ASCO 2026 Annual Meeting: New Research, Real Impact
The American Society of Clinical Oncology (ASCO) Annual Meeting is the largest cancer conference in the world, bringing together more than 44,000 clinicians, researchers, industry partners, and advocates.
PCF Chief Medical Officer Dr. Phillip Koo and urologic oncologist Dr. Zachary Klaassen break down some of the latest advances in treatment for localized prostate cancer, advanced disease, and survivorship.
This video discusses emerging research, including treatments that are not yet FDA-approved or standard of care. Please talk to your doctor about how these findings may apply to you.
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Localized prostate cancer
1. Proton radiation therapy has similar cancer control compared to conventional (photon). The COMPPARE study compared regular (photon) radiation to newer proton therapy in over 2,500 patients with prostate cancer. The two treatments worked equally well for cancer control, and using a “rectal spacer” device reduced side effects with both types.
High-risk localized prostate cancer
2. Giving apalutamide before and after surgery improves cancer control. The large, Phase 3 PROTEUS trialadded the drug apalutamide to hormone therapy around the time of surgery in 2100 men with high-risk prostate cancer. Adding apalutamide led to a 20% lower risk of the cancer spreading, and longer time to needing another treatment, compared to surgery and hormone therapy alone.
Metastatic hormone-sensitive disease
3. Pausing hormone therapy may be safe for some patients, though more & larger studies are needed. In men with metastatic prostate cancer that responded well to combination therapy (ADT + a newer hormonal agent), this small study tested whether treatment could be safely paused. After 2 years, nearly 40% of patients stayed off treatment without their cancer getting worse.
4. A tumor test can personalize the decision to start chemotherapy. This study used a genomic test called Decipher on patients from an older hormone-therapy trial (ENZAMET) to see who benefits most from adding chemotherapy. Patients with higher-risk Decipher scores benefited more from adding chemotherapy, suggesting the test could help personalize treatment decisions.
5. Benefit of talazoparib shows importance of germline genetic and somatic testing. The Phase 3 TALAPRO-3 trial tested adding the drug talazoparib to enzalutamide in patients with metastatic prostate cancer who also have changes in specific genes involved in DNA repair (like BRCA). The combination lowered the risk of the cancer worsening on scans by 52% compared to enzalutamide alone, with the strongest benefit in patients with BRCA alterations.
Metastatic hormone-resistant disease
6. Promising responses in an early phase trial of Actinium-225-PSMA-617. The Phase 1 AcTION study tested a new treatment that delivers radiation directly to prostate cancer cells. Patients had advanced disease that no longer responds to standard treatments. The treatment was generally well-tolerated (mainly causing dry mouth and mild anemia) and shrank PSA levels in 60–80% of patients.
7. CHAMP trial aims to help patients with advanced cancer live longer. This small study combined two chemotherapy drugs with two immunotherapy drugs in patients with neuroendocrine prostate cancer, an aggressive, late-stage form of disease. The combination kept cancer from progressing for 6 months in 74% of patients (versus about 55% historically). On average, patients lived an additional 12 months.
Survivorship
8. Darolutamide is linked to less decline in memory and ability to plan complex tasks. The PCF-funded ARACOG study compared two similar hormone-blocking drugs, darolutamide and enzalutamide, to see which had a smaller effect on memory and thinking skills. Darolutamide caused less impact on cognitive function than enzalutamide, likely because it doesn’t cross into the brain as easily.
Transcript:
Phillip Koo, MD [00:00:01] You know, ASCO, we talk about it every year for those of you who follow roughly 44,000 professionals in oncology gather in Chicago every year to learn about new findings, share data. The big news for those who follow this is this new drug that really improved overall survival for people who had metastatic pancreatic cancer. And we know that pancreatic cancer is a terrible disease. You know, obviously that’s not applicable to prostate cancer, but I think it really shows the impact of science and the way in which science really helps transform hope into a reality that will now reach patients. And I think that’s why I think you saw so many people excited, whether or not you treat pancreatic cancer patients or not. I think the whole field of oncology was excited whenever you see such a huge advance in the way we’re able to improve survival for patients. So, I think that’s what really keeps us going and we’re excited today to cover some of those findings in the prostate cancer area that will impact clinical care today and in the near future. There are other studies that are much more earlier in development that which we are not going to cover and those we save for another time, and I already see a few questions asking questions about that. So, Zach, welcome, always so appreciative for your knowledge and taking the time to educate all of us regarding some of the great work that’s being done across the world. So let me turn it over to you and we’ll get started.
