Advances in the Treatment Genitourinary Cancers

How are the latest data shaping real‑world care in genitourinary oncology?

In this episode of Podium Perspectives, leading GU oncology experts Petros Grivas, MD, PhD, FASCO and Rana R. McKay, MD, FASCO distill key findings and emerging themes from this year’s GU research—focusing on what matters most for clinical practice. From evolving treatment paradigms to promising therapeutic strategies gaining momentum, they discuss how new data may influence patient selection, sequencing decisions, and future standards of care.

 Designed for busy clinicians, this focused conversation translates high‑impact congress insights into practical takeaways—bridging evidence from podium to practice.

 Listen now to stay current on advances shaping the treatment of GU cancers—powered by Vaniam Group.

This podcast is for informational purposes only and does not constitute medical advice.

Transcript

SPEAKER_02 0:02

Welcome to Podium Perspectives, powered by Vanium Group.

SPEAKER_00 0:11

Welcome to Podium Perspectives, Advances in the Treatment of Gentle Urinary Cancers, Ascode U highlights, a new podcast that shares up-to-date insights across oncology and rare disease. I'm Dr. Petrus Grivas. I'm a professor at the University of Washington and Fred Hartz Cancer Center here in Seattle, and I'm so excited and thrilled to participate in this series with my great friend and colleague, an awesome contributor in the landscape change in geooncology and global leader, Dr. Rena McKay from UC San Diego. Rana, welcome.

SPEAKER_01 0:44

Oh my goodness, Petra, thank you so much for the kind introduction. It's really great to be here with you all. In today's episode, Vanium Group has brought us together to really discuss all of the highlights from GUASCO, which just happened. And gosh, so many amazing data getting presented. It's like hard to keep up. So totally excited to dive in.

SPEAKER_00 1:05

Thank you, Rana. And uh needless to say, you know, you're an amazing faculty, you're a leader, you're a mentor. GU Cancer's program at UC San Diego with major contributions. And uh, you know, it's amazing to see the data from ASCO GU. And uh I know we're sitting together there watching some of those presentations. And uh I'll start us off um uh discussing a little bit about bladder cancer, and I would love your opinion too. Uh I was really, really, you know, uh excited to see data from Keynote B15 trial that our dear friend and colleague uh Dr. Matt Galsky presented. Uh and the data from Keynote B15, just to arrange the audience briefly, uh, is this a phase 3 trial randomized, randomizing patients uh 2 and 4 move adotin plus pembrolyzuma, the new very promising combination that has shown overall survival and PFS benefit in metastatic disease from Lyme with the V3O2 trial. So EV Pembroke was compared uh to uh neoaljuvan uh gem cysts, and the EV Pembroke was given in a perioperative fashion, both neoadjuvant and adjuvant before and after radical stectomy and left nodissection. Uh that trial uh it of course applies to cisplatin eligible patients uh with localized muscle-based bladder cancer, uh, and the predominant histology had to be urthelial conventional histology carcinoma. Uh, EV Pembroke perioperatively, again neoaljuvan and adjuvant, uh, significantly prolonged event-free survival and overall survival and resulted in a very promising, much higher pathological complete response rate, reaching 56% in all cameras in the intended treat population, uh, which is much higher than what we have seen with GemCs in this trial and also historically. Uh, we're awaiting uh for regulatory review uh about if Pembroke is already approved uh for supplanting ineligible patients in this setting, uh perioperative based on the Kynote 905 trial, but uh we're waiting also for the expansion of that approval uh based on Kinote B15, based on the ASCO GU data. Of course, you know, toxicity is very important to uh review and comment. I would say that uh if pembro requires close attention. There are multiple side effects that can happen, or immune related with pembroly zoom up, and of course, uh enforcement of adotinate related, peripheral neuropathy, skin raspuritis, hyperglycemia, anorexia, weight loss, fatigue, um uh lose tool, nausea, uh taste changes to name a few. Cytopinias are much less common with this regimen. Uh, and of course, the other big question, Arena, and I would love your thoughts, is what about the new adjuvant and adjuvant therapy phase contributions? Do we need both? I tend to go with trial design for now and try to do both if I can, but based on toxicities, I may potentially adjust. Uh, what are your thoughts?

