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 ESMO 2025
We'll start with prostate cancer, where I'm pleased to be joined by our discussing Doctor Atti Shory. Um, we'll be discussing 4 studies across two disease states. So first, to add or to not add, and so we'dmide for non-metastatic prostate cancer, and then really the dawn of precision medicine and castrate sensitive prostate cancer. We know for patients with localized prostate cancer that the addition of ADT2 radiation improves not only metastasis-free survival and overall survival. However, an outstanding question is, what is the benefit of intensifying hormone therapy for patients with Non-metastatic prostate cancer. We know that it's pretty standard practice for patients who meet stampede criteria with ultra high risk non-metastatic prostate cancer to add abiratero. However, the NSA study, um, looked at extending that, um, that patient population to early, even earlier disease states. Um, NZRAD was a, uh, a large phase 3, academic led and investigator initiated clinical trial, um, led by none other than our own Dr. Paul Nyin. Um, it was, uh, I heard it was 13 years in the making, and about 100 of the 800 patients were enrolled at Dana-Farber, so, you know, really some homebred, uh, science and clinical data that we discussed here. Really the question that Ensad was. Investigating was for patients with high risk localized prostate cancer, was the addition of 2 years of enzalutamide to LHRH and radiation. Did it improve metastasis-free survival relative to LHRH plus radiation alone? Um, I will note that that primary endpoint was MFS by conventional imaging and that patients who had positive PSMA PET alone were insufficient to meet that, um. The primary endpoint. Um, the patients included, there were about 10% of patients who were no positive by conventional imaging, 90% of patients with Gleason 8 to 10, and about a half of patients had clinical T3, T4 disease. We saw Ezab did not meet its primary endpoint. There was no improvement in metastasis-free survival by conventional imaging with a hazard ratio of 0.88 and a P value of 0.34 at a median of eight years of follow-up. However, enzalidomide plus, uh, the enzallodamide containing arm did improve PSA progression free survival with a hazard ratio of 0.78. When we look at overall survival, we see again no improvement in overall survival for the enzoiddmide containing arm relative to control. And I think the good news for all of our patients with high risk localized prostate cancer was that your prostate cancer specific survival was 96% to 97%. So these patients do well long term with ADT plus radiation. Not surprisingly, in the enzalutamide arm, we did see higher rates of fatigue, nervous system and hypertension events, although no difference in cardiac events or seizures. When they broke down the data by pre-specified endpoints, those patients who had node positive disease, although a small subset, they did have an improvement in metastasis-free survival with the hazard ratio of 0.43. Those patients who maybe didn't have node positive disease but had another indication for pelvic field radiation had a MFS hazard ratio of 0.47, and that there was not a difference in patient in MFS by a very high risk group. What we saw was MFS was correlated with overall survival both in these patients who were regional node positive by conventional imaging and the pelvic field radiation subgroup. And at the end of the day, I think enide is definitely practice in forming. It tells us that a majority of patients with localized prostate cancer do not need the addition of enzalutamide. However, those patients who were node positive or had another indication um did seem to benefit from ADT plus enzalutamide. Some of the outstanding questions that we have is how do we contextualize this with what we know the benefit of ADT plus aberrateone is per stampede criteria, and are there additional biomarkers that we we can use to select for who are those patients who need this intensification for high risk localized disease? I will note there were some differences between NSRAD and stampede, so higher numbers of clinical T3, T4 disease, higher numbers of N1 positive disease by conventional imaging. And that there was some really intriguing data that came out earlier this year using multimodal AI, so integrating clinical data, digital pathology to come up with a multimodal AI score. Which we saw did um did correlate with an improvement in the addition of abiratero. So on the left hand side you see patients who had MMI low risk. There was no benefit to adding abiratero, whereas those who were MMII high risk, they did benefit from the addition of abiratero in that subgroup. Moving on to the biochemical relapse group, we saw an updated analysis of the Embark study. As many know, EmARC was a study of the addition of enzalutamide plus ADT for patients with