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 GU 2024.
My name is Jake Buruk. I'm a medical oncologist at the L Center for genital urinary oncology. And I'm joined today by several of my colleagues to discuss the updates in genital urinary oncology from as Ogu. Um I'm gonna start by talking about prostate cancer. We have Doctor Xu to, to speak about kidney cancer. Doctor Mantia to cover bladder cancer and doctor uh Turi to discuss testicular cancer and uh with, with distinguished discussants for each of those. So I will get into prostate cancer updates. Um As doctor Shri alluded to, there weren't any um clear um practice changing clinical trials in prostate cancer, but um a few notable um phase threes as well as some, some interesting phase two studies to report on. The first is the contact 02 study that was presented by uh Doctor Neri Wall that looked at Cabo an plus a EUM a somewhat novel combination for metastatic castration resistant prostate cancer. Um as as many of, you know, um immunotherapy, uh sort of immune checkpoint monotherapy has not been terribly successful uh in metastatic prostate cancer. Um But there is some data uh that um cabozantinib A, a Tracy Kinase inhibitor has activity in MC R PC and some uh data that it, that it may um uh synergize with immune checkpoint inhibitors. So that was the concept being tested here. This is a randomized phase three study comparing cabozantinib plus talli to uh uh either Aber Aaron or Enzalutamide. These were patients who had progressed on one of those agents previously and um prior chemotherapy was allowed but not mandated. Um and uh patients were randomized 1 to 1 to receive these 21 of these two arms with a primary endpoint of PFS and overall survival. Um I I included the baseline characteristics here to point out as Doctor Gerwal did. These are um yeah, in both arms, uh about a quarter of patients had liver metastases which we know are associated with poor prognosis. Um The high rate of visceral and bone metastases. So, relatively high risk population for um having progressed on an NHT. Um this is the um PFS uh data that it was, it was technically a positive study. You can see uh um uh uh has a ratio of 0.65 with a P value of 0.0007 which met the statistical primary end point um um for for improved RPFS. But um a as you can see if you look at sort of the clinical benefit, um about 2.1 months was the added benefit beyond um second NHT which, which we'll chat about more at the end of this. And then um doctor um Choudhary, I imagine will comment on this but, but it is a probably not standard of care um uh systemic therapy for, for patients in this um setting who who weren't mandated to have received chemotherapy. Um The benefits seem to be relatively consistent across subgroups. Notably, um patients with liver metastases seem to um respond preferentially to the co tizo over um NHT switch. And um here were Kaplan Meyers um based on um pre specified subgroups. Um suggesting that compared to NHT Cabo Tizo um had improved PFS for um prior live or patients with liver METS prior to Taxol and um bone metastases. The overall survival was um immature has a ratio of 0.79 did not meet statistical significance but trended in AAA about a month and a half improvement um uh over this uh control arm and that was similar for the subgroups. Um sort of AAA again sort of alluding to the, the control arm being a not terribly active um systemic therapy. The, the objective response rate was only 4% on the control arm compared to 13% for the Cabo Tizo, which did um achieve 73% disease control as best uh response. Um Here uh just they, they, they pointed out that most patients received good dose intensity for the Cabo tizo. Um The side effects I would say um were in line with what we'd expect for a cabo, um a tizo uh with higher grade three, grade four compared to NHT but um not no new safety signals. One thing that was interesting is, you know, relatively low proportion of patients on both arms went on to receive um sys systemic therapy. Beyond um what they were randomized to, you can see 23% for the cabals and 32% for the NHT speaking to, you know, seeming to speak to the high risk um or, or um sort of aggressive nature of the disease for, for patients in this um study, you know, again, sort of underlying that that NHT switch was probably not uh an adequate control arm. And so, um Doctor Ral concluded that it was a um positive study with a um improvement in PFS compared to a second NHT, it was a, a benefit seen across subgroups. Um overall survival was immature and no safety signals were seen. And so, um you know, uh the conclusion was that this is a potential new treatment option for patients with MC R PC just to be clear, this is not received FDA approval. Um And, and I think, uh you know, eager to get Doctor Choudary thoughts at the end on, on this combination and whether there's gonna be a role for it uh moving forward in MC R PC, um Doctor uh Kimchi gave commentary on this study and, and I thought a couple um uh comments that, that I think were relevant, I think I highlighted a lot of them. But um you know, the while being a positive study, the actual um clinical benefit was relatively modest. And um here he, he again, sort of commented on the, the um inadequacy of, of A RP I switch. Um When we know that dose Taxol cabazitaxel PTO all are life prolonging in that