Zachary Klaassen, MD, MSc [00:01:33] Yeah, thanks so much, Phil. Always great to chat with you and the invite from the Prostate Cancer Foundation, and just a huge thanks to the 635 and counting people and their families that are on this webinar. I think it’s just so humbling and encouraging from a provider’s standpoint to see people that are really wanting to hear what’s going on. As you mentioned, this ASCO meeting is the biggest cancer meeting in the world, and it partners with the GU ASCO, which we talked about in February in the European Society meeting in October, but this is really the pinnacle cancer meeting and I’m excited to discuss some of these trials and findings with our patients and their families surrounding prostate cancer. All right, so we’re gonna talk about eight different studies tonight. Basically, we’re going to work from sort of localized disease all the way to more advanced disease and hit on survivorship. And so, the first study we’ll look at is called the COMPPARE Trial. And I want to just focus our listeners on the top left. This is looking at IMRT, which is photon radiotherapy. This is what people think of as regular radiation. And then proton therapy is a little bit more of a newer type of delivery of radiotherapy. And you can see in these maps, the take home here is that with photon therapy, we’re able to affect the non-prostate tissue a lot less, so about 50% less. And so, there’s new ways of delivering radiotherapy, this is one of the newer ones. And so, there hasn’t been a lot of prospective data with photon therapy, there’s been a lotta work in other disease spaces like breast cancer, for instance. So, this trial looked at a prospective comparison of outcomes between patients that were treated with photons, sort of regular radiotherapy versus proton therapy. It was a big study. So, 51 centers, over 2,500 patients between July 2018 and October 2022. And really, they looked at several of the key outcomes. If you look at the bottom left, there’s a red box around the key results. We’re looking at bowel urgency, bowel frequency, these are common side effects of radiotherapy, GI toxicity, and then from a cancer standpoint, early days in terms of localized prostate cancer, look at this outcome, but making sure there’s no deviation in freedom from disease progression at three years. The take home here is that these are basically equivalent, and I look at this as proton therapy may be new, but at least when we’re looking at the toxicity profile, Looking at early cancer outcomes, there’s no difference between the two. I think that’s encouraging. Get a lot of questions about types of radiotherapy. I like this study because it tells us, at least in a prospective evaluation, not necessarily a trial, but prospectively looking at this, that there’s no difference between the two modalities. I included the figure on the right because I think it’s important. There’s a lot of data around rectal spacing. This is a device, usually a gel, that is put between the prostate and the rectum to protect the rectum during the radiotherapy, And it was encouraging to see that both for the regular photon as well as the proton therapy, those that had the rectal spacer had less grade two plus toxicity. And that is a call out to if you’re getting radiotherapy, ask about rectal spacing, it certainly can decrease that GI toxicity. So that’s the summary from the COMPPARE trial.
Phillip Koo, MD [00:04:58] You know, this is great, Zach, and I think, as you know, this is a question that comes up all the time. Patients see advertisements, discussions about proton, the latest and greatest, you know. I think originally it would cost a billion dollars to install one of these centers at a facility. And I think there’s always a temptation to want the latest and greatest, but this data, you know, though it could change over time, showing that whether you get protons or the regular treatments, it’s the same. So, I think it’s reassuring for those patients who might have received a sort of standard that you’re not putting yourself at less chance of better outcomes just because you received that. What’s next? So, are there more trials that need to be looked at this?
Zachary Klaassen, MD, MSc [00:05:42] Yeah, you know, I think when things are sort of out of the box, it’s hard to do head-to-head trials, but I think that’s why this prospective evaluation of really looking at this in a concerted manner of comparing toxicity, looking at outcomes. I think we need longer term cancer control. You know, the way I think about proton therapy is similar to people might have heard about CyberKnife or SBRT. The sort of the conclusion around these sort of alternatives are that it’s more radiation, less visits. So, it’s a little more convenient if you’re going, let’s say, four or five times versus four to six weeks of radiotherapy. So, I think safety’s obviously huge. You’re giving a big dose of radiation in a small amount of time and also making sure we’re not compromising cancer control. So, I think credit to the presenters and the investigators for this because we have some prospective data now. And I don’t know if we’ll see head-to-head trials, but I think at least looking at long-term cancer outcome, as well as long-term toxicity outcomes will be important.
Phillip Koo, MD [00:06:40] That’s great. And I think the take home message is, it’s not just the technology, it’s the technology and it’s also the people behind who are working the technology that really makes a difference. So, it’s really the combination of two. All right, well, so let’s go on to the next one. Really hot topic. Lots of discussion. PROTEUS.
Zachary Klaassen, MD, MSc [00:06:59] Yeah, so PROTEUS was, just to give our listeners a little bit of a background into how big this trial was, there’s seven trials at ASCO that are in the plenary session, which is the biggest session of the whole meeting over the four days. Seven trials across all cancers. PROTEUS is one of those seven. So prostate cancer is well represented in that session. And really the reason it’s a big trial is because it takes a long time to do big phase three trials that have important results, particularly in the localized setting. So, this is high-risk localized disease. This is patients with high PSAs, high Gleason scores, high tumor stage. And what happened, just to sort of summarize the left side of the trial design, is patients were randomized to everybody getting surgery. So, they’re randomized to ADT hormone therapy plus apalutamide, one of the common medications we give in terms of treatment intensification, versus placebo plus ADT. Six months, surgery, another six months of that treatment. So, 12 total months of treatment, sort of around the time of that surgery. And then there was a host of outcomes, the primary outcomes you can see in the top right. This was pathologic complete response or minimal residual disease. This is what the prostate looked like under the microscope. So complete response, meaning no tumor present or minimal residual disease, I won’t get to the definition of that, but basically a huge downstaging of that tumor was 10 times more likely in the people getting ADT plus apalutamide versus ADT plus placebo alone. The other co-primary endpoint was metastasis-free survival on the far right. This was statistically significant. This showed a hazard ratio of 0.8, so a 20% reduction in metastases for patients that got the apalutamide versus the placebo. So, this is the first time we’ve seen a trial intensifying treatment around the time of surgery for high-risk patients that showed an improvement in metastasis-free survival. Couple of other interesting end points at the bottom, I’ll just quickly run through event-free survival, this is a combination of several things, biochemical recurrence, regional recurrence. This also favored the apalutamide arm. A really important endpoint for patients, first subsequent local or systemic therapy. How long does it take to get to the next treatment? That’s important for patients. This had a 35% improvement in time to next local or systemic therapy. Then we look at the far right, I’ll just go through that real quick. This is freedom from disease. This is also important to patients. No evidence of disease at four years. The absolute improvement was 3.5% for those receiving the apalutamide around the time of surgery. So, this is a big trial published in the New England Journal of Medicine. I would anticipate this will get an FDA approval rather quickly. And so, this is something for those that have high-risk disease. You know, there’s other options like radiotherapy plus ADT, plus or minus Abiraterone, but for those that are surgical candidates, this does offer some potential treatment intensification during that time.