SPEAKER_01 3:48

Oh my goodness, this data is just game-changing, right? Like E. V. Pembroke really across the board. Um, and I think it's gonna change the way we treat patients in the perioperative setting. Um, I think this really has supplanted uh cisplatinum-based uh chemotherapy for a large uh proportion of individuals. The path CR rates are just so high, and I think it leaves a lot of individuals questioning okay, what's the utility of the outback treatment post-resection in the adjuvant setting? How can we better optimize that? You know, I believe it's my understanding that patients receive three cycles pre and the remainder of the therapy post. So this is three cycles of treatment. It's actually not a lot of treatment, um, was able to um, you know, elicit a pathologic response of, you know, over 55%. So a lot of questions about what to do.

SPEAKER_00 4:40

Absolutely. You said it so well, Rana. And you know, it's amazing to see the field moving so fast forward. As you mentioned, you know, there are many patients who get neoadgeva and ivipembro. Uh, many of them, most of them were the vast majority went on to radical cystectomy. And the reassuring uh, I think, data point is that the uh proportion of patients who underwent radical cysteomy lethal dissection was very similar in the two groups, uh, showing that EV Pembro is feasible uh and uh it does not compromise the ability of patients to undergo curative intent therapy. So I think it's very important to note that. And also the time to surgery seems to be comparable, at least based on the Kino 905 trial. And of course, the big questions about the adjuvant therapy phase contributions. About two-thirds of the patients uh went on and received uh the adjuvant E. V. Pembroke. Uh, and in the consort diagram, we saw the reasons why people may not have uh proceeded with that therapy portion. And your amazing colleague and mentee, uh Dr. Tyler Steele, did a great job in that discussion, Rana.

SPEAKER_01 5:40

I know it's amazing. A lot of uh it's really an exciting time in bladder cancer. You know, I think uh patients are living longer, they're living better, and hopefully with this therapy, we're actually curing more people from ever-developing metastatic disease. Um, and uh it's gonna be really exciting to see the long-term follow-up from the trial.

SPEAKER_00 5:59

Absolutely, absolutely. And uh, I think the last quick comment I would say, we still wait, of course, for the manuscript. Uh, but uh the you know it's very hard to achieve both EFS and OS benefit in the pay operate trial trial in muscle-based bladder cancer. And I think the keynote B15 in susplatin eligible patients comes to complement the data from keynote 905 trial that we saw from Dr. Chris Wolstecki uh at ESMO2025 in Berlin, and that now is published at the Newgame Journal of Medicine. Very briefly, keynote 905 is EV Pembro, same combination perioperatively before and after radical selective left nodection versus no perioperative therapy in susplatting ineligible patients. Again, that is published at the Newton Journal of Medicine and led to the F the approval of EV Pembroke as perioperative treatment in susplatting ineligible patients. There are some nuances in terms of the number of cycles. Neoadjuvantly, for example, there were three cycles given neo-adjuvantly and keynote 905, which is plotting ineligible patients, four cycles uh in Kinote B15 is platinum eligible patients, mostly for logistical reasons to try to match up the Gem 6 in the Kinote B15 trial. Uh but overall, I think the data look very strong, and as you said, and uh we look forward for the expansion of the label uh in uh muscle vegetables in splatin-eligible patients. Moving along now, uh it's so much talk about, of course, in bladder cancer. Of course, there are many other data sets, posters, presentations, uh retained to trial by Dr. Catalia, and uh great discussion by Dr. Jonathan Wright, my colleague here. We saw data from Dr. Belmont uh uh about uh in vigor 0-11 trial, uh, Dr. uh Professor Powell's about uh disidamovedotin data. So a lot to cover in bladder cancer. We don't have the time to dive in today, but I know hopefully we'll have more time in future um podcasts, Rana. It's really amazing to see the field moving forwards. Uh, of course, in um uh the other quick thing I will before we go to prostate, um, what's your thoughts about city DNA in the adjuvant setting? Are you incorporating C DNA testing based on the Invigor Zero 11 trial? Are you extrapolating to peroperative neoadgevan immunotherapy trials or you you keep it only in the niche of patients?

