials reporting by that. Let's go to 2015 to 2016. Docetaxel was already approved in this setting now, and we can see some patients received docetaxel, but a small minority of patients received docetaxel. And then let's move to 2018, which is 4 or 5 years after docetaxel data had been presented by Dr. Sweeney in the ASCO plenary session. And abirateron was approved in 2017, and we are still seeing even like almost 2 years after -- we are still seeing the vast majority of patients being treated with standard androgen deprivation therapy or standard deprivation therapy with bicalutamide. So 62% plus 19%, we are talking about almost 80% of patients still not being treated with standard of care treatment, which is androgen deprivation therapy plus docetaxel, or androgen deprivation therapy plus abiraterone at this point of time, and now we have 2 more drugs available, which include enzalutamide and apalutamide in this study.

Another interesting thing was if you look at the patients who belong to minority populations, so let's look at African American patients compared to Caucasian patients. The use of intensified therapy was numerically lower. So in Caucasian patients, we are seeing higher use of intensified, as we call them, intensified therapy, or therapies which are considered standard of care, compared to African American men. So overall, the use was lower across the board, but if you look at African American men, the usage was even lower. So this is definitely concerning. I call it alarming, underutilization of life-prolonging therapy in patients who are being diagnosed with newly -- or new diagnosis of metastatic prostate cancer, and we definitely can improve this. We can definitely offer better care to our patients. It is not acceptable in my view to have 30% or less patients receiving standard of care therapies. So with that, I'll go to the next study.

 Greg Guthrie: Great, thanks. And this study is, “Health-related quality of life and patient-reported outcomes at final analysis of the TITAN study of apalutamide versus placebo in patients with metastatic castration-sensitive prostate cancer receiving androgen-deprivation therapy.” And you were the presenting author of this, Dr. Agarwal?

Dr. Agarwal: Yes, Greg, thank you for giving the opportunity to present this study. And this is basically the continuation of the previous trial. I will not delve into in-depth analysis of these data. I just wanted to show that quality of life is not being impacted adversely by using intensified androgen deprivation therapy, so if you are using these drugs, which improves survival in a very significant fashion, and they are not being used in our patients, as we just saw in the previous study, what could be the reason? Is it the concerns about quality of life or adverse impact on quality of life? If that is the concern, this study, I think, helps refute those concerns. And in this study, which was a large study known as the TITAN trial, which led to approval of apalutamide for patients with hormone-sensitive or castration-sensitive metastatic prostate cancer and showed improved survival and radiographic progression-free and overall survival. We looked at quality of life data as reported by these patients, and these quality-of-life data were assessed by very standardized, validated scales known as FACT-P, or Functional Assessment of Cancer Therapy Prostate scale, or Brief Pain Inventory tool. And there are many other tools. So I will show you the results. And we can see here consistently there was no difference in quality of life as reported by the patients, or I would say any adverse impact on quality of life for these patients in any of these questions. As they were taking these questionnaires. So whether it was physical wellness, emotional wellness, functional well-being, social, or family, we go in and look at fatigue and there was no adverse impact on quality of life. At least from this perspective, we should not be concerned about using these drugs up front in our patients who have newly diagnosed metastatic prostate cancer.

 Greg Guthrie: Great. And so what does this mean for patients?

 Dr. Agarwal: From patient perspective, we can see here very clearly that using standardized tools, very validated tools, which have been used in multiple trials in the past, patients are not reporting any adverse impact on their quality of life when being treated with intensified androgen deprivation therapy. In this context, apalutamide.

Greg Guthrie: Great. Alright. So let's move on to our next study, which is, “Phase 3 study of lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer.” The VISION trial.

