The Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute presents a succinct summary of all the genitourinary cancer clinical updates you need to know from ESMO 2022
Thank you everyone for attending tonight. Um today we'll be discussing the highlights pertaining to geo oncology. From Esma 2022 focusing on prostate then kidney, bladder and testicular cancer. Today will be starting with prostate cancer which I'll be discussing with comments and questions from Dr. Sweeney after the presentation. These are disclosures. So I'm gonna be covering four broad topics tonight. Um And the data that was presented for each of these um The first and probably one the single area will be spending most time on is what is the role of androgen deprivation therapy in patients receiving radiation in the post RP setting. Um uh One trial in the biochemical recurrence space. A few updates in the metastatic hormone sensitive space and then a few M. C. RPc updates as an overview. Um Very little in the way of sort of clearly practice changing data but I think some practice informing and and some interesting results that that are worth discussing. So starting with the role of A. D. T. For radiation. Um This was an oral presentation. The radicals HD trial um That was presented by DR Clark really. Um You know this is a background slide but essentially the question that this study was trying to address is in patients who've undergone radical prostatectomy and our plan to undergo radiation either in the agreement setting or in the salvage setting for rising P. S. A. What is the role of adding androgen deprivation therapy Or is there a role for adding androgen deprivation therapy and if so what's the appropriate or optimal duration. These are the eligibility criteria really. They were quite broad essentially. As mentioned patients undergoing radiation after radical prostatectomy. And the trial design was a little complicated. I'm gonna just show this briefly because it does affect the comparisons in the trial that were performed initially. Um a randomization, three way randomization from radiation alone with no A. D. T. To a short course of androgen deprivation therapy of six months versus a long course of 24 months was planned. Um But due to um the sort of practicality of enrolling to this trial they ended up splitting out to a two way randomization. Um And so you can essentially think of these results as to clinical trials one studying randomization to know hormone therapy versus six months and one trial comparing six months of hormone therapy to 24 Four months. So asking two slightly different questions and um you can see that some patients about 500 underwent three way randomization but really the bulk of patients underwent randomization is part of these 22 way randomization trials. And as a result the results from this presentation focused separately on those two um questions. These are the patient characteristics for the two studies and and I'll highlight that um Looking at some of these high risk criteria. T three T. Four disease at least 10 positive margins really does seem to be um more prevalent in this in this randomization of short course sources long course A. D. T. And that makes sense as clinicians. Um You know with these high risk patients the question of duration of A. D. T. Not whether or not they need it um Makes sense. So moving on to some of the results. This is the results for the patients that were randomized to know A. D. T. With radiation versus six months of A. D. T. Versus radiation. The four outcomes studied were metastases free survival time from freedom from distant metastasis. Um Time to salvage hormone therapy and overall survival. And you can see that of these outcomes patients did very well for all of them over with 10 years of follow up. And the only one where we saw a significant improvement um was in time to salvage hormone therapy with the hazard ratio of 10.54. For the addition of six months of A. T. T. To versus no A. T. T. And there was no discernible improvement in metastases re survival or overall survival in this population with the six months of A. D. T. And that was consistent across subgroups. However when in the randomization between six months of A. T. T. Vs. 24 months of A. D. T. There was a significant improvement in a task. This free survival with about with 10 years of follow up there was a 23% reduction in the rate um metastases free in metastatic events. Um Improvement from 78% 72 for 72% to 78%. Um Overall survival uh showed a trend about uh has a ratio of .88 towards improvement with long course hormone therapy. However there were relatively few events and as a result this has not reached physical significance. But um as you can see I think we're waiting for longer follow up and longer um and and more events to see how this plays out. But um dr Sweeney can come in more on this during the discussion. But uh you know, metastases free survival is a well established surrogate for overall survival. And the the magnitude of improvement of metastases free survival correlates well with the overall survival that would be expected. And so I think we're eager to sort of see this play out with further data. There is no difference in the subgroups analyzed and I include this which I'll touch on very