SPEAKER_01 8:13

You know, very good question. I think many of us are ordering it as a data point um just to understand uh prognosis because it is informative in the discussion around prognosis. But whether it's actually being used, especially now with the um EV Pembroke data, whether it's actually being used to guide the type of therapy that somebody gets is still uh to be determined. Um, you know, the modern trial is going to be looking at uh therapy escalation, de-escalation strategies for patients that are positive or negative. And I think um, you know, hopefully there'll be additional insights from that. Um, but I think it's an incredibly useful tool. But I think um it we need better prospective data now aligned with the current standard of care. You know, the standard of care keeps changing in bladder at every meeting. It's you can't keep up with it.

SPEAKER_00 9:05

Totally agree. And very, very briefly for the audience, InVigor 011 trial was designed to confirm the hypothesis of Invigo 010. Uh, this was uh a population of patients who had radical cystectomy and they were tested for uh uh by the signature tumor-informed assay. If they were still DNA positive, they were randomized to a tesolysumop antipDL1 uh versus placebo, and that uh trial, randomized trial, showed significant uh benefit, uh disease free survival and overall survival benefit with a tesolisum up versus placebo, and a tesolism up reduced DNA levels, increased the clearance in many patients. The big question is whether this survival benefit in those immunotherapy naive patients, how do we extrapolate that uh in patients who had received already immunotherapy in the neo-advan setting? So many questions are uh still uh pending, but definitely very important trial in Vigor Zero 11. And to close the bladder cancer session, quick uh comment uh the movein, anti-HERE2 antibody drug conjugate. We saw data by Professor Powell's looking at high response rates in here too high and even here too lower level of expression in merastatic urethyl carcinoma with this anti-HERE2 antibody drug conjugate uh having the same payload with M4 Movidotin, the MMAE. Rana, do you see a future with DV, the serum of a dotin after EV, or do you think it may be hard?

SPEAKER_01 10:27

No, I absolutely do. I mean, I think we need to, I think for me, her two is an actionable target in your thelial cancer, and it needs to be leveraged to improve outcomes for patients. The biggest question is how do you, how are you gonna sequence this within the existing landscape? I think the frontline study is challenging because the bar is incredibly high with EV Pem, bro. So how do you integrate? Is it something that you're gonna do frontline, or is it something that you're gonna do post exposure to EV Pem and what's gonna be the activity in uh a tumor that's been exposed to EV? So I think I think it's definitely here to stay. It's just a matter of how to integrate.

SPEAKER_00 11:11

Very well said, Rana, as always. And I let you uh uh comment and discuss the exciting data in Rima Cell carcinoma. It's so much going on, and you have been leading the field.

SPEAKER_01 11:21

You know, it was really exciting to see two large phase three trials readout in RCC that are likely going to be um practice changing. So, first we'll start with Light Spark O22. Um, this builds on the successes of keynote 564. Keynote 564 was a study that was conducted for patients that had a um high risk of relapse post-nephrectomy, getting adjuvant pembrolyzomab, um, and looking at disease-free survival and overall survival. It's the first therapy that's ever demonstrated an improvement in overall survival, um, you know, from thousands of uh uh different patients that have enrolled on multiple adjuvant studies in the cytokine era, the TKI era, the first study to actually demonstrate an improvement in OS. And now this has become a standard of care. And so LightSpark O22 basically looked at the addition of Balzutophan to the backbone of pembrolizomab compared to pembrolizomab for patients with high-risk clear cell RCC post-nephrectomy. And, you know, here the study was positive. It met its primary endpoint, resulting in a statistically significant improvement in disease-free survival of combination therapy versus pembrolizomab. Um, and this is, you know, against a very active control arm that improves overall survival. I think the toxicity that was observed was that akin to what we would expect with uh belzudafan, a HIF2 alpha inhibitor, which can cause um anemia, in some cases hypoxia, and also pembrolizomab as a checkpoint inhibitor. So I think um there's many questions that remain unanswered regarding who um, you know, like who should be getting um escalated therapy. Um actually the first question is who should be getting adjuvant therapy? And then answering the, okay, of the people that get adjuvant therapy, who should be escalated? Like how should I administer the therapy? Just Pembroke alone or Pembroke with bells? So I think there's gonna need to be additional follow-up on OS. The OS data are still quite immature. But um, you know, I think that uh this data are really uh, you know, definitely shaking the field. It's it's not like the TKI era where we tested a bunch of TKIs that were all negative. I think the tolerance to a HIV-alpha inhibitor differs from that of a TKI. And I think to see a really profound DFS improvement in the context of this robust study is really great. So I'd love to understand your perspectives around, you know, um therapy escalation in the adjuvant setting. You know, we treat, there's probably a subset that are going to be cured with surgery alone. There's probably a subset that are gonna be destined to relapse regardless of what you do. But how do you leverage that group that's in the middle that you could potentially cure with an adjuvant strategy?