Dr. Agarwal: Thank you. In my view, this is 1 of the most important studies presented in the 2021 ASCO Annual Meeting. This study was a phase 3 study where 7,000 patients were recruited, and they had metastatic castration-resistant prostate cancer and had disease progression on a prior novel hormonal therapy such as enzalutamide or abiraterone and the patients had received a taxane chemotherapy. So at least 1 taxane chemotherapy was required before the trial, and the patient had to have disease progression on a novel hormone therapy. These patients were randomized in 2 to 1 fashion to a novel drug, which is a type of radiation, intravenous radiation, as I would explain to my patients, and this is known as beta radiation. And this is a novel radiotherapy where radiation particle, which is delivering beta radiation particle to the cancer cells, is tagged to a molecule, which binds with the prostate cancer cells. So I'm simplifying it for the sake of our patients. And this particle or this compound was added to standard of care therapy and patients were randomized to standard of care therapy versus standard of care therapy plus this new compound. And standard of care therapy was a novel hormonal therapy or anything which did not include chemotherapy or radium 223, which is another type of radiation particle, but a different kind of particle known as alpha particle. So in this study, radiographic progression-free survival and overall survival were primary endpoints. We can see here that the study met both primary endpoints. There was a significant improvement in radiographic progression-free survival with an almost 5 month, 5.4 months, to be precise, improvement in radiographic progression-free survival, with a 60% reduction in risk of disease progression or death. If you look at overall survival, it was also improved in a significant fashion in patients who received the new compound known as lutetium-PSMA-617, and the median survival was improved by 4 months with an approximately 40% reduction in risk of death.  This was a well-tolerated drug overall, and if you look at hybrid side effects, treatment, and emergent side effects, there were 52.7% of patients in the experimental arm, and 38% in the control arm had those treatment-related side effects. So overall, Wwell-tolerated regimen with improved overall survival and radiographic progression. Thank you very much.

Greg Guthrie: Thank you, Dr. Agarwal. This is really interesting, and it will be interesting to see if this treatment does change standard of care based on this research. Let's move on to Dr. Grivas and bladder cancer research. Let's see, so Dr. Grivas, your first study is, “Avelumab first-line maintenance for advanced urothelial carcinoma: analysis of clinical and genomic subgroups from the JAVELIN Bladder 100 trial.” And Dr. Grivas was a co-principal investigator in this trial and is senior author of the New England Journal of Medicine publication and co-author of this abstract. Go ahead, Dr. Grivas.

 Dr. Grivas: Thank you so much, Greg, and thank you to Cancer.Net for the opportunity, and thanks to the audience. We welcome questions. I would like to update the audience today about the data we saw at the ASCO meeting, and I would like to place this data in context, and I would remind the audience the JAVELIN Bladder 100 trial that changed clinical practice was initially presented last year at the ASCO Virtual Meeting 2020 by Professor Powles. And this particular trial tried to answer the following question: does the immunotherapy, especially the PD-L1 inhibitor avelumab, add value in patients who completed chemotherapy in the first-line setting of metastatic urothelial cancer compared to just best supportive care in terms of longer life, in terms of overall survival, and time until the cancer grows or death, progression-free survival? This is important because until this study came about last year, the practice was, in the setting of spread metastatic urothelial cancer, when the chemotherapy stops, was we cannot give it for a long time because of potential side effects. Usually you used to wait until the cancer grows back, it progresses, or grows. So this trial compared this approach, the best supportive care, versus the immunotherapy with avelumab and the best supportive care. This particular trial, so the significant improvement of life expectancy and overall survival as well as progression-free survival, time until progression of the cancer or death, in the patients that received this immunotherapy drug avelumab as a way to maintain or sustain the benefit that is seen with chemotherapy. So we call this a maintenance therapy approach because we tried to maintain or sustain the benefit with chemotherapy. I want to highlight that this was published in the New England Journal of Medicine and the audience can retrieve that from PubMed if one wants to read the manuscript. The bottom line is this trial changed practice, and we can go now to updates. We saw this in this particular meeting, ASCO 2021, and I think the main question was, are there any particular subsets of patients, different categories of patients, who benefit more from the avelumab maintenance approach, or does this benefit all the patients? And we saw at the ASCO meeting, we saw that the benefit with this immunotherapy appears consistent across the board, across different subcategories of groups of patients. And I think that it's important to point out that we looked at patients who had what we call local disease around the bladder, that was invading this area, and the pelvic side wall that was not amenable to surgical rejection and also patients with spread of the cancer in distant sites, what we call metastasis. And we look at patients who had a primary origin in the bladder or higher up in the urinary tract, what we call kidney pelvis, or ureter, and we call this upper urinary tract, versus the lower tract, which is the bladder, and we also look at patients who had metastatic spread in the lymph nodes only or other parts of the body. And with the bottom line, we saw that the benefit with the immunotherapy was consistent across the different groups of patients. So many patients benefit from this treatment, again, with variable degrees, variable magnitude of benefit, but overall, the bottom line is, take home message is if you have clinical factors or other molecular factors, we do not have a reliable, accurate tool to select which patients should go with avelumab, so we offer it nowadays in every patient who has no contraindication to get immunotherapy and has received some disease control. Meaning a response of the cancer or stabilization of the cancer with the chemotherapy phase. So that has real clinical implications, and I encourage the audience to discuss with their oncologist about the optimal roles of immunotherapy with this maintenance setting after chemotherapy when this is controlled with chemotherapy.