high-risk biochemical relapse of prostate cancer. This was initially published in 2023 in the New England Journal of Medicine, led to its FDA approval. treatment for many patients with this high-risk biochemical relapse. To remind folks on the design of embark, these were patients who had a PSA of greater than 1 after prostatectomy, greater than 2 above the 8 after radiation, with a PSA doubling time of less than 9 months and no evidence of metastatic disease by conventional imaging, bone scans and CT scans. Patients were randomized in a 1 to 1 to 1 fashion to enzalutamide plus ADT, ADT alone, or enzalutamide alone. And then at 36 months for those patients who had a PSA of less than 0.2, treatment was suspended and then reinitiated later on at pre pre-specified endpoints. Again, we saw this study met its MFS benefit. What we saw at ESMA was an update of the OS benefit. Again, really briefly, just for contextualization, the median PSA doubling time on this study was about 5 months, median serum PSA level was 5, about 25% of patients had prostatectomy alone, 25% of patients radiation alone, 50% of patients with both prostatectomy and radiation. What we saw from Embark was that the combination of enzalid mite and ADT improved overall survival relative to ADT alone with a hazard ratio of 0.59 and a statistically significant p value. The um the absolute benefit of 8 OS rate was 79% relative to 69%. Um, so again an overall survival benefit, um, in this study. Key secondary endpoints also favored the combination of enzaludide to ADT relative to ADT alone. I will note that enzalutamide, um, while it had a trend towards improvement in overall survival, um, it was not statistically significant. Not surprisingly, the enthalidomide containing arms did have higher rates of treatment related adverse events relative to ADT alone, and some takeaways that we have from embarker that that prior MFS benefit does appear to have translated into OS benefit, albeit with higher toxicity. One of the outstanding questions here is that this study was also launched many years ago, um, before we were really using a lot of PSA PET imaging. So how do we integrate these results into our standard practice? This is a retrospective study of patients who meet the criteria for high-risk biochemical relapse of prostate cancer, and we know that on this retrospective study, about 84 patients had PSMA positive disease, about 50% of those patients had uh M1 disease, and about 25% of patients had polymetastatic disease in greater than 5 sites. There's also been many studies done uh more recently looking at the role of metastasis directed therapy, so not only intensifying hormone therapy, but also intensifying radiation therapy to these oligometastatic sites either with or without intensification of hormone therapy and Uh, for those who haven't seen this paper yet, it's a great, um, publication led by our own David Einstein of Beth Israel, um, which was a NCI working group on biochemical relapse of prostate cancer, which really urge us to better define this disease state by patients who have PSMA positive by PSMA imaging, as opposed to those patients who are truly biochemically relapsed with negative PSMA imaging, negative conventional imaging. And not only looking at metastasis-free survival as one outcome in this population, but also looking at patient centered endpoints, things like treatment-free survival in patients who we realize they have a very protracted disease course and we're looking at the toxicity and the burden of treatment for many of these patients as well. Um, now moving on to the second two public uh publications that we'll talk about is the dawn of precision medicine and castrate sensitive prostate cancer. As many know, the goal of precision medicine is really to target the right treatment to the right patients at the right time, um, to hopefully improve outcomes and minimize toxicity. And that currently much of what we use to decide treatment for metastatic prostate cancer has to do whether the disease is de novo or recurrent or whether the disease is low versus high volume, um, and we're largely deciding between ADT ARPI or the triplet ADTARPI plus chemotherapy. One of the tools that we have in our toolbox, both as a diagnostic and now a therapeutic target is lutician PSMA, which as we know from vision on the left hand side, has shown a PFS and OS benefit in the castrate resistant prostate cancer setting, and then from PSMA 4, we know that um luticium had an RPFS benefit but no OS benefit when used prior to uh docetaxel chemotherapy, although I will note there was crossover on that study. We saw early evidence that moving luticium earlier in the disease course into the metastatic castrate sensitive setting in the upfront PSMA showed a PS PSMA PFS benefit to two cycles of PSMA prior to 6 cycles of dose Taxol relative to dosetaxol alone, however, no RPFS or OS benefit. Again, a small phase two, but showing evidence that lutician may be active earlier in the disease course. All of this sets the stage for PSMA addition, which was a um an all comer randomized phase 3 trial, the first phase 3 study of radioiodin therapy. Um, in, uh, metastatic a sensitive prostate cancer, um, patients were randomized in a 1 to 1 fashion to 6 cycles of Pluto plus ADT and ARPI relative to ADT plus ARPI, the primary endpoint of RPFS, and we'll note that there was crossover allowed for those patients who had confirmed radiographic progression of disease. Um, again, this was an all-comer MCSPC population. 