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 2023.
Excellent. Well, thanks so much. And uh you know, for anybody who's signed on since uh since Vincent started, uh these, these are ESMO 2023 highlights. Um I'll be talking about a few abstracts with prostate cancer. Certainly some really exciting data with PSN A with immunotherapy. Certainly, uh some questions that were answered and, and uh and uh unfortunately, or fortunately, um a lot more um questions arose. And so our brief outline, we will be discussing PS A four NZAP um some of the anti PD one based uh trials in prostate cancer, a new form of immunotherapy as a T cell, Gr Alam and then um talking about revised stratification for patients with high risk or localized prostate cancer. So, for any folks who, who aren't familiar with that with two ti or uh or fluto, it's uh a radio Lagan therapy uh that recognizes PS A on the surface of prostate cancer cells. It then becomes endocytosis and uh releases beta wave um radiation within prostate cancer cells um has been quite dramatically effective in, in patients with uh CR PC. You see in this um in this picture here, on the left hand, side, that's a PS ma pet scan before lum and then after just six cycles of treatment, this patient had a a radiographic complete response. And so, so certainly for the right patient, uh this, this seems to be an effective therapy and one uh one that has made its way to clinic. Um we know that there is uh a level one evidence for the use of Lation in CR PC for patients who have progressed on a RPIS and taxing based chemotherapy. So, on the left hand side, that's the vision trial um which was uh first presented and published back in 2021 showing an overall survival benefit for lut in addition to standard of care compared to standard of care alone. And then on the right hand side, that therapy study showing a PFS benefit for TIC over cabazitaxel again in the um the CR PC setting. And so the natural kind of progression is to say, can we move this effective life prolonging therapy to an earlier setting? And so that's what the PS MA four study investigated. This was a large randomized phase three clinical trial in the taxing naive setting. Um And it was presented by Oliver Sark. Um So inclusion criteria, these were patients with MC R PC who had a gallium uh PS MA pe T scan of note, if they had PS MA negative lesions, they were excluded from this study and patients had to be um had to have had A RP I and the CS PC setting to be eligible for a switch to other A RP I. Um Also patients could not have been candidates for CARP inhibitors. Obviously, those would, those patients would be have gotten a Carp inhibitor in this setting. And so patients were randomized, went 1 to 1 fashion to Lation for six cycles or A RP I change. And primary end point was radiographic progression free survival. Um By central review for patients who did have progression disease, they were eligible for crossover to the LAIT arm, which is um obviously fantastic for patients who who are on this study. Um A, a pretty typical um you know, treatment uh chemotherapy naive uh CR PC setting. Um uh you know, only about five to, you know, maybe 3% of patients had a liver metastases, the majority of patients had had either Enza or Abby in the CS PC setting. And um and so, um uh the Consort diagram, I think uh great to see that there was a very low rate of, of uh screen failures. Um Only about 20% of patients on the nutrition arm experienced progression of disease and came off therapy that number about three times high higher in patients who had a RP I change. But of those 100 and 46 patients who had a RRP I change 100 and 23 or 85% of patients were able to cross over um which again may have affected the long term outcomes of this study but was for great for patients in ro on trial. Um PS MA four did meet its primary end point. Uh an improvement in radio in uh radiographic PFS by central review has a ratio of 0.43 with the median of 5.5 in er P I change versus 12 months in ti um you see in the forest plot, um small numbers of subsets really hard to discern who um I if any one population garnered more benefit than others really. Um just across the board, uh patients who had reti I be better than those who had A RP I change. Um secondary endpoints, high response rate to reti about 50% compared to 15 in A RP I change. High rate of complete response 20% versus 2.7%. Um And then when we look at our PS, a waterfall pot, so A PS A decrease of 50% and 57.6% of patients who got tissue compared to just 20% in those with A RP I change. Um I really important, you know, kind of patient uh patient um centered endpoint at time to skeletal events lower in um in nutrition compared to A RP I change. And then also the um time to health related quality like decline or pain worse and also favoring nutrition compared to A RP I change. Um When we look at overall survival, this was uh data presented on the I TT population. So did not account for crossover. We see the hazard ratio was 1.16 with medians that were about 19 months in both arms. Again, a lot of crossover in between arms and so they did have a pre specified um uh uh crossover adjusted analysis. And we