Just for context here, I want to highlight the options the patients have in clinical practice. And when someone is diagnosed with spread urothelial cancer, they can be offered nowadays avelumab as a maintenance strategy to maintain the benefit of chemotherapy, and the other options include immunotherapy up front, like drugs like pembrolizumab or atezolizumab, and I will come back to that question how to select your treatment in my last slide. And I want to point out these are the options, and obviously clinical trials are always a great option for patients, and they should ask their oncologist about those options. So since I talked about immunotherapy, I want to point out that the ideal chemotherapy is cisplatin-based chemotherapy. Not everybody has enough fitness of the body to tolerate cisplatin. For those patients, we think cisplatin may be too much, we use carboplatin/gemcitabine, and we use avelumab maintenance in that scenario. What about immunotherapy after that? Is there data supporting that use? And the answer is yes. There is some data suggesting that immunotherapy can be an option for some of the patients, and in this particular slide, we update the data from another clinical trial. And I will let Greg, you can read the title of that.

Greg Guthrie: Sure, so this study is, “First-line pembrolizumab in cisplatin-ineligible patients with advanced urothelial cancers response and survival results up to 5 years from the KEYNOTE-052 phase 2 study.” Dr. Grivas, you're a co-author on this study.

Dr. Grivas: That’s right, thank you, Greg. This trial presented longer follow up to see what happened in patients who received the immune checkpoint inhibitor anti-PD called pembrolizumab because they were not fit enough to get cisplatin chemotherapy. Keep in mind this was designed before the previous study I showed you presented the results and included patients who were not fit for cisplatin, but some of them could have been fit for carboplatin. There was no comparison here, everybody received pembrolizumab as a single agent, alone, and in this particular study, we would try to see the degree of shrinkage of the cancer and the overall response rate as well as how long people lived over time. So with longer follow-up, by the way, we published this study in the Lancet Oncology years ago, and we have longer follow-up, and what you see here is a degree of shrinkage of the cancer, what we call overall response rate, was about 29% in what we call all comers, and it was higher size of tumor shrinkage in patients with high PD-L1 expression. PD-L1 is this brake of the immune system, the checkpoint of the immune system and highly expressive measured by particular assay that pembrolizumab works better in those patients. However, some patients even with low PD-L1 measured by this CPS score I put in the slide still might have benefits, so the take-home message here is there is a particular proportion of patients who can benefit from the checkpoint inhibitor pembrolizumab. PD-L1 can be used in that setting to help decide between chemotherapy and immunotherapy. However, we have not compared directly the chemotherapy followed by the available maintenance with immunotherapy up front, so this question is still lingering. However, if the patient has a response shrinkage to pembrolizumab, many of those patients may have a long-lasting response. We tried to figure out with research how can we predict who is going to benefit more from this treatment as a matter of ongoing research.

Greg Guthrie: Dr. Grivas, can you really quickly define CPS for our audience?

Dr. Grivas: Absolutely. Great question. CPS is a tool we use in the pathology labs to measure the PD-L1 expression. It can be measured by different assessing antibodies, and the pathologists use a score to define if the PD-L1 is high or low. In this particular study, CPS of 10 or higher defines PD-L1 high expression, CPS below 10 defines PD-L1 low expression, and this appears to have some association with a chance of the tumor shrinking with immunotherapy with pembrolizumab.