Phillip Koo, MD [00:10:04] Great. Thank you, Zach. This was presented by Dr. Mary Ellen Taplin from Dana-Farber. You know, at PCF we’re very proud to have funded many of, you know, she’s received two awards from PCF in 2014 and 2016 looking at this type of treatment where you intensify, to your point, you have high-risk disease. We know these patients are going to recur. How can we hit them harder earlier to make sure that period of disease-free survival lasts longer, and I think this study is showing that that it is working. Zach, what are your thoughts on, you know, any data signs on some adverse events? There’s a question in the chat about incontinence or sphincter and other things, but just in general, adverse events.
Zachary Klaassen, MD, MSc [00:10:46] Yeah, there’s always going to be side effects with surgery, whether we do it without treatment intensification. There’s a period of urinary incontinence typically lasts up to three months, even longer to six to 12 months. The sexual function or erectile function always goes down after surgery. People that come in with good sexual function will often regain part of that back over about the course of about 12 to 18 months. But anybody that’s going to go into surgery, you have to understand that incontinence and erectile dysfunction are going to be part of the package. Important to partnership with urologists that are good at treating those side effects. We’ve talked about that on these webinars before. So those are standard. I don’t think there wasn’t any increased incidence of those complications during this trial. We saw the usual side effects that we see with apalutamide and ADT, nothing out of the ordinary. Most common of those are hot flushes. We’ve talk about that before on this webinar. So, the adverse events were kind of as expected for patient receiving ADT and apalutamide as well as surgery.
Phillip Koo, MD [00:11:45] Great, you know, I think this it’s probably we don’t have enough time to talk about it, but clearly these neoadjuvant treatments whether it’s ADT, ADT plus apalutamide are very confusing topics. I recommend people to speak with their surgeons or urologists to see what is best for them And now that we have this data, I mean apalutamide enters into discussions when you’re making those decisions. So, let’s go on to the next study…
Zachary Klaassen, MD, MSc [00:12:11] I’ll just reiterate one more thing. I think it’s important people have to be surgical candidates first to be able to have this treatment. Radiation plus hormone therapy a very good option. We use it all the time So that as you mentioned there’s nuances around this discussion. We can probably have a whole webinar on that discussion and this trial, so I think just so people know it’s not everybody’s gonna get surgery, it’s surgical candidate first and then going on onto treatment.
Phillip Koo, MD [00:12:34] Great point, yeah, thank you. So, let’s go to the next one. It’s called the A-DREAM Trial.
Zachary Klaassen, MD, MSc [00:12:40] Yeah, really cool trial. I think Dr. Choudhury from also Dana-Farber looked at this trial. This is a really interesting trial because we’re looking at are there people that we could maybe de-intensify treatments? So, we’re moving on to metastatic hormone-sensitive prostate cancer. So, this is a little more advanced than the previous topics we’ve talked about. The way this trial worked, and I’ll just sort of summarize the top left briefly, the patients were all started on an ADT and ARPI. ARPI, that’s one of those, is apalutamide, enzalutamide, darolutamide. They’re treated for 18 to 24 months, roughly 75 patients, so a phase two trial. Those that had a PSA of less than .2, then stop the treatment. And the benefit of that is, we know there’s side effects from these treatments, so if you’re able to safely stop this with a good response. What sort of outcomes happen after that? There’s certain triggers to restart it. You can see a list of their PSA goes up to more than five. There’s changes on imaging. There’s symptoms from prostate cancer. But the primary endpoint here was interesting. It was treatment-free testosterone recovery at 18 months. So, if we stop this treatment, it’s worked well. How many patients at 18 months get recovery of their testosterone, which makes them feel better. This is the side effects that we see with these treatments. And it’s really interesting that two-thirds of these patients had a recovery of testosterone above 150. So, what we call a eugonadal or a normal, low-end of normal testosterone. So, some other interesting end points as well to talk about on the bottom left is the time duration off of treatment was roughly two years. So, it’s almost like you get this treatment, you do well. The median time to starting the treatment again was about two years, that’s pretty good. And with two thirds of those patients recovering their testosterone, quality of life improvement for sure. What’s also encouraging, at least early data, shows that the radiographic progression-free survival did not suffer stopping this treatment. So, the median or the time to about 50% of people having radiographic regression was not reached. So that means that majority of these patients are still without disease progression. So, I think this is interesting. It’s phase two, it’s a small number of patients, but we know these drugs work. Do we have to do them forever? The answer right now is yes, but we’re starting to see some data with A-DREAM, some other bigger phase three trials that will probably get data in the next couple of years that may allow us to safely decrease or stop or intermittently do therapy after a good response.
Phillip Koo, MD [00:15:16] This is great. So, you know, it’s interesting. In PROTEUS, the study we talked about right before, we’re talking about treatment intensification. How do we add on more drugs to hit it harder? And this one, it is this concept of maybe stopping certain things earlier, because obviously you want to improve quality of life. So, you mentioned phase two. How do you recommend patients have these discussions with their physicians?
Zachary Klaassen, MD, MSc [00:15:40] Yeah, it’s a great question, Phil. I think it’s one we spend a lot of time. Again, we could probably spend a good chunk of a webinar on this topic. The important thing to remember is when people come in with metastatic hormone-sensitive prostate cancer, this is a potentially lethal non-curable disease. What’s important though is that some people will do very well with the treatment intensification. And the question is, can we safely decrease that intensity? There’ll be also some people that don’t do very on this and they’ll need treatment intensification. So, the guideline recommendation in 2026 is still continue this therapy, no matter how good it’s working until you either progress to worse disease. So, I think the message has to be that, but also knowing that if there’s good responders, perhaps we’re gonna see some people we can decrease that intensity, decrease the side effects. But it’s very much, as you mentioned, a discussion with your clinicians. I’m hoping in the next three to five years we’ll have a lot more data. To tell us importantly who we need to de-intensify, but also as importantly who need to intensify even further than that doublet therapy.
