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 2025.
And without further ado, we'll delve, uh, first into our abstracts on prostate cancer, um, where I'm going to be joined by Doctor Ati Shori for some expert commentary after we review our abstracts. So, um, I've got 3 themes that ran throughout the presentation of, um, Prostate cancer abstracts were first has genomic informed therapy arrived in castrate sensitive prostate cancer? We'll then move on to discuss some patient-centered outcomes of hormonal therapy, and lastly, we'll discuss some novel therapeutics um that have shown promise in rate sensitive rate resistant prostate cancer. Um. So for the selection of first line therapy, I think it's um important to reflect on much of our decision making is driven by tumor burden, so high versus low volume metastatic disease and the timing of metastatic disease in advanced prostate cancer. So, Um, oftentimes for patients with advanced prostate cancer, we're having that discussion of double therapy with ADT plus ARPI versus triple therapy, ADT ARPI plus docetaxel. And one of the questions that we've always had is, can we use biomarkers, can we use some genomic features to try to, um, my slides may be advancing quickly. Um, can we use some genomic therapy to better select patients for Um, for optimal frontline treatment. Um, this is a, a study that was actually published today, um, which looked at patients with castrate sensitive prostate cancer, um, and those patients in particular with HRR mutations, which they estimated was about 20, 28% of the patient population, or BRCA1, BRCA2 mutations. Um, these were patients with castrate sensitive prostate cancer treated with ADT plus ARPIs and you In that 12% of patients with BRCA mutations, the median overall survival is just 26.6 months, just over 2 years, relative to patients who did not have BRCA mutations, they have a much prolonged uh benefit from ADT plus ARPI. We see similar but perhaps more attenuated differences in the HRR mutated patients. So again, these are patients who are um genomically high risk disease. Is there an opportunity to introduce more targeted therapy earlier? And so, obviously, we know we have PARP inhibitors that are approved for patients with advanced prostate cancer. Um, the first set of studies now published about 5 years ago showed PARP monotherapies, um, that have now been FDA approved. We now have 3 PARP plus ARPI therapies that are approved for patients with advanced castrate resistant prostate cancer. So the rationale is, can we move these up earlier into the castrate sensitive setting. And so, there have been a number of studies that have been launched to to investigate this question. Um, at ASCA 2025, we saw the first of those randomized phase three trials presented in amplitude. And again, this is for patients with metastatic castrate sensitive prostate cancer with an HRR mutation as delineated in the box and red. Patients were randomized in a 1 to 1 fashion to the triplet of neuropro, abiratero and ADT or the placebo plus abiratero and ADT. Primary input was looking at RPFS, um, In amplitude, again, this was a high risk patient population, about 87% of patients had synchronous metastatic disease. 80% of patients had high volume disease. Amplitude met its primary endpoint, the triplet of neuropera plus abiratero improved. RPFS in both the HRR and the BRCA12 um subpopulations. You see on the right hand side, the hazard ratio in the HRR population 0.63, and then on the left-hand side, patients with BRCA mutations had a hazard ratio of 0.52. And the bottom two graphs, again, these are an interim first look at overall survival, which was immature. Um, however, you do not see much daylight between those two curves, so it's going to be important for us to continue to follow these patients out and see if there's a delayed separation of the curves with early introduction of, um, of PARP inhibitors. What did patients get after um they had progression of disease? Well, about 80% of patients did receive subsequent therapy. A majority of those patients did get chemotherapy, which I think is a standard regimen to use in that, um, in this population. You will note that patients on the placebo. arm, about 36% of patients did receive PARP inhibitor. I would actually argue that's a pretty good number considering that some of our non-BRCA HR mutations, and PARP inhibitor wouldn't be the first therapy I reach for in that population, but, um, certainly, um, Certainly would be interesting to see, um, how those patients fared in the long run. Um, with triplet therapy, so neuroperri, um, we did see higher rates of grade 34 treatment-related adverse events at 75%, higher rates of treatment discontinuation or dose reduction in the triplet versus doublet therapy. And when we look at, um, uh, adverse events of special interests, again, we see higher rates of anemia at 30% in The triplet arm versus just 5% in placebo, and hypertension at 27% versus 18% in placebo. Um, of note, we do not see, um, the long term outcomes of, um, cytopenia, myelodysplastic syndrome, VTE that we've seen with previous PARP inhibitor studies. So I think, again, very interested to see how um we can track those adverse effects over time. Um, at the end of the day, amplitude was a positive randomized phase 3 trial, which met its primary. Point of an improvement in RPFS in HRR