Greg Guthrie: Great. Thanks, Dr. Grivas. So our last study is, “Pembrolizumab versus investigator's choice of paclitaxel, docetaxel, or vinflunine in recurrent, advanced urothelial cancer: 5-year follow-up from the phase 3 KEYNOTE-045 trial.”

Dr. Grivas Very quickly, this study compared immunotherapy, pembrolizumab, the anti-PDL1, compared to chemotherapy with paclitaxel, docetaxel, or vinflunine, the latter one is in Europe, after progression of cancer growth on platinum-based chemotherapy. This was published in the New England Journal of Medicine a few years ago, and pembrolizumab prolonged survival, people lived longer compared to the chemotherapy. And this longer follow-up presented by Dr. Bellmunt and colleagues, showed the sustained results with follow-up, this population of patients had already received cisplatin-based chemotherapy and the cancer progressed, growth, despite that chemo, and in those patients, pembrolizumab appears to produce better results compared to this salvage chemotherapy shown in that slide. And this has implications because immunotherapy can be used in those patients after progression on platinum-based chemotherapy.

And just to wrap up here the discussion, I just want to give the options to the patients, see if someone has a new urothelial cancer, options include cisplatin/gemcitabine, or if someone is not fit enough for cisplatin, carboplatin/gemcitabine, and both of those scenarios can be followed by avelumab, and those with shrinking or stable disease, patients who have progression on platinum-based chemotherapy can get pembrolizumab and of course other options available. We can go into another podcast, and I encourage the audience to look and discuss with their oncologist about those options, and the take home message, the clinical trials is what got us here, and I recommend clinical trials to be discussed with your oncologist. Thank you so much, and I'll be happy to take questions.

 Greg Guthrie: Thanks, Dr. Grivas. So we're going to move on to Dr. Zhang, who is going to talk about kidney cancer. So our first study today is, “Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for patients with renal cell carcinoma: a randomized, double-blind, phase III KEYNOTE-564 study.”

Dr. Zhang: Thanks, Greg. I'm really excited to be here today and thanks, everyone, for joining. KEYNOTE-564 was presented at the ASCO plenary by our colleague Dr. Toni K. Choueiri, and this is a highly anticipated study in the adjuvant space for kidney cancer and enrolled patients with high-risk clear cell kidney cancer who had undergone either nephrectomy or a metastastectomy, removing their few sites of metastatic disease and treating those patients with either pembrolizumab for up to a year or placebo. And the endpoint was disease-free survival, and enough events had occurred by this ASCO for us to see the primary results. So the overall -- the study was positive. For the primary endpoint, disease-free survival improvement was met with a hazard ratio of 0.68 and the estimated disease-free survival rate at 2 years was 77% for patients treated with pembrolizumab versus 68% for patients treated with placebo. The overall survival favored pembrolizumab, but it was not yet statistically significant, and follow-up will be needed. Overall, we see an improvement in disease-free survival delaying time until recurrence for patients treated with pembrolizumab, and this was the first study in this adjuvant space showing checkpoint inhibition has a role in adjuvant treatment of renal cell carcinoma.

 Greg Guthrie: Thanks, Dr. Zhang. Our next study is, “Pembrolizumab plus axitinib versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma: results from 42-month follow-up of KEYNOTE-426.”

Dr. Zhang: This study, KEYNOTE-426, we are all very familiar with. Pembrolizumab and axitinib has been used for the last 2 years in the first-line treatment of clear cell metastatic kidney cell cancer, and it's a longer-term follow-up, more events and more understanding of what happens to these patients once they're treated in a longer term, so primary endpoints of course of this phase 3 study were progression-free survival and overall survival. When we're looking at this medium duration of follow-up at 42 months, so about 3 and a half years, pembrolizumab and axitinib improved both median overall survival as well as median progression-free survival. We'd point out that the -- at the 3 and a half year mark, the overall survival rate for patients treated with the combination was about 57.5%. And the progression-free survival rate was about 25%, so about a third of patients had not had progression of disease at 3 and a half years. Which is quite meaningful if they can stay on their first-line treatment for that long. The objective response was 60%, and of note, the complete response rate had been updated to about 10%. So there are some patients that do have delayed complete responses. And no new safety signals were observed. So overall, certainly still provides a lot of evidence to treat with pembrolizumab and axitinib for patients in the front-line setting.

