So starting off, we'll be discussing the first of six important abstracts with the Phase III KEYNOTE-905 study that we'll be evaluating perioperative enfortumab vedotin plus Pembrolizumab in MIBC patients who are cisplatin-ineligible. So we know based on data from the EV-302 trial that was presented by Dr. Tom Powles back in ESMO of 2023 when we compare enfortumab vedotin plus Pembrolizumab to a cisplatin or a carboplatin based chemotherapy regimen, we saw that enfortumab vedotin in patients with metastatic or locally advanced urothelial carcinoma, that EV plus Pembrolizumab outperformed chemotherapy, both with regards to progression free survival where we saw a hazard ratio of 0.45 with a median PFS of 12.5 versus 6.1.
And most importantly, we saw a significant both statistically and clinically meaningful benefit with regards to overall survival in favor of EV plus Pembrolizumab, with a median overall survival of 32 months with EV Pembrolizumab versus 16 months with chemo. And so this trial ushered EV plus Pembrolizumab as the first line metastatic urothelial carcinoma option in this setting. So it makes sense that we would want to evaluate this in earlier line settings and importantly in patients who cannot receive cisplatin based chemotherapy.
So to this end, the KEYNOTE-905 or the EV-303 trial will evaluate patients who are cisplatin ineligible or cisplatin eligible who are refusing or declining cisplatin treatment naive. And they're clinical T2, T4a, node negative, M0 or they have in the positive nodes. And these patients will be randomized approximately 857 into one of three arms.
We have Arm A, which is Pembrolizumab given 200 milligrams IV every three weeks for three cycles. And this mirrors the PURE-01 trial design, which gave Pembrolizumab in the neoadjuvant setting. We have Arm B, which is observation alone, and we have Arm C, which is neoadjuvant EV given at a dose of one point 25 milligrams per kilogram plus Pembrolizumab, 200 milligrams IV given every three weeks for up to three cycles, followed in all arms by radical cystectomy plus a pelvic lymph node dissection.
And importantly, this is not only a neoadjuvant trial, but also in the adjuvant phase. Patients will also receive the neoadjuvant drug in this setting as well. So Arm A will receive pembrolizumab as well, 200 milligrams IV every three weeks for 14 cycles. Arm B will continue with observation and then Arm C will receive EV plus pembrolizumab as described in the study illustration.
The primary endpoint in this study is event-free survival and namely the comparison of Arm C, which is EV plus pembrolizumab versus observation. And key secondary endpoints are the comparison of the event-free survival or EFS in Arm A versus Arm B as well as overall survival, important pathologic complete response, which we know historically is about 40 to 45% with cisplatin-based regimens, disease-free survival, and of course safety and tolerability.
So what are the implications of a positive trial for the EV-303 trial? So we know that about 50% of patients with muscle invasive bladder cancer are cisplatin ineligible in practice. And so EV plus pembrolizumab could represent the first non-chemoperioperative option for the cisplatin ineligible patients. So it really adds a very important treatment for these patients and not just proceeding directly to radical cystectomy or considering pembrolizumab alone.
This may have huge implications for future bladder sparing options as well. We know still that cisplatin-based chemotherapy is considered a radiosensitizer in this setting. So if we see improved results here, potentially we may incorporate EV plus pembrolizumab into our treatment paradigm for these patients. But the important question remains if these patients receive EV plus pembrolizumab in the perioperative setting and then progress to a locally advanced or metastatic state, how do we treat them? How do we rescue these patients when we've already "burned" EV plus pembrolizumab as an option? So this is going to be important for future trial design and considering first, second, third line treatment settings in this new paradigm of EV plus pembrolizumab for-naive patients.
Next, the second trial we'll be discussing is the ENZARAD or the ANZUP 1303 trial that will be presented by Dr. Paul Nguyen from Boston. And this is a randomized phase three trial ADT with radiation therapy, plus or minus Enzalutamide for high-risk clinically localized prostate cancer. And this will be presented Sunday, October the 19th. And so if we take a step back and we look at the NCCN guidelines and the treatment paradigm currently for high-risk localized prostate cancer in patients who are symptomatic or have at least a five-year life expectancy, the first line therapy is still radiotherapy plus ADT and they say here 12 to 36 months, but typically it's in the higher range, 24 to 36. And we may also consider abiraterone for very high-risk patients based on the STAMPEDE data.
And so in this trial, this will include about 800 patients who have localized prostate cancer and considered candidates for external beam radiotherapy and are at high risk of recurrence based on the NCCN stratification. And these patients will be randomized one-to-one with the randomization stratified by Gleason score stage and PSA and study site to one of two arms. The experimental arm will receive enzalutamide for two years and LHRH agonist for two years as well as radiotherapy. That will be started week 16 or 24. So they start hormone therapy before and then radiotherapy 16, 24 weeks. And in the control arm, they'll be receiving the same treatment, but instead of enzalutamide, they'll be receiving only six months of a non-steroidal anti-androgen such as bicalutamide or flutamide.