see there that the hazard ratio is 0.80 median is about the same. Obviously, a lot of bias goes into a uh an analysis like this. Um But trying to account for those patients who may have um progressed and then gotten nutrition. Um these data remain immature and so we'll obviously continue to follow these so time. Um But as of right now, no evidence of of an overall survival benefit. Um nutrition very well tolerated. You see um relatively low rates of grade 34 adverse events at just 34% compared to 43% with A RP I change low rates of um of dose adjustment or discontinuation only about 5% in hr um big things that we think about with nutrition are xerostomia, dry mouth, only about 1.3% of grade three adverse events in nutrition. Um relatively low rates of anemia at 6% in both arms. And um you see no, no grade 34 neutropenia thrombocytopenia in this earlier disease setting. Um And so, in summary, obviously, LTI showed AAA prolonged RPFS benefit compared to A RP I change um was across all early disease endpoints, PS A response, overall response, um patient and center and end points all favoring lut um but remains un uncertain as to whether or not this early intervention using nutrition is going to extend to overall survival. Um but certainly an a a favorable adverse effects profile for this um potentially life prolonging drug in an earlier disease setting. Um I think certainly many more questions of how do we use this in combination with our A RPIS, how do we use it in sequence with some of our other effective therapies in the um in the, in the taxing uh naive setting, but just a, a fantastic um you know, uh option for patients who did not have access to TI um before, before this point. Um One of the other trials that was presented was the NZAP study. This was also using LUM but it was an investigator initiated trial um using an uh an adaptively dosed uh lutricia, which is um um you know, just really a fantastic way to try to use biomarkers to, to really um guide our, our treatment uh therapies. And so this the NCP study, this included patients again with CR PC who were uh chemotherapy naive patients on the study had to have greater than two high-risk features for early samide failure. And we'll go through what those are on our next slide and they also had to have a positive uh PS ma pet scan. Patients were randomized in a 1 to 1 fashion to enzalutamide or enzalutamide plus Lation. And the dose here was 2 to 4 doses as opposed to PSN A four where patients got a standard six doses. Um and the primary endpoint of this study, again, a smaller phase two study. So primary endpoint was psapsapfs and then secondary endpoints as listed um screening criteria, patients had to have a SUV max of greater than 15 at one site and an SUV of greater than 10 at all measurable sites. However, mismatch on diagnostic CT was not an exclusion on this study as opposed to PS MA four. On the right hand side, you see patients uh who had high risk features for early um for early progression, I enzalutamide those patients with de novo metastatic disease less than three years since their initial diagnosis, greater than five bone metastases, viro metastasis, we know that these are the patients who would probably benefit from um from more intensive therapy upfront. And so that's it was of the rationale behind combining these. There's also maybe some evidence that um when you give enzalutamide, you may increase uh expression of PS MA and um and that may actually augment the effect of, of Lation in that setting. And so, um based on patient characteristics, you see about 60% of patients had greater than 20 ps A avid metastases, about 6050 60% of patients with DeNovo metastatic disease. Um and a low number of patients who had had prior a. Um and so this uh timeline, I think really nicely shows the flow of patients. So at the beginning, patients had PS MA pe T scan, then they would start their experimental treatment with um with enzalutamide. And then after day 15, they would have a second PS ma pet scan. This was really done more for translational research purposes. But then they would be eligible to get their first dose of LU tissue if they were on that arm, and they would get doses every six weeks and have a day 92 scan. And if they still have residual disease on that scan, they'd be eligible to get those additional two doses. So four total doses of tissue. If there is no evidence of radiographic disease, they could actually stop tis. So it's really trying to get at um using this first scan to say who could we potentially deescalated therapy and and potentially spare toxicity of of LTI in that uh again, similar to our previous PS MA four study, a low uh pet uh uh a low screen value rate only about 18% of patients. Um and a total of uh about 81% of patients did end up receiving the full four doses of TI So about 20% of patients actually didn't um and, and just get those two doses. Um The study met its primary end point with an improvement in P SI A PFS with the hash ratio of 0.43. You see also there was a trend towards improvement in radiographic PFS with a hazard ratio of 0.67. You see the median PFS uh uh PSAPFS and RPFS as shown below. Um again, similar to PS MA