The Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute presents a succinct summary of all the prostate cancer clinical updates you need to know from ASCO GU 2023.
So if you're just joining us today, we'll be discussing the Eu oncology conference highlights from Moscow G U 2023 starting with updates pertaining to prostate cancer. I'll be presenting the updates and we have a teacher challenger here is discussing it. I'm gonna present updates from three trials. The Triton three and Tala Pro two studies were the first reports of these randomized phase three studies and metastatic castration resistant prostate cancer looking at different parts inhibitor approaches. Um The propelled study was the final plan of survival analysis of another part inhibitor strategy and M C R P C. And then we're going to switch gears and discuss formula 509 which was a intensified um androgen deprivation therapy. Um Next generation hormonal therapy combination um in the salvage radiation setting presented from our, by our very own Dr Paul knew in. So as you can see most of the updates focused on prop on on part inhibitors in the metastatic castration resistant prostate cancer space. The first study was Triton three. The background for this study is that um just mentioned that Rock Opera is FDA approved for EMC RPC, but specifically in patients with P R C A mutations who have progressed on both our pathway inhibitor and taxing chemotherapy. So here, um the triton three study was, was looking at um rick operative versus physician's choice and this is important. I'll comment on that in a second in patients with M C R P C with the Greco or A T M mutation. Here's the study, schema patients with who are who prior chemotherapy was a lot allowed in the castration sensitive metastatic setting. But we're chemotherapy naive and EMC RPC setting as I mentioned, had either bracket or A T M mutation and had progressed on one prior next generation hormonal therapy patients were randomized to receive group Capra versus physician's choice, which was either dose attack axel or a second generation. Our pathway inhibitor abiraterone er and Saluda meid. Um this is significant and we talked about this a little bit later on because the prior um randomized studies of apartment inhibitor monotherapy have been against air pathway inhibitor only. And importantly, patients who progressed on the physician's choice were then allowed to cross over to receive. Of which 75% of patients did quick mention of the statistical plan patients. The primary endpoint was radiographic progression free survival and the bracket subgroup. They then looked at the I T T population, which was Bracha 12 plus A T M and then moved on to the secondary endpoints of overall survival and response rate. Here's the primary data Um So in the brackets subgroup are PFS was significantly improved, there was a 50% reduction in risk of progression or death with recap versus physician's choice. Uh And median overall median progression free survival is prolonged from 6.4 months to 10.2 months. They then looked at radiographic correction for survival in the bracket patients by the control arm, whether patients received those attacks versus second generation air pathway inhibitor and saw a significant improvement in our PFS regardless of whether this tax or air pathway inhibitor were used. And so this is the first demonstration that part inhibitor in this setting results in superior RPF S relatives chemotherapy. Now, this is showing um the the A T M sub group you can see compared to the bracket patients which again a 50% reduction. Um The hazard ratio is essentially one um suggesting that, that A T M does not improve our PFS compared to physicians choice in this setting. Here's the overall survival in the breakfast subgroup. Um The hazard ratio is 0.94. The curves are pretty similar. However, the data is immature but to date the RPF S benefit in the breakfast subgroup is not translated into an R P F S benefit. Um I'm gonna skip, this is really for reference. If people have questions, I'm gonna skip over the the patient characteristics and, and make a few comments on the safety summary. Um What theme you'll be seeing is that carp inhibitors have significant neurologic toxicity. So, if you look at the, the, the the dose interruptions, 53% with Capra versus 27 20% with physician's choice. Um The anemia, um 47% grade 3 24% significantly higher than with those attacks. Solar air pathway inhibitor and 29% of patients treated with mccaffrey received one or more blood transfusions compared to 2% on the physician store son. So the conclusion is that um uh try a method study, endpoint Capra significantly improved our PFS versus positions choice and the M C RPC first line setting. Um This is the first demonstration that Park inhibitor improves our PFS relative to taxing chemotherapy. And I think sort of hammers home that, that really the bracket to record 12 patients were the patients that benefit A T M. Um The benefit was really um nonexistence and, and, and I think, um you know, we can talk about this a little bit later on, but um overall survival um which is a trend in these parts inhibitor studies is immature but but not positive despite a really robust are