Chapters Transcript Video 2022 GU ASCO Prostate Cancer Highlights Back to Symposium Prostate Cancer Highlights featuring Jacob Berchuck, MD and Chris Sweeney, MBBS Welcome to the Oscar G 2022 highlights. Um we're going to move on to discussing prostate um which I will be presenting and we'll have time for discussion with commentary from Dr. Sweeney afterwards. Here are our disclosures. So um I think the sort of field feels like uh prostate cancer probably had the closest to practice changing studies really sort of these are practice informing studies potentially these three air sense propelling magnitude. A response was a metastatic hormone sensitive setting and propelling magnitude. Both looked at abiraterone plus part inhibitor in the first line EMC RPc setting. So Harrison's was presented by Matthew smith from MGH. Um This builds upon the Peace One data that we saw asthma in september. Um So this is looking at men with metastatic hormone sensitive prostate cancer and um is randomizing men to receive A DT plus. Does attack cell? And the control arm versus A DT plus. Does attack Cell Plus Dare allude abide in the intervention arm with the primary endpoint of overall survival. +11 notable feature of the study design is that it was conceived of in the pre charted era. And so there was no specification by high volume versus low volume per chartered criteria. Um They did stratified by M. One A one B verse M one C. Um but but not high volume, low volume. And also in this analysis did not report um outcomes by high volume, low volume. Well we'll just mention um a few uh baseline patient characteristics really well balanced for the most part across the two cohorts. I highlighted that about 80% of patients in both arms had gleason eight so so high risk at diagnosis. Um The majority 85% or so in both arms had de novo metastatic disease and um you know a reasonably high percent 18% or so had M one C. So visceral disease. At the time of um treatment. Here's the primary endpoint of overall survival. As you can see the addition of Daryl Hmeid to A. T. T. Plus. Does attack cell significantly improved overall survival with a 32.5% reduction in uh death has a ratio of 0.68 that did be pre specified um threshold for statistical significance. And you can see at 40 Eight months um the median survival was not reached in either arm and um you know, was was only excuse me, 38% of men had had died at four years in the triplet arm. And and this is uh this improvement in overall survival was in spite of a high rate of life prolonging subsequent life prolonging therapies in the A. T. T. Plus dose of tax alarm. You can see in the column on the far right that 3/4 of patients in the 86 tax alarm received subsequent life prolonging therapy and and more than half Received. I think it was about 2/3 received subsequent HR Pathway inhibitor. The um uh plot here shows pretty much benefit across all pre specified subgroups. And looking at overall survival by de novo metastatic disease versus recurrent metastatic disease you see um has a ratio of .71 that that did not cross one for the Lenovo. Um and and a lower has a ratio of .61 that did cross one for the recurrent patients. Really a function of um only a minority of patients, about 20% had recurrent disease prior to treatment, pretty much all key secondary endpoints. Time to see our pc time to paint progression time to first skeletal symptomatic skeletal event in time to subsequent uh Antonio plastic therapy. Also all pharaohs favored the addition of derelict amounted to 80 T plus toast axl in terms of adverse events really I would say no new safety signals that that you'd expect beyond um what's known about the dist axel and darien hmeid. Um We we think of derelict mind as being relatively well tolerated in terms of the air pathway inhibitors. And um you can see really compared to police placebo only a slight increase in the discontinuation of of Daryl hmeid and no difference in the discontinuation of dist axle. These are the specifically the air pathway our inhibitor associated um adverse events and no signals no signals there. And so um dr smith concluded that in light of the significant reduction in mortality with the addition of derelict amid a DT plus those attacks allowing patients with metastatic hormone sensitive prostate cancer. Um Despite a high rate of subsequent life prolonging systemic therapy that um this should be considered as a new standard of care um for treatment of these patients. Um You know, just to put this into context, the hazard ratio for peace one was I believe 0.82 and here it was 0.68. Of course accounting for differences in study populations etcetera. We shouldn't necessarily compare those directly but I think really solidifies triplet therapy as a standard of care option for patients with metastatic hormone sensitive prostate cancer who are candidates for dose of Paxil. Um And exciting and I would say practice changing results for the metastatic hormone sensitive patients. Moving on to the first of two parts inhibitor studies which was propelled presented by fred saad. So I included a background slide just because I think it's it's pertinent to both of these trials. And and you know the rationale for combining abiraterone with part inhibitor is is based on pre clinical data suggesting that