Greg Guthrie: Great. And our last study here is, “Health-related quality of life analysis from the phase 3 CLEAR trial of lenvatinib plus pembrolizumab or everolimus versus sunitinib for patients with advanced renal cell carcinoma.”

Dr. Zhang: This was the phase III trial in first-line treatment of metastatic clear cell kidney cancer that was reported at GU ASCO in February of 2020, and it was a 3-arm randomization to lenvatinib with everolimus in the standard study, and lenvatinib with pembrolizumab or sunitinib alone, and we saw the efficacy data in February, and here we're seeing the quality of life outcomes, and looking at how patients are doing, patient-reported outcomes on these treatments. And so with multiple quality of life measures, we're seeing improvements in patients that had better disease-related scores of symptoms when treated with lenvatinib and pembrolizumab versus sunitinib. We're seeing pain scores improve and patients having less diarrhea, appetite loss, when we're comparing against sunitinib. Of note, it's hard to specifically tie a particular symptom, if that's improved, because they've had better disease control or if it's more from the treatment side effect itself. So still hard to tease out a causality in these quality of life measures, but overall, improvement in patients' quality of life when treated with lenvatinib and pembrolizumab. And certainly provides some more data for patients receiving this combination.

And so I just wanted to highlight our ongoing phase 3 combination trials and first-line metastatic kidney cancer. PIVOT-09 with bempegaldesleukin has completed accrual in the first triplet of COSMIC-313 with ipilimumab, nivolumab and cabozantinib has completed accrual, so the actively enrolling studies currently are PEDIGREE and PROBE. These are studies that are being carried out in the cancer cooperative groups, as well as a triplet belzutifan lenvatinib with pembrolizumab, a study that Merck is running and all 3 very important studies we will continue to learn from and answer some important, clinically relevant sequencing treatment discontinuation, nephrectomy side effect questions. Thanks to everybody.

Greg Guthrie: We have 1 more. So, “Clinical activity of durvalumab and savolitinib in MET-driven, metastatic papillary renal cancer.”

Dr. Zhang: Dr. Rodriguez from Spain presented this of papillary renal cell carcinoma treated with savolitinib and durvalumab, and specifically looked at the MET-driven subset of 14 patients out of these 42 patients. The efficacy primary end point was objective response rate. And of note, and median progression-free survival for the 42 patients who were all treated, it was 4.9 months and in MET-driven disease, so savolitinib targets MET, so MET-driven disease was 10.5 months and the median overall survival in everyone was 14 months, versus MET-driven was 27 months, and also higher response rates for patients with MET-driven disease. So I think personally, hypothesis generating, we will likely be seeing more trials with durvalumab and savolitinib in MET-driven papillary renal cell carcinoma.

Greg Guthrie: Thank you, again, Dr. Zhang. And Dr. Gilligan, we're going to talk about some testicular cancer research now, and the first study is, “Testicular cancer in the cisplatin era: causes of death and mortality rates in a population-based cohort.”

