ASCO 2025 - GU Cancer Highlights: KEYNOTE-564, AMPLITUDE, ARANOTE, NIAGARA

ASCO 2025 GU Highlights: KEYNOTE-564 in RCC Hello and welcome to another episode of the Oncology Brothers Podcast. I'm Rahul Ghossein here with my brother Rohit Ghossein. We're both practicing community oncologist and we continue to use this platform to focus on recent practice changing studies in cancer care for our fellow community colleagues. Today we're diving into Gu malignancy highlights from ASCO 2025 Annual Meeting. We're thrilled to have Doctor Tian Zhang from UT Southwestern, a Gu medical oncologist, to guide us through four key abstracts in this space. Tian, thank you so much for joining us. Speaker 2 Thanks Rahul and Rohit, always a pleasure and it's always fun to distill the data from ASCO to see what might be practice in forming and changing. Speaker 3 Indeed. Tian, welcome back. We have now done few of these conference highlights with you sticking with the same format. That is on next few minutes we'll be focusing on practice changing and forming highlights from ASCO 25 focusing in Gu portion. We'll start off with Keynote 564 in RCC space. Then we'll switch on to prostate cancer covering AMPLITUDE trial and error note study which has resulted in approval of darlutamide, closing off with Niagara trial and the role of CTDNA in bladder cancer. So let's start off with RCC where in localized disease prior to pembrolizumab approval, we were doing close surveillance, but this changed after pembrolizumab approval in 2021, which was based off of DFS data. But now we have more mature data showing OS benefit here. TN can you touch on the steady design for Keynote 564 and it's finding from ASCO 2025? Speaker 2 Sure. So Keynote 564 was the registrational trial for adjuvant pembrolizumab and enrolled patients with post nephrectomy kidney cancers that are of higher risk of recurrence. So T2 grade 4 or sarcomatoid T3 any grade or T4 any grade or any pathologic T stage with node positivity we know those patients are at higher risk for recurrence and metastatic disease that randomized 1 to 1 to either pembulizumab every three weeks or placebo. The primary endpoint was disease free survival. As you mentioned the initial publication was back in 2021 and we already a disease free survival improvement. Subsequent one was about a year ago and we saw the overall survival improvement. This is a follow up analysis with medium follow up now almost six years, 69 months that preserved ongoing overall survival benefit of patients treated with pembrolizumab over placebo. Of note the hazard ratio 0.66 was statistically significant. They had preserved some power for overall survival analysis and so confirmatory on what that early analysis showed us, these patients are certainly living longer. There's a portion of patients that improve. I think the question becomes then, how do we decide which patients are the ones that we pick for the adjuvant pembrolizumab treatments? Speaker 1 Yeah. Thanks, Tian for touching on that. Rohit, as you stated, this all started back in 2021 and this became standard of care based on DFS. The overall survival just continues to reinforce that this is the current practice in intermediate or high risk TN. You touched on those components T2 with high grade T3 or T4 or any lymph node positive disease. That is what needs to be on our radar post nephrectomy. AMPLITUDE Trial: PARP Inhibitor for HRR Prostate Cancer Now pembrolizumab continues to show overall survival benefit can now on to prostate cancer. Let's dive into AMPLITUDE trial which looked at PARP inhibitor Neraparab with abiraterone and metastatic castration sensitive prostate cancer with homologous recombinant repair gene mutation. Tim, can you break down the study and its key findings? Speaker 2 So AMPLITUDE was a follow up of magnitude what that we saw in metastatic castration resistant prostate cancer where this combination neraparib and abiraterone already has a label. Now we're seeing in the metastatic hormone sensitive prostate cancer space, how can we find the right populations to treat with a PARP inhibitor? This AMPLITUDE study was a global phase three trial, very carefully selected patients for homologous recombination defect and alterations in that list that you see there. These patients were not allowed to have any prior PARP inhibitors or AR targeting therapies. They were allowed to have hormone suppression up to six months and a prior dose of Taxol if they had already received it and abiraterone if they had just started abiraterone for less than 45 days. These patients were randomized 1 to 1 to either receiving ADT with abiraterone and placebo or with abiraterone and ERAP rib and the primary endpoint was radio graphic progression free survival, secondary endpoints, time to symptomatic progression, overall survival, and safety. Patients were stratified upfront by bracket. 2 mutations versus CDK 12 versus all other HRR alterations as well as the presence or absence of prior dose of Taxol treatment Radio graphic progression free survival was improved in patients, particularly those with BRCA 2 and BRCA 1 alterations in prostate cancer we have a little bit more bracket 2 than BRCA one, but improvement there of progression free survival has ratio 0.52 favoring those patients treated with a combination of abiraterone and eraparib. If you take all intention to treat HRR mutated patient populations, we're seeing here in the wrap rib with abiraterone compared to placebo with abiraterone when an improvement has a ratio of 0.63, this was also statistically significant. When we're thinking about these alterations, we need to think primarily for the BRCA 1-2 mutated patients are having the most benefit. And what we also didn't see from this analysis was the subsequent treatments and all of these combination studies. We're always asking that question, is combination better than and sequential monotherapies. I think time will tell in terms of how did these patients do if they had the combination versus