part inhibition may increase activity of of our pathway inhibitors. And in this um and pre clinical data suggesting that androgen receptor is signaling is involved in DNA damage repair. So by inhibiting our activity it may create a Hr deficient um situation and make tumors susceptible to part inhibition. So with that basis um And and I think it's what we'll call out differences in the propellant magnitude study because I think they're important um And they actually are quite different in their design. But the propel study was first line metastatic crp c um no prior abiraterone was allowed and um a er pathway inhibitors were allowed if they were stopped more than 12 months prior to treatment. These were patients with good performance status and they were stratified by cida metastases and prior taxing chemo. They were randomized to abiraterone with placebo or a lap forever. In the primary endpoint was radiographic PFS by investigator assessment. Um DR SAAD was pointed out that these were fairly symptomatic patients. If you look at the B. P. I. S. F. Greater than four and or opiate use about 25, 25% and higher on the elaborate farm, about 23% on each arm had this attack sulfur from insensitive disease. And um so going back to the study design quickly, patients were randomized first and then underwent genomic profiling. And fortunately The the genomic analysis showed that that the% 27.8 and 29% ended up being fairly, really nicely balanced between the two arms. So for the primary endpoint of RPF S. Uh they observed a 34% reduction in progression or death with the addition of elaborate to abiraterone. Uh You can see a hazard ratio of 340.66 that was statistically significant and met um pre specified thresholds. The media and our PFS improved by 8.2 months with the addition of elaborate uh compared to placebo. They they performed blinded independent central review as well. And that actually showed even more uh larger magnitude with his ratio of .61 and Improving the media and our PFS of 11.2 months with the addition of the Labyrinth. So um the comment Dr Saad commented that that the effect was consistent across all subgroups. I did want to point out the uh stratification or the HR subgroups. So H. R. R. Mutant versus HR wild type. Um If you look at the bottom you'll see uh has a ratio of 0.50 for Rpf S and H. R. Mutant subgroup. And um 0.76 in the HR wild type subgroup that does not cross one but certainly consistent with expectation the HR mutant um subgroup does have a greater magnitude of benefit. Here's the overall survival data. We'll just show this and mentioned that it's immature and um doesn't You know, has a ratio of 0.86. Not significant but really early and more time is needed to um see this day to make sure in terms of adverse events I would say. Um Overall no new safety signals, You know, grade three events were significantly or were higher in the uh elaborate farm. And um but in spite of that really the discontinuation rate was um I think reasonable 13.8% for elaborate. And importantly there was no um increase in the rate of discontinuation of abiraterone with the addition of elaborate this. This just highlights the specific adverse events and I would say no new signals there. And importantly quality of life was not impaired or or I should say was was similar between the two groups during the analysis period. So DR side concluded that elaborate plus abiraterone led to a significant and clinically meaningful improvement in our PFS in the first line EMC RPc setting. This was irrespective of HR mutation status and um is the first study to show clinical benefit for patients in the first line EMC RPC setting with the addition of the crib, you respect the addition of part irrespective of HR mutation status. I'm gonna refrain from commenting at this time. We'll move on to magnitude and then um have a few comments and then we'll have a bit of a discussion about these results with dr Sweeney moving on to magnitude. This was presented by kimchi, as I mentioned, very different study designs. So uh somewhat similar patient population. First line EMC rpc. However, up to four months of abiraterone were allowed prior to um study enrollment. Uh you can see the stratification factors. Um And what's different about this study primarily is that patients underwent genomic screening. So they were tested for the list of HR genes that you see there and then once they're biomarker which they abbreviate to be em once they're biomarker status was known, they were allocated to a biomarker positive. So HR deficient or biomarker negative. HR wild type group and then randomized to receive abiraterone with placebo or no rap arab. Um you can see the sample size there and the primary endpoint of our PFS by central review. So because of the different siskel design of this or the different study design, I think it's important to quickly touch on this. So for the biomarker they essentially had two studies within this study, a biomarker negative and biomarker positive cohort for the biomarker negative cohort. They had a planned futility analysis um after a specified number 200 patients with 100 25 events that uh and then the fire marker positive cohort. They had a hierarchical statistical plan where they first looked at the back of 12 subgroup um you know based on