Dr. Gilligan: So this study was looking at what happens with testicular cancer patients who are cured of their cancer, are they at risk of dying of other causes? They looked at over 5,000 men treated between 1980 and 2009, so it's important to recognize that some of the treatments given back then are a little different than the way they're given now. And it looked at the risk of death from causes other than testis cancer compared to men without testicular cancer in the general population, and the concerning finding from this study, and it's not the first study to report this, was that the risk of non-testicular cancer death, that is, death from other causes, was increased by about 28% in men who had been treated with radiation therapy and about 23% in men treated with chemotherapy. There's a risk of non-testicular cancer death, the risk, excuse me, was doubled in those whose treatment included both. So it was higher with either radiation or chemo and it was actually 100% higher or double than both those who had chemotherapy and radiation. As you got more chemotherapy, the risk went up. There was no trend towards the increase with just 1 or 2 cycles. We started to see the increase with 3 cycles, and it became statistically significant with 4 cycles. But there wasn't much difference between 3 and 4 in terms of the absolute number that was seen. In terms of death from other cancers, so why is this happening? Other cancers are a major issue after chemotherapy or radiation. Again, the risk was increased 60% after radiation therapy and 43% after chemotherapy, and those who got both, the risk of cancer was 3 times higher than the general population. So that's in men who had chemotherapy plus radiation therapy. Fortunately, there are not a lot of men who get both of those treatments anymore. Non-cancer deaths increased 17% after chemo and 55% of treatment included both. So the risk for non-cancer deaths was not as high as the risk for death from secondary malignancies. Interestingly, the risk of suicide increased 63% in men treated with chemotherapy. That's not affecting as many men as those other numbers, even though 63% number looks high, but it is a concern. Those treated only with surgery did not have an increased risk of non-testicular cancer death. What does this mean for patients? It really means when we can use surgical treatments instead of chemotherapy or radiation as an additional incentive to try do that, and what that may mean is there should be a larger role for retroperitoneal lymph node dissection as an alternative to chemotherapy or radiation therapy. Secondly, for patients getting chemotherapy, it's important to minimize the number of cycles of chemo as long as we're not sacrificing long-term cure rates, because the biggest risk of death is dying from the cancer, but that means limiting to the 3 cycles instead of 4 cycles is probably a good idea, and I think it's an argument to use 3 cycles of BPE instead of 4 cycles of EP because it’s really the etoposide and the cisplatin that is linked to the secondary cancer risk, not the bleomycin, as far as we know. And then lastly, we need to pay attention to the mental health needs of men treated with chemotherapy. That there is more emotional distress and we’re seeing here a higher risk of suicide.

 Greg Guthrie: So our second trial is the, “SEMS trial: result of a prospective multi-institutional phase 2 clinical trial of surgery in early metastatic seminoma.”

Dr. Gilligan: So if we're going to use more retroperitoneal dissection and less chemotherapy or radiation, 1 place to do that is in stage 1 and stage 2 seminoma, and many centers around the country have started doing that, and this was a trial that looked at that approach. So these are men who normally would be treated with chemotherapy, 3 cycles of BEP, or radiation therapy to the back of the abdomen and part of the pelvis potentially. This study looked at the small number of patients, 55 men, low volume, stage 2 seminoma up to 3 centimeters of size and maximum dimension. And what they reported of those men undergoing retroperitoneal lymph node dissection, 10 relapsed, so 18% relapsed after median follow-up of 24 months, they were all alive at the end of the study. No deaths. 8 of 10 relapses were treated with chemotherapy, and 2 were treated with additional [surgery]. Out of the 55 men, 8 ended up getting chemotherapy. Normally, all of them would have gotten either chemo or radiation. Relapse-free survival was 87%, overall survival was 100%.

Seven (7) patients developed complications after RPLND and 5 of them were mild. Two (2) were more severe. So it’s a well-tolerated treatment, if it's done at a large volume center, it's worth noting that the centers participating in the study were large volume centers. Again, if not treated with RPLND, all of these men would have gotten chemo or radiation. The relapse rate after chemotherapy or radiation is about 5%. So the relapse risk is higher after surgery, but in the sense, if we take 100 men with early stage 2 seminoma and do an RPLND instead of chemo or radiation, we can spare 80% of them the long-term effects of chemotherapy or radiation. Alternatively, if the priority is simply to prevent a relapse, radiation therapy and chemotherapy are more effective at that, the relapse risk being 5% but at the cost of long-term side effects from chemotherapy or radiation. Bottom line there is an additional treatment option for low volume stage 2 seminoma for men who prioritize avoiding the complications of chemotherapy or radiation therapy. Both of which are associated with an increased risk of death from other causes. The price we pay for that is the relapse risk is higher with RPLND compared to the other approaches. Not all centers are going to be offering this, but major centers that do a lot of testicular cancer, this is becoming a new treatment option. With the caveat that we have less experience with this approach. This is a relatively small study. And we have a lot more experience with chemotherapy or radiation. I don't think there's a one size fits all here, but I think patients should talk about it with their doctor. If they have early-stage seminoma, they should talk about surgery as an alternative to radiation or chemo.

