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 GU ASCO 2025. Highlights in this video include:
• TALAPRO-2: Talazoparib + Enzalutamide improves OS in mCRPC with significant enrichment in HRR population
• ENZA-P: 177LuPSMA + Enzalutamide improves rPFS, OS and QOL in mCRPC
• WOLVERINE: Meta-analysis demonstrates benefit of metastasis-directed therapy in oligometastatic prostate cancer
Dive into the data in prostate cancer. And I would say a theme that I saw across many of these, uh, abstracts that we present is, um, intensification of therapies. So, um, first, we'll go through adding, uh, the CARP inhibitor talazoprib to enzalutamide and first line metastatic CRPC in the Talaro 2 study. Then we'll look at lutician plus enzalutamide in the first line MCRPC setting on nzip P. and then we'll look into two, Large meta-analysis, the stopgap and Wolverine studies, which looked at ARPIs and castrate sensitive prostate cancer as well as the role of metastasis directed therapy for patients with oligometastatic prostate cancer. And lastly, we'll finish out with, um, a study that was really aimed to try to better understand an age-old question for patients with high risk localized prostate cancer, do patients benefit better from a radiation-based approach or a surgery-based approach with regard to risk of distant metastasis? So again, we'll start with the tallopro 2 study. Um, we know patients with HRR mutations, particularly those with BRCA1, BRCA2, benefit from the use of PARP inhibitors in refractory prostate cancer. What Talaro 2 and what several other studies have done is Trying to bring PARP inhibitors earlier in the disease paradigm in combination with ARPIs. So Taoprous looked at um tallioper plus enzalutamide versus enzalutamide in the metastatic castrate resistant prostate cancer setting. Um, I will say that there were two cohorts presented. The first was presented. Um, in an oral, and this was a 8 cohort one which was 800 patients unselected for, um, or an ITT population unselected for HRR mutations, and then there was a poster presented of about 400 patients who had HRR mutations. We'll go through that on both. of those, um, and, and hold those together. So again, um, about 800 patients, talazarib plus enzalutamide versus enzalutamide alone. Primary endpoint was radiograph for progression free survival. What we saw at GUAO was the first, um, look at overall survival. Patients on Tower Pro 2, again, this study was started many years ago, so, um, in the first line metastatic CRPC setting, we see that only about 5 or 6% of patients had received an ARPI with abiratero. A majority of these patients, um, had lymph node or bone metastasis, and very few, uh, maybe about 10-15% of patients had visceral metastasis. When we look at um the breakdown by HRR mutation status, um, about 20% of patients on the tlaro to ITT population had HRR mutations. You see the highest percent were CDK 12 or BRCA2 mutations and then lower rates of other HRR mutations. And again, most of these mutations were detected by examining tissue, only about 15% of patients had CTDNA analysis. The updated analysis of the primary endpoints, so RPFS by BICR showed that the combination of tallazop plus enzalutamide improved radiographic progression free survival relative to enzalutamide alone with a hazard ratio of 0.66. And then when we look at overall survival, we saw that again the combination did have a benefit relative to enzalutamide alone with the hazard ratio of 0.79 that was statistically significant. However, The devils in the details. And so when we dive into and look at the forest plot of those 20% of patients who are HRR deficient, we see a marked improvement in overall survival with the hazard ratio of 0.54. As opposed to those patients who are HR non-deficient or unknown status, the hazard ratio was much higher at 0.87 that crossed over 1. When they removed those patients with BRCA2 mutations, BRCA1 or BRCA2 mutations, they found that the overall survival benefit was maintained with a hazard ratio of 0.74 on the left hand side. On the right hand side, when they removed patients with HRR alterations, they saw again that hazard ratio started to drift up and that P value started to increase as well. When we look at the combination of talus oper plus enzalutamide, we see high rates of grade +34 adverse events at 75%, high rates of uh dose interruptions or dose continuations with the combination relative to enzalutamide alone. As we continue to follow these patients over time, it's reassuring that no additional cases of MDS or MDL were detected in the combination arm relative to placebo. Now again, that was all in cohort one, which was unselected patients. This was data that was presented from cohort 2 in a poster, which was again about 400 patients who were known to be HRR deficient. And when we break down overall survival in the top curves, patients who had BRCA1, BRCA2 had an improvement in overall survival with the hazard ratio of 0.49. As opposed to those with HR1A2 HRR mutations, the benefit was much more attenuated there with the hazard ratio of 0.72, the P value that was greater than 0.05. So what do we take away from Calaro 2? Well, clearly there's a benefit