SPEAKER_00 14:13

That's a great summary. I agree with you. I think it comes down to refinement of patient selection. And we're getting there. We need more work with biomarkers. I know in the field of phrenal cell carcinoma, a lot of work with chem one levels, circulating humor DNA, maybe coming with you know better acids with better performance characteristics. I think, you know, I I remember uh, you know, when we talk about prognostic estimates and prognostic nomograms, can this help us calculate the risk of recurrence and then help inform the dialogue? Uh uh since we lack predictive biomarkers for now, maybe Kim One may be validated in that regard. So I think it comes down to patient selection. I think disease free survival is a meaningful end point. Uh, and I say that because you know patient advocates say that, and I know you and me talk to many advocacy groups, and also uh because if we think about over survival, which is ideal and the goal standard and preferred to see, of course, but sometimes can be confounded by actual subsequent salvast therapies, effectiveness of those salvastic, and many other factors, so uh, you know, comorbidities and stuff. So I I think OS is the goal standard, but this this free survival I think is a very reasonable, in my humble opinion, acceptable endpoint, but it has to be balanced to your point uh with toxicity and quality of life, patient report outcomes, metrics. Uh it comes down to individual patient decision making, right? Pros and cons. For now, Pembrolizum app, uh based on keynote 564, has OS benefit, is safety approved, have to see what will happen with Belgi Fun addition in that context. And uh if it gets approved, I think individual decision making balancing toxicity uh and and benefit uh and uh you know cost considerations, of course, is another factor.

SPEAKER_01 15:53

No, absolutely. I think uh all well said around you know what's uh what's the you know benefit versus the risk, and you know, for any given patient, that scale of what's my risk tolerance for what I'm gonna gain is different. And you can have 10 patients in front of you and they're all gonna make a slightly different um decision, even though the their risk may be the same given you know, patients have um you know their different states, different things that they may value and different social environments and networks. And so I think uh uh there's a lot of um perspective around risk in that regard, you know. So uh super exciting to also have another phase three reported out at the same meeting, two back-to-back phase three oral presentations, super exciting. So the second um large study that read out that is you know practice changing, even I think tomorrow is like Light Spark 011. This was a phase three of Belzudophan lymvatanib versus cabboxantanib post uh PD1, PDL1 exposure for people with advanced clear cell RCC. So this was a um study that was looking at therapy escalation in the second line setting post uh modern day IO treatments. You know, I think the sequencing of treatments in the context of advanced disease has really been an open field because a lot of the old studies of secondline therapies were not done in the modern era where patients were receiving IO combination strategies frontline. And we gleaned some insights from contact three, looking at the control arm of cabal xantanib in that study, and um, you know, other um, you know, T NEVO, for example, T NEVO two that looked at um uh tvozinib nivulomab and looking at the activity of tavozinib in patients that may have received more modern-day frontline IO, but there hasn't necessarily been a specific study designed at what's the appropriate sequence or escalation strategy in later line. And so this was really great to see this data. Um it was a positive trial demonstrating an improvement in PFS of the combination compared to Cabo Xantinin, um, with also an improved objective response rate. I think the OS data are still, you know, immature, um, though there is a numerical uh difference in uh OS, uh, you know, like longer with the combo. You know, what was really striking to me about this data that I think was a little bit unexpected was the duration of response. And so there's a subset of patients, um, probably at about a third of patients, like when you look at the landmark PFS, about a third of patients were alive and um progression free at two years, which is really a unique thing when you're talking about a second-line therapy strategy. Um, so some of these responses I think tended to be quite durable. So I think it's gonna be really important to understand um, you know, um how that evolves. Um, you know, and I think as we think about mechanism of action of Belzudophan as a HIF2 targeted agent that very specifically targets HIF2 alpha, um, you know, I think it's positioning probably earlier not in less heterogeneous disease that's more addicted to the VEGF HIF pathway is probably um uh you know going to be um uh informative and impressive. I think we saw that in 022 and um now with 011. So I I love your impressions. Um, you know, if you have a patient before you now and progressing on frontline, is this something that you would consider? Or how how do you how do you uh strategize?