deficient metastatic aro sensitive prostate cancer. Again, we do see an enrichment for benefit in the BRCA12 population. However, we did not see the hazard ratio for the non-BRCA HRR population. So it's a little unclear is that RPFS benefit also present in that subpopulation. As we said, we're going to continue to follow this data over time to see what the overall survival looks like, um, and again, um, a high, not surprisingly, the triplet did have higher adverse effects. Um, it will be very interesting to see what our regulatory authorities do with this data and whether or not neuroprorib does get approved in the, um, castrate sensitive prostate cancer setting. Um, if it is, then obviously, I think there's a couple of factors that will, um, will come into play on whether or not PARPs are used in this setting. Obviously, which type of alteration are used, BRCA or are, are found BRCA or HRR, what the durability of benefit is, what some of the chronic toxicities are, and then we also have to think about alternative regimens. So in the castrate sensitive prostate cancer, it's becoming a crowded field with triplet therapy with docetaxel, um, radio therapies, soon to be, um, hopefully approved in this setting. So I think a lot of, um, patient selection, um, remains important, um, in this castrate sensitive setting. Um, we are interested in evaluating this, um, approach of using genomics to help direct therapy for metastatic prostate cancer. This is the PRIT study, um, which is a cooperative group alliance study led by our own, um, Misha Beltran. However, this is looking in the castrate resistant prostate cancer setting where patients, um, have their tumors analyzed by a molecular tumor board, for those who have an actual alteration with RBOs, they'll receive the ECH2 inhibitormitastat, and those who have 2 out of 3 suppressor genes will get cabazitaxel plus carboplatin. Those patients who do not have a steady defined alteration will actually get um physician choice. So, again, trying to better inform how we care for patients with metastatic disease and use genomic biomarkers to help us accomplish that goal. Um, the second theme that we'll talk about are, are some patient-centered outcomes of hormonal therapy, as many of us who treat patients with advanced prostate cancer, ADT remains, um, the foundation of treatment that we build on. Um, and obviously, we're interested in improving outcomes and helping patients live longer, but, um, but the patient experience is actually much more than that. So we're looking at things like, um, quality of life, what are some of the chronic Toxicities of therapy, um, what are ways that we can hopefully minimize pain and other symptoms while patients are on hormonal therapy. So, um, I stole aside from Alicia Morgans, whose talk we'll reference, um, later, but again, I think it's very important for our patients, um, who are on hormonal therapy to think about what their experiences and other opportunities to both intensify or de-intensify therapy, um, based on certain biomarkers. So, um, the first abstract within this subgroup that we will talk about is the Ironman study. This was a retrospective study for patients with metastatic castrate sensitive prostate cancer who are treated with ARPI plus EDT and looking at what is the prognostic significance of PSA level after 6 months of therapy and then after 12 months of therapy. And what the, um, investigators asked was, um, can we use this information of uh PSA Nad or, you know, PSA level at these two time points to better inform escalation strategies for patients who have a persistently high PSA as well as de-escalation strategies for patients who, um, whose disease responds very well to hormone therapy. Um, the Ironman is a registration, uh, registration database of over 5000 patients, uh, from 120 active sites, 15 countries around the world, um, with, uh, metastatic prostate cancer. What this, um, Analysis looked at was the 120 patients who had castrate sensitive prostate cancer and were treated with ADT plus ARPIs. You see about half of patients were treated in North America, half of patients treated outside of North America on this, um, study. Again, 1200 patients, 75% had de novo metastatic disease, 25% had treatment to their primary. Um, 90% of patients were treated with the double ADT plus ARPI and maybe um 10% of patients at ADT + ARPI and docetaxel. On the bottom right, you see a pretty even distribution of different ARPIs that were, um, that patients were treated with on this um retrospective study. And what they first looked at was the 6 month time point, and they found that about half of patients had a PSA of greater than 0.2 and half of patients had a PSA of less than 0.2. And then when they looked at the second time point at the 12 month, we saw a migration. So only a third of patients had a PSA of greater than 0.2, whereas 2/3 of patients had a PSA of less than 0.2. When they looked at baseline characteristics to try to better understand, you know, how patients, um, landed in each of these two groups, um, we saw that patients who, um, whose disease had a low PSA at that 12 month mark in the first column, um, tended to have PSA graded less than 20 at baseline. Alkaline phosphatase less than 150 at baseline, um, lower chance of de novo metastatic disease and an increased, um, uh, chance of treatment to their, their primary