All right, all right, thank you. Thanks for inviting me, um, appreciate the opportunity to come and speak. um, so I'm gonna, um, try to do a little bit of uh carate resistant prostate cancer in a really short amount of time. So I'm gonna do a sort of a brief, brief history of the landscape over the past decade or so and talk a little bit about some of the sort of current therapies we're using, including radio ligand therapies, um, the use of a second, uh. Oral hormonal drugs, um, HARP inhibitors, um, and other therapies. So, um, so I, I, I, I drew the prostate cancer straw here, um, and this is not a talk that I give, um, that often, and so, um, sort of behind the scenes inside baseball, so I went back into my slide deck to see, you know, what prostate cancer, uh, slide decks I have and the last one I had given was in 2017, so it's been a while. So I figured this would be a good time to look back what I was telling people in 2017. So this was the overview of treatment for metastatic prostate cancer, um, that I talked about then. So, um, in the, you know, early dark ages, long before a week ago, um, we had very little, including very ineffective treatment, um, and then we developed, you know, castration and, and ineffective treatment. Um, we, um, then started to get a combined androgen blockade, um, and still minimally helpful chemotherapy. Um, and then we started to get new therapies as we got, um, oral anti-androgens and docetaxel. Um, oh, there's a scissors there, OK. Um, and so, and then this was the sort of landscape when I last gave this talk, um, in 2017. Um, so you had hormone therapy for castrate sensitive disease, and then you had, um, sipuloLT, um, we had the beginning of aberratedone or enzalutamide, but only for castrate resistant disease, um, and then you tried the other one, we got radium 223 and, and then we had chemotherapy, um, and so that was the status and then this was sort of what I said was the, this was the, the new age in 2017, um. Um, where, um, we now had, uh, moving therapies up to the castrate sensitive space, but a lot has has sort of happened um in that timeline. And so now we have um different doublet and triplet combinations for castrate sensitive disease, and we have a slew of therapies for for castrate resistant patients, um, with a lot more on the way. So how do we sort of keep track? How do we decide, um, what are the right options? And so thank you to AI for helping me create this this picture that I would never have had otherwise, um. So I'm gonna try to go through this with a case and I'm gonna sort of use this to illustrate sort of the different decisions that we make with our patients, um, you know, in the clinic. Um, so 67 year old male, history of Gleason 8 prostate cancer, had a prostatectomy, um, PSA started rising, um, and imaging revealed, um, some adenopathy, bone metastasis, um, they were treated with um therapy for metastatic disease with. um, and aberrateone and prednisone, um, PSA came down and they did well for a while and then PSA started to rise, um, and here are some shots of uh a PSMA PET scan, um, demonstrating some various areas of disease for those who aren't used to looking at these, the some of the yellow spots. I don't know that I can really highlight them, but, um, um, are, uh, evidence of, of metastatic cancer. Um, and so the question is sort of what would you choose in this patient and I give you some options, um, so enzalutamide, lutetium, PSMA, docetaxel, or something else. So, um, what are some of the data? So, um, I think one of the important recent trials that we've had here would be the PSMA4 trial and so this is looking at, um. At radioligan therapy with uh Lutein PSMA, um, so this is a PSMA targeted agent that essentially distributes, um, this radioactive element to the different sites of disease, um, patients who with new castrate resistant prostate cancer were randomized to leticium or switching their, um, oral um um agent, um, to another oral um hormonal drug. Um, and this is basically the sort of, um, key slides so the primary endpoint of this trial was, um, radiographic progression free survival, and you see, um, uh, a significant improvement with the Letitian PSMA compared to, um, the alternative, um, oral agent. Um, and then, interestingly, this is overall survival, and so you see not, um, not, not really a difference here, um, at this point based, um, based on these curves. Um, and so, you know, one of the reasons that, um, you know, when we, as we move therapies up, we want ultimately want to try to see that that we're. Improving long term outcomes, um, and, and not just, um, not just shifting things around, um, so you, you really wanna see is there a benefit in in toxicity and and less toxicity or are you improving overall survival, um, and not clear yet that we're seeing that by moving forward, um, these radioligan therapies, um, interestingly, this is, um, a curve of the uh PSMA reduction, um, and you know we certainly see increase, uh. Uh, drop in PSA in patients receiving um the radio ligand therapy, but we do see some patients who do seem to get a benefit from a second, um, oral anti-androgen. Um, and then, um, another trial in this space was the splash trial. Um, this was, uh, looking at a similar, um, PSMA targeted radio ligand therapy, um, and the design was, was also relatively similar, um, patients were randomized to the Lettician-based agent, um, or, um, uh, an oral anti-androgen, um, uh, patients were randomized in a 2 to 1 fashion, um, and were able to cross over to the, um, Leticia arm after, uh, after they had