sequential sort of PFS 2 analysis? Speaker 3 Thanks for covering that. With regards to where the PFS stands, it is impressive what we are seeing here, but is it ready for standard of care therapy today or rather you would consider this in second line in metastatic castration resistant prostate cancer and rely on PARP inhibitors then? Speaker 2 That's a great question. At this particular moment in June 2025, the label for NURAP ribbon abiraterone still sits in the metastatic castration resistance setting in the United States. We're using it. We're still mostly using it in that CRPC setting unless we have another trial open in this space. The general shift of prostate cancer treatments is that if we know things to be relevant in the castration resistance phase, they are also, you know we're seeing those improvements in the hormone sensitive space. It's important that we're sequencing those patients upfront, finding the patients with the relevant alterations, particularly the BRCA 1-2 mutated patients. They tend to have poor prognosis especially on the standard therapies. As the label expands, I think it will be potentially practice changing for that subset of patients. Speaker 3 For now, we'll await the FDA approval. But the biggest take away here is the importance of somatic and germline testing in prostate cancer compared to other tumor types. We've seen low incidence of us doing this NGS testing here. Now that we have found a mutation, we should keep in mind that responsiveness is not the same in all HRR mutation in amplitude. ARANOTE Study: Darolutamide's QoL Impact & Approval Majority of the benefits was driven by BRCA mutation as you stayed at TN, OK sticking with prostate cancer, we also saw health related quality of life data from Erranode study. But shortly after the presentation darlutamide was approved by the FDA for metastatic hormone sensitive prostate cancer. TN Can you please touch on the findings that we saw at ASCO 2025 and the recent approval of darlutamide? Speaker 2 This was error note a trial mostly global non-us study that enrolled patients with metastatic hormone sensitive prostate cancer and randomized them two to one to either receiving Darrell Ludamide with ADT or ADT with placebo. And we saw at ESMO 2024 that there was an improvement in terms of progression free survival. Overall survival was a secondary endpoint. So not enough events have been reached based on that data. The FDA approval synced up nicely with the ASCO presentation. We received notice of that approval right on the last day of ASCO this year. Doctor Morgan's Alicia Morgan's presented this health related quality of life data. What you're seeing on this slide is radio graphic progression free survival benefit as the primary endpoint has a ratio 0.54 as well as time to pain progression was improved in patients treated with that darrelutamide with ADT versus ADT with placebo and then also time to deterioration of the fact P score. Fact P is a well validated quality of life measure for prostate cancer when all of these measures for secondary endpoints quality of life was better than in patients treated with ADT with pussy bones. So I think really encouraging results especially adding to the primary endpoint of RPFS, primary improvement for darolodamine treated folks. Speaker 1 You know with Darley, to my recent approval, the quality of life data presented here at ASCO 2025 is very relevant. And Tien, as you pointed out, the improvement was seen in pain progression, overall well-being. What does that really mean? Social well-being, functional well-being, improved urinary symptoms. Historically, we felt that derelutamide might be better tolerated than our other treatment options. Has that been your experience? How do you pick the right androgen receptor pathway inhibitor in your practice? Speaker 2 Yeah. I think it's a great question, one that many of our trainees also ask. These really have not been compared head to head. We have Apalodamide approved from Titan and Enzalutamide approved from Enzimet and ARCHES, which we also saw an update on Arches at this year's ASCO and then Darrelutamide just had its approval on error notes. So we have three approved great options for patients. I think you know, in the in the realm of they're not compared head to head, the efficacy signal is great for each of these drugs. In my mind, what I say often is the right pill is the one that we can get in their hands and in their mouths. When a pill has cost barriers or access barriers, we can't get it into their hands. I always tell my patients when we're going through prior authorization and co-pay issues, ask about patient assistance programs. There's always, I mean be some help out there for patients to help with co-pay payments but they can't afford it and then getting it into their mouths. The side effect profile is important for how patients are taking these drugs. We often start out with either apalutamide or darulutamide and then insurance doesn't allow and we go back to enzalutamide, sometimes abiraterone. The side effect profile really takes over. For your initial question about the the nuance side effect profile for Darulutra, I do think it's better tolerated. If you look at the side effects across trials, the fatigue rates are a little bit lower for daraludamide. Cognitive dysfunction is a little bit lower. Hypertension I think is similar across, but daraludamide as an agent, it's a little bit more polar as a molecule and so it doesn't cross the blood brain barrier. I think the the quality of life differences are are pretty palpable and patients who are on daraludamide in terms of their feeling well and able to take it and keep on treatment longer in my practice at least we're able to keep patients on. The final note I'll say is that our patients are on these agents. We're all learning anecdotally from our practices. There is actually a trial that specifically looked at daralutamide versus enzalutamide from a cognitive function perspective. It's called Aracog that