Phillip Koo, MD [00:16:47] This is great, I think it really empowers patients to bring up the subject, let their wishes be known, and figure out what works best. Because just because the recommendation is forever, if your quality of life is suffering, maybe that conversation needs to sort of take a different lens. So, this is wonderful. Also like to point out Dr. Choudhury, PCF Young Investigator. So, we’re really proud when these types of things come together.
Zachary Klaassen, MD, MSc [00:17:14] Phill, I’ll just add one more thing to that trial. I think, you know, there is situations and in clinical practice of the real world where people are really not tolerating therapy. And so, this discussion to de-intensify becomes an easier one because quality of life certainly is an important aspect. So, I think there’ll be situations where we’re not forced to, but we have to maybe decrease a dose or take a treatment break. That’s different than what we’re talking about here. We’re talking with people that are doing well, they have a great response. Can we safely decrease it? So, I think there’s a little nuance there I just wanna mention as well.
Phillip Koo, MD [00:17:46] You know, Zach, there’s the question that came up, and this is something we talk often amongst our community, is obviously overall survival is what we’re aiming for, but you have these other endpoints. Do we have to wait till overall survival or are these other end points valid?
Zachary Klaassen, MD, MSc [00:18:02] Yeah, great question, Phil. I think the quick answer to that is overall survival, obviously, is the golden endpoint in cancer care. But with especially localized disease, as we saw with PROTEUS, and even in metastatic hormone-sensitive prostate cancer with such good treatment options, these trials take a long time to show overall survival benefit. These patients may not be followed long enough to show that, but we do know that certain endpoints, maybe they’re surrogates for it, maybe they are not, but they’re clinically relevant. Metastasis-free survival is one of those. So, time until your cancer spreads, time to castration-resistance is a clinically relevant endpoint. So radiographic progression free survival. So, the discussion between, do these correlate with overall survival is probably a different one outside the scope, but are all these trials being powered to show overall survival? No, some of these patients have to be followed for 15 to 20 years to show a benefit.
Phillip Koo, MD [00:18:55] Great. Alright, so let’s stay in the metastatic hormone-sensitive space and move on to a trial called Ability. Oh, I’m sorry, ENZAMET, the Decipher, uh, ENZAMET.
Zachary Klaassen, MD, MSc [00:19:11] Yes, ENZAMET is a trial we’ve heard a lot about over the last probably eight years now, it’s an older trial, where it was basically looking, we talked about treatment intensification in the metastatic hormone-sensitive space. And so, the first sort of read out of this was a number of years ago, showing that Enzalutamide plus ADT benefited patients more than ADT alone. And so, what’s interesting about these trials is they collect a lot of data, they collect a lot of tissue. What this analysis looked like is the Decipher genomic classifier, we’ve talked about genomic classifiers on these webinars before. Decipher is a very robust genomic classifier that we use all the time in the clinic. What this tells us is that the way to explain it is it’s a genomic snapshot of what’s going on under the hood of this tumor. And so, Decipher has an array of mutations they’re looking at, and they’ve built this into validated prospectively many times in different scenarios to sort of help us guide the treatment or the prognostication, how well patients are going to do. And so, this analysis specifically was looking at decipher in that ENZA-MYC cohort, which is an older trial. So, this was a very statistically, to be honest, confusing at times, and very dense analysis. So, I’ve tried to sort of lay it out into what the take home messages were. The take home message is where in this decipher score goes from zero to one, they looked at patients that had a score of less than 0.85, and more than 0,85. And not surprisingly, on the bottom left overall survival, you can see that those that had a lower Decipher score had a better survival. So, there was no huge surprise with that. I think where this gets interesting is in some of these points on the right, there was some of these patients in that Enzalutamide and ADT arm that also may have received docetaxel, that’s chemotherapy. So, they had the option to take docetaxel or not take docetaxel. And where the Decipher score looks like it’s gonna help us is in whether we give docetaxel. So, in those with a Decipher test greater than 0.5, patients had a worse overall survival with ADTN enzalutamide, that’s what the left figure shows, but there was also evidence of benefit from adding docetaxel to the ADT and enzalutamide for those patients with a Decipher test that’s high. I think that’s really important. So, who do we treatment intensify with three treatments versus two? When we look at the Decipher tests less than 0.5, there was less evidence of benefit of adding that chemotherapy. So, this may allow us to say, hey, your Decipher test is this, we are gonna add chemo or we’re not gonna add chemo based on that test. And so, I think when we talk about trying to personalize treatment care, treatment intensify, even above and beyond what Enzalutamide and ADT would offer, I think this test has the ability to help us decide on that docetaxel conversation.
Phillip Koo, MD [00:22:03] You know, this is great. I think a lot of the people on the line may have received Decipher testing for their biopsies or perhaps their prostate after they were surgically removed. This is a little bit different, but I love the concept of being able to use this test to predict whether or not you’ll respond, whether or not it’s worth getting the chemotherapy because we know chemotherapy isn’t a walk in the park. And obviously you want to know as best as possible if you’re going to derive a benefit from that. And I love this concept and I think we all really hope we have more of these types of tools to help inform our decision making. So very exciting to see something like this being published.
Zachary Klaassen, MD, MSc [00:22:41] Yeah, I think, Phil, the interesting thing is a lot, you know, the two that sort of jumped to mind are Decipher from Veracyte, ArteraAI from Artera. The AI model, the genomic model, they’ve done a really nice job of looking at these populations in sort of the active surveillance cohort, whether we give hormone therapy with radiation. Now we’re seeing them being looked at and validated in these more advanced settings. And so, I think this is just the tip of the iceberg for helping us decide who needs X treatment, Y treatment, Z treatment.