PFS benefit notable that that they did allow crossover in this study and, and 75% of patients to cross over. But, but I think we'll need to follow up overall survival from the study as well as the others sort of determine how we're going to use this data to better treat our patients, the segues nicely into the tele Pro to study which um compared Saluda meid in first line EMC RPC with Placebo versus talese's another apartment. So these are first line in CRP C patients stratified by whether patients received Abby or just tax sensitive setting um as well as by gene alteration status. This included all commerce. Notably, this is a different patient population. This is all patients with M C RPC regardless of um hr mutation status. Uh And that testing was done subsequently, patients were randomized to tells opera placental unified or N C plus placebo with a primary endpoint of PFS. And overall survival is the key secondary endpoint. I'm gonna again skip over the patient characteristics. I don't think there was much there to comment on but, but I will point out here that um different from propel um where, where I think a significant portion of patients receive tumor testing based on C T D N A here. Um um The vast majority of patients um you can see all but one patient in the study had tumor tissue, some of them also had cell free DNA but, but all but one patient had tumor tissue, which was, which is um nice to see. And there's a breakdown of the alterations kind of pretty standard in terms of the sitting practice. So here's the primary endpoint RPF S in the over in the all comers population by behind an independent central review um the RPF S was significantly prolonged with a hazard ratio of 0.63. With the addition of Talas opera, an improvement of about five months in the RPF S media RPF S. Uh This is uh you know, down of the subgroups. I'll just draw your attention to the second to last one where hr status you can see um significantly, significantly but a but a qualitatively lower hazard ratio in the hr deficient versus non efficient and unknown population. Um We get a little bit more granularity there here, the capital meier curves you can see on the right. Um the non deficient with unknown with has ratio 0.7 versus 0.46 and the hr deficient um sort of corroborating that last slide. Um And and they did do because there were some patients in that group that had unknown status. Essentially, the tumor testing failed, they did do a sensitivity analysis and the only sort of bona fide non deficient patients by the tumor testing that was done and did see a significant improvement of our PFS with Dallas opera Overall survival is immature only 30 31% maturity. Um but but again, um there was no real significant difference or really seemingly suggestive of survival response rates were significantly higher in the um accommodation versus the ends up. Again, I think this is important, higher rates of of treatment emergent adverse effects, higher rates of dose interruption dose reductions discontinuation. Um And I think this really tells the story that if you look at the at the toxicities that had um you know, the highest incidents and instance of grade 34 anemia, neutropenia anemia leukemia, as well as fatigue neurasthenia. So very similar with that patient reported outcomes were looked at and and seemed to be maintained if not slightly better on the Dallas opera, but despite the high rate of the middle ages toxicity. And so, so I'll comment on this a little bit more in a few minutes. But the, the investigator who presented Dr Aggarwal, his conclusion was that the results support the use of Talas opera plus as first line treatment in patients with M C RPC regardless of H R G and alteration status. Um I'll maybe I'll pause here to just comment and to teach, feel free to jump in or, or we can sort of get all your thoughts afterwards. But I I Dr Elena Castro is discussing for this, crossed out the word regardless and I think I agree with her. Um You know, I think we're clearly seeing different um efficacy of adding tells operate in these different patient populations. So, um you know, I think um maybe teach will, will turn to you after the next um part inhibitor study in your thoughts. Um But, but I think because it's so related the final overall survival data from the propelled study, which was Abiraterone in the lab. We've seen the first publication or presentation of this data, but this is the final pre planned overall survival of patients shown here. First line M C RPC randomized to Abiraterone, placebo versus Abiraterone plus the labrum. So we previously saw the RPFS significantly prolonged in the ITT population um hazard ratio in .66. Um This, I think really telling again that the bracket patients had had by far the largest magnitude of benefit um with, with hazard ratios moving more towards one for the um non bracketed non hr patients. So here is the updated overall survival. Um There is um It was still immature, it's 48% mature, but there is a trend, it's a p value of .0544. So that's significant. Um you can see the threshold there but, but a trend towards improvement in overall survival again though it doesn't meet the threshold. So for the follow up is needed. Um And, and