four, we see rather robust PS MA PS A response rates um about 50% P SS A response in 93% of patients on the combination versus 68%. Um and an even greater P SS A response in, in uh 78% of patients compared to 37 on insulin. Um The combination is, is pretty well tolerated. You see grade 34 adverse events only about 10% on insulin plus L tissue. Um relatively low rates, less than 5% of patients with anemia, fatigue, uh thrombocytopenia um compared to, to enzalutamide one. Um And so this was uh you know, really intriguing trial showing that we can combine uh A RSI S with Lation. Um It did show pretty robust early end points of Psapfs response rate. Um and, and um and an improvement. Uh and I, I think the real benefit here is, is trying to investigate, you know, how to do we, how do we incorporate PS MP S A pet into the clinic? How do we um you know, potentially change our treatment either to escalate or deescalated treatment based on that ps that um that first PS A pet scan and um has the potential to not only reduce toxicity but reduce cost and, and get patients on more effective therapies if they're not responding. Um And so this was a slide by uh the discussion Chris Sweeney um who um kind of tried to put PSMO A four in the context of other studies. So vision and therapy, um we don't yet know if, if nuts in the prechemotherapy era is going to improve overall survival, but certainly shows benefit in that population. Um And, and perhaps seeing it as another uh kind of um part of our arsenal to, to treat patients with uh CS P therapy, chemotherapy naive CR PC. Um This was a really great uh heat map that Chris had put together. On the left hand side, you see all of our um uh our chemotherapies and uh A RPIS Park inhibitors. And on the top, you see uh patients put into categories, whether or not they had had NHT or dose of Taxol and in green showing clear benefit in purple, showing modest benefit in red, showing little benefit. Um And so you see PS MA four kind of moving the uh the needle as far as uh moving PSN A into an earlier disease setting. Um And so, you know, uh Chris also went on to discuss well, how do we use this in the clinic? And I think um he brought up really good points of not only using this data but also looking at our germline genetic testing to see who are patients who may benefit from a, a Carp inhibitor. Um How do we use PS MA and those kind of mean suvs and, and really try to select those patients who are most uh likely to benefit from TIC and then for patients who don't have any of those things, um Do they have those tumor suppressor genes this more aggressive um genomic unstable tumors um who may benefit more from chemotherapy and, and, and uh and platinum based treatment in the future. And so that's, you know how I've started to think about this, but obviously, this is just another step on the road of, of a PICO in the clinic and, and, you know, trying to figure out what are the sequences, what are the combinations that are gonna work best for our patients? Um The second kind of set of abstracts, we'll talk about our um our immunotherapy in prostate cancer. We know that um you know, unfortunately, our anti PD one checkpoint inhibitors have not been as effective as we'd like them to be. Um but these were two large pha phase three clinical trials that investigated Pem bro with Enzalutamide. Um The first was the keynote 641 study which was for patients with CR PC. Um And this randomized patients who had um CR PC with prior NHT no, prior chemotherapy um to Pembrey plus enzalutamide versus enzalutamide alone. Um Their primary endpoint was OS and RPFS. And um you see here, those lines completely overlapped showing absolutely no benefit to the addition of Pembrey in unselected patients. Um The second study was just kind of been one uh disease setting earlier. So, um pembrolizumab for hormone sensitive prostate cancer, this is the keynote 991 study. Um similarly uh randomized almost an identical number of patients to enzalutamide plus pembroke versus enzalutamide alone. And similarly showed absolutely no benefit in OS or RPFS um for the addition of pembroke to um to enside. And so, you know, unfortunately, there really is no evidence that we should be adding anti PD one therapy and unselected patients with uh with prostate cancer. I think certainly for those patients with high T MD M si high, you know, maybe immune infiltrated tumors. There, there could be rational investigating immune checkpoints of uh inhibitors in those patients. But I think clearly we need better combinations, we need new immune therapies with uh with novel mechanisms of action. And so I think that transitions really nicely into um into some very intriguing data that came um using uh Zal Rig um which is a um A T cell engage your A bici antibody targeting ST one which is highly expressed on the surface of prostate cancer cells and then bringing CD three. So bringing our T cells into the tumor microenvironment. This was investigated in patients with CR PC and presented by William Kelly. Um So, again, a little bit of background on Salutin cause I think, you know, a pretty novel drug um in early development. But um again, we know step one is highly