disease. I think all of these are, um, you know, biomarkers that, that confirm um perhaps a more indolent disease process. And the primary endpoint of this study was looking at that um 3 year overall survival rate. So when you look at the green line, these are patients who had a PSA of less than 0.1 at that 12 month mark, you see a rather high 84% 3 year overall survival rate. You contrast that with patients in the purple line, where patients had a PSA of greater than 0.2%, we see that three year overall survival much lower at 45%. Um, we see in conditional progression free survival, um, very similar tracking curves, um, in the difference between patients whose disease had a PSA of less than 0.1 versus those who had a PSA of greater than 0.2. Um, when we look at that earlier time point, at that 6 month landmark, we see similar outcomes, although the curves are a little bit closer together. Perhaps I'm suggesting that it takes just more time for this data to mature and for, um, groups to separate out for us to get, um, a better, a better appreciation for how the disease is responding to hormonal therapy. Um, what we do know is that patients who have a PSA of greater than 0.0.2 at that 12 month mark, um, have a very poor prognosis with a fivefold increased risk of death relative to patients um who had a PSA of of less than 0.2. Again, I think a very important biomarker that, you know, is clinically actionable that you can take back to the clinic and um and potentially make treatment recommendations based on it. Um, so again, some takeaways from this, um, the PSA at 6 and 12 months is powerfully prognostic. And suggests that perhaps patients with a PSA of less than 0.1 at these time points may have a more favorable prognosis and may be eligible for treatment intensification, whereas those patients with a PSA of greater than 0.2 have a poorer prognosis, may actually benefit from more early intensification of therapy. Um, there are certainly limitations to this type of large retrospective study, variable PSA assays, um, PFS was a composite definition of of disease, but I, I think, you know, um, really gives us some insight into how PSA can be used as a dynamic biomarker. And this um concept is, is being brought forward in two studies, um, one on the left hand side, the triple switch study, so patients treated with EDT plus ARPIs who have a PSA of greater than 0.2 at the 6 to 12 month mark, are randomized to either receive dosecetaxel early, so early intensification. of therapy or continue on standard ADT plus ARPI that's power to actually look at overall survival. And then on the right hand side, um, as many are familiar with the Dream study, um, which is led by our own Ati Choudhry, um, which is asking the opposite question. So for patients who have a PSA of less than 0.2 at 18 to 24 months, can we actually de-escalate hormonal therapy, um, and continue to monitor for a recurrence of, of, um, Of disease at that point. So again, I think a very patient centered endpoint, something that is, uh, you know, potentially actionable to use in the clinic, um, and a really important biomarker that we could use. Um, the next, um, abstract that we'll talk about is the health related quality of life outcomes on the phase 3 Aeronote study. This was presented by our own Alicia Morgans, and as many are familiar. Arano was a global phase 3 clinical trial of patients with metastatic castrate sensitive prostate cancer, randomized to dallutamide plus EDT or placebo plus EDT. It was powered to look for uh radiographic progression free survival by blinded central review, and Arano did meet its primary endpoint with an improvement in RPFS and a hazard ratio of 0.54. And on the right hand side, you see very similar adverse effect um profiles between the two groups. Um. What Dr. Morgan's presentation looked at was actually at the health-related quality of life in patients treated on Anut, and they looked at two different inventories. First, the DPISF, the Brief Pain Inventory Short form, and the FACTP total score, that's the functional assessment of cancer therapy specific to prostate cancer, which is a composite measure of well-being from the physical, emotional, functional well-being, um, and again specific to prostate cancer. Um, And what they found was that um patients on Darolutamide plus EDT had delayed pain progression relative to placebo with a hazard ratio of 0.72. And I think really interesting, especially in the context of our previous discussion. They found that patients who had an ultra low PSA of less than 0.02 actually had an even longer time to pain progression than patients who had a PSA of greater than 0.2, again suggesting that, um, we could use this PSA biomarker, um, to not only look at outcomes but also health related quality of life. The second outcome measure was looking at that FAP score, um, and again, the drilutamide plus ADT arm had an extended median time to deterioration of 5.1 months with the hazard ratio of 0.76 relative to ADT + plus. Again, similarly, we see patients whose disease um had a PSA less than 0.02, improved outcomes improved um FAP relative to those patients with a PSA of greater than 0.2. Now, it's important to put this data into context. Um, none of our other ARPIs have shown an improvement in health-related quality of life, um. So it's a little tough to compare across trials, but we'll