you know, when you look at the subgroups based on overall survival, we see a very similar trend of the RPF S where the bracket to patients um seem to clearly benefit from the addition of elaborate abiraterone. Um maybe a A benefit or 95% confidence role that does not cross one for the HR patients and, and for the non applications and has a ratio that costs with a confidence interval that crosses one. And this is the breakdown of overall survival in the the Kaplan Meier Curves kids supporting that. Um I'm gonna sound like a broken record but, but very similar. And I think important trend with, with pretty significant neurologic toxicity and it's enough for patients treated department better. Um Although quality of life was maintained in this quality metric, so they concluded that there is a uh study met its primary endpoint that overall survival is trending towards um improvement with the addition of abiraterone. Um They say that the benefit is preserved across subgroups which again, um Dr Choudhry would, would welcome your input on. And um you know, I think if I were to summarize sort of these, these two studies of combination NH T with ARP inhibitor, I would say that the RPF S benefit um could be summarized by a very clear and strong benefit um for patients with bracket to alterations, a seemingly real but much smaller magnitude benefit for hr our patients with hr alterations in other genes um which is greater than all comers benefit and greater, you know, and patients with no H R R alteration. Um But I think this needs to be weighed against really clear, consistent significant neurologic toxicity of Park inhibitor. Um and none of these studies showing a overall survival benefit which um you know, it's not a given based on studies like this and others. Um improv cancer as well as Carbon Hitler studies in other tumor types that are PFS benefits going to translate to an overall survival benefit. So, so maybe a teacher before I move on to formula 509, you know, I know you, you have expertise in this area thought deeply about these trials, would love to hear your thoughts about how you're thinking about this data and, and whether it changes your practice and um where we go from here is a field. Yes. So, so much to sort through. And I, I don't know how much justice I can do in a short commentary. I would say that these studies are incredibly interesting and they're interesting both biologically. Um and also clinically in terms of Haitian management. So, biologically, the question is, you know, is there evidence that there is synergy between part inhibition and er pathway inhibition in patients with metastatic castration, resistant prostate cancer. And I would say that the jury is a little bit out on that particular question because we really don't know how much of the effect that we're seeing is really related to activities of these agents in combination, that is something more than what would be expected based on the combinatorial activity of the single agents. And so that's a little bit to imply that we don't know exactly what Palace Opera and elaborate um activity would be as monotherapy and an un selected population because certainly some patients and as your research suggests, um have a homologous recombination repair deficiency phenotype, even without detection of a homologous recombination repaired um gene alteration. So I would suggest that the negative finding from the magnitude study in the H R minus population really kind of calls into question, how much the energy between these classes of agents are we really seeing in, in human beings? I understand the pre clinical data, but no one has really demonstrated those same pathway alterations in tumor biopsies. And I would love somebody to, to do that because that would give us a lot more clarity around that biological question. The second is obviously the clinical question, who are the patients that you're going to treat with these combinations? And these studies were done in a first line em crp set see setting and didn't propel these are patients who were naive to um potent air pathway inhibitors. And in the tallapoosa study, only 5% of those patients received abiraterone. And so if you had a patient who was treated with a D T alone or A D T plus does attack cell, you knew they had a B R C A two gene alteration and particularly if they had um bulkier symptomatic disease, I think that these data provide very good justification for doing those agents in combination in this setting, um particularly combined with the data from Dr Maha Hussein's breakaway study that was presented at a prior meeting um preliminarily. Now, would you use these combinations in patients within hr without an H R G and alteration based on our pfs benefit only without an overall survival benefit. I would say, what is your real advantage to the patient at that point? Because these drugs add not only the risks of um pharmacologic toxicities that you mentioned, but but there was a non negligible increased risk in pulmonary embolism in both propel and in hell a pro two. And while that was a bit minimized by the presenters of both studies, when our cancer patients have pulmonary emboli were basically subjecting them to anti coagulation. Lifelong. From