the idea that those that's gonna have the biggest magnitude of effect. And if that was statistically significant would move on to evaluate all HR are positive patients. Um the other thing to point out is that 50% of patients in the HR positive were specified to be Bracco 12. So here's the primary endpoint or actually the composite endpoint are PFS for or progression free survival Excuse me for for the HR negative cohort in in the futility analysis and and it did meet um the criteria for futility um you can see pretty much overlap of the curves here. Um the composite endpoint that they used for this analysis did include um RPF S as well as P. S. A. And progression. You can see actually more than half of the events where PS A progression. And so there is some question about whether this may have been um terminated a little early and that that you know, if given more time and based solely on our PFS maybe a signal would have emerged. But certainly um this stands in pretty stark difference to the results of propel and and the results seen in the HR wild type um subgroup there. Moving on to the biomarker positive cohort, I will just point out that there was a um Higher proportion on the character of arm of Ecac one, so a little worse performance status and also a higher um percent of patients in the Iraqi army that had visceral including liver disease at enrollment. So here are the primary endpoint for the 2nd 12 mutated cohort. You can see that um There was a significant reduction, has a ratio of .53. So 47% reduction in the risk of progression or death with the addition of you're a prick to abiraterone by central review and similar 0.5 oh um when uh with investigator assessed response. Now looking at the overall biomarker positives, including all HR genes, you can see uh smaller magnitude but still statistically significant um improvement in our PFS hazard ratios of 0.73 and 0.64. in the overall biomarker group. This is still the biomarker positive group. And looking at pre specified subgroups will just point at the Bracha versus non Bracha or other HR are you can see um interestingly the hazard ratio is 0.0.55 Um for Bracha and .99 for all other genes. So um you know I think the test for interaction does not um it's not significant. However you can see pretty um I think clinically meaningful likely difference in the hazard ratios for the Bracha versus non Bracha and and that clearly needs to be parsed out a little bit more. The overall survival is is immature won't really spend time beyond saying that and and further follow up is needed. However they did do a multi pre specified multi variant analysis accounting for baseline characteristics that showed a hazard ratio of 0.767. In the overall biomarker positive cohort um Not statistically significant but a trend towards improved overall survival with the addition of the labrum. Um really uh no no surprises with the safety profile. And um we'll just point out that the median dose intensity and the wrapper of Abby arm was 99% suggesting that that really it was fairly well tolerated and patients were able to stay on treatment and and there was no difference in quality of life during the study period. So dr Fauci concluded that um that no rapper and Plus Abby has a manageable safety profile with no new safety signals. Um That really in the HR positive subgroup um there was a significant improvement in the primary outcome of our PFS as well as key secondary endpoints. And that magnitude um you know a different conclusion magnitude highlights the importance of testing for H. R. R. Alterations and EMC RPc to identify those who will benefit from the addition of park to abiraterone. And um this supports the use of the wrapper of Abby as a potential first line treatment for patients with M. C. RPC. Who harbor HR mutations. Um Last slide before turning it over to a discussion. Um I I again wanted to highlight the difference in the study and and how that impacted the the sample size you can see. Um because magnitude pre specified a a cohort that were HR positive, They had 423 patients compared to um propel which had 226. So differences in sample size and as a result um the the exact number of bracket patients and propel wasn't reported but but is likely based on just sort of the incidents of these alterations in that range of 25 to 40. Um So so many more bracket patients in the magnitude study. Um We're not able to really compare to many metrics because we have limited data at this time. Um But but in the HR our cohort at least with the investigator assessed RPF s. Um which is sort of the one sort of common uh endpoint reported in both studies. There seems to be a similar um or I should say a consistent uh effect of improvement in our PFS with the addition of uh park inhibitor to Abby for for this HR mutant cohort. I think beyond that with with a greater magnitude of benefits seen with the bracket patients seemingly beyond that. I think there's a lot of questions that remain, you know. Um This is is taken from th pagano who who did the discussion of these two abstracts and I'll just you know, I think kind of summarized what she just what she had on her slide. Should should abiola crybaby first line for all patients with RCC. No we need to await OS data and I think better understand which patients benefit