setting. Um Moving on um the, the next uh abstract I'm gonna oral presentation that I'm gonna speak about is a bra away study which was a randomized phase two study looking at Aber own plus or Aber olaparib and the combination. And then with MC R PC, here's the, the overall study design. Um The study that was presented focused on arms 12 and three, which as I mentioned was men with MC R PC um who had not previously received a parp inhibitor or a R pathway inhibitor who were randomized to receive a or and predniSONE ela of monotherapy or the combination. Um with the primary end point being um radiographic progression free survival. Um I included this here um for reference and we'll sort of move on. There were no new safety signals. Um The, the striking observation here was that compared to ARA and oral laid monotherapy, the combination had a pretty dramatically improved um media and radiographic progression free survival of 39 months compared to eight and 14 months respectively. Um with a with a numerically higher uh objective response rate and PS A rate as well. Um Here are the waterfall plots of best PS A response. Again, you can see sort of pretty clearly by eye. The combination had a, had a deeper and more um consistent uh PS A responses. And here's the Kaplan Meyer showing the radiographic progression free survival for the three arms. Again, highlighting the um um pretty impressively numerically longer um RPFS for the combination compared to either monotherapy, um crossover was allowed in this study. Um So patients who received aber atone could were offered to cross over to a la and vice versa. Um The, the it was a relatively small study to begin with and about half of patients on each arm or less than half of patients crossed over. So we do have, you know, with the caveats, these, these numbers are very modest and um impossible to make definitive conclusions from. But um when we, when we do look at the crossover, so essentially giving the two therapies sequentially, as opposed to in combination, the um the, the sequential um PFS was around 16 months with crossover on both arms for the patients who did cross over compared to 39 months for the, the combination and, and that's shown here in the swimmer plot. So the conclusion from the study, I think um you know, that, that, that clearly um RPFS was, was um prolonged with a combination compared to monotherapy and suggestive of longer compared to sequential but, but with incredibly small sample size, nothing there are no definitive conclusions. But I think um this was a really intriguing study. Um and and really the first of its kind that provides data on the Aboone or the air pathway inhibitor parp inhibitor combination relative to parp inhibitor monotherapy. And I think um definitely um an unmet need in in sort of the first data of its kind to support the potential for combination over sequential therapy. Um for the sake of time, um I'm gonna skip over the the common terry slides from Doctor Chi that I added um because I think I covered the main points moving on. Um This is another randomized phase three study and um you know, we'll be eager to see if there are any of our radiation oncologist oncologists on the call, who, who want to comment on this. But this was a randomized phase three study that looked at um 80 gray versus 70 gray in combination with long term androgen deprivation therapy for localized high risk prostate cancer. Um That was essentially the the study question patients with um kind of standard high risk prostate cancer criteria were randomized to receive 80 gray or 70 gray along with three years of um of uh androgen deprivation therapy with a primary endpoint of progression free survival, which um a as as they note here was um either biochemical or clinical progression. Um So it was a composite endpoint of biochemical and radiographic progression. Um um This highlights that the majority of patients had one high risk factor. Um about a quarter had uh two high risk factors. So, here are the, the results. So this is the primary end point, the progression free survival. Um And what it did show was there is a 44% reduction in the risk of events um for patients who received 80 gray uh of radiation compared to 70 gray, it was statistically significant. So um the primary endpoint was met in favor of uh 80 gray compared to 70 gray in combination with long term ad t um cancer specific survival. So, prostate cancer survival was also um significantly in favor of 80 gray. Um interestingly as was overall survival. Um It has a ratio of 0.61 with a statistically significant um value in favor of 80 gray. Um reassuringly, uh long term toxicity was similar. Um both janitor urinary as well as G I toxicity was uh similar with um the two arms as in it appeared that quality of life was also maintained. Um So, uh the the presenter concluded that um that uh you know, 80 great clearly sort of met the primary end point as well as improving prostate cancer specific and overall survival and high risk prostate cancer without um increasing toxicity. And did conclude that this was a new standard of care for men with high risk localized prostate cancer. Um I'm gonna move on from uh these phase threes to, to some interesting phase two data. Um This was a study that was presented by our colleague uh Doctor Beltran on a new tris specific DLL three targeting T cell engage in