So next is uh Doctor Annari who is an assistant professor and um she actually spends 2 days a week at East Norton seeing only GU patients so uh she sort of holds the fort there. She is a PI in several prostate cancer trials she sees. All GU but really I think has a love for prostate, uh, cancer, uh, and, uh, sort of is just sort of uh extraordinary clinician in that regard, and she's gonna talk to us about biochemically recurring prostate cancer. There have been certainly changes in the paradigm there and um something important for us to uh know. All right. Thank you. I have no disclosures. So the objectives for tonight, we're gonna go over options for biochemically recurrent prostate cancer. We're gonna go over some definitions, imaging, we'll talk about salvage therapy options, uh, the Embark trial and some updates over the past year. Um, and Karen already talked about metastasis directive therapy. I'll go into a little bit of detail on some of those trials. So not to belabor the point here, but it's important when we're thinking about prostate cancer to think what are our goals. Active surveillance is when we monitor these patients with the goal of, uh, curing them whenever we do intervene in the medical oncology space. um, often what we're doing is observing them and they may not be on treatment, but when we do treat, it's with palliative intent and then some definitions of, you know, what the PSA should be after the radical prostatectomy or after radiation therapy, uh, differ. So what is biochemical recurrence? So after radical prostatectomy, we know that even if these men recur, they can still live long lives. Um, the, um, Kaplan Meyer curve that you see here is from 2005, but it's a study by Friedlandet all that basically shows men with negative conventional imaging can live a really long time. The 15-year cancer specific survival is greater than 50%. That's really important because as we're using PSMA PET scans more and more, we really need to make sure that we're not overtreating a lot of these folks who are generally going to do well. So conventional imaging, we think about CT scan, bone scan, MRI. These are not all that sensitive compared to the PSMA PET scans that we have now. You can see here on these curves from the, uh, the chart from the Condor trial that you're gonna pick up at it with a PSA of 5 or above 98% of, uh, prostate cancer recurrence. So here's just a little flow chart of how I think about prostate cancer in this setting. So first, we'll talk about salvage therapy. I'm not going to talk about any of the urologic interventions in this setting, so we're not going to cover cryotherapy or, or hyPU or anything like that. But post prostatectomy, a lot of what we see in the medical oncology world is if they have high risk features, meaning they had positive margins, SV invasion, extracapsular extension, particularly a detectable PSA in a space where you think they should have undetectable PSA. These are the folks that were generally recommending that they undergo salvage radiation. Uh, with or without 6 months of ADT. There were 4 clinical trials in this space that really looked at ADT, um, with adjuvant or salvage radiation. I we'll go into these a little bit. So these are the four clinical trials. The 9 RTOG 9601 looked at using radiation with or without two years of bioluamide. Their primary endpoint was overall survival. Um, the Jetug study looked at radiation with or without six months of, can you hear me OK? Uh, 6 months of Gorellen, that was a freedom from progression, which means it was a PSA guided, um, primary endpoint similar to the sport trial or RTOGO 534, similar in that they looked at radiation with 6 months of ADT. They also had a component of that that looked at pelvic nodal radiation. Um, and then the radicals HD trial, primary endpoint was metastasis-free survival. So again, not a PSA driven primary endpoint. Um, and that looked at not only radiation alone, but also had arms of 6 months and 24 months of ADT. And what you can see here is that the RTOG trial did have an improvement of OS of 76% versus 71% at 12 years. This, um, was primarily driven by patients with a PSA of greater than, uh, 0.7. Um, the Jetug study did not have an OS benefit, but there was a PFS benefit of adding, um. Of adding ADT of 64% versus 49%, the sport trial also no no OS benefit, but there was an improvement with freedom from progression. Um, the best outcome was when patients had pelvic nodal radiation with prostate bed radiation and 6 months of ADT, um, and then the radicals HD trial had no MFS benefit with short term ADT and no OS benefit either. So a little bit discordant from the other studies. They did look at short-term ADT versus long-term ADT and at 10 years, there was a metastasis-free survival benefit of about 6%, um. I think in this setting we really need to weigh the risks and benefits of putting men in this setting on ADT for 2 years and really weighing the other side effects such as hot flashes, sexual dysfunction, fatigue, muscle mass loss, bone density loss, all of these things I think are really important when thinking about committing