to adding Talioprib plus enzalutamide with regard to RPFS and overall survival in the ITT population. We also see that the magnitude of benefit is marked, there's a marked improvement with patients who have BRCA1, BRCA2, relative to those who have HRR deficient, relative to those patients, the majority of patients on study who did not have HR mutations or whose status were unknown. This combination did have high rates of adverse effects, and one of the limitations of this study, because it was started many years ago, is that many patients who we now see in the first line metastatic CRPC setting do receive ARPIs in the castrate sensitive setting as opposed to Talaro, which again only had 5% of patients with prior abiratero. I think what this highlights for us is that we really do need to do genomic testing to optimally select patients who may benefit from combination PARP inhibitors in the um in in prostate cancer. There are several ongoing studies that are evaluating intensification of therapy using PARP inhibitors. The Talaro 2 and Amplitude are specifically looking at patients who have known HRR mutations, whereas EOPAR um does have a large cohort of patients who are non-HR mutated. Moving on to NZAP. So, um, NZAP was a, um, phase two investigator initiated trial out of Australia, um, that has previously been reported to have an improvement in radiographic progression free survival. This analysis was looking at overall survival on this study. And the hypothesis behind NZP is that we know AR blockade up regulates PSMA expression and thereby if you use AR blockade with a radio therapy target against PSMA, you may have an enhanced benefit or synergistic benefit to that approach. And so what NSAP did was randomized patients with bine metastatic CRPC who had greater than 2 risk factors for early enzalutamide failure and had a positive PSMA PET scan. Patients were randomized to either enzalutamide or enzalutamide plus 2 to 4 doses of luticium, and the primary outcome was looking at PSA PFS. Um, baseline characteristics for these patients, again, a majority of patients, 50, 60% had greater than 20 PSMA a metastasis. A majority of patients had de novo metastatic disease, as well as um early dosecetaxel for hormone sensitive disease, so a somewhat sicker population than we may may have expected. Um, the, again, the adaptive dosing on NZipp was unique um relative to what we typically see with flutician studies. So patients started on 2 weeks of enzalutamide therapy, and if they were randomized to receive fluticium, they would get 2 doses, have an interim PET scan, and if they were having benefit, they would be eligible to get an additional 2 doses, and it was noted that about 80% of patients did end up getting the full 4 doses of fluticium as opposed to 10% who only got 2 doses. NSP met its primary endpoint with an improvement in PSA and radiographic progression free survival with hazard ratios of 0.4 and 0.6, respectively. And when we look at overall survival, we see an improvement in the combination relative to enzalutamide with a hazard ratio of 0.54. It is notable that patients who were treated with the enzalutamide, um, on the control arm, uh, 40% of those patients did end up getting luticium off, um, off protocol therapy, um, so perhaps removing some of that crossover that we may have expected to see. Um, the combination of lutician plus enzalidomide also improved, um, quality of life across multiple different domains, so physical functioning, overall health status, fatigue, um, pain, all of those outcomes were improved with the combination relative to enzalutamide alone. Um, the combination had similar rates of grade +34 adverse events at 44, 46%. Um, although it was noted that patients treated with fluticium as expected, had higher rates of grade 12 anemia, nausea, dry mouth consistent with the mechanism of action of the drug. So what are our takeaways from NZP? Well, certainly again this combination. Of lutic plus enzalutamide improved PSA RPFS, and overall survival relative to enzalutamide alone. This benefit was maintained across quality of life and seemed to be pretty well tolerated when compared with enzalutamide alone. As with Talero 2, again, the standard of care for me for castrate sensitive prostate cancer has shifted such that many of our patients are getting ARPIs earlier in their CCD course, whereas in NZP only 30%, 13% of patients got prior abiratero. Again, I think the adaptive dosing, um, investigated here warrants further investigation, and it really for me calls into question what is the ideal partner and disease set in for lutician-based therapy. EnzipP is one of many different studies that are looking for what's that ideal partner for lutician. So there's several studies looking at cabazitaxel, PARP inhibitors, immunotherapies, in, um, sequence with radium, um, and one of the studies that we're doing here at Dana-Farber led by one of my colleagues, Dr. Robbie is looking at luticium plus carboplatin, and this is for patients who would ordinarily qualify for gluticium as we use it now. So after ARPIs after Taxans in the CRPC setting and investigating several um several dose levels of carboplatin. Next up, we'll talk about