Greg Guthrie: Here we go. “Surveillance after complete response in patients with metastatic non-seminomatous germ-cell tumor.”

Dr. Gilligan: So this study is looking at the question, if you take a man who has retroperitoneal lymph nodes that are enlarged and metastatic non-seminomatous testis cancer with lymphadenopathy in the back of the abdomen and you put them through chemotherapy and at the end, all retroperitoneal nodes are now within normal limits, normal size nodes, and no bigger than 10 millimeters or 1 centimeter, do we need to do a retroperitoneal lymph node dissection on those patients? Some centers recommend it and some don't. This looked at 388 men in that situation. They were put on surveillance. These men did not undergo the post-chemo RPLND. Two years survival, overall survival was 97.8%. Two-year progression-free survival was at 90%, 34 patients relapsed, and 10 of the men died. Men who did relapse had surgery, chemotherapy, or both as subsequent treatment. There's a prior similar study that was multicenter that had longer follow-up of 5 years, and they reported of ;161 men who had a complete response to the first-line chemo, 10 relapsed (that’s 6%) and none died. If we combine these 2 studies together, the bottom line is you would have to perform a post-chemotherapy retroperitoneal dissection, which is a big operation, on about 550 men to prevent potentially at most 44 relapses and 10 deaths. We don't know if we would prevent or how many of those relapses and deaths we would prevent. But there's a lot of operations with a relatively low yield. In the future, we hope to have blood tests that will tell us which men need surgery. And even right now, we're close to the point that we have blood tests that will detect residual cancer. And the chance is we worry about residual cancer in these patients and we don't have the blood test to pick it up. But the bottom line is in the meantime, the preferred management strategy is surveillance rather than surgery for most men. There's some men for whom RPLND may make sense in the center in this setting and some centers that will probably continue to recommend it for most men. I think this data really casts doubt on whether we ought to be doing this operation in these men as a routine practice as opposed to an exceptional practice for men who have particular characteristics. Thank you.

Greg Guthrie: Thank you, Dr. Gilligan. And now we can move on to answering some questions.

What is the average time expected to see a decline in PSA in patients treated with lutetium-177 PSMA?

Dr. Agarwal: I think this a great question and I think we're waiting for the manuscript published to go through the nuances of those data. Right now, what Dr. Michael Morris from Memorial Sloane-Kettering presented were the high-level data on pre-survival and overall survival and some secondary endpoints. We are anxiously waiting the full data in the form of a manuscript. And until then, I will not be able to answer that question. I would like to add that usually the median time, if you look at how -- for how long patients were receiving lutetium, it was 5 to 6 months. If I -- if my recollection is correct.

Greg Guthrie: Is radiation required prior to initiating chemo if there's tumor presence? And Dr. Gilligan, you responded. “We rarely use radiation therapy for testicular cancer at this time. Sometimes it is used for stage 1 or stage 2 seminoma as primary treatment instead of chemotherapy.”

And I'll just read these aloud for our viewers here. If a patient has both prostate and bladder cancer, how do you decide which therapy should take priority, also, is the CPS typically included on the biopsy report? And Dr. Grivas, you responded, which I'll read here. “This is a bit of a complicated scenario that requires detailed discussion with a urologist and medical oncologist. Regarding CPS, the possible role is only in the first-line setting of metastatic disease to help somewhat decide between chemotherapy followed by avelumab maintenance and immunotherapy. However, it's not a perfect biomarker and not part of the pathology report, it's a special test that requires specific ordering.”

I have a question for you, Dr. Zhang. Why do combination treatments seem to work better in kidney cancer? Wouldn't you have more side effects because you're taking 2 drugs at the same time?