progression. Um, and I don't know how well this is showing up. I can barely see it, but, um, there was, um, an improvement in radiographic progression free survival, um, but if you sort of look at the numbers, and of course it's always hard to compare across trials, um, there did seem to be, um, uh, some differences and maybe not quite as much of a difference in this Lutician-based agent versus, um, the, the, um, other agent that that is proved from PSMA4. Um, and again if you look at overall survival, really not much of a benefit, um, and so I think one of the things about, um, this, and this drug is, is not, uh, at this point being pursued, um, for approval and so I think one of the questions is, you know, what is the difference in, in this trial and why did we see a benefit, at least in RPFS and in with one agent and not with the other, um, one of the differences with these. Um, agents, um, is, is, you know, this is still radiation and does dose matter and so one of the interesting differences about this trial is the splash drug, um, was dosed, um, at, uh, is a different, um, essentially radioactive dose, a different dose of radiation, um, that you see there and it was also given 8 weeks apart as opposed to 6 weeks apart. And so this schematic trying to show you sort of the total dose. Of radiation that patients received on trial and basically with the the PSMA4 trial you're basically giving a higher dose um to the tumor um closer together and so ultimately your total dose um uh exposure is much higher at the end and this very well may explain some of the differences that we're seeing with the approved drug with the drug that was given on the splash trial. Um, so one option for these patients absolutely could be Letitian PSMA. Um, we see it in a uh a benefit. Um, it's a well tolerated agent. Um, but is that the right choice for everybody? So, um, I'm gonna alter the case a little bit. So uh this patient comes in same history, but this time patient comes to clinic, um, to review their scan. Um, their biggest complaint is is incontinence. They're just constantly wet all the time. They, they have sort of, you know, urine soaking their clothes, um, on a constant basis. They live with their adult daughter, son-in-law, um, and 14 month old grandchild, um, as well as um a. Um, their daughter is pregnant with a second child, and the patient, um, helps watch his, his young grandchild every day. So, um, in, in this scenario, is, is Luitian PSMA really the, the, the best, the best agent. Um, um, I don't know how well this shows up. So, you know, this is a radioactive agent, these radio ligand therapies, patients are essentially emitting. Radiation and um uh having radiation uh in their urine um over the first few days after treatment and so we give a lot of precautions to patients about um how they can keep their family and friends safe um after their treatments. Um, this includes trying to keep a safe distance from people, uh, not being close to, to pregnant women, to young children. Um, and so these are things that we have to think about. Um, it's also excreted in the urine, so patients who are incontinent, um, are at risk for, um, skin toxicity and, and other complications. Um, we've had one patient who had an, um, an artificial sphincter which, um, became very problematic with flute. We don't know for sure if that was related to their treatment, but, um, possibly may have been related to the radiation. So this patient that I that I described maybe isn't ideal for Leticia-based therapy. They, they wouldn't be able to take care of their grandchild for the 3 days after treatment, um, wouldn't be able to be near their daughter who's pregnant and so things that you need to think about with these therapies. Um, so in that case, is a second ARPI an option? Um, one of the things that we sort of talk about at meetings with a lot of these trials is, is that really the proper proper control arm? Should we be, um, giving patients a second oral anti-hormonal drug because we know that it tends to not work as well as the second one. If you look though at the control arms um um of these trials as well as profound, which is a trial I'll talk about in a minute, um, you know, we see we do still see some activity for the second, um, androgen receptor blocker, um, medium PFS is in the, um, often 5 to 6 month range, um, uh, median overall survival, um, for several years, and there is a percent of patients who get some response. And so I think there is potential. scenario where this can be an option for some patients. So for this patient who maybe feels well, doesn't have a lot of symptoms, Leticia isn't the best agent. Maybe they want to get through the period when when his daughter gives birth and and isn't pregnant anymore, and then they might be more willing to consider a therapy. Maybe trying um a second hormonal agent is reasonable like enzalutamide, um, and seeing if that can buy them 6 months before they can get to the next therapy. Um, all right, so another scenario. So patient comes to the clinic to review the PET scan. Um, in, in this situation, there, um, NGS also comes back and reveals a BRCA2 mutation. And so that, that opens up new opportunities for this patient. Um, so PARP inhibitors certainly have a, a clear role in, um, in metastatic prostate cancer. Um, we have evidence from the profound and Triton 3 studies looking at um Olaparib as a single agent or recarib as a single agent compared to, um, physicians Choice. Um, the Triton 3 trial, I'm sure a significant improvement, um, in primary endpoint of RPFS, um, and you see some of the, um, key