do it anyway. And so on the left hand side, you see um the difference between treatment arms on the Aeronote study, and you see very small differences um in fatigue, falls, fractures, adverse events, whereas on the right hand side, this is data from the ACEs study which investigated enzalutamide relative to placebo. See relatively higher rates of adverse events in that study. So again, an imperfect comparison, but I think speaking to the tolerability of Daylutamide as um in this study. So, again, Dayluamide is the first and the only ARPI to show an improvement in health related quality of life relative to EDT alone. As we said, it it delayed time to pain progression and Extended time to fact to factP deterioration and um that accomplishing a PSA of less than 0.2, um, was associated with improvement in health-related quality of life. Um, independent of this presentation, we also saw that the FDA extended the label for drolutamide to include patients with metastatic castrate sensitive prostate cancer. So, Again, very um important news for our patients and other ARPI um added to our armamentarium in that doublet regimen. Um, Doctor Morgans is building on this work, um, with the ERICOG study, um, which is investigating, um, droludomide relative to enzalutamide, looking at a number of different outcomes related to, um, functional status and quality of life. So we certainly look forward to more data in this space. Um, the last thing that we'll talk about is actually novel therapies in castrate resistant prostate cancer. And the first of those is the Parutame drug, which is a bi-specific T cell engager targeting human calerine2 or KLK2 gene, which is highly expressed on prostate cancer. You see in the um graph on the right hand side, HLK2 seems to be more specific for the prostate and for prostate cancer relative to PSMA, which is both expressed on the prostate and other organs in the body, so thought to be maybe a more specific target. And so again, postsritame binds to HLK2 and then the other um arm binds to CD3 to bring T cells into the tumor microenvironment. Um, this data was um from the phase one study looking at 45 patients in the safety population, 33 patients in the efficacy population. That it was interesting that this, um, by specific T cell was given all as an outpatient, um, which I think certainly is, um, speaks to the feasibility of using this drug. In this setting, um, very quickly, um, patients, um, had a median of 4 prior lines of therapy for advanced prostate cancer. All patients had received ARPIs, um, 80% of patients have received taxan-based chemotherapies, um, and a number of patients also had received radioligand therapies. I think the really notable part about this postrutame drug on the left hand side is that it had very, very low rates of cytokine syndrome, only 8.9%, and they were all grade one. Um, and only 24% infusion related reactions of note, no patients required to sillizumab, no patients required steroids, no patients, um, had DLTs. um, so it really seems to be a well tolerated drug. Again, given in the outpatient setting, um, seems to be, um, a very feasible. drug to use and then some of the early outcomes data we saw, um, about a 36% um confirmed PSA 50 response and the median duration of response was about 8.9 months. Again, small numbers, early data, um, but certainly some promising efficacy. That we see there, um, that extended to an RPFS of 7.9 months. Again, about 20% of patients are still actively on study, so we'll see um how this data matures over time, but certainly some um robust long term benefit is seen in a subset of patients. Um, so again, phosphritami is a novel by a specific T cell engager to KLK2 and CD3. Um, seems to be well tolerated, um, with early efficacy data. Um, I will say to stay tuned for a randomized phase 3 trial of Parudime which is soon coming to Dana-Farber. Um, if you don't want to wait for Parutami, um, we do have another by specific T cell engager which is now in a phase 3 trial open at Dana-Farber. This is Zalrutame, um, for patients with metastatic castrate resistant prostate cancer, randomized to Zalrutame or investigators' choice of cabazitaxel or second ARPI, um, so certainly look forward to um enrolling patients on this study at Dana-Farber. Um, last but certainly not least, um, we'll discuss the B7H3 antibody drug conjugate for patients with castrate resistant prostate cancer. We know B7H3 is an immuno regulatory protein that's highly expressed on the surface of of prostate cancer cells and that the payload of this antibody drug conjugate is a topoisomerase 1 inhibitor. And this drug has shown early activity in castrate resistant prostate cancer, and it's actually um received FDA fast track designation for treatment of this disease. We saw data from cohort 4, which was the dose optimization of about 42 patients randomized to either 6 mg per kg IV every 3 weeks or 9 mg per kg IV every 3 weeks. Um, very similar to the prior presentation, we saw a median 4 lines of therapy. All patients have received novel hormonal therapies. 