the castrate sensitive setting, and this was looking at the stopgap meta-analysis using individual patient data to try to understand which patients benefit most from intensification of therapy with ARPIs. We've been saying this for many, many years that patients with metastatic a sensitive prostate cancer benefit from intensification of therapy, but we don't really know, is there any particular class of ARPIs that benefit patients more? Are there any particular disease or patient characteristics which may lend to more of a benefit than others? And so that's what this meta-analysis sought to investigate. What they did was they used individual patient data from several completed trials, and they investigated a few outcomes. So looked at overall survival, progression free survival, prostate cancer or specific survival. The studies they included were um 7 large studies of over 7700 patients, um, and 4 of those studies used abiratero, and 3 of those studies used are ARPI's enzalutamide or apoluamide, as um as shown here. And what we see across these studies is that a majority of patients had synchronous uh metastatic disease, had high volume disease, and most patients were aged somewhere between 60 and 70 on these studies. Not surprisingly, we see that patients benefit from intensification of therapy, and to put some numbers behind it, the addition of ARPIs improved overall survival with a 13% absolute improvement at 5 years, and patients benefit with regard to PFS with an absolute benefit. 21% at 5 years, there was no difference by class of agent. Um, I will note that while we had 100% of the data from patients with with abiratero, we only had about 50% of the patients uh 50% of data for patients treated on the AIDS. When we looked at some of those additional factors, so patient characteristics, tumor characteristics, volume of disease, um, Gleason score at baseline, location of mets, ECOG performance status, all of these across all of these categories, patients benefited from intensification of therapy with regard to PS PFS, which again I think is reflective of our clinical practice. However, when we broke down ARPI benefit by age group, whether patients were less than 65, 65 to 75, or 75 or over, you see that the magnitude or the effect size decreases as patients get older. To further investigate why that, and that's with regard to both PFS and overall survival. To try to better understand that, the investigators looked at the abiratero studies and you see on the right hand side, you see, while there was still a statistically significant improvement in prostate cancer specific survival in patients over the age of 75, on the left hand side, those patients over the age of 75 appeared to have an increased risk of Of, um, appear to have no, no benefit in overall survival when ARPI's were when aberrateine was added and it really I think calls into question, were there other causes of death that may have impacted overall survival aside from prostate cancer and were those potentially related to adverse effects of aberratera? When we look at the same analysis in patients who had received AIDS, you see across all of those um pre-specified age groups, there was PFS and OS benefit for the use of AIDS. Again, I will throw in the caveat that only about 50% of data was available during the time of this analysis. Put another way, again, patients under the age of 75 benefit from intensification of therapy, whether it's with abiratero or the amides, however, patients over the age of 75 appear to have less of an OS benefit with abiratero relative to the amides. Now what do we take away from this? Well, again, I think it confirms our clinical practice that most patients with metastatic castrate sensitive prostate cancer benefit from intensification with ARPIs. Under the age of 70, it's clear that there's benefit regardless of which ARPI we choose. Over the age of 75, I would maybe give second thought to what are some of the risks associated with abiratero and what are some of the comorbidities that um patients may have. And then I think it's important to also think about much of what we use to to um to determine what's the optimal treatment for patients with castro sensitive prostate cancer relies on clinical factors. So high versus low volume, chemo fit versus chemo unfit, kind of high. Beholder, and are there additional things that we can use such as genomics, such as PSMA PET that can optimally guide both treatment intensification for patients who need it, but also the intensification for patients who are benefiting from their first time therapy. And this was a slide that I really loved from the discussing Doctor, uh, Doctor Tanya Dorff, where, um, she really shows that a majority of patients, um, will be in kind of this first, uh, bucket in the center where they're gonna get, where if they have low volume or if they have high volume, unfit for chemo, they'll get doublet therapy with ADT plus ARPI of your choice. If patients are fit for chemo, on the right hand side, they will often get triplet therapy. However, on the left-hand side, if they're over the age of 75, you may want to consider an AR antagonist, patients are really frail, perhaps ADT monotherapy