with magnitude. Should should we use Aveeno rapper of his first line crtc for all patients with H. R. Mutations. Uh She said no await OS data and the biomarker analysis and and um should we use the wrapper of Abby's first line for EMC Rpc bracket 12 patients maybe highlighting that this is a poor prognosis group um tend to have significant benefit with the addition of park as we saw in both studies with the RPF s and um it may be reasonable to consider this in these patients and I overall agree with um sort of those conclusions. There's a lot to parse here um how the HR alterations were detected is RPF RPF S. An adequate circuit for our OS that we think this will translate to an OS benefit in these studies. We clearly need the mature OS data. Um we're all interested to see a granular analysis of gene by gene analysis for the HR mutations and um the teleport to study which ends up plus minus talas operable is um should read out I'm not sure when but but will be a third randomized phase three study that will hopefully give us more data and more clarity into this question with that. I will invite dr Sweeney to come on video and um maybe provide a little bit of commentary around these three studies and if anyone has any questions please feel free to throw them in the chat. Can you hear me okay, check yep. So one of the first things I would say to begin with is that these were pharmaceutical sponsored studies and pharmaceutical industry have a goal to get drugs on markets and get a bigger label as possible. So I think we, as investigators and physicians need to just take a good hard look and say is there enough benefit for me to justify the treatment and look at these things and a little bit more of a careful line. First thing I just want to correct some history. So charter was reported in 2014. This study had its first position in 20 November 2016. Long term follow up data for charges was actually presented at Asthma September 2016. The company and the steering committee knew about the volume data but they chose not to do it. So the narrative is that they I didn't think the data is actually, they didn't think the data was compelling enough to look at things by volume. That's not a problem. That's that was what they decided at the time saying that they didn't know about the data. It's a little bit disingenuous. So I just want to say there's a bit of rewriting of history that needs to be put into perspective. But the study was clearly designed to get as bigger label as possible. So that's what is probably driving the fact that they didn't want to limit the label and it's limited to high hold both volume and whatnot. Um So yes, I think they're strong enough data to say patients who have a poor prognosis benefit from the triplet. If you look at it closely, the dozy In the M. one and the in the Andean Zurich Group. I hate both lee both the same as antoine de novo metastatic if you look at the child of data 48 months and the same as the end zero who have the survival benefit those attacks as well. And that also attracted around about the 75% of four year survival. So the control arm behaved exactly as chartered. So in the high volume. So it indicates to me that it's predominantly high volume patients who were referred to this study because the physicians thought they would benefit from those of taxes. How I look at it. There's nothing here to suggest. I think it would benefit patients with a better prognosis. Now what is unknown is to be determined if you treat patients with CNN HD only. Um do you get the same benefit as a D. T. D. O. C. There are lieutenant if you're treated with a DDT darrow or same with abiraterone that is unknown. And there is no data anywhere to support that. But a lot of people are justifying are saying that what I would say is stay tuned. We actually will have data to some degree to address the Dublin versus triplets question at ASCO for the ends and met study. So that's that data is percolating now. And the question is of to get to a meeting of longer than five years for the dean of a high volume like they Karim Fizazi presented with the triplets. Can you get to that with one or two of the double? It's in a modern era. Stay tuned for that. Um So I do think that our job is to intensify therapy as much as possible. I think the backbone of therapy is and then we decide who we think would benefit from adding a dose of tax or two or radiation to the prostate for the owner of a low volume? I don't know if there any questions coming in around that. The moving on to the magnitude and propelled studies. First of all. Again, you can see how the Astrazeneca merkel group study was designed to get as big a label as possible and extend beyond the biomarker positive group. So um that's one question. Uh So I personally think the magnitude study with a biomarker directed study for a biomarker study is for a biomarker For a targeted 80 is far more appropriate. That's a personal judgment. There is a lot of unknowns. As you point out jake about what is the biomarker and negative group? A lot of those are actually buying. We do not know how many of those are biomarkers indeterminate because they couldn't get ct demonic or tissue. And could some of those actually be harboring a break of one or break or two. So that's the big unknown there. Um