90 over 90% of patients have received Taxin-based, um, Taxin-based therapy. So again, a very treatment refractory, castrate resistant prostate cancer, and again, actually pretty similar response rates and somewhere in the 40% range, um, in both dose levels that we're seeing, very low rates of primary progressive disease, and the and, um, and the, the duration of response. Um, is, is, um, is not evaluated, um, as this is a little bit, this is an early data cut. However, we did see an RPFS rate at 6 months in the 60% range, um, so again, we'll continue to see this data mature over time, but um certainly showing some early responses. However, when we do look at those two dose levels, we did see an increase in grade 3 treatment-related adverse events. Um, many of them were related to hematologic toxicities and GI toxicities, um, however, only about 10% of patients, um, had discontinuation due to toxicities. Again, um, the main toxicities that we saw were GI and hematologic related. Um, and again we seem to be dose dependent, um, in these two cohorts. So again, I think this is a, um, interesting antibody drug conjugate and we don't have many of those um in castrate resistant prostate cancer, so I think, um, interesting to see how this will play out and, and, um, make its way into the castrate resistant prostate cancer setting. They're also actively enrolling patients in the post, um, PS post-luvito and post-axing. Um, cohort, so we'll continue to see more data with this drug. And with that, um, I'll invite Doctor Ati Shodhry um for his expert commentary on these abstracts. My apologies by mouse uh decided to cut out on me. Um, so in terms of, uh, can you see me? I can't see you. I can hear you. That's very odd. OK, there I am. Um, so I think the hormone sensitive prostate cancer space is becoming a lot more complex and a lot more interesting, um, with all the data that's coming at this point, cause right now, um, we have kind of a choice of these 4 different ARPIs and then a decision on docetaxel versus not. Uh, and then there's a decision about radiation to the prostate versus not. But now, uh, at ASCO this year, um, there's a lot more biomarker directed treatments that are, um, being evaluated. So there was an RPFS benefit to comparative seen in the Capitella trial with P10 loss. Here we're seeing an RPFS benefit to um. Neuroperri in the HR mutated population, uh, we saw in PSMA positive, HSPC that in uh PSMA addition, there's an RPFS benefit to luteum and we also heard about this uh P10 loss, um, biomarker based on decipher, um, as being a predictor to docetaxel. And so when we're thinking about individualizing treatment, Um, we have to take into account pre-treatment factors, the volume disease, the biomarker positivity, but, um, the presentation on the PSA, um, decline, uh, less than 0.2 being an important prognostic marker, does allow a more adaptive approach as well and does allow us to think more about, um, adaptive approaches for discontinuation too. So for neuroper specifically, Um, I think that there's pretty compelling data on an RPFS benefit in the BRCA2 population which I think, um, is not too surprising. Uh, I don't think it's a drug that will necessarily use for all HRR mutated patients, but if somebody has relatively bulky disease and a BRCA2 mutation. Um, it is something that I think if it's approved that we would, um, be forced to consider, um, either after prior docetasol chemotherapy or instead of Docetaxel chemotherapy. Um, but when we think of the, um, downsides of of neuroprob as daily treatment, 29% grade 3 anemia in the hormone sensitive space when a lot of people do well on ARPI alone is kind of a lot, um. Having to do frequent blood count checks, uh, basically for the rest of your life, um, when from the hormone sensitive setting is not that appealing, the cost of the, this additional drug on top of abiratero, which is now generic, um, is also something that can be a little bit prohibitive. So I think we also have to think about adapting and potentially interrupting the treatment for patients who have an excellent response, though that wasn't studied in this particular trial. Um, in terms of the Iron Man study, I think, uh, again, thinking of the right approaches to, um, de-escalate treatment and the appropriate patients and then potentially escalate patients based on not achieving that particular PSA threshold at a particular time is probably the way that, um, we're going to have to adapt treatment in this particular setting. And Certainly the health related quality of life in Aerote was um quite appealing and of note, the discontinuation rate of placebo was actually higher than of dallutamide in Aerote, um, which is uh something to think about in comparison to the other drugs. Um, what was so impressive about these pedi and B7H3 um presentations was that in this late stage CRP. settings, they're really not that many drugs after this many prior treatments that have waterfall plots where almost all the um arrows point down. So the clinical activity is very intriguing and the um very tolerable toxicity profile of the peermi um certainly means that it's something that would be more um Relevant to a lot of our elderly patients who might not want to be admitted for their first dose of a drug, um, and something that we can reasonably do on the outpatient side. And the lower dose of the B7H3 drug, um, seemed to show activity with, with pretty manageable toxicity. So we're pretty excited about where these drugs are gonna go in the future. Um, happy to take any questions offline. Fantastic. Thanks so much, Yish for your, um, as always, uh, comprehensive but succinct um summary of, of the, um, presentation.