What are the potential implications of a positive trial for the ENZARAD trial? So by further intensifying with enzalutamide in this setting, this could potentially be a cure for high-risk localized prostate cancer patients by targeting those that may have escaped the therapy when it's ADT alone. Furthermore, this trial offers the potential to move ARPIs further up the prostate cancer treatment landscape, as we have seen with the STAMPEDE trial previously with abiraterone.
The questions remain similar to what we discussed in the EV-303 trial. How do we treat therapy failures? So in patients of already seen an ARPI who progressed to a metastatic state, have we burned this? Is there any value in giving them abiraterone later on? If they initially respond and there's a treatment or a recurrence free interval, let's say two or three years, there's going to be a lot of nuance here. And who do we consider as an abiraterone failure versus not? So these are questions to be answered.
And then the second thing is what is the toxicity of further intensifying therapy? We know that ADT is associated a lot of side effects, and when we add ARPIs, be it cardiovascular toxicity, quality of life, hot flashes, etc, how will patients handle the additional two years? And so this really highlights the importance of shared decision making, explaining to patients the risk of their disease as well as the quality of life implications and making a shared decision between the patient, physician, and importantly the family as well.
Next, we'll be presenting or discussing the overall survival results from the EMBARK trial that will be presented by Dr. Neal Shore on Sunday where we look at overall survival of Enzalutamide and biochemical recurrent prostate cancer. So the EMBARK trial has been previously presented initially at AUA 2023, and as a refresher, EMBARK included patients who failed after either radical prostatectomy alone or radiation alone, or both radical prostatectomy and radiation, and they needed PSA greater equal to one after radical prostatectomy or at least two nanograms per mL above the nadir for primary EBRT.
Importantly, these patients had a PSA doubling time that was quite short, nine months or less, and they had a negative metastatic workup with conventional imaging. So these are biochemically recurrent patients with a negative CT/bone scanner on MRI. They had no prior hormonal therapy at least nine months before randomization, and most patients were hormone naive in this trial.
Eligible patients over a thousand randomized one of three arms, either enzalutamide monotherapy, which was an open label arm, or they received an LHRH leuprolide alone, or they received both enzalutamide plus leuprolide. And the primary endpoint was MFS here with a key secondary endpoint for overall survival, which will be presented at ESMO. For the primary endpoint metastasis-free survival and the comparison of enzalutamide plus leuprolide versus leuprolide alone. We saw a significant benefit in favor of adding enzalutamide in this setting with a hazard ratio of 0.42. And then also for the comparison of enzalutamide alone versus leuprolide, there also was an MFS benefit in favor of enzalutamide with a hazard ratio of 0.63, which was also statistically significant.
We already know that enzalutamide is the only ARPI approved in the high-risk biochemical recurrence space based on this MFS benefit, both for the combination of enzalutamide plus leuprolide and enzalutamide monotherapy, but a further overall survival benefit or demonstrating that at least would further establish enzalutamide in this disease space. And so this would be very important work in this setting. The question that remains and has remained for a while is, well, most of these patients with biochemically recurrent disease after primary therapy are being staged nowadays with a PSMA PET, whereas EMBARK uses conventional imaging. So how do we translate the results that we see with EMBARK to a patient who staged with PSMA PET? And a lot of important work is going on in this setting, and this remains to be answered.
At this point, I'll be turning it over to Zach who will be discussing PSMAddition as well as two other very important trials that be presented ESMO and contextualizing these results as always in the setting of how they may change our practice.
Zachary Klaassen: Thanks so much, Rashid. So the fourth abstract we'll be discussing is presented by Dr. Scott Tagawa on Sunday, October 19th in Berlin. And this is the phase 3 trial of lutetium combined with ADT and an ARPI in patients with PSMA positive mHSPC. As you mentioned, the PSMAddition study of this is one that everybody's pretty excited to see the data for. We did have a positive press release saying that it met its primary endpoint. And so this complements well what we've already seen in mCRPC for 177Lu-PSMA-617.
Of course, in 2021, we had the VISION trial, which showed an overall survival benefit for lutetium in mCRPC after docetaxel and an ARPI 38% reduction in mortality. This was a positive trial. And then more recently in 2024, we saw the PSMAfore rPFS benefit hazard ratio 0.49, and this was lutetium after an ARPI before docetaxel in the mCRPC setting.
So when we set the landscape for PSMAddition, this is obviously metastatic hormone-sensitive prostate cancer. We look at the population, this is a pretty typical population for HSPC. These patients will receive standard of care in both arms, ADT and an ARPI with the addition of six weekly cycles, excuse me, six cycles every six weeks of 177Lu-PSMA-617. The primary endpoint will be radiographic progression-free survival. And so this will really potentially move up 177Lu-PSMA-617 a little bit further up in the disease space into the mHSPC setting.