expressed on the surface of prostate cancer cells and not very highly expressed on other uh cells in the body. And so I think it's got a good target effect. Um And uh obviously brings T cells into the tumor microenvironment to kind of try to invigorate immune response there. This was at the first in human open label phase one study, um inclusion criteria, just patients with CR PC who had had both NHT and a prior taxing uh therapy of no patients with um alternative histology. So small cell neuroendocrine features, they were excluded from this as well as those with a active autoimmune disease. Um Primary endpoint was really just looking at safety and tolerability, maximum tolerated dose. And so again, you see pretty heavily treat pretreated population. Four prior lines of therapy, 85% of patients had had a prior attacking. And um you see here, this was their dose uh exploration uh algorithm. You um after their first F seven cohorts, they actually added a step with premedications using corticosteroids to try to mitigate uh the risk of CRS. And we'll see that actually ended up making a big difference, but their maximum tolerated dose ended up being 1.5 mg IV, every three weeks, they did have a stepwise increase. As we've seen with a lot of these uh T cell engagement therapies as listed there. Um, adverse effects were, were really consistent with the mechanism of action of this T cell. Gr. Um, they were relatively high. So grade three adverse events were 76% sae rate of about 57% and about a 20% rate of discontinuation due to salary Tomic. On the right hand side, you see in our tornado plot, um relatively high numbers of CRS. And then, um you've seen a lot of patients uh experience these kind of myalgia or intense uh skeletal pains, especially while increasing the dose. And so I think that's certainly an adverse effect that we're gonna wanna keep a close eye on. Uh, but certainly consistent with the mechanism of action of this medication. You see on the left hand side, relatively higher rates of CRS. And then after adding that premedication, lower rates of severe adverse events suggesting that, you know, we're getting better at, at, at administering these medications. And then I think, um obviously these are really early data showing uh some showing some pretty promising efficacy. So we see our confirmed PS A responses in the high dose cohorts, um was about 60% of a PS A 50 decline at 60% compared to just 40% in the low dose cohorts and um and about 36% in it firsts 19 where PS A drop of 90%. And you see, in those years, those are the high dose cohorts in blue, those are um those are our lower dose cohorts. Um overall response rate about 40% in uh the high dose cohorts to just three and low dose cohorts. So clearly dose matters and if you're able to get a uh a more tolerable dose in, you can see that potential benefit um responses were pretty rapid. You see uh uh in as highlighted blue, this is when patients um tended to show that first ps A 50 response and then obviously the swim plot, there's um now, I think 10 out of 16 patients who had response uh still had response ongoing. Um And so the median duration of response is about 99.2 months again in a very heavily pretreated patient population. So, you know, in summaries, al RTI is the first T cell engage targeting step one that's um shown some pretty promising efficacy. I still think we have a lot of work to do to, to try to figure out who are the patients who are gonna benefit most from this. Obviously, a lot of toxicity, a lot of inpatient management um as we try to get work out those issues, but really a a promising drug in, in a, in an area that has not um had much in the way of immunotherapy for prostate cancer. Um The last object I'll talk about is actually from one of our own pro Robbie Wan Wang and um multiple other folks using the ice Cap uh consortium. And this is really trying to get at the question we know that um from Doctor d'amico's criteria. Years ago, we've got patients with high risk or high risk, localized prostate cancer, lymph node, positive disease. You know that those patients are at risk for early um clinical decline. But you know how do we use information that we have available to us to risk stratify those patients and potentially increase therapy for those patients who may have um may have poor response long term. And so this was looking at a multiple trials done over many years and about 3600 patients who had gotten who had high risk localized disease or lymph node positive disease, about 3600 patients who got long term ad T plus radiation therapy and looking at their outcomes. Um And so, so in this cohort, about um 60% of patients had high P SAS. So PS A is greater than 20 about 50% of patients with pleasing scores 8 to 10, um about 70% with uh with clinical T three or T four disease and only a small number of patients, maybe about 10% with lymph node positive disease. And um and we know that each of these risk factors alone is um I is a risk factor for early aggression of disease on a RPIS. Um But um when we aggregate those, um I thought this table was just absolutely fascinating. So if you look on the left, upper left hand side, these are patients who