briefly. Very few patients were um were randomized to the three way randomization of um no A. D. T. Vs. Long course of A. D. T. And um we didn't see any difference in in metastases free survival for that comparison. But this was small numbers and I think it's hard to interpret um with when considering toxicity there was really no difference in zero versus six months of A. T. T. There was um a higher rate of grade three adverse events with long course versus short course of A. D. T. Before talking about conclusions from this trial, I'm gonna mention the dad sport meta analysis. Um The this was a meta analysis that sought to essentially look at the same question but but by combining results from several studies with um the list of studies included shown here for overall survival when looking at six months versus no A. T. T. There was in 24 months versus no A. T. T. There was no significant difference. However when um they combine the results of the radicals trial with the N. R. G. R. T. R. G. Studies they did see a significant improvement in five year metastases free survival with the addition of six months of A. D. T. Compared to zero to know A. T. T. This was about a 2% absolute improvement in in the tests free survival. So here's the summary of results. I'm not gonna go through it for the sake of time but but here for you to to sort of as a summary. Um And I think you know conclusions are that you know I think we all wish that this data was a little cleaner and gave us some more clearer answers. Um We can discuss with Dr Sweeney a little bit more at the end of this prostate session. But I think it's pretty clear I feel convinced that that there's a subgroup of patients some patients are going to benefit from A. T. T. And and the data suggests that for patients with higher risk features T. Three Before disease gleason 8-10 positive margins that longer course of hormone therapy may um improvement that metastases survival compared to short course. But I think we need better biomarkers and really um considering the patient's disease characteristics, age comorbidities and preference is gonna be really important in terms of um informed decision making around this question for patients in clinic moving on to biochemical recurrence. The presto trial was presented by rahul Agarwal. This was a study looking at patients with biochemical recurrence defined by P. S. A. Is greater than 0.5 and a short doubling time less than nine months. With negative conventional scans. And these patients were randomized to A. T. T. Alone, 80 T. Plus Apple Hmeid and 80 plus Apple Hmeid and abiraterone. Um With a primary outcome being P. S. A progression free survival. I'm not gonna spend a lot of time on this study because I don't think it was terribly practice changing or was practice changing? Um The P. S. A. P. F. S. Uh Events for the P. S. A progression free survival was significantly improved with the addition of Apple Hmeid and Apple ID plus abiraterone relative to a. D. T. Alone. Um As you can see with the plot here the absolute value is about a four month improvement in P. S. A progression free survival. And so um you know I think clearly was a positive trial in the sense of how the trial was designed. But we know that P. S. A. PFS. Doesn't necessarily predict long term um benefit for patients in in in a way that we may define is clinically meaningful. Um And and as we will talk about in other studies and and we've seen kind of over and over is the addition of the combination of Abba Abby and Apa did not improve upon aPA alone. Um And then I think it's important to consider that this is a shrinking clinical space due to PSM A pet scans. And and these patients being um found to have potentially recurring or distant disease on on pet scans that we are treating differently. Um And and certainly can discuss that with dr Sweeney at the end in terms of how we're thinking about that disease day. But I think um takeaways from this study is is that it's um positive but but probably not going to change practice for metastatic hormone sensitive prostate cancer. Um There were two or one trial from stampede and then one analysis of peace, one that I'm gonna touch on the stampede study presented by Dr Richard asked the question of essentially is uh abiraterone plus it was a it was a meta analysis of two studies asking is abiraterone plus absolute um I'd better than abiraterone when added to standard of care which was A. D. T. With or without dose of Paxil in the metastatic hormone sensitive space. The these are the metastases free survival curves for abiraterone alone in this setting. And abiraterone plus N solidified. You can see the curves look very similar and when they looked for a treatment effect between her interest between trial heterogeneity, there is no evidence that that Abby Enzo was better than Abby alone. Overall survival was essentially the same story. However. Um there was a significant increase in the adverse event profile and so pretty clearly sort of like I mentioned with the presto trial and and like we saw with the stampede radiation trial really. Um Enza should not be added to Abby for for metastatic hormone sensitive, it only adds toxicity without any clear increase in efficacy. The Peace one study. And and so I would say