and Um, and, and obviously clinical trials for, for patients who um who may qualify for them as well. Um, again, looking at some of those biomarkers, um, of genomic biomarkers, PSMA PET, this is a vision for the future of how we can potentially, uh, optimally select the best uh treatment for patients with castrate sensitive prostate cancer. And not only is treatment intensification important, but also the intensification. And um Doctor uh T Shore's, um, um, study, the ADream study, which is a cooperative group study in Alliance, which looked at the intensification of therapy for patients who are getting, uh, exceptional response to their first line ADT plus ARPI therapy, for patients who have a PSA of less than 0.2. After 18 to 24 months, stop their therapy, and then we're looking at a host of, uh, the primary endpoint of treatment for survival, but also, um, time to testosterone and duration of time off therapy. Again, I think this is something that we as investigators and certainly our patients are very interested in what are these outcomes and, and what is there an opportunity to dial back and if patients are having an exceptional response. The last two studies that we'll look at are actually looking at, um, um, radiate a lot of, uh, radiation, and we'll go through these rather quickly, but, um, metastasis directed therapy is something we commonly use in the, in the clinic. However, the level of evidence really comes from a lot of phase two studies, retrospective analysis. And so what Wolverine did was try to put together a lot of this data into a large meta-analysis to investigate what the benefit of metastasis directed therapy is relative to standard of care. So, this, uh, put together 5 studies across Two different continents, um, and done over many different years, and it was about 500 patients in total, even split of about half patients with castrate resistant prostate cancer, half patients without cast with castrate sensitive prostate cancer, and this was in an era where PSMA-pet really wasn't, um, wasn't a standard of care, so only about 50-60% of patients had PSMPpe at baseline. What we saw was that uh the addition of metastasis directed therapy improved uh progression free survival with a hazard ratio of 0.45 relative to standard of care, and you see the median uh PFS of 32 months versus 15 months. And when we look at the subgroups, all patients, whether they were castrate sensitive, castrate resistant, whether they were imaged with PSMA PAT, whether they had 1 to 2 or 3 to 5 metastasis, all patients appeared to benefit from the addition of metastasis directed therapy versus standard of care. When we look at longer term outcomes, so in patients with castrate sensitive prostate cancer, the time to castrate resistance was also favored in the metastasis directed therapy with a hazard ratio of 0.58 relative to standard of care. And when we look at overall survival, we see that metastasis directed therapy um led to an improvement in overall survival with the hazard ratio of 0.64 and a P value that was 0.057. Um, so a trend towards overall survival benefit, but I certainly reassuring to see some of those long term end points. So what's her takeaway with uh with Wolverine, again, metastas directed therapy is something that we often discuss in multidisciplinary tumor boards, clearly has some short and long term benefits to it, um. Again, one of the limitations of this analysis was now we're using PSMA PAT much more, much more frequently. However, to try to account for that, there are several ongoing studies that are both using conventional imaging and PSMA PAT to investigate the role of metastasis directed therapy. Last but certainly not least, um, is trying to answer that age-old question for patients with high risk localized prostate cancer, um, do patients benefit more from a radiation-based approach versus a surgery-based approach? And while we know that, um, many patients are offered either option in clinic, there's no high level evidence to know for sure which patients are optimally selected for either approach. And so what this analysis did, and a lot of the, um, ways that we compare these are looking at. studies, retrospective analysis, which are fraught with biases and confounding factors. And so what this study did was um took data, individual patient data from two large phase 3 cooperative group studies, the Punch study and RTOG 0521. Um, to try to analyze, um, the different, um, which patients benefited more from a radiation or surgery-based approach. Really quickly, punch was for patients with high risk localized prostate cancer who are eligible for surgery. Patients were randomized to either get surgery with personalized post-op therapy or 6 cycles of neoadjuvant dose of Taxol plus ADT plus surgery, and then personalized post-op therapy. So triple or quadruple therapy of note about 50% of patients did end up getting adjuvant or salvage therapy, uh, as opposed to 72% who were on surgery alone. On RTOG again, patients got either the standard radiation plus ADT or 6 cycles of uh of uh docetaxel plus ADT plus radiation therapy. And again, they used individual patient data from these two studies to look at distant metastasis with