there on out, all of these drugs have costs, all of these drugs have pill burden. And you really want to subject patients to the inconveniences, hassles extra complications, extra drugs if they're going to have some sort of meaningful benefit in terms of symptoms or survival. And so in the absence of an hour overall survival benefit, I just can't see how a patient in front of me who is, does not have an hr gene alteration and is asymptomatic that I'm going to recommend a combination like elaborate and abiraterone or callous suburban and solidified until we have some better data, really understanding who are the patients in the H R R minus group. Um that really have benefited. I think a lot of the studies that you're doing to try to identify um hr deficiency even in patients without H R G mutations is part of that. I don't know what your additional thoughts are based on those comments. I I couldn't have said it better myself. I couldn't have said it that. Well, I think that was a phenomenal synopsis of both sort of the importance of the biological rationale, which we haven't compelling the scene in patients. And, you know, the really lack of a compelling case of benefit outweighing risk for patients without hr alterations. So I don't really have much to add, um, very quickly. You don't today in prostate cancer, where would you use? And with what part inhibitor you don't use them for prevention, you don't use them for neo adjuvant or adjuvant. Let's start by metas. You don't use them for P S A recurrence. You use them for metastatic where do use them single agent or not. And let us agree because I think all of us agree, use them on a setting. At least I do them in setting off braca one or two mutations. Yeah. So I would say that there's not data to use it in a hormone sensitive metastatic setting. Yet, the Amplitude study and the tele pro three study are currently enrolling and that question will be answered. So the we would use it in an M C RPC setting. I would say that in patients who received prior abiraterone or, and solidified, the most compelling data is to use it as elaborate or rock opera as monotherapy. Um In the B R C A two population, there are other gene alterations that there's some suggestive evidence based on small numbers of patients in um threatened to, for example, um that have led to alterations, franconia alterations, rad 51 alterations. Um things that are really bona fide hr gene alterations that I would consider those agents as monotherapy. For me, that combination of abiraterone or an elaborate or if and when it's approved palace operator and, and, and salute, um I'd would really be in the indication in which they were tested, which is in a first line M C RPC setting um in patients who have hr gene alterations who are naive to abiraterone or in Saluda Meid, I think if you've received prior abiraterone or in Saluda Meid, um The mono therapy data is really more compelling and I know that that's the point of disagreement of a lot of people I talked to at the U S cho who felt that combinations were uh indicated even in patients who had prior um potent hormonal therapy, but, but that trial hasn't been done. So I'm not sure that we can make that conclusion. I once again agree with the fish and um thank you. That was a phenomenal discussion. And for the sake of time, we should probably move on um talking about formula 509. This is a study as I mentioned, presented by our very own Dr Paul knew in that um you know, we've known for a long time that six months of A T T is a standard. Um hormone therapy to be given with salvage radiation prostatectomy for biochemical currents and formula 509 essentially sought to look at a more intensified hormone therapy regimen with adding abiraterone and apple Ooh Hmeid to for six months to A D T. Um compared to standard A D T and by qualified patients enrolled were um had a rising P S a great point. One after practice tech to me and one of the at least one of the unfavorable risk factors shown here, patients were randomized, as I mentioned, stratified by P S A 0.5 above or below and node status and randomized to the therapy I mentioned as shown here. Primary outcome was PFS with um metastases free survival being a secondary outcome. I'm gonna skip over patient characteristics for the sake of time. But, but we'll mention that that a third of patients had um Gleason nine and a third of patients had P S A greater than 90.5 30% no pasta. Um So this is the primary outcome. Um The hazard ratio was 0.71 for um progression free survival, favoring uh close to but not quite statistically significantly favoring the addition of Abby Apa. Um just, just uh flashing back, the one sided alpha P less than 10.5 was the threshold for significance. So it didn't quite meet that but, but a trend. Um and, and here's the metastases free survival again, pretty robust hazard ratio supporting the addition of A D T with Abby and APPA um but what was really striking and was not the primary outcome but, but stratify NG results by P S A greater than, versus less than point oh five. Um You can see the patients with P S A about 50.5 seemed to derive greater benefit than the all comers population. And, and perhaps most excitingly, a 