SPEAKER_00 19:46

I think your points are well taken. And you know, it's hard to get you know positive phase three trials, right? And especially in the post-immunotherapy setting and metastatic inner cell carcinoma, we have seen previous trials utilizing a rechallenge of immunotherapy strategy uh that were not positive, and you know, the dioric challenge remains a question in other cancer types. Uh, but I think this trial, uh, based on the results you quoted, uh, the response rate, you know, the signal for OS, uh, even if it did not reach significance, it's still, I think, a numerical difference there. There's a trend, and also, you know, putting together uh the totality of the data in this setting, I think uh uh balzutanol and vatinoid represents a very reasonable option. And of course, again, comes down to individual discussion with the patients, medical accommodities, you know, particular factors in the individual patients. But I think it's a it's a very compelling, I would say, option for patients. Uh, and uh uh we we need to optimize the therapy sequence. We do not know the perfect, the optimal sequence, but usually we try to use the best you know treatments as early as we can, to your point. Uh, and maybe we can learn more from biomarket analysis. But I agree with your uh comments about you know reviewing the data. Of course, if that it's approved, I think it's a very viable option to at least discuss, and I'm sure it's going to uh be used uh for a proportion of patients.

SPEAKER_01 21:06

Yeah, super exciting. All right.

SPEAKER_00 21:08

Absolutely.

SPEAKER_01 21:10

So uh that's kidney. I think there's gonna be a lot to come over the next uh couple of meetings as these data get further dissected with subsequent subgroup analysis. So kind of taking us home here is prostate, and uh, you know, I think that we saw top-line data from piece three, uh, the final OS. Uh maybe Petras, you can walk us through uh the piece three uh data that were presented.

SPEAKER_00 21:33

So I'll try to do keep it brief because time uh runs fast. Piece three randomized phase three trial looking at the combination of radium Bluetooth 3 plus enzyletamide versus engelatamide alone in patients with metastatic castrous resistant prostate cancer with bone metastasis. 446 patients with mild symptoms or no symptoms uh were randomized, and uh there were specific selection criteria, of course, because of the use. Of radium in this population based on the uh older data uh from the Al Simca trial that led to the Radium 2 to 3 FDA approval back in the day. Uh, this trial, as you mentioned, was positive for overall survival. Uh, it's interesting because uh if we look at the capile maybe curves, there is some crossing of the curves. Uh, and looking at uh uh uh at that statistically, it may violate the proportional hazards model uh assumption. So that created a lot of discussion. I think Dr. Evan, you did a great job uh in his uh discussion at the meeting, which we attended together. Overall, I think one major point is that the vast majority of those patients did not receive prior ARPI, uh anti-hydrogen, androgen axis inhibitor, a bit other orange altamide or APA or Daro. So these were technically the vast majority, you know, uh ARPI naive patients, and this could be an option for patients, you know, in the first line setting of metastatic CRPC. Uh I think overall uh it it uh reminds us of the value of radium 223. Uh and it's an active drug. It's probably one of the few agents with two positive phase three trials. Uh, and I think it's important to remember that. So in in selected patients who, for whatever reason, uh, you know, did not receive prior RPI, I think radium 223 plus and zultamite uh looks a very reasonable option. And the question is, how do you extrapolate in those with prior RPI exposure? I think that could be a role in selected patients. I would love your thoughts, Rana.