So what are the implications of a positive trial? We know that we have a ton of options for mHSPC. This will move RLT into this new disease space. There's several important questions though when we look at the data that will be presented in Berlin. And so one is how good does the rPFS benefit have to be in order to compete with the established OS benefits from several of the trials we already know about such as ARASENS, et cetera.
Does the rPFS have to be 0.6, 0.5, 0.4? This will be topics of discussion, I'm sure following the presentation by Dr. Tagawa. And what are the potential long-term toxicities of radioligand therapy in this earlier disease space? These patients clearly live longer typically than mCRPC patients, so we may see some late toxicities with RLT that we haven't seen to date. And finally, as I mentioned in the trial design, this will be paired with ARPIs and this will be probably several ARPIs. We have several available. They'll be paired with RLT, which is the best one to pair with RLT in the mHSPC setting. So very excited to hear this trial PSMAddition presented at ESMO.
The fifth trial moving to bladder cancer will be presented by Dr. Sheng on Sunday as well in the Presidential Symposium. This is LBA7 Disitamab Vedotin plus Toripalimab versus chemotherapy in first-line, locally advanced or metastatic urothelial carcinoma with HER2 expression.
And so when we look back at the DV plus Tori story, this was presented at ASCO GU 2025, some really impressive data for DV plus Toripalimab for MIBC and HER2 expression. You can see the trial design here. Patients received neoadjuvant treatment followed by radical cystectomy and then followed by adjuvant Toripalimab for 20 cycles. And so the key results from this trial presented at ASCO-GU were the pathological complete response rate was over 63%. The pathological downstaging, the less than or equal to T1 disease was almost 76%. So a really impressive signal for this combination in the neoadjuvant adjuvant setting in patients with MIBC with HER2 expression.
So what are the implications of a positive trial here? So this would be the second ADC plus IO first-line metastatic urothelial carcinoma. As Rashid mentioned earlier, EV plus pembrolizumab is currently the clear number one first-line option in 2025. So this would potentially add to that armamentarium. And importantly, this would also be a potential biomarker specific option for HER2 expression patients. And so we're starting to see some personalization in the metastatic setting if this is a positive trial.
Of course, several questions remain. How does the toxicity profile compare to EV plus pembrolizumab in this metastatic setting? And what are the treatment options going to look like for these patients that failed treatment? What's the second and third-line options going to look like? Our final trial last, but certainly not least, is LBA8 presented by Dr. Tom Powles on Monday, October 20th in the Presidential Symposium. This is IMvigor011, a phase 3 trial of ctDNA-guided adjuvant atezolizumab versus placebo in muscle invasive bladder cancer.
And what's interesting is the atezolizumab adjuvant story has now been around for about five years. We've heard at ASCO 2020 that adjuvant atezolizumab in this setting has no DFS benefit in the intention to treat population hazard ratio of 0.89, 95% confidence intervals crossing one. However, to the credit of the trial and Dr. Powles and colleagues, they did some really, really nice ctDNA studies published in nature in 2021 and really showing that ctDNA in this neoadjuvant setting or adjuvant setting can really guide patient selection.
We certainly see here that if you have a negative ctDNA, whether you receive atezolizumab or not, you're actually going to do quite well. And if you do have a positive ctDNA, they're not going to do as well, but you're going to do better with atezolizumab compared to observation. So this really was the genesis for setting up the IMvigor011 trial. This is the trial design here. This is high risk MIBC patients cystectomy within the past 6 to 24 weeks with no evidence of residual disease. Primary endpoint investigator assessed DFS.
And basically the setup here is a little bit complex, so I'm going to walk through it. They had a ctDNA negative arm, which they presented results at ESMO 2024 confirming that patients with negative ctDNA actually do very well. Where we get into the randomization is in the ctDNA positive arm. So this is where patients are going to be randomized two to one to atezolizumab or placebo for one year. And again, the investigator assessed DFS is the key endpoint, and this is what will be presented as well, 2025.
So what are the implications of a positive trial from IMvigor011. So one year of adjuvant atezolizumab for ctDNA positive MIBC after radical cystectomy could become standard of care. Really taking those patients that have that ctDNA positive status and following them with treatment based on this study. This would become a personalized biomarker selected adjuvant treatment strategy for high risk MIBC patients. Several questions that remain. What's the best treatment option after atezolizumab fails? And how do we continue to use ctDNA testing? Do we follow it serially? Do we treat until patients have a negative ctDNA?
These questions all remain to be answered, and certainly this will be a very interesting trial as we move into more personalization in this disease state. So we want to thank you very much for listening to our pre-ESMO potential practice Changing Data recording. Don't forget to register for exclusive UroToday, ESMO 2025 coverage. Here you can see the URL at the bottom of the slide. We're excited to bring you written coverage straight to your inbox. This is summaries written by clinicians like Rashid and myself for you as clinicians. And so we all look forward to ESMO 2025 in Berlin, Germany, October 17 to 21. And thank you for your attention to our recording.