these approaches. Perhaps not surprisingly, patients who were enrolled on the surgery study were younger, so about 90% of those patients were under the age of 70. There was an equal distribution of Gleason 910 between the two. And then for patients who were enrolled on the radiation study, again, perhaps not surprisingly, they had higher baseline PSAs, higher, um, higher, uh, very high risk by stampede criteria. And, um, And when we look at the primary endpoint, we see in the overall cohort, patients who had radiation, a radiation-based approach had a, um, risk of had an incidence of distant metastasis of only 16% relative to surgery at 23%. That was statistically significant with the hazard ratio of 0.56. When we look at kind of our standard of care options, so ADT plus radiation or Surgery plus personalized post-op therapy, that incidence of distant metastasis was still statistically significant. This, I think is a really important slide and, and, um, and one that I want to, uh, hammer home. In the investigation or the experimental arms where we added docetaxel to either radiation or surgery, we saw that again, the benefit was seen more in patients who received a radiation-based approach relative to those who received surgery. However, when we compared our standard ADT plus radiation to ADT chemo, surgery, and personalized post-op therapy, it seemed like that risk of distant metastasis was lower. And I think, um, when we look at, uh, when we look at prostate cancer specific survival in a radiation versus a surgery-based approach, prostate cancer specific survival was equivalent between the two. On the right-hand side, you see patients who underwent radiation had a higher risk of death without progression or distant metastasis. And it's hypothesized this may actually just be because patients who were enrolled in the surgery arm were older when they first enrolled in study. So what are some of our takeaways? Um, again, the radiation approach appeared to, um, result in a lower risk of distant metastasis relative to a surgery approach. Patients who underwent surgery, 80% of those patients either had recurrence or required further treatment. I think this really highlights that early adjuvant or, um, salvage therapy remains critical for these patients, and that patients undergoing neoadjuvant therapy prior to surgery appeared to have similar rates of metastasis relative to those who underwent EDT plus radiation. Again, limitations of this analysis, um, low use of PSMA PAT and the fact that EDT plus abiratero plus radiation is now our standard of care for high risk local cause prostate cancer with um with additional risk factors. And so, Um, I don't think it definitively answers it, but I think it brings up some really interesting questions. There are two studies that I think are relevant in high-risk prostate cancer. One is the SPG, um, 615 study, which directly compares radiation, uh, plus ADT versus surgery. So hopefully that will give us more evidence. And then there's Gun study, which is for patients with high-risk localized prostate cancer, um, using genomic testing to try to, um, intensify neoadjuvant therapy prior to surgery. And this is, uh, a trial that we've been working on, trying to get up and running here at Danna Harbor for, um, for a little while, and hopefully, you know, that, that will be coming soon. Last but not least, I want to invite um Doctor T. Shodhry for some additional comments. Uh, this is him pictured with one of our CRCs, Autumn, presenting a poster on um recovery of testosterone in patients who discontinued ADT early. With that, I'll invite AT Shaan for some comments. Yes, thanks so much for the various shout outs along the way, Mike. Uh, so these were 5 interesting studies, but how they influence our standards of care, I think, is really to be determined. So just starting with the last 3, so all of these were based on analysis of individual patient data, which is higher quality um comparisons compared. To just kind of bulk comparisons across trials, but that being said, these aren't randomized comparisons, so all of the conclusions have to be taken with a bit of a grain of salt. So for example, in this high risk prostate cancer um comparison, they show a difference in distant metastasis, but for some reason this difference in distant metas. does not play out as a difference in actual prostate cancer specific survival. And so biologically speaking, how does that really make much sense? Um, it's hard to wrap my head around it and so I don't know if the way that they're calling distant metastasis in the surgery trials compared to the radiation trials is exactly the same, um, or where the sources of. Biases could be in this non-randomized comparison. I think what this tells us is that radiation with hormonal treatment is an excellent treatment option for high risk localized prostate cancer, but you're not compromising overall survival um by treating these patients with surgery. And in fact, could there be some risks, uh, in terms of overall survival. With radio hormonal therapy, as we've talked about across multiple studies, ADT itself has some um cardiovascular and other risks associated with it, um, and so could