Phillip Koo, MD [00:23:13] And there’s a question about this. The tissue for the Decipher testing and ENZAMET, was it on the metastatic lesions or where was the testing done?
Zachary Klaassen, MD, MSc [00:23:21] That’s a good question. I have to go back and look. I think it was on the metastatic lesion because these patients were metastatic hormone- sensitive patients. So, I honestly, I don’t know off the top of my head, but I would imagine it’s from a metastatic setting.
Phillip Koo, MD [00:23:32] Alright, good. So, let’s move on to another study in the hormone-sensitive setting. So, there’s a question about this. This is the setting in which your cancer is still responding to traditional hormone treatments and not progressing, but in this case, it is still metastatic. So, we had this study called TALAPRO-3.
Zachary Klaassen, MD, MSc [00:23:51] Yeah, really huge study, also presented at ASCO by Dr. Neeraj Aggarwal, who’s just an incredible thought leader in this space and a really fantastic clinician and researcher. This was also published at the same time in the New England Journal of Medicine, a really big study because it’s highlighting genetic testing. So, we talked about genomic testing with Decipher. We’re talking about genetic testing of either germline or somatic. We’ve talked about that, the differences about that on previous webinars as well. And what it’s doing is, again, giving us an opportunity to personalize our treatment. So, this was patients that had metastatic hormone-sensitive prostate cancer, excellent performance status. They were tested to see if they had one of several genes we call DNA repair genes. So, these are genes that we know are associated with not just prostate cancer but pancreatic cancer, other cancers as well, the common ones we know about and people have probably heard about the BRCA1 one, the BRCA2. There’s some other ones that are also somewhat common, ATM, CDK12, CHEK2. They all kind of fall into this umbrella of DNA repair. And we know that the PARP inhibitors, such as Talazoparib, are exquisitely sensitive to those patients. And we’ve seen in TALAPRO-2, which looked at the metastatic CRPC state, so a little more advanced than this trial, that these treatments work very well. And so, there was a good rationale to take it from the mCRPC space. Test this in the mHSPC space. And so, this is the trial looking at talazoparib plus enzalutamide versus placebo plus enzalutamide, also continuing the ADT as well. So, when they took all the patients with all these mutations, we call that the intention to treat population. This is on the top right of the screen. We saw a 52% reduction in radiographic progression-free survival. Sorry, I forgot the end point. Yes, radiographic progression-free survival. They’re still looking at overall survivals early for this trial. So basically, is the cancer getting worse on imaging and there was a 52% reduction in that which I think is excellent. Which is a little bit better than may be expected There was another trial that looked at niraparib plus abiraterone in the same disease space their hazard ratio was 63 so a 37% reduction in radiographic progression-free survival. And when we look at the subgroups of these, not that surprising is it works very well in this BRCA subgroup. So, in the BRCA subgroup, the hazard ratio was 0.37, so a 63% improvement. What I think is really important is this conglomeration of 12 genes, the non-BRCA subgroup, and we know it works very well in that BRCA group. We also saw a benefit in those other mutations. And so that hazard ratio was also 0.57, so 43% improvement. So, I think this trial is really important for allowing targeted treatment in the metastatic hormone-sensitive space, not having to wait to the mCRPC space. I also think this will probably get FDA approval in a short amount of time, just because the implications of being able to treat these patients with these mutations with this combination is super important. Again, overall survival data, immature, they’ll continue to follow those patients and hopefully we’ll see an overall survival benefit but certainly from a radiographic progression-free survival which was the primary endpoint for this trial, this was a robustly positive trial.
Phillip Koo, MD [00:27:29] You know, this is really exciting. This is precision medicine in prostate cancer. And I think we need to see more genetic testing, and we need see this type of approach being incorporated into everyone’s care as we move forward. So, what advice do you have for all the patients and their caregivers listening on how to start that discussion about genetic testing with their urologist or their oncologist, whoever they might be?
Zachary Klaassen, MD, MSc [00:27:54] Yeah, it’s super important, Phil, and I think it’s always a good call out to have the patients and their families advocate for this. If you look at the NCCN guidelines, one of our main governing bodies for guidelines, anybody with a Gleason 8 or higher tumor should have testing on their tumor for genetic mutations like this. So that means everybody with mHSPC should have it, but even the high-risk localized patients should also have it. So, there’s no question that your physician should be advocating for you for this, but absolutely the patient should be asking about it. It may not guide treatment at the immediate time, but it may guide it later. We’re seeing now with this trial that even in the mHSPC setting, we have targets that we can use, and I hope this gets FDA approved very quickly.
Phillip Koo, MD [00:28:41] So if patients are out there listening, have that conversation, especially if you have metastatic disease. We at PCF, we’re also very proud to have funded the research studies that map the gene alterations in advanced prostate cancer, which really led to so many developments in these PARP inhibitors. And just kudos and thanks to everyone out there who helped fund and allow us to fund these types of research projects that have led to transformations and really a new era of precision medicine in prostate cancer.
Zachary Klaassen, MD, MSc [00:29:12] You know what’s great, Phil, just real quick on that. It’s been 10 years since one of the seminal papers came out in the New England Journal of Medicine in 2016. You know, I think when we think about 10 years in prostate cancer, it feels like the dark ages. And it really kind of is. I mean, we’ve come a long way in a decade. I finished my residency that year and I don’t feel that old. But when I look at the numbers, that’s 10 years ago. And I think that’s really exciting how far we’ve come. Not just in prostate cancer specifically. Precision oncology with these mutations that are now leading to phase three trials that are actually impacting patients.