68% reduction in the risk of development of metastatic disease or death. With the addition of Abby Apa to A T T, Um which we know um the test free survival being a surrogate for overall survival. And really, you know, I think a clinically very significant, you know, almost 20% reduction in in the absolute risk of absolute of metastases survival at three years with a very reasonable number needed to treat of five patients um shown here sort of the magnitude of the benefit the subgroups and this was all sort of tolerated as one would expect. And so, so this was one of the last slide that Dr one showed before his conclusions, comparing the MFS and the hazard ratio for MFS in all patients in the P S A great and then 10.5 subgroup from radicals HD comparing to radicals HD, which we saw it as the last year, which randomized patients to six vs 24 months of, of standard 80 T. And you can see that in all patients and, and particularly in the patient's point, um P S A greater than 800.0.5, the hazard ratios with all the caveats and not comparing across trials, the hazard ratios do favor six months of intensified hormone therapy, um, to 24 months of standard A B T. And um this concept is being formally tested in the prostate I Q study, which all is leading with some other investigators. So I think, um, you know, with what we've seen with moving hormone intensified hormone therapy in the earlier disease settings for no positive high risk patients. Um You know, I I think um I find this data to be highly, highly promising that sort of a six month intensified regimen may may really um reduce not only the necessary survival but potentially overall survival in these really high risk locations from the early salvage therapy. Um So, so those were essentially doctor, no one's conclusions that um it didn't meet the pre specified threshold for significance in the primary analysis. But um certainly some very, I think compelling and promising data for, for the role of intensified therapy and in high risk patients undergoing salvage radiation to receive intensified hormone therapy. With that, I will conclude, I'll open it up to a teach um to see if any comments on this. And I and I will promote doctor if he's still here just for any last word on that. So I'm quite biased because I like the study. I like Dr. Yuen and I enrolled many patients to the trial. So I agree with you that the, that the findings are pretty compelling. What I would say is that so many questions remain because our management now in 2023 is really not the same as when this trial was enrolling. One is that we probably will use a combination of A D T with abiraterone and absolute. Um I'd altogether um in our patients, we would probably choose the intensification with one agent or another. But the big elephant in the room is um the PFC A pet because in so many of these patients in the salvage setting, we're getting pet imaging and is um APSA greater than 0.5, a bit of a proxy for early Macroscopic disease where we would consider uh intensification whether or not this trial was reported. But what's very, very compelling is that um the hazard ratios for benefit uh seem to compare favorably in terms of the intensification compared to the prolongation as was seen in radicals. HD. So obviously, that's a cross trial comparison. It's different populations. Uh So that part is hard to know. So, in, in our current standard and in our current setting, who are the patients who don't need A D T, who are the patients where six months of androgen deprivation alone is adequate? Who are the pain, Who you would consider six months of intensified androgen deprivation? Who would you consider 24 months of androgen deprivation alone. And who would you consider 24 months of intensified androgen deprivation? I honestly don't know. I think that we have all had discussions about patients. Um individual patients in our practice is based on their gleason score, their PSA, their pathology, their psm a pet scan. And I think um without randomized data in the current context with PSM A pets were a little bit trying to piecemeal the data from all of these trials to come up with a reasonable plan for our patients, including their own preferences, their own comorbidities and um how aggressive they want to be to try to come up with a plan because it's such a hodgepodge. I don't know, doctor knew. And if you have any comments that you wanted to state, we are over time for prostate. It's been a fantastic discussion but any last word on the topic. Yeah. Look, I totally agree that you, sorry, the host isn't letting me on mute. So my, my video, but Um I totally agree with the tissue. Just really appreciate everybody here because everyone here is who enrolled on this trial date. If I was like 40% of the trial, Mary Ellen supported this from the beginning. So, you know, this is our trial, really appreciate everybody. And I think, you know, I totally agree with that in terms of the results and we'll be testing this against 24 months of ADT and incorporating pet into that as well. So, you know, hopefully can get some of the answers that you're looking for fish. Great. That's I'm really looking forward. Thank you, Dr Nguyen. Thank you, teach for a fantastic discussion.