Dr. Zhang: It's an interesting question. You know, our immunotherapy backbones seem to have good treatment benefit for these immune responsive diseases. The VEGF inhibitors that blocked blood vessel formation for many of our patients with clear cell kidney cancer, they tend to have an immunomodulatory role, so if we normalize blood vessels in the tumor microenvironment, the thought is that the T cells and immune cells can actually get into that space more readily. And so many of these blood vessel blockers are hypothesized to have increased immunomodulatory times of behaviors and the combination actually can be more effective than either agent alone, and we've certainly seen that in practice and really excited to see these combination strategies thrive and be standard of care for our patients now and first-line treatment. For the side effect question, you know, I do think that sometimes we do have to tease out which of the side effects is related to the oral treatment, the blood vessel blocker versus the immune therapy. But it's often experienced oncologists who are able to manage these side effects. We can try to tailor and see which of the side effects is due to which treatment and how to reduce or hold treatments when necessary.

Greg Guthrie: Great. I just got a follow-up question for you, Dr. Zhang. Are there any studies for papillary type kidney cancer with sarcoma?

Dr. Zhang: I would assume you're asking about sarcomatoid renal cell carcinoma within papillary, so for papillary type of kidney cancers, there are ongoing studies. For example, with FH mutations and FMH loss. For sarcomatoid disease, this is a special type of histology that can occur with any of our actual histologies of kidney cancer. And we know from our phase 3 trials in clear cell sarcomatoid renal cells that these tend to respond to the immunotherapy combinations. And so I would urge using an immune therapy combination in patients who had sarcomatoid renal cell carcinoma.

Greg Guthrie: Dr. Agarwal, here is a question for you. There were several studies in here that showed many patients did not receive combination ADT with other novel therapies, which you describe as the standard of care, including the one you discussed. Is this something that patients should proactively bring up with their doctors?

Dr. Agarwal: Fantastic question. I'm so glad you asked. The answer is yes: It is our responsibility as physicians and providers, but it doesn't hurt if our patients are educated and challenge us in our decision-making. It is a shared decision-making, it is not the doctor's decision. In my view, it's the patient's decision with help from the doctors. So, yes, please go do it. Doctors usually welcome that.

Greg Guthrie: Great.

Dr. Grivas: I see one for Dr. Gilligan about surveillance imaging that just popped up. [Is there any data on the benefits vs. risks for imaging based surveillance (CT, MRI, none) for longer-term follow-up periods (e.g. 2+ years)?]

Dr. Gilligan: Yeah, they're asking whether there's data on benefit versus risk for imaging-based surveillance and it's actually a very timely question in the sense that we're starting to get data that MRI is very accurate for this. And may likely become a substitute for CT scans at some point in the future. This is something we talk about a lot in terms of surveillance for testicular cancer patients, can we switch to MRI from CT because CT has ionization that can cause other cancers, and MRI does not. The good news is it looks like with current CT scanning, which is lower dose than older CT scanning, the risk of cancer from the CT scan seems really miniscule. Ultimately, it would be great to get it down to 0 and not do them, but we're still doing them. The switch to MRI is being held up by the fact that when you go in and get an imaging study for surveillance, your scans get looked at by a radiologist and also by the oncologist and all of us who do a lot of testicular cancer have multiple stories of catching stuff that the radiologist missed, and they also catch stuff that we miss. It goes both directions, and we're having 2 different people read the films to get a more accurate read. With MRI, most oncologists are not competent to read an MRI well and some radiologists are not great, and the centers where they have excellence have shown that MRIs are just as good as CT scans if read by fully qualified people. And the concern is: are they going to be skillfully read? So the switch to MRI will happen in the future, and I have spoken with people very recently about this that are practicing around the country and the people I talked to were not ready to make the switch because of the concern that stuff might get missed. And I think we can be reassured with the modern lower-dose CT scans, the risk seems to be quite small, and I look forward in the future to making that switch at some point.

 Greg Guthrie: And I think that's going to be our last question this afternoon. Thank you to all our participants for sharing this great research with us, as well as your expertise, it’s been a real pleasure on this live webinar here.

ASCO: Thank you Dr. Agarwal, Dr. Grivas, Dr. Zhang, and Dr. Gilligan.  You can find more research from recent scientific meetings at www.cancer.net. And if this podcast was useful, please take a minute to subscribe, rate, and review the show wherever you listen to podcasts.

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