neuroendocrine prostate cancer. Um So DLL three, I think this is work from Doctor Beltran's um research that um DLL three is highly expressed in uh neuroendocrine prostate cancer um shown here on this slide. And so um led this uh uh phase one study of um uh uh this um DLL three targeted um T cell engage or uh in, in patients with neuroendocrine prostate cancer as well as other high grade um neuroendocrine tumors that express DLL three. Um The adverse event profile is shown here um actually um relatively well tolerated. Um sort of uh in line with what we've seen um with other um by specific tris specific T cell engage type therapies. Um Cytokines release syndrome being the most common um treatment, but grade three toxicity was relatively uncommon. And here's the uh response data on the left is showing for all tumor types and on the, the right showing um the responses for uh gu malignancies um including both neuroendocrine prostate cancer as other as well as other gu um neuroendocrine tumors. Um The overall response rate was uh 58% in the GU cohort. Um with um a disease control rate of 83% and hear the duration of responses. Um folks who take care of patients with um high grade neuroendocrine prostate cancer will know this is an aggressive um tumor subtype. So, you know, um obviously, it's not the, not the rule but seeing um durations of response approaching a year is really um exciting for, for this uh aggressive um phenotype to see activity. Um So, so, you know, I think um DLL three expression given this is a target of therapy is is of interest and, and they did some work sort of correlating um expression with um response and, and I think there's a lot more work to be done there. But in general, um this, this DLL three T cell gr is, is a promising um novel therapeutic approach and therapeutic target for patients with neuroendocrine prostate cancer. And, and I imagine we'll see more from Doctor Beltran. Um uh with this approach in the future, I'm gonna wrap up in my last few minutes with um I think two additional um rapid oral abstracts. Um One was uh the quality of life data from the formula 509 study. This was a study led by um uh Doctor Nguyen, um where uh patients with high risk prostate cancer were uh randomized to receive. Um uh uh oh, here we go. Um The six months of therapy with standard of care, combined androgen deprivation um with uh with balut amide versus intensified hormone therapy with aber aone and apalutamide um the, the, it was, I believe, technically not a positive study. Um But intriguingly in the subset of patients who are high risk with a ps, a greater than 0.5. Um in, in the salvage setting, there was an improvement in metastasis free survival with the intensified hormone therapy. Um And so, you know, uh I, I skipped through to the end, but essentially the conclusion was that quality of life was really um maintained or or not compromised with the intensified hormone therapy. So, um you know, it lends credence to um there clearly seems there's the data is suggestive of um of activity, greater activity with the intensified hormone therapy and it appears to to not come with a detriment and quality of life. So, um again, we need more data in that space but um I think uh potentially uh an appealing option for our high risk patients who have biochemical recurrence. Um Finally, I think this is the, the last um abstract, which is the ace study. Um something that, that we as prostate cancer clinicians are well aware of is that um yeah, the, the different sort of air pathway inhibitors have slightly different uh side effect profiles. And this ought to sort of uh uh formally invest, get that comparing um quality of life uh for aber aone versus enzalutamide in men with metastatic castration, resistant prostate cancer. Um with several um uh patient reported outcome, health related quality of life. Uh end points and again, skipping to the conclusion was that um overall cognitive outcomes were comparable. Um But um uh Enzalutamide had higher rates of fatigue, depression, and um subjective deterioration in cognitive abilities and slow reaction time compared to aper atone. So, so we have some nice sort of formal data now to um you know, be able to counsel patients on, on the side effects for these commonly used therapies. So with that I will wrap up and, and uh if, if people have questions, please feel free to put them in the chat. Um And before I turn over to doctor Choudary for um commentary, we'll just conclude with that contact 02 while technically a positive trial um uh you know, showed very modest um clinical activity relative to a um uh a a sort of non-standard of care or, or, or sort of maybe um non optimal control arm. Um Arain and Olaparib. Um we saw uh data comparing the combination to um monotherapy for the first time, particularly Parp inhibitor monotherapy with data um small numbers but suggestive of of potential um uh benefit with the combination relative to Parp or API monotherapy in BRACA ATM U MC R PC. Um 80 gray compared to 70 gray improved um was a positive study with three years of ad T improved OS prostate cancer specific survival and PFS. And then promising data for DLL three tris specific and neuroendocrine prostate cancer. With that I will uh turn it over to Doctor Choudhury, any um commentary you'd like to make on these studies? Um Please, um I will try to be brief which is very difficult