40% of patients had visceral metastasis, 70% of patients had high volume disease, and about 50% of patients had de novo CSPC. On the left hand side of the consort diagram, you'll see about a third of patients, their ARPI was abiratero, 13 was aallutamide, 3 was Eza or Daylutamide, and then about 85% of patients got all 6 cycles of luticium, 93% of patients got greater than 4 cycles of luticium, and then on the right hand side, those patients who were in the 82 + ARPI, about 16% of that. Control arm ultimately did cross over to receive lutic um on protocol. PSMA addition was a positive study. It did meet its primary endpoint with an improvement in RPFS of um a hazard ratio of 0.72 that was statistically significant. In subgroup analysis, we saw that benefit was both in patients with high and low volume disease as well as de novo and recurrent disease. An interim look at overall survival so it shows no improvement in overall survival with a hazard ratio of 0.84 and a p value of 0.12. Key secondary end points we see higher complete response rate, uh, time to PSA progression, time to MCRPC all favoring the lutation containing arm. Not surprisingly, the addition of lutic was associated with higher grade 3 for adverse events than the ADTARPI arm. Many of those adverse events were dry mouth, nausea, GI side effects, known adverse effects of lutic treatment. And then when we look at key um endpoints or key adverse events of cytopenia, renal events, secondary malignancies, all of them were higher in the lutician arm. It'd be very interesting to see how these mature over time again, in an all comer population where we hope our patients live for many years with the diagnosis of castrate sensitive prostate cancer. Some of our takeaways again, the addition of luticium earlier in the disease, um, improves our PFS. Relative to ADT plus ARPI, although this triplet did come with higher toxicity and there was no improvement in OS or health related quality of life at this time. Again, thinking about things from a precision medicine, does lutician in the cash rate sensitive setting help patients live better and help patients live longer? And is there a way that we can use this PSMA pet as a biomarker to select who's going to benefit from lutician PSMA? From the discussion that Arun Azad, um, Presented, I think one of the maxims of nuclear medicine and radioigin medicine is that we treat what we see what we treat and we treat what we see. Um, and it's, um, there have been many retrospective studies that have looked at um vision where we saw patients who had high levels of PSMA expression in yellow had better outcomes with luticium as opposed to patients who had low levels of PSMA expression. We also see in the therapy study that patients who had a high SUV mean had higher PSA 50 response rates at 90% relative to those patients who had low SUV means on the left hand side, where their PSMA 50 response rate was 29%. Another really interesting part of that discussion was again, patients who have a lot of PSMA expression on their scan as visualized on the right hand side, much of the treatment and do symmetry is given to the tumor. However, on the left hand side or in the middle of our screen, we see patients who have a low amount of PSMA expression, much of that. Uh luticium actually goes to native organs, so in the parotid glands in the GI tracts and therefore overtreatment may actually lead to more toxicity and especially in patients who have a remarkable response to ADT plus ARPI alone, we may be overdosing a lot of our patients in a castrate sensitive setting and so thinking about is there a way that we can integrate or adapt our our our doses of PSMA rather than just give everybody six full doses. So again, lutic is one biomarker that we have to potentially um direct what type of therapy we give in the first line setting, um, but there's also a lot of genomic testing that we know about. Um, on the left hand side, again, we know patients who have BRCA mutations, HR mutations, they are a poor prognostic indicator and also, uh, especially with BRCA seem to predict benefit from PARP inhibitors. The P10 story also is similar in that we know patients who have P10 deficiency have a poor prognosis and may benefit from targeted therapy