practice informing. Um But but I don't think a lot of us were doing that in the first place so probably won't change practice. This is a analysis of the value the prognostic value of eight month P. S. A. From the piece one study again, Peace One randomized patients from uh to um 80 T. Um with or without those attacks and then randomized to the addition of abiraterone um or placebo. And what they saw this is a very high level. Um But but what they saw is that essentially for the P. S. A. Cut offs of 0.2. So looking at outcomes for patients um with PS A nadir at eight months less than 80.2 versus greater than 0.2. Um This was highly prognostic and it was really prognostic across treatment groups whether people received A. T. T. Uh This attack cell with or without abiraterone that P. S. A. Value is really prognostic. And so and and and in the bottom right panel you can see that they did this analysis using a P. S. A. Cut off of four and again highly prognostic whether your PSN NATO was above or below that. But it doesn't seem to be terribly predictive. If you look at each of those four quadrants the curves look pretty similar whether or not they received abiraterone or not. So I think um when thinking about how this informs practice really I would say that the eight month P. S. A. Seems to be highly prognostic to provide information about how the patient is going to do long term a few updates in the M. C. R. P. C. Space. Um I'm gonna start with the capacity or capacity trial. Um Which actually I think is the only clear practice changing trial potentially in this whole asthma in the prostate cancer space. This is an interesting study where it analyzed uh uh different regimen of administering Kabbah's attack cell in the M. C. Rpc space of every two weeks instead of every three weeks. And this was focused on patients who are older age 65 older um And uh had reversed had geriatric impairments. So so significant comorbidities. Um using a geriatric assessment score. Um as you can see patients were randomized to campus attack cell. Um Standard 25 mics per meter squared every three weeks versus taxes 16 migs per meter squared every two weeks. Um And um the primary endpoint was actually a safety endpoint but obviously they did look at secondary endpoints of efficacy. So what I think is really impressive is this clinical trial enrolled patients with a median age of 75. So really I think you know if you look through here fairly representative of an elderly patient population that we might see in clinic, the primary endpoint of um Neutra Penick grade three or higher and are neutropenia complications was really impressive with a markedly lower um rate of events for the capacity tax of 16 migs per meter squared every two weeks compared to the standard regimen. Um And you can see there were no events of febrile neutropenia actually in the past attacks of 16 migs per meter squared arm. It's a really impressive um sort of reduction in toxicity. And if you look at the secondary efficacy endpoints of our PFS and overall survival um There was no statistically significant difference. Um And and no detriment in efficacy. Clearly with the the capacity taxes every two weeks P. S. A response, 50 responses were similar as well as over objective responses. Um and then this is again highlighting if you look here any grade three or higher adverse event was was 14% lower with every two week dose ng. So in my mind for older frailer patients with M. C. R. P. C. Who who won't tolerate or can't tolerate as a tax of 25 makes me two squared every three weeks. I think this is a option for for those patients and you know I think potentially practice changing for me and and curious to hear what others think. Moving on to an updated analysis of the propelled study of abiraterone and um with or without a lap rib in the M. C. Rpc. First line setting. Um I'm gonna skip over this for the sake of time. Um But they first presented a subgroup analysis which which we didn't see in the first presentation earlier this year. Um On the on the top you can see the original R. P. F. S. In the intention to treat overall population in the bottom you can see the curves broken out by um H. R. R. Mutant or not as well as bracken mutant or not. And we see the expected um I I think the expected results where we see a larger magnitude of benefit in the homologous recombination deficient group and the largest magnitude of the Bracha mutant group. And this is um updated our PFS data. It looks very similar to the original are PFS data and here's the overall survival data um updated with the newer data on the right panel. What I think is notable is that the hazard ratio is similar and and actually a little bit more favorable with a little bit more maturity in the overall survival data. And and there may seem to be a curve that's uh tail to the curve that we're starting to see with the addition of to abiraterone in this setting. Um You know, I think this is a complicated space in terms of the patient cohort that was enrolled and I think a lot of um um questions about the sort of science behind whether there's synergy or not um and and how the different biomarker groups were defined but I think, you know, we can't ignore that the overall survival um in the I. T. T. Cohort is trending