Phillip Koo, MD [00:29:49] And the need is even greater today and I think you know we’ll just keep pushing forward and it’s exciting to see all these advancements. So now we’re going to go a little bit further down the disease state and talk about metastatic castration-resistant prostate cancer. That’s when your disease stops responding to the traditional hormone treatments and then now we have phase one study called AcTION.
Zachary Klaassen, MD, MSc [00:30:16] Yeah, so AcTION was, this is really exciting. Just a little background on AcTION. So radioligand therapy is basically targeting the tumor and taking the radiation right to the tumor essentially. Most people out there may be heard of lutetium or Pluvicto. I think this is all over the lay media now. Some patients may have already received these treatments. And so, this is sort of what I think about as version 2.0 of radioligand therapy. So. Without getting too much in the weeds, it’s a little different mechanism of delivering radiation to the tumor than lutetium is. And so, this was a phase one trial. Now, Becky mentioned some of these treatments are still early. I’d probably put this in the early one, but I think we’re gonna see a lot of data with different radioligand therapy treatment options over the next couple of years. Phase one means basically early, early phases, trying to get the right dose and seeing if there’s a clinical benefit. And so. When we look at this treatment, they group these patients into three groups. It’s very sort of all coming, if you will. Group A was prior chemotherapy and an ARPI, such as we’ve talked about apalutamide, darolutamide, et cetera. Group B was no prior chemotherapy or ARPI. And then group C, which is interesting, is patients that already receive lutetium were in that group C. And so really anybody with advanced prostate cancer, they had a group for you. And I liked how that this is a pragmatic phase one trial. So, patients received, roughly 100 patients received six cycles of this treatment. And really the goal of these phase one trials is to figure out the recommended dose for the phase two trial. They’re also really focused on safety and tolerability. And then some early cancer response metrics, such as PSA-50 and the patients have a 50% reduction in their PSA. So that’s the top left of the trial design. Looking at the top right, this is the key safety aspects, you know The one that we see with radioligand therapy is dry mouth and there’s certainly Dry mouth associated with lutetium there also is with actinium. I think what’s interesting here is When you look at these groups the majority these were not grade three events And so those are the really bad events the grade three or higher the majority of these were grade one and two, and so I think that’s encouraging, maybe perhaps some side effects are a little more tolerated than lutetium. When we look at anemia, this can also be a side effect of radioligand therapy. Roughly 14 to 40% of patients, again, majority of these were less than grade three. So overall, I think a well-tolerated treatment and certainly is one that’s gonna continue to be explored in phase three trials already. When we looked at some of the early cancer outcomes, we look at on the bottom left. This is the PSA 50 responses and this range from roughly 60% up to 80% so we’re seeing good PSA responses when we look at the objective response rate This is it changing on imaging also encouraging roughly 33 to about 43% in the early sort of look at this this new radioligand therapy, so I think this is just, again, the tip of the iceberg on other agents that are going to be looking at radioligand therapy. Lutetium has blazed the trail. The last five years of radioligand therapy has been super exciting. I would argue the next five are going be even more exciting than the first five. There’s a lot of targets that we’re looking at. We’re going to start to see phase three trials, hopefully reading out with things like actinium over the next couple of years.
Phillip Koo, MD [00:33:55] Thank you, Zach. This was presented by Dr. Louise Emmett from Australia, another PCF-funded investigator, and we also funded the early work on PSMA, which really made all this possible. I think for the patients listening, it’s important because now we live in this world where Pluvicto is so common, used very widely, and that’s great. Now we’re thinking about, all right, what are some other options out there? And we’re still trying to figure things out. Actinium is a different isotope. As you mentioned, Zach, there are multiple trials now open looking at actinium, especially in those patients who now recur after Pluvicto, after the Lutetium. So, it’ll be very interesting to see how we start managing these patients. And it’s great that we sort of see this continued progression and advancement with these radiopharmaceuticals. Okay, so we are going to… So, there’s a question about some side effects in radiation. They talk about radiation cystitis. I’ve never seen radiation cystitis with these radiopharmaceuticals. Have you had any experience with that?
Zachary Klaassen, MD, MSc [00:34:59] No, I think if you think about the way that the radiation’s delivered, so this is a, I wanna say, more sophisticated way than sort of regular therapy, but it is targeting the tumor because we’re targeting, in this case, PSMA, which you know is expressed on cancer cells. So, when you’re targeting the prostate in, say, localized radiotherapy, the prostate sits very close to the bladder. We talked about rectal spacing to protect the rectum. The bladder’s a little harder to protect because it fills up, it empties, it changes shape. So, people can get some sort of off spray of the radiation that can affect the bladder. When we’re thinking about radioligand therapy, we’re thinking about what’s the side effects of taking the radiation directly to the tumor. Those side effects are pretty minimal. But what we know is that the salivary glands, the reason we get dry mouth is there’s some PSMA expression in the salivary glands. And so that radioisotope, as you mentioned, is going to the saliva glands, which leads to the dry mouth. It’s a long-winded way of saying. Cystitis is not common in radioligand therapy. It’s more the dry mouth that’s affecting the bone marrow to a degree while we see the anemia. So just different modalities and different targets of delivering radiotherapy.
Phillip Koo, MD [00:36:11] Great. All right, so we’re going to stick in the metastatic CRPC setting, and they’ll talk about a trial using chemo immunotherapy. So, for everyone out there, we’ve talked about immunotherapy in the past. You know, it really hasn’t been very successful for most patients with advanced disease. But you know, there’s some interesting data here using chemo immunotherapy.