And but I think the other question really comes down to is that our PFS benefit Great enough. So would maybe getting RPF .5 translate into an overall survival potentially. But .7 probably not. We saw that with aces and the other studies. B so we're left now trying to say is there enough clinical benefit. So right now the arctic verses an asymptomatic delay delaying in asymptomatic radiographic progression. Is there enough clinical benefit. And I really I'm not seeing it actually for the increased talks. Think that double the co pays the double the toxicity for delaying the radiographic progression where maybe they do just as well with sequential and you don't compromise survival. So um and I think you're David Einstein asked the very good question. What is the rate of subsequent park interpreter use? Are they salvaged? Well by using it. It's not reported. So I think we need to look at this data yet. So I in a lot more detail I personally do not feel comfortable the need to ad apart inhibitor to a patient with on abiraterone or any of the others yet. I don't know how others feel about that. But I'm not I don't think the data is strong enough to do that yet. Can I put you on the spot and just say you know um come next Tuesday healthy you're a relatively healthy fit. Um Youngish younger patient. Um Who who sort of would meet criteria and has germline bracket to um with loss of the other and you're thinking about starting abby, would you consider, would you lean towards or lean away from um given the abbey elaborate in that patient, I don't see that. I would give people keep saying that they had seemed to have a poorer survival. But even in the what I would like to do is just map up the Cougar 302 data to these patients. The median survival of three years in Cougar 302 The seven. It looks like about 6070% of patients are liable to you. So it's tracking to maybe a 16 month Sorry 5 3 Year median survival as well. So I just need to see this data mapped out a lot more. Um And I I honestly would say your hormonal therapy of choice and then if not progressing we'll switch over to a park inhibitor. Quickly chris I mean with what's happening, do you foresee getting a quadruplets or quintuplets at some point like you know A. D. T. Androgen um receptor inhibitor part those attacks all. I mean the quadruplets are coming perhaps first and high volume disease you know. But you know so the answer the answer to that is it's going to be hard to combine those therapies. So I think it would be induction A. T. T. NH T. And if you have a running of that and then randomized to um can new agent our market director, New Argent I think it's gonna be hard to add it to the chemotherapy. So if there's a chemotherapy triplet I'd say you get through that and then you run NH T maintenance plus or minus the new agent. The study that I've I'm trying to put together is called the bespoke trial whereby we enrolled patients they get their standard of care A T T. NH T radiation to the prostate of chemotherapy P. S. A less than 0.10 point two. They go on de intensification protocol. The gradient 0.2 at six months after that induction N. D. S A T T. The standard NH T plus or minus half inhibitor plus or minus. Um and a KTM had the plus amount of civilization. So I think what we need to do is try and get to an intensification de intensification program based on the bond markets in the future. That's in the future. I'm all you know, we did that in our C10 years ago. The problem is on trial. The attrition rate that happens. I mean you lose those, you'll end up from from 500 to 100. And the entity that is the problem then you'll end up with. Even if you start at 1000 you'll end up 80 versus 80 un interpret a ble. And I totally agree with me. That's the one that's the way to do things. So we're putting together the bespoke cap trial. So this is what we're going to try and do. So I need you to raise $500 million dollars from Tony to get the study. No but actually there are a number of companies have actually, so the question is where do we go from here? And I think the data is strong enough to take a torment sensitive in a bio market directed. And a number of companies I've been speaking to are actually interested in supporting the bespoke trial bespoke cap, you've heard it here first time actually mentioned on your omega plugging my own trial. But I think a bio market directed studying hormone sensitive is next and what we will need to do is get um C C T G P C C T C in the US Canada UK Ireland. So good. The spanish the french everyone feeding into the trial designs as a platform and there's actually some interesting so there is some early goodwill for doing that chris from your mouth to their ears. Let's hope to see it happen. I'm going to wrap up just by um a teacher chowdhury in the comments said magnitude mostly enrolled in Russia and europe and not a lot of subsequent parts and and did comment that in a niche case of first line EMC RPc with high volume disease air pathway inhibitor, naive and known bracket to he thinks this gives us data to consider this as an option, not the option. Yeah, I can yeah, I can't disagree with that at all. So um well thank you chris always appreciate your insights in this space and what that will wrap up prostate Published March 16, 2022 Created by