someone to 2 years of ADT in this setting. Next we're gonna go into if there's no salvage therapy option meaning these are the folks that I think about who have mostly had radical prostatectomy and then have had their salvage radiation with or without ADT, um, and then PSA doubling time really comes into play here when thinking about how do we treat them? Do we observe them and intervene when we need to, or do we think about doing some sort of intermittent therapy? I like this calculator. I learned about this in fellowship. Sloan Kettering, you plug in their PSA, uh, and their dates and it'll give you their PSA doubling time. This gives you a sense of their velocity or pace of their disease. Again, why does this matter? We know that metastasis-free survival is impacted by Gleason score by PSA doubling time. Someone has a PSA doubling time of less than 3 months, um, their metastasis free survival is on the order of like less than a year as opposed to if it's greater than equal to 15 months, you're looking at 15 years. So PSA doubling time is really important in this setting. The, um, prior to the embark trial coming out, there was really no level one evidence, um, on how to treat these folks. um, patients could get continuous ADT, they could get intermittent ADT, intermittent had better quality of life. So I think that's generally what we would opt to do. And then the Embark trial came out. I talked about this last year, so I won't kind of go into too much detail again, and I'll talk about some updates, but this was looking at the use of enzalutamide in the biochemical recurrent setting. And here, um, men had to have a PSA doubling time of less than or equal to 9 months. Um, conventional imaging had to be negative. This was not using PSMA PET scans. Um, they could have received prior, um, ADT, but it not for at least 9 months prior to coming on to the trial, and they were randomized to get Eza monotherapy, um, ENSA with ADT or they got ADT alone. Um, and then at 36 weeks, they were allowed to discontinue therapy if their PSA was less than 0.2. These men, um, median age was 69, majority were Caucasian. The median doubling time was 5 months with a median PSA of 5.2, and about half the population, um, fit where I think this study makes the most sense, which was prior radical prostatectomy and prior radiation. And what you can see here was that the 5-year metastasis-free survival was the best in the ADT Eza arm. Um, the enzalutamide monotherapy was also pretty good at 80%, and the ADT alone was 71%. In the subgroup analysis here, you can see that regardless of, um, you know, they're doubling time where they lived, um, across the board, including enzalutamide, um, was favored in this scenario. Some secondary endpoints, um, 5 year OS for all of these guys was just about 90%. So again, these people are going to live a long time. But then when you think about other important factors for men is freedom from PSA progression at 5 years was the highest in the combination arm at 97% versus Enzimano was about 89%. Um, freedom from chemo at 5 years, which I think is a really important landmark for patients, um, also was the highest in the combination arm at 83%, and then the Ezome monotherapy was about 75%. So who got to ultimately discontinue therapy? Um, about 91% of men in the combination arm got to discontinue therapy at 36 weeks as opposed to 86% in the enza monotherapy arm, and then the ADT alone arm was 68%. Not surprisingly, the enza monotherapy arm had the shortest duration of therapy because their testosterone was not suppressed, so they were able to kind of add the fuel back to the fire as soon as the enzalutamide was taken away. In terms of adverse events, again, not surprisingly, hot flashes were worse than those who had ADT, um, but then the gynecomastia, breast tenderness, nipple pain, all of that was worse, um, in the enzyme monotherapy group. Over, um. You know, it's important to think about side effect profile when thinking about what to give these folks. um, the hormone treatment related symptoms were obviously going to be worse in the ADT arm. The sexual the uh the sexual function and sexual activity scores were better and better in the end a monotherapy arm. There were a couple updates this year at ASCO and ESO that we'll talk briefly about, um, At the ASCO meeting this year there were updates on quality of life that was pain global quality of life data and what they basically found is that coming off therapy actually didn't significantly change quality of life, just not all that surprising because generally in this setting men don't have pain, um, so scores were really similar across the board, but one metric that did improve within, um, stopping therapy were like hot flashes. Sexual activity score, while it does seem to improve with time, was not felt to be clinically significant after stopping therapy. And then the hormone treatment related symptoms by week 49, so these guys stopped therapy at 36 weeks. By week 49, um, it was starting to get better and then it started to actually get a little bit worse around week 97. Um, the only thing I can really explain this is