Zachary Klaassen, MD, MSc [00:36:34] Yeah, so the CHAMP trial I think is really interesting. Again, this is a smaller trial, sort of looking for a signal that may be able to be developed into bigger trials. This is really advanced mCRPC. So, when we think about patients that have had multiple treatments, whether that be in the high-risk setting, the metastatic hormone-sensitive setting, even several lines of therapy in the mCRPC setting, there’s changes at the tumor level, mutations that are happening that almost change the biology of how the tumor is acting, how it responds to treatment. And so, patients may have heard of things called neuroendocrine prostate cancer or aggressive variant prostate cancer. This is a result of all of those treatments trying to get control, the tumor outsmarting these treatments, eventually leading to almost a different biology of sort of what we call the regular prostate cancer, so this is an aggressive sort of late variant of prostate cancer so really important trial to see if we can improve quality of life and certainly quantity of life for these patients. So, this was a little bit of a fact-finding mission. So, these patients received every three weeks carboplatin chemotherapy, cabazitaxel chemotherapy, nivolumab, which is an immunotherapy, and then every six weeks they received another immunotherapy called ipilimumab as well as ongoing ADT. So really aggressive treatment intensification. In the setting of neuroendocrine prostate cancer. And then after that, after they received that treatment, they underwent maintenance with nivolumab every three weeks, ipilimumab six weeks, and ongoing ADT. And so, what they did for their primary endpoint was radiographic progression-free survival at six months. This was a single arm trial. You’re really trying to benefit everybody and using a historical control to see if this works. So, I’m gonna jump actually down to the bottom left. First, the, the historical control for these patients was an RP-FS of about 55% at six months, so not very good. This combination was able to increase that to 74%, which was statistically significant. So, I think clearly there is an advantage to hitting this tumor from multiple directions after it’s transformed into this neuroendocrine entity. Moving up to the top right, median overall survival was 12 months. For an aggressive variant, this is actually pretty impressive. Median RP-FS, again, 6.1 months. Objective response rate, which is basically, is this working? Are we getting partial responses? The answer is yes, 37% of patients. So, a lot of work to do in this space. There’s a lot of important work going on, looking at different targets on these tumors. We’re gonna see a lot more data coming out for neuroendocrine prostate cancer patients which I think is really important. This is really the late, late stage of mCRPC. So, I think this combination works. There’s other stuff coming out. We need to continue to look at improving quantity and quality of life for this specific subset of patients.
Phillip Koo, MD [00:39:37] Great. Thanks, Zach. So, this is, you know, for the listeners, this is a phase two trial, not something that you’re going to talk to your doctors about and get. I love the fact that even though there have been so many negative trials of the immunotherapy, it doesn’t really stop investigators from continuing the study of it. And then you see signals that, again, it might work in this very, very late-stage patient population. So, it’s nice to sort of see the diligence and resilience of a lot of the research out there to continue asking and getting answers to these questions. So hopefully this will lead to more answers and possibly this will be a treatment that will be available for patients with that neuroendocrine aggressive variant disease. All right, so we’re going to go to the last topic area which is survivorship, and this is obviously very important, certainly not the last but not least topic, and it’s a study called ARACOG.
Zachary Klaassen, MD, MSc [00:40:33] Yeah, ARACOG is a really important study, I think, Phil. A little background as to why this study came about. So, over the last 10 years or so, we’ve seen that treatment intensification, whether that’s ADT plus apalutamide, ADT with darolutamide, ADT, plus abiraterone, ADT plus enzalutamide. We know that treatment-intensification versus ADT alone works. And if you look at these trials, they all work. Relatively about the same. So, the message is treatment intensification is super important. Very few people should be getting ADT alone. There’s never been a head-to-head trial looking at one of these agents versus the other. So, whether it’s apalutamide, darolutamide enzalutamide, abiraterone, it’s hard to do these head-to-head trials. There’s a lot of stakeholders that have to agree to do this trials. We know that they all work, there’s never a head-to-head. So, the reason for this trial wasn’t to show that one works better than the other. It was to see, is there different cognitive effects for one versus the other? So, the trial design is essentially, and the investigators in terms of Chuck Ryan and Alicia Morgan did a really good job working with different specialists in psych oncology to come up with some metrics that are frankly beyond the sort of scope of this discussion but looking at cognitive assessment. They had this tool, they evaluated these patients at various time points. And had patients randomized to either darolutamide or enzalutamide with continuing the ADT. Again, very pragmatic advanced prostate cancer. So, we had some patients with mHSPC, mCRPC, non-metastatic CRPC. And what they found was the top right is really sort of the key take home is that darolutamide had less impact on cognitive function than enzalutamide did. So, for example, what this means to the patient is there was less effect on change in visual memory. What this example may be is getting lost in a familiar parking lot. There was less effect on executive function. So, the reduced ability to plan next steps to complete a complex task. There was less change in working memory. So, losing a train of thought when telling a story. Less loss of executive function, which is a reduced ability to plan steps to complete the task. So, a very interesting study design, but very important. So, we’re used to seeing, does this improve radiographic progression-free survival? Does it improve overall survival? So, the investigator should be congratulated for designing this with cognitive outcomes as the primary endpoint and showing that the benefit or that there was less of an effect with darolutamide on cognition than enzalutamide. I included the box at the bottom is looking at crossover. They did allow patients to crossover from Enzalutamide to Darolutamide or Darolutamide to Enzalutamide. And really what the take home here is there was 30 crossovers from Enza to Daro, and no crossover from Daro to Enza. So, an important study. This is the thing about this trial is we’re not waiting for an FDA approval to say use one versus the other. We have approval for both of these. And I think, again, this allows patients to talk to their physicians about options. I think, you know, we’ve been waiting to sort of see this head-to-head, again, not for seeing which one’s better in terms of how it doesn’t work, but how the effect on quality of life, specifically cognition, is important.