that be part of the difference. So I, I would just say that um that study is very reassuring that both of our standard approaches to high-risk prostate cancer um tend to have very good outcomes. So the Wolverine study was very interesting because again this was in individual patient data um and so this wasn't a large randomized trial, but the trends that they recorded across all the studies in the CRPC space and in the HSPC space are to a degree where it's difficult to ignore. There doesn't appear to be a safety signal in terms of metastasis directive therapy in terms of harms. Uh, in terms of overall survival, so I think it does add to our armamentarium of uh data to suggest that MDT um benefits a subset of patients, whether it benefits all patients who present with some oligo metastatic disease diagnosis or oligo progression, again, hard to say, but again, a very promising data here. Stock cap was very interesting and similarly to the other studies because it's not a randomized comparison, the conclusions that they draw have to be taken with a grain of salt, but at the same time, the data that they present that there's no overall survival benefit with abiratero for the patients aged 75 or older, I think it's a little bit hard to ignore because we know that abiratero does have toxicity. Cities um that might be more prominent in patients um who are older and have more comorbidities. So if you're going to prescribe abiratero to an elderly patient, I think it's going to be important that their other comorbidities are well managed in terms of cardiovascular risks, diabetes, etc. and that um there's a reason why you're selecting that agent over the others when um the others are approved. Um, the NZAP study is a little bit hard to get, uh, all the way into. I think that we know that lute PSMA is an active agent, so combining it with enzalutamide would not be unexpected to lead to improved outcomes compared to enzalutamide alone. Uh, so in terms of the magnitude of the overall survival benefit, um, can that be completely explained by um the fact that 60% of the people on that arm never did receive lutician PSM into the future, um, very well could be, so it really doesn't answer that sequencing question. And so getting back to TelePro 2. It was very reassuring that talus operated and salutomide showed an overall survival benefit in the way that the trial was designed. And so being a purist in terms of clinical trial design, it's not appropriate actually to look at the subgroups and say that one of the subgroups there the hazard ratio for benefit overlapped with one and then conclude that that subgroup doesn't benefit. And that's because the trial is not powered to look for benefit across all the individual subgroups, but now we have to think about the patient in front of us and how we're counseling them. And is this a regimen that we're going to recommend for most of our patients who present with uh first line CRPC without ADHR mutation. So obviously there are risks associated with this combination in terms of anemia. There's also some risks associated with AR pathway inhibitor, CARP inhibitor combinations in terms of um VTE, uh, so. It's a little bit hard to say that it's without risks. These patients require transfusions. They require dose reductions, very close monitoring, um, certainly things that are not required with enzalutamide is monotherapy. So I, the label for the talusoperative benzalutamide right now is actually fairly restrictive in terms of the number of genes that are I I've included to be HR um. Deficient, whereas we know that there are other genes that are not in the panel like R1, FAL, the different RA 51s that might confer homologous recombination repair deficiency. There's certainly biomarkers that people are exploring to try to identify the patients in this non-HRR group who might benefit from this combination. But again with this data, it's a little bit hard if you have absolutely no inclination. And that this is a patient who might benefit from the PARP inhibitor to apply this uh trial finding broadly to say all patients were progressing to CRPC, uh, where you're planning for enzalutamide should be getting Talazoprib in conjunction with it. So it brings us to a lot of questions for those patients who progress on an AR pathway inhibitor and and HSPC, which is what most of us are seeing, what is actually the most appropriate. Next line of treatment. Should it be just ARPI switch alone? Should it be Ezoradium? Should it be Eattala when Luicia gets a pre-chemo approval, Should you give Luicia alone? Should you give it with ESA? I think all of these questions are really unanswered and we'll have to, and they probably won't be answered based on phase 3 trials. So we're going to have to use a lot of our own clinical judgment around the um. The patient and their comorbidities and their preferences to make kind of individualized decisions around how we're going to treat these patients. So I know I went a little bit long, but, but there's a lot to discuss. a ton to discuss and, and, you know, lots of options coming our way and I, you know, really appreciate you um giving your, your, uh, thoughts and analysis of each of these studies.