have a pretty good five year metastasis free survival. Um and those are shown in the, the numbers in green. But as you work your way towards the lower end and you accumulate higher t stages, higher Gleason scores, higher P SAS. These are patients who, who don't have as good response to AD T plus radi radiation. And clearly that um that population at the bottom that 10% of patients lymph node positive disease. I think these are patients who um who unfortunately don't do as well long term. And so um really trying to identify it's not just whether or not you have these risk factors but it's a multitude or, or uh in a combination of these risk factors. And when you look at that Kaplan, my analysis, there's really clear delineation of those patients on top with one risk factor um in black with 2 to 3 risk factors and in blue, those patients with lymph node positive disease. So again, I think this has real implications for helping us understand who are these patients who are at risk for early decline on our typical A RP I or or androgen deprivation therapy? Plus uh radiation and that this is really a um a, a platform on which we can build uh to um yeah, as an end point for adjuvant trials to help select these patients. Um So with that, I'll um I'll close again, say there's really enthusiastic data on using Lation in an earlier disease setting. Um immunotherapy with anti PD one therapy for unselected patients who should not be doing it. Um But that's albut is, is certainly uh you know, a new um immunotherapy that we're excited about in prostate cancer. So with that, I'll close um open it up for questions and discussion by doctors camp. Hi, everybody. Great job, Mike. Uh My job is easy because these are very straightforward um projects that were presented um As far as um the luteum one PS MA four. I, I think the one thing that comes to mind for me is like, what a waste it is to have to do these trials twice like post chemotherapy and then prechemotherapy because, you know, there's never been a difference, right? With starting with Abby and then Enza and then A LA and, and uh now they're so ii A while it may be quicker by, I don't know, 6 to 12 months to get to market, it takes a lot longer for the prechemotherapy patients to get access to the, to the treatment like this. So that's the one thing that came to mind. It's more an editorial comment than um you know, discussion of how to treat our patients in the clinic. But I think we're all looking forward to the FDA um liberalizing um UT and PS MA for um for the pre chemotherapy MC R PC patients. Um and then as far as the Australian trial that ends A P, um I think adapted dosing is really something to pay attention to when you think about it as you give treatment and the patients are responding, you, you're losing your target, you know, so um it just makes all kinds of sense to not just give everybody six. And I think we've all probably had these difficult discussions in the clinic. I'm at four, I'm at five. My mouth is really dry. I'm miserable. Do I need to get five? Do I need to get six? And you know, we have no data to, to share with patients to help make that decision. So, um I really, you know, lo love this data and love, love thinking about it and um it's biologically rational to um look and see what's going with going on with the PS MA target as, as we're treating these patients. Um So that's those two. And then um as far as um PD one inhibitors not working in prostate cancer, everybody knows my opinion on that. Um II I think it's time to move on as Mike Mike said and uh the AM G 509 is, is very exciting. Um you know, really, except for um uh CUS LT which was developed in a time when there were really, we really didn't have access to life prolonging therapies other than DOCEtaxel. This is the first, you know, immunotherapy to have a potentially broad response rate in metastatic castration, resistant prostate cancer. So, you know, I think everything Mike said is what pertinent and what we have to pay attention to especially toxicity and toxicity mitigation. Um But those response rates in such an advanced group of prostate cancer patients, you know, median of four prior therapies for N PR C MP, metastatic castration resistant prostate cancer. Very exciting PS A responses. Um you know, partial responses of 41%. So uh more to come with that drug, I think um you know, uh we should look into getting one of the larger trials open, I guess to have access to that for the patients in this area. Um And lastly, you know, congratulations to Pr and Chris Sweeney and Wan Ling and the ice cap team for uh putting together the, the risk stratification analysis. I think it's helpful how we think about patients. And you know, it will be interesting. I'm sure they have this on their long term plans but looking at how node positive patients by ps ma pet rather than conventional imaging, um you know, we'll, we'll change this, it probably will line up with, with what we're seeing here. But uh you know, as we get more pets in these patients for staging. Uh looking at the difference in um node positivity by nuclear imaging versus, you know, sort of older conventional imaging will, will be um illustrative.