for me, but I'll, I'll make a single comments on, on both of them on all of these. So uh the contract to trial, I think Doctor Chi did a great job of um discussing the findings and the limitations. I think overall that we all know clinically um that patients with visceral metastases and A RP I switch is not an appropriate standard of care. And so the part that was concerning about the trial conduct of this study was that patients who um completed treatment on this trial did not, many of them did not receive any uh anticancer treatment after enrollment. And so the degree to which uh treating somebody with a regimen that is unlikely to provide them benefit, the PS A response rate was only about 10% and the RPFS was about six months, which is about the same as Cabo alone and the degree to which that delays their receiving actual um treatment that has a survival benefit in the population and is likely to prolong their survival is a big problem. So uh if let's say the FDA does approve this particular regimen, the question for us as clinicians is who would we treat with this regimen? And I don't think that we have really good by markers to understand who are the patients who really benefit. And so in that context, it's hard to really understand uh which patients are really appropriate for it. So that's something that we'll have to kind of figure out in our own practice and see if they do uh come up with any buy marker data that's associated with the trial to help us with that clinical decision. Um About the second study, the breakaway study, this is the only study that asks the question about the comparison of the combination of aber aone, an elaborate versus sequential aone, an elaborate. But one thing that one needs to be aware when you're comparing sequential treatments until progression is that um the progression is defined by prostate cancer, working group three criteria. And um and so oftentimes you will have rising PS A without radiographic progression but will not have considered progressed for a crossover study and only a minority. Um So, and not all of the patients who are on the study actually wound up crossing over. So, but conceptually speaking, I think the idea that for patients with BRC A, one or BRC A two alterations who progressed to MC R PC without having received an A R pathway inhibitor. Um certainly, if they have high volume or symptomatic disease, I, I do think that there's compelling data that says there's an advantage to using a combination of a neural lain compared to um sequential single agents. But in practice, we have very few patients who progress to MC R PC um not having received an A pathway inhibitor. So, the clinical question that we're faced with is if somebody is for resting on aone, would you add olaparib and give them combination treatment? Would you switch them to elaborate monotherapy or would you switch them to Tali Opera Andal? And we really don't have the answer to that question because certainly combination treatment have more side effects, increase pill burden and to what degree it benefits um, patients who received a prior er P I, uh we really don't know um on the third trial, um this 80 degree versus seven gray. Um I think understanding the context and understanding the, the type of radiation that's administered here is going to be important in understanding this result. I am not a radiation oncologist and don't aim to speak for them. But what I would say is that um we were dose escalating to the prostate at 79.2 grades over 44 fractions. And uh there have been studies that hyperfractionated to 70 grades, let's say over 20 f, 28 fractions is about equivalent in terms of dosing. So I don't think that this study changes what we're doing in our practice, but I think does uh just demonstrate that appropriate dosing of the prostate is associated with a survival advantage even in the context of prolonged AD T. And Doctor d'amico did leave a comment that he did want to from the investigators, if the duration of AD T was identical between the two arms, we don't actually know that. Um And then in terms of the DLL three, I think we're just very excited to see where this goes. I don't have further comments on that. Um But the, uh in terms of the last two studies, um I thought that they were both interesting in terms of their findings around different aspects around quality of life. Um What I would say is that it was reassuring that the quality of life detriment to Aaron and aide compared to Balamine, um didn't show is anything being really significantly different. But in our own practice, we know that when there's such a significant pill burden from both Avara and ay together when there's a problem with hypertension, when there's problems with rashes and thyroid issues that the tools that we use for quality of life um are kind of blood and don't really capture everything about the patient experience. So I think that that's something that we have to keep in mind when we interpret quality of life. And then the same thing around the cognition that it was just interesting that there were differences around perceived cognitive ability. But when you actually tested um using cognitive tools that um there weren't any big differences. So we just really need to understand the tools when we incorporate them in our trials. Thanks so much for the opportunity to talk about all of the studies.