towards a benefit with the early elaborate um we need more time. Um and and again, you know why the wild type subgroup is benefiting is unanswered. So I think um this is not practice changing for me but but I think you know interesting and certainly very interesting to follow up or the more mature overall survival. This was a negative study embolism and plus a lap versus uh NH T for patients. Uh nm cr P C I'm gonna go through this quickly for the sake of time but essentially patients um with with progression after either abby or ends. Uh And those attacks were randomized to receive the other NH T or Pembroke plus elaborated with the primary endpoints of our PFS and os um this is the RPF s um you can see that there was essentially overlapping curves with no um however uh I think as when you look at the subgroups, not surprisingly, the bracket mutated patients elaborate was in the investigation alarm. Um did did benefit um from the member elaborate relevant relative to the other NH t. Um but no other subgroups really stood out overall survival of very similar trends. So so I'd say um this is a negative study and and there's no role for this combination in un selected patients with M. C. R. P. C. I think, you know, we all we all probably know that these these two treatments um tend to have more efficacy and biomarker selected populations. And so interested to see if if those studies are ongoing and and sort of more of a selected cohort. Another negative M. C. Rpc study the Sac 0814 improved study which was looking at the role of Metformin um nm CR P. C. The study enrolled patients with progressive M. C. R. P. C. To either end Saluda might alone or combined with Metformin, there's um some some observational data and science to explain why this might uh Metformin may have activity. Um But essentially a negative study, you can see looking at the disease control rate. Um there was there was really no discernible difference with the addition of Metformin um hmeid, so you know, seemingly no role based on this study and um you know I'll wrap up with sort of a summary of the high level takeaways in my mind. You know practice changing. I harped on this but I think the capacity you know every two weeks as a taxable regimen for old frail patients is something that I will consider um for for that population in my clinic for potentially practice changing results or uh you know the radicals HD study does suggest that 24 months of A. D. T. For men with high risk features. Um Maybe superior uh for metastases free survival and and with more time could be um improve overall survival with with further follow up remains to be seen. But but I think this is something that that I will be discussing with patients and will inform how I have that conversation. Um I would say practice informing studies stampede. Don't add add to to abby piece 18 month P. S. A highly prognostic in patients undergoing triplet therapy as well as patients receiving a pT test axle. For for jury still out propelled data needs further maturity. Um The presto study was positive but I don't think we'll change practice and then we have two negative studies in the M. C. RPc setting. With that. I will invite dr Sweeney to join the chat. Um I I would welcome any questions in the chat um that that either myself or dr Sweeney can answer and chris are you able to join us? I can't loud and create great. I know you have some thoughts um And so maybe we'll just give you the floor for a few minutes if anything you want to comment on. And yeah looking for and we'll keep an eye on the Q. And a look forward to answer questions. Um That's a fantastic summary of a lot of data check. So well done. Just a couple of quick thoughts about um endpoints really. So for presto the biochemical relapse the uh radicals HD we look at overall survival and that is the scenic wandering for sure. But for a disease where we've got a very long time from relapse to progression to death. Uh We need to work out what are the meaningful intermediate endpoints that are meaningful for a patient? A slight delay in the P. S. A. For the presto study? Not um Probably enough as you say. But are there other evidence does that lead to much less subsequent hormonal therapy? Uh Much less disease? Uh S. P. R. T. For relapse or something like that. These are all things we need to work out but I agree we wouldn't be acting based on that interestingly enough. So I think the radicals HD is an MRC approach where they lump everyone together and then they analyze everyone together and really do not have a willingness to look at subgroups. Others are much more willing and hopefully we will be able to get some subgroup analysis as part of an individual patient data analysis with multiple data sets, but we should remember that 96 01 did have an overall survival benefit in high risk patients, which was two years of big loop with 150 mg, which is only slightly less inferior to regular LH Rh agonist. So uh there's two studies that look very similar for patients with poorest disease. Uh so it's not a stand alone that this study actually supports that. It's interesting. Uh OS gets discounted here, but in other settings we have mFS benefit supported by always and we will take that on like disease free survival with liberalism and