that men just got older and these things can get worse with age. And then at ESO 2024 they also looked at, um, age in men, uh, on the Embark trial comparing men less than 70 versus greater than 70 and the take home message really was there were clinically meaningful improvement in metastasis free survival regardless of age. And again, not surprisingly, the side effects were worse than the older folks, but again, no, um, there wasn't really very many significant, uh, treatment related adverse events. Those were relatively low. So in conclusion, enzalutamide with or without ADT has been an FDA approved option in these patients, um, since November of 23. So Karen already touched on this, so I won't go into too much detail, um, but I think oligometastatic disease is a really growing space as the truly biochemical recurrent setting is shrinking. We're diagnosing more oligometastatic disease, you know, this is really when I think about this, I think about limited disease burden. This is usually guys that have 1 to 5 sites of disease. This is not standard of care, but there are, I think, some clinically, uh, meaningful improvements and some outcome, particularly delaying time to ADT. Um, so I think when considering metastasis directed therapy, it's really important to take a really individualized approach. What's the site of disease? What's the time frame to when they developed the metastatic disease? What are the patient's other comorbidities? Um, all of these are really important to take into account. So the saber comet trial, this was not just prostate cancer specific. There were 16 of 99 patients. These patients had a controlled primary with 1 to 5 metastases, and they were basically randomized to get, um, standard of care treatment versus standard of care plus, uh, the SBRT. Oh, sorry. um, and what they found is that there was a median OS and median PFS benefit, um, when SBRT was added to the standard of care therapy. The stomp trial was a phase two, prospective trial that looked at 62 men with oligo recurrent prostate cancer. They used cole PET scan, not PSMA PET scan, to define this. Um, men had to have a testosterone at least greater than 50 to enter, and they were randomized 1 to 1 to surveillance versus metastasis directed therapy. I think it's important to note that the stomp trial and the oral trial that I'll talk about next, um. Neither of these used intermittent ADT. If this was compared to surveillance alone. Um, and what they found here is that the 5 year ADT free survival, um, was improved in men who got the metastasis directed therapy. The oral trial was another phase two trial looking at men with oligo recurrent prostate cancer. They defined oligo metastasis based off of CT, um, bone scan, MRI, so conventional imaging, but there was also a blinded PSMA PET scan component here. Um, and again, men were randomized to get SBRT versus observation and their primary endpoint was PFS at 6 months. Um, and what you can see is that again, there is an improvement, um, in their primary endpoint when adding SR or when patients were treated with SBRT rather than, um, observation. So a little bit about, you know, how I think about how we, um, image folks now. So they use conventional imaging to define metastasis, but then they also had a PSMA PET scan component. And what happened was, They compared the two groups that either had Radiation therapy to all PSMA detected sites versus those who just were based on conventional imaging and what you can see here, um, is that from that the progression free survival was improved and those who had all PSMA avid sites radiated so this supports at least my current practice, if someone has biochemical recurrence, if I'm thinking about they might be a candidate for intermittent ADT, I think it's really important to get. For me, I used to do CT and bone scan primarily. Um, I, I've been incorporating more PSMA PET scans because I think this is an opportunity to really layer in radiation therapy. So in conclusion, I think this biochemically recurrent setting for prostate cancer is really shrinking and our oligo metastatic prostate cancer, um, these patients are expanding. I think if they're truly biochemically recurrent and they've had radical prostatectomy, it's, you know, reasonable to pursue salvage therapy with radiation with or without ADT. Um, there's some studies like the Indicate trial that we're participating in in the AeroStep trial that are also looking at layering in PSMA PET scans for decision making and how we treat these guys. Um, and oligometastatic disease, the standard of care is technically lifelong ADT. You layer it in AR directed therapy. Um, I think this overtreats a lot of guys, so I think metastasis directed therapy is a good way of kind of kicking the can down the road to when they actually need ADT and to encounter all these toxicities. Um, and I think something else to think about that's being studied is how do we incorporate ADT and an ARSI potentially for a finite period with metastasis directed therapy. I think these are some unanswered questions. Thank you.
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