Leisha Morgan's ran and LED in the Alliance Cooperative Group. It's fully enrolled and we're hoping to see outcomes of that trial in the next few years so that we can actually have that finite definitive objective criteria to say, hey, darulutamide actually looks when compared head to head a little bit better in terms of cognitive side effects. Speaker 1 Absolutely. It's not just about their approvals. We have to keep our patients on these medications long term and quality of life should be at the center of all this. NIAGARA Trial: ctDNA in Bladder Cancer & Episode Recap OK, now on to our last abstract. Looking at the hot topic of CTDNA to set the stage based off NIGRA trial which is dirvalumab with chemotherapy upfront followed by surgery and then additional dirvalumab in muscle invasive resectable bladder cancer was now FDA approved and is our preferred option for this subset. Here at ASCO 2025, we saw additional data around CTDNA by Doctor Tom Powells, CTN. What did the study show? And importantly, what does it really mean for us out in the practice? Speaker 2 Yeah. I think CTDNA is a really interesting marker for minimal residual disease in solid tumors. It's really made its initial splash in colon cancer, but we're starting to see a good amount of data in our bladder cancer trials. The initial one was in the in VIGOR trials with adjuvant atezolizumab or CTDNA positivity was associated with poor prognosis. We're seeing that another cohort here in Niagara mirrored quite well the patients who have positive CT DNA after surgery. These are patients who have a bit poorer prognosis for event free survival over the first three to four years. When we're looking at the benefit of durvalumab added to neoadjuvant chemotherapy, you see a late separation of the curves for CT DNA positive disease, but these curves do separate and then in CT DNA negative disease, interestingly there is also an improvement of adding diralimab in that patient population. It says to me that CT DNA is not perfect as a biomarker, but it also says to me that diralimab has a benefit across populations. We really need to be finding those patients at highest risk for recurrence and trying to intensify their therapy if you will and then post cystectomy that disease free survival by CT DNA detection. I think here you're seeing really that CT DNA positivity have the poorest outcomes. Some of these patients are drifting off and having disease recurrences within that first year to year and a half. So I think those are the patients that we really need to be intensifying treatment upfront. What's humbling is that even in CT DNA negative disease, right, even in post cystectomy, we're seeing a benefit which really means we don't have the most accurate biomarker and we need to be thinking about intensifying treatment. Certainly if it's a negative post op CT DNA result, it actually is a good news for our patients as we're incorporating CT DNA into some of our practices. Some of our surgeons are starting to send this off. We're helping our patients interpret this. So for now it's a good prognosis marker. But certainly across population, I think we should be thinking about Doralimab for that intention to treat population for Niagara. Speaker 1 Absolutely. And we've seen this over and over in all disease sites that CT DNA positive remains a poor prognostic marker. Before we close TN outside clinical trials. Are you using CT DNA in any particular settings in your clinic today? Speaker 2 Mostly bladder cancer. For Gu cancer we have the most data for CT DNA based on the signature assay in bladder cancer, less data for tumor informed signature testing. In kidney cancer, there are some tumor free if you will, tumor non informed CT DNA strategies that I think keeping an eye on in terms of their relevance with methylation status for kidney cancer and then prostate cancer, it's really hard to beat PSA as a biomarker. I think much more to come in terms of what will be clinically useful for prostate cancer and whether we can find something that will add to what we have in terms of just positive versus negative. I do think the gene specific mutations when we get down to really drilling for the somatic alterations as we just discussed earlier, I do use CT DNA in terms of the garden Tempest liquid, Foundation liquid, Keras Liquid, those types of profiling that give me gene level data and we'll use that in prostate cancer. Speaker 3 The panel consensus has been that it is not a perfect tool, but certainly associated with poor prognosis. DN Thank you so much for walking us through these four important abstracts from annual ASCO 2025 for our listeners. Let us go real quick recap. Speaker 1 In this episode with Doctor Tian Zhang from UT Southwestern, we've covered four key Gu malignancy abstracts from ASCO 2025 First Keynote 564, which continues to reinforce the role of adjuvant pembrolizumab in renal cell carcinoma based off mature overall survival benefit. And here the hazard ratio is 0.66 and median overall survival with pembro has not reached. That's a good thing. Then we touched on AMPLITUDE trial and metastatic hormone sensitive prostate cancer where PARP inhibitor with abiraterone improved progression free survival in homologous recombinant repair mutated disease. Speaker 3 Oh, as I had mentioned during our discussion, to me this study highlights the importance of germline and somatic testing in prostate. Speaker 1 Cancer. Yeah, absolutely. We then also discussed Aronote study where darrellutamide plus ADT improved the quality via flight for a metastatic hormone sensitive prostate cancer patients and talk about timings. Minutes after this presentation, their aleutamide was approved in this space. Speaker 3 Right. And to close off, we discussed the Niagara trial where CTDNA shows prognostic value in muscle invasive bladder cancer with peri and post of Durbel map. Thanks for joining us. Check out our other episodes for more conference highlights and treatment algorithms. We are the oncology brothers.