to P10. Um, again, P10 is um known to be um a um Alternative pathway for driving prostate cancer growth in a subset of patients, um, and it's driven by PI 3 kinase and AKT pathway uh growth, and so there's maybe an opportunity to target AKT inhibition with one of the therapies cap of assertive that we'll talk about this, um, approach has been studied in metastatic castrate resistant prostate cancer. This is work that was led by Chris Sweeney, um, and the eye potential study which showed that For patients with P10 deficient castrate resistant prostate cancer, iPadasertib led to a PFS benefit but no OS benefit. Um, when they looked at a subgroup analysis, they found they saw patients with P10 deficiency had an enrichment for benefit to AKT inhibition. Um, ultimately, this did not become an FDA approved regimen, um, but certainly the science is there, and that paved the way for Capitello, which was a phase 3 study where they screened 6000 patients with castrate sensitive prostate cancer to identify. 1000 patients who were P10 deficient, which they defined as a IHC P10 or 90% loss, and then randomized patients to Capivaserti or we'll call Capi plus Avired relative to placebo Avired with the primary endpoint of investigator assessed RPFS. Again, this was different than PSMA addition. This was a biomarker defined population, which we know has poorer prognosis. We saw a preponderance of bone metastasis, 80% of patients with Gleason greater than 8%. 75% of patients with high volume metastatic disease, of which 20% had visceral metastasis. We saw Capitella met its primary endpoint with an improvement in investigator assessed RPFS with a hazard ratio of 0.81 and a P value of 0.03. Similar to what we saw in eye potential, we saw an enrichment for response in patients who had a greater degree of P10 deficiency. P10 deficient complete loss was, was at 100%, had a hazard ratio of 0.68 as opposed to the general population which was 0.81. Um, really interestingly, when they looked at some of the secondary end points, you see in time to PSA progression, all, all of these favored the Capi containing arm relative to the control, but the area under the curve of time to PSA progression is rather large compared to time to castrate resistance or symptomatic skeletal events. And that patients may be experiencing castrate resistance or skeletal events prior to developing PSA progression of disease. So perhaps some interesting biology that needs to be worked out and how we monitor these patients. Um, when we have an inter look at interim overall survival, we say no improvement in the Cape containing arm with a hazard ratio of 0.90. Again, we'll have to continue to follow this data as it matures over time. The triplet containing arm did have higher rates of grade 34 adverse events as well as dose interruptions and discontinuations. Adverse events of note are diarrhea, hyperglycemia, rash, all consistent with the mechanism of action of the vasartib. So what are our takeaways again, they needed to screen a lot of patients to pre determine these patients with PAN deficiency, which we know have poor prognosis. This study did show an RPFS benefit to kept assert. Um, however, no OS benefit and higher AEs. So again, we have to think about, does this drug. Used in this setting help patients live better and live longer, and can we optimize the P10 biomarker to see who's going to benefit from AKT inhibition. Um, again, these are some retrospective analysis done from the eye potential study showing that there is a concordance between IHC and next generation sequencing and that on the bottom panel when they sub-select patients who are NGS, um, Uh, P10 deficient, they saw not only an enrichment in RPFS but also a trend towards overall survival benefit, suggesting perhaps NGS might be a better marker of P10 deficiency than immunohistochemistry. With that, I'll um close the prostate cancer part of the presentation and invite both Doctor Atti Showdhury and Doctor Paul Nin on um for their comments on these studies. Um, why don't we start with Doctor Nan? Great. Oh, thanks so much, uh, uh Atish and, and Mike, I just wanna really, you know, thank everybody here on this call cause it really was a huge effort from, from this team, these colleagues, you know, all, all of us. That made this trial possible. Um, as Mike mentioned, 100 out of the 800 patients came from from the Dana-Farber uh team here. So, you know, it was really, uh, you know, a wonderful homegrown piece of science. And I think that in the end what it shows us is that it's good news for the vast majority of patients now with high risk prostate cancer, especially, you know, gosh, now we're doing PSMA staging, so we're screening patients out. The vast majority of these patients do not need intensification with an RP. That 2 years of ADT plus high quality radiation for these screened patients, uh, is gonna go great