SPEAKER_01 23:23

No, totally. You know, I think the trial didn't specifically obviously um answer that question. I think that's the the big question in the field now as the frontline space is is changing. But um, I mean, I think this was an incredibly active regimen. And when we look at the long-term um overall survival, you know, pretty impressive to see an overall survival of 38 months, I think, in the combination. So, you know, um, it's gonna be interesting to see how people end up uh like using radium. I mean, in my practice, I want to ensure patients have access to every single life prolonging therapy when they have MCRPC. MCRPC is grossly undertreated. Most 25% of patients never actually see any treatment. And of patients that see frontline, 50% never see second line. And many people don't ever see um, you know, subsequent life prolonging therapy. Um, most people mainly see a subsequent RP as their main life prolonging therapy in in the MCRPC setting. So we've got work to do. So I think this is definitely hopefully gonna help provide another um uh therapy for individuals that could improve their outcomes. And I think with that, maybe we'd segue into uh uh PSMA edition, uh, updates from quality of life that were presented, um, the initial data from PSMA edition presented at ESMA last year. This was a trial that looked at uh the addition of lutetium PSMA 617 to the backbone of ADT RP for patients with PSMA positive, hormone-sensitive, uh, metastatic hormone-sensitive prostate cancer. And here we see the subset analysis with regards to the health-related quality of life. And while patients had escalated therapy with a different triplet regimen, if you will, ADT RP and uh radiopharmaceutical, we didn't see any major um signal with regards to compromise quality of life or pain control in this context. Um, you know, time to symptomatic skeletal-related event uh was not reached in either arm. So, you know, I think we're gonna, there's a lot of questions that remain around how to integrate lutetium into the frontline setting in the hormone-sensitive setting. How much lutetium? Should people get all six doses? What's the right patient population? Um, so I think there's a lot of uh questions that remain to be had about its integration. So I don't know if you have uh thoughts um on uh the PSMA addition and the integration of upfront uh radiopharmaceutical therapy.

SPEAKER_00 25:53

Great points. Uh Rana, I think we are struggling to optimize you know therapy duration, especially in this setting, right? Do you need all those six doses, right? If you get a great response and you you know saturate the targets, let's say, do you need to go beyond two or three cycles? That's an open question. I think we need some potential de-escalation trials. And I know you're working uh, you know, in interesting trial designs, you know, through Alliance and cooperative groups, uh, because you know it's amazing to see pay trials that met uh the primary end point, and that's important to note and acknowledge in PSMA addition. At the same time, uh, I think questions remain about the optimal uh threp duration utilization, patient selection, uh adaptation, right, using PSMA PET, for example, during treatment. And I hope that we can get those answers potentially through cooperative good trials. I think it's good to have options for the patients. We saw, you know, Capitello 281 trial, PSMA addition, amplitude. We're starting to create buckets and categories based on biomarkers. Uh, I mean we need to sort out uh you know logistics, patient selection, um, optimal therapy duration toxistic management. So we'll see what happens with regular review, but uh I I enjoy your comments.

SPEAKER_01 27:04

Now, super exciting time to be uh caring for patients with uh GU cancers. Um, a lot of exciting uh therapies and biomarkers and diagnostics coming down the pike. So it's been really great um, you know, having you all listen to this uh episode of Podium Perspective. Um, Patrios, why don't you take us away?

SPEAKER_00 27:23

Rana, such a great pleasure to talk to you. I get energized and inspired every time since 2013 when we first met at the AACR Ascovale workshop, and we, you know, we keep working together. Uh it's amazing to discuss. I want to thank the audience for attending. Please follow and share to stay current as new data come out so rapidly and so quickly. This podcast episode with Dr. McCain and myself is for educational purposes only and cannot be used for medical advice, of course. Please uh stay tuned and I hope to see you again next time. Thanks again for the time, and thanks, Joanna, for your time too.

SPEAKER_02 28:02

Thank you all. Thanks for joining Podium Perspectives, powered by Vanium Group. This episode is for educational purposes only and is not medical advice.