numbers here, um, I'm not gonna sort of get into those, um, and then similar results really if you look at a laparib in the profound trial, um, significant improvement in our PFS, um, major difference between the arms, um, and relatively sort of similar in the same ballpark, um, numbers. Um, and then we also have the combination trials. So this is looking at PARP inhibitors, um, combined, um, with a second ARPI. Um, we have, uh, propel, which is a laparib and abiratero. It's a trial that we participated in, um, Talaro 2, which was, um, a telazoprarib and azlutamide, and then magnitude, just neurapparib, um, and. Um, aberrateone, um, there are some key differences to this trial, um, so, so it's hard to compare these exactly across because how they accrue the patients differ, um, some of them, uh, selected the patients for the, uh, uh, BRCA or an HR mutation up front, and patients were, um, were randomized based on that while others it was done retrospectively, um, and so that does differ the, the pool of patients that get into the trials, but overall relatively similar. Um, and you see, um, you know, these were sort of the, the top line numbers, um, for these trials, all with, um, excellent median RPFS's, um, overall survival, um, some of the differences in numbers, for example, the magnitude numbers are because of the, the slightly different patient populations that they used. Um, I think all of these drugs and. Combinations um are potentially active and really good options for patients with with um BRCA and some other um HRR mutations. So in this patient, um, who comes in with a new BRCA BRCA mutation, um, a PARP inhibitor with or without an ARPI, um, may make sense uh as a great combination for that patient. So what about chemotherapy? I, you know, that's been sort of our, our, the drug that we've go go to in this space for a long time and I, I've sort of ignored that one up till now. Um, so I'll also try to hit on some interesting, um, updated data from ESO. So this was a, a trial that, that caught my attention. This was a, a randomized um phase two trial where patients, um. Uh, this was the Canadian groups love these crossover trials, so patients were um selected to get either lutetium or docetaxel, and then, um, when they, when, and then switched basically. Um, and, um, interestingly, um, the primary endpoint of RPFS, there was really no difference in the randomization to docetaxel versus Lutician PSMA, um, and then overall survival, there actually seemed to be a little bit of a separation of the curves and a benefit in the favor of, of Docetaxel, of the chemotherapy arm. Um, and so those patients actually seemed, uh, on the whole, to, to possibly do a little bit better. This is not statistically, um, um, significant, um, but there certainly seems to be a trend looking at the curves there. Um, so how do we select? How do we know, you know, are there patients that might be, um, ideal, uh, for, um, for Docetaxel, um, and so there's been some interesting data coming out about that. Um, this is uh from a study, um, looking at patients with, um, with P10. and showing that that may be a potential biomarker um for patients who may respond to chemotherapy. Um, other mutations like like P53 um also have been associated with, with chemotherapy benefit and so some of these patients sometimes we refer to as having aggressive variant prostate cancer, really chemotherapy may be the best option for them. So, um, so, you know, in with the right patient, docetaxel also I think is absolutely um a reasonable option for these patients. So, um, I'll end with just some, some new exciting therapies on the horizon. Um, there's a lot of great drugs out there. Thank you to a lot of our industry partners who are bringing these drugs to us, um, and we're excited to be able to offer them to our patients. Um, I'll mention just a few. This is certainly not, not all of them, um, zalarriammi, which is a by specific antibody, so, um, a new mechanism action coming into the prostate cancer. Space this is targeting steep one, which is highly expressed on the majority of prostate cancers, um, and then attaches also to CD3 which is a a T cell, um receptor so trying to bring the T cell to the to the to the cancer tumor micro environment, um, and there's a phase 3 trial which we're are participating in, um, uh, looking at at this drug compared to cabazeaxol um. Uh, there's also another by specific targeting another highly expressed prostate antigen, um, KLK2, um, which is peurammi, um, and this seems to be a very well tolerated drug also moving into later phase studies. And then finally newer radio ligand therapies, um, coming along the line, particularly with this, um, actinium, um, agent, which is a, uh, a radiolabe alpha particle, um, which is also in, um, several different trials in both the cas resistant, um, and carate sensitive space. So in conclusion, we have lots of great options that really now exist um for prostate cancer and it's really a question of how do we choose uh the right drug um for our right patient. Um, we don't really know the optimal sequence and, and really it's patients specific. I think it's probably cause there's not an optimal sequence and it really depends. Um, on the patient in front of you, um, we're hopefully getting to the point where biomarkers will help us in making these decisions, um, and we have even more drugs on the way. So my, my next slides, um, another 8 to 10 years when I have to give these they're gonna look even more different. So great, thank you.
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