for them. The patients that did seem to benefit are the clinically node positive patients. And I think that um. In terms of how do we put this in light of the stampede results that did show a benefit to abiratero in some patients who were clinically no negative, I think the answer is that patients at the very, very highest end of high risk, those patients probably do need some intensification, but remember on the stampede trial, those patients typically had a PSA above 40. The median PSA on that trial was, uh, it was about 30, 35, 36. So most of our high risk patients don't have a PSA, uh, anywhere near that high, but if your PSA is kind of in the 40, 50 range and you look like a stampede patient, yeah, maybe there is a role there, but I think for the majority of our high risk patients, I think they're gonna do great with radiation in years of ADT. So that's what I have to say about that, but would love to hear other people's thoughts. Perfect, so I won't add too much about the conversation there. I agree with everything. Again, PSMA PET is definitely a bit of an elephant in the room because who knows how many patients in Stampede and NZorad might have had some PSMA PET positive disease and are the patients who had node positive or um metastatic disease um by PET imaging, the ones who might have benefited from the intensification and both studies we really don't know. Um, similarly, in embark, um, PSMA pet again remains an elephant in the room because where the sites of disease, how much disease is there, um, and how much benefit is the enzalutamide really adding, cause another question to ask in that study is, uh, about the control arm because you only add the enzalutamide on the control arm at the. Time of radiographic progression. So even if somebody has a PSA doubling time of less than 9 months, if they have, you know, tiny lymph nodes that are never going to cause symptoms, is there really an advantage to very early treatment and intensified treatment? It's really very hard to say. So I think it gives us some data to maybe just adding enzalutamide in the very highest risk patients, even if there's no disease seen on conventional imaging. But I think we have to really take into account our patients' preferences, their competing risks, the actual burden of disease, and how likely they're going to suffer some symptoms related to cancer, um, when we kind of make our treatment decisions about. When to um start ADT in the first place and then whether to intensify or not. Um, the CSPC studies are very, very interesting, and I would think just in summary, I'm actually a little bit disappointed with the results and that we were hoping that in a P10 null subgroup that adding an AKT inhibitor would provide really meaningful, uh, differences in terms of clinical endpoints. Um, radiographic progression free survival, and overall survival. And while there was some improvement in the ones with the real like 100% loss of P10, that's a minority of the population that enrolled on this trial, and you, and those benefits are accompanied by quite significant side effects of diarrhea, um, hyperglycemia, rash, as was noted. And similarly in PSMA addition, there was an RPSS advantage and there was no um overall survival advantage. There was a little bit of a trend towards overall survival, but again in the um ADT ARPI group, they couldn't cross over to receive the luticia until actual radiographic progression by um. By central review on conventional imaging. So it's not really an apples to apples comparison of layering on luticium at initial rise in PSA or PET progression as we might do in our practice. So when I think about these studies, living better, living longer, and also not causing. Too much harm along the way, we really have to think how much are we really losing by deferring some of these treatments until progression, since a lot of these patients actually do do well with ADT and ARPI alone. And again, the elephant in the room on these studies is docetaxel, which is a cheap, um. Intensification, 6 cycles with known side effects. Um, main long-term side effect is neuropathy, but without risks of MDS, AML and these significant long term um hyperglycemia and rash that you would get with continuous treatment with copovasertive. So again, we have to be really thoughtful about, you know, in whom and when and why we're adding these additional costly and toxic drugs and and to whose benefit. So, um, I'll just end there. Yeah, it's certainly a crowded space, you know, we saw Amplitude and, you know, what role um Neuropa plus apparatum is going to play in this space. Um, so certainly, you know, I think like you said, trying to integrate all of this data is going to be challenging, um, but, but great to have options for our patients and, and potentially use these therapies in a more rational way.
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