the agent renal has been adopted by many with a trend in OS with an earlier end point. Um but we seem to be less reluctant to that as well. So I would say, I think there's enough emerging here, as you say to if you have a really patient with high risk features and you want to decrease the chance of death. Maybe it's only 12% has a great 120.88 as the following with the MFS and less hormonal therapy, I think there's every reason to use to use hormonal therapy in those high risk patients, as you say, Tony points out the capacity study. Um 25 mg per meter squared is known to be more toxic. And have I how would that study have looked with 20 mg per meter squared which is out standard. But if a patient is too frail for 20 I think there is something to consider using the 16 if we can get it on the formulary. Um And uh the other thought is um basically they were the main thoughts is I think if we are trying to decrease the death rate of patients I think of prostate cancer I think the best thing we can do is possibly not forget the hormonal therapy for the high risk patients. And if you're going to do it two years with salvage radiation and we'll see how other people respond to them. There is one final question. Any role for beside A. D. T. Chemotherapy only dos attacks cell and and not an HD in any indication in castration sensitive metastatic disease. So what we show what's shown clearly is that testosterone suppression plus, does attack cell is inferior to testosterone dose attacks or plus and NH TB at abiraterone or derelict there two studies. So even in patients with high volume disease who benefit from those attacks, they're also the ones who seem to have the biggest benefit from the triplet therapy. So I do not see a role for adding testosterone suppression to standard A. D. T. For anyone. The standard therapy I think is an N. H. T. Plus. Testosterone suppression for all subgroups attack, bonus low volume all the way to synchronous high volume with the worst prognosis and then I would only I think the data that we're seeing is only the poor prognosis patients who benefit with a single agent with those attacks and deprivation therapy are the ones who are benefiting in the triplets setting. So that's the only setting where I feel comfortable from the data that I see where all three drugs are needed. Otherwise it's just A. T. T. Plus Abby and Apa darrow, whatever you can get. Great Doctor Taplin. Did you want to make a comment? I do. I guess they just want to have a little more discussion on the 24 months of ATT for those high risk guys Absging that 24 months of hormone therapy can be life altering for the rest of their life in terms of weight gain and never getting back their muscle tone. And um you know I'm just wondering how many of these men are really gonna Live long enough. Like is there an age group that we would consider it in? You know the young guys but not people say over 70 ISH or and what's the absolute benefit in overall survival. Like it's a you know what's most of these guys don't die from prostate cancer. So Maryland I'll double down on that. I agree 100%. So we really need to pass out those who have a rapid relapse and you know they're going to do poorly and I think we know who those are. So patients have a P. S. A. That rises within a year to this year of the surgery. They had Gleason nine and the P. S. A. And and seminal vesicles invasion. So within the dazzle study we've gotta salvage cohort. And we've projected there 75 metastases free survival at five years is 75% for these super high risk patients. So so for a 65 year old I would say with the only evidence that we prolong anyone's survival in that setting is the high risk patients in those two studies, be it? R. T. O. G. 96 01 and now this one. But I agree. So a 72 year old with police with police in seven with a margin positive. They could probably just get by with radiation alone. So it's I would say the young patients who have a really poor risk high risk features and likely to die of prostate cancer if we don't double down. But there are other patients. Absolutely right. We need to just like we do with, we talked about it the other night and the MBT is we need to start thinking who's radiation alone who's six months of hormones? Who's two years And I think only the high risk patients are the ones we should be doing that. How do you respond to that? I just don't think all you know if you have a gleason eight only and you know otherwise not looking bad, like I'm not sure, I would be sure 70 you know, you know so little investable invasion with maybe some tertiary five. Yeah. Absolutely. I think we need to really refine who those high risk patients are. But what I don't what I stress is that the way chris parker left uh the presentation is that really is there any role for any hormonal therapy for anyone? Um And I think that's the intensifying therapy based on very um incomplete non informative data set because they didn't pass it out for good risk, intermediate risk and poorest patients in a way. Yeah. Um Well I would love to continue this conversation. It's it's probably the most valuable part of this session. But I think for the sake of time we need to move on to the next disease. But thank you to all the discussions for your comments.