Phillip Koo, MD [00:44:12] There is, so this was presented by Dr. Alicia Morgan from Dana-Farber. We were very proud through a generous grant from Bayer to fund this trial through one of our Challenge awards. So, it’s interesting, you had these head-to-head trials. I think the take home I think some patients may think, oh, darolutamide is a better drug than enzalutamide. That’s not necessarily true either. I think we know darolutamide doesn’t cross the blood-brain barrier, and that’s perhaps why you’re seeing less of these cognitive effects. I think this information really helps us figure out when to use which drugs and which people at what time, which is really the goal, so we can sort of maximize those benefits. So, Zach, this question has come up several times in our chat, is when they hear, you know, PROTEUS talking about apalutamide, then you have ARACOG talking about darolutamide, is it okay to interchange the various drugs darolutamide, apalutamide and enzalutamide abiraterone. Tell us about that, because obviously that’s not how it works, but educate all of us on this topic.
Zachary Klaassen, MD, MSc [00:45:16] Yeah, I think, you know, it’s important for patients to know that we use all these drugs in different disease spaces. So, for instance, we’ve talked about high-risk biochemical recurrence. You know, there’s an approval for Enzalutamide in that setting, and so that’s what we use in that setting because that’s where the approval is. There’s a patient that may come in who is, let’s say, elderly, they’ve had some cognition issues. This trial of ARACOG may say, okay, I’m probably gonna lean towards darolutamide for that patient, because I have data that says the cognition is probably less likely to be affected in that patient. So, I think it depends on your disease state that you’re in. It depends on maybe the medications that you are on, what your overall quality of life is, your physical function. There’s a lot of decisions that go into it. I think in terms of interchanging them, for the most part, and this is a very broad generalization, there’s less of the interchanging that should be quote unquote allowed. We know that one may not work better after the other. I think there’s probably time for a different type of treatment. For instance, in the advanced cancer space docetaxel often is favored or lutetium after one of these drugs fails. It’s a very complex space because there’s options in different spaces. There’s approvals for certain ones in different places. And generally, this is a really good opportunity to pepper your physician, your medical oncologist, your urologist, your nuclear med physician about those options, because it’s hard for even us as providers to keep up with it, going to all these meetings, but certainly from a patient standpoint, there’s a lot of nuances into selecting types of treatments. In specific disease spaces.
Phillip Koo, MD [00:47:07] So, you know, Zach, in a lot of the slides you showed, you talk about metastatic-free survival or PSA response, so many other different endpoints, and obviously we talked about how overall survival is the gold standard, but we need to come up with these other intermediate endpoints. In general, how is progression measured? Maybe, like, let’s step away from all these trials. You as the physician, how do you figure out when a patient is progressing?
Zachary Klaassen, MD, MSc [00:47:35] Yeah, there’s several ways to do that, Phil, and they’re all equally important. I think it’s understanding all of them. I think that there’s really three in my mind. So, if there’s symptoms that are occurring, something needs to be investigated, whether that’s new bone pain, whether that’s altered mental status, whether that’s… those are probably the more common ones. Let’s go with those ones. So, any change in the patient’s sort of overall function. The more sort of I guess objective ones would be imaging is super important. We’ve talked about PSMA PET on these webinars, conventional imaging. I still think there’s, even if the PSA is behaving itself, there’s a role for imaging, whether that be every four to six to 12 months in the advanced prostate cancer setting, I think depends on how the disease are responding. That’s probably a topic we can delve into further in another time, but imaging is certainly important to see if this disease has changed for the worse or for the better. And then certainly PSA, PSA is still a very good metric as to how the disease is responding. I think when we look at the metastatic hormone-sensitive trials, the trials of the doublet therapy versus the ADT alone, and there’s now several of them which we touched on briefly tonight. We know that the PSA whether it starts at 50, starts at 20, starts at 100, starts at 500, the goal is to get it down to less than 0.2. And we know that that metric is a very objective one. We can see that number in the chart. And we know that if we can get that number to less than 0.2, ideally within six months, maybe over 12 months, that’s a patient that’s responding to therapy. And so, it’s really a combination of all of those assessments for whether the treatment is working that’s really important. And none is really interchangeable with the others. They all have to kind of be involved in that assessment.
Phillip Koo, MD [00:49:30] You know, I think that’s great advice. I think for patients and caregivers out there, you need to be open and honest when you have those visits. Oftentimes how you feel, whether it’s pain, fatigue, can be a trigger to get imaging or a PSA or something, or maybe even on its own is enough to maybe say you are clinically progressing. So, you know, there are no heroes in not sharing, you know how you feel, be sure you share how you felt. Alright Zach, we’re going to wrap things up. Another wonderful ASCO meeting. I think everyone leaves very excited about what the future holds. What are some big take-home messages that you walked away with?
Zachary Klaassen, MD, MSc [00:50:09] Yeah, I think treatment intensification continues to move up in the disease space. We saw with PROTEUS that we’re starting to, once we get FDA approval, gonna have options in that high-risk setting. Treatment intensification in the mHSPC space with TALAPRO-3 [2]. The radio ligand therapy story is already here for five years. It feels like it’s just the tip of the iceberg. I think we’re gonna continue to see exciting stuff there. Survivorship is always key. Quality of life having patients and their families advocate for themselves. Having a family member, a friend or a significant other come with the patient to the visit, really letting us know how they’re doing is super important. And I think if we look at all those aspects, ASCO was incredibly exciting and certainly more to come with ESMO later this year. That’ll be our last sort of big of the big three meetings in a couple of months. And so, I think it’s just super exciting. I wanna thank everybody again for joining us and hope everybody has a safe and happy 4th of July.
Phillip Koo, MD [00:51:11] Great, thank you, Zach. And thank you all for joining another wonderful webinar and really appreciate your time, Zach, and for just really educating all of us. So good night and enjoy your evenings.