Dr. Manish Shah (Host): Welcome to Weill Cornell Medicine CancerCast: Conversations About New Developments in Medicine, Cancer Care, and Research. I'm your host, Dr. Manish Shah. And today, we'll be talking about research from the 2026 American Society of Clinical Oncology, or “ASCO”, Annual Meeting. ASCO is the world's leading organization for physicians and oncology professionals caring for people with cancer, and focuses on collaboration, research, education, and the promotion of high-quality, equitable patient care.

The ASCO Annual Meeting is the largest international oncology conference, with approximately 45,000 attendees every year. The meeting brings together oncologists, pharmaceutical companies, and patient advocates to hear state-of-the-art research presentations and the latest oncology insights from professionals around the world.

Joining me today is Dr. David Nanus. Dr. Nanus is the Division of Hematology and Medical Oncology Chief at Weill Cornell. He is internationally recognized in the treatment and care of patients with genitourinary or “GU” cancers, including prostate cancer, kidney cancer, and bladder cancer. He is also actively involved in research, serving as a principal or co-principal investigator on several clinical research trials that incorporate novel targeted therapies for his patients. He's a friend and a mentor, and I'm really glad to have you, David.

Dr. David Nanus: Thank you, Manish. It's my pleasure to join your podcast. And it's great to speak with you about the recent ASCO meeting. You know, I've been to ASCO for over 30 years. It's grown in the complexity, the number of people there, the number of companies that come there to meet with investigators. And it's a great place to meet your colleagues, to catch up, but I think more importantly, to learn about some of the newest groundbreaking research, as well as have conversations with colleagues, pharmaceutical companies, et cetera, to really figure out what are good strategies for new approaches to treat patients with different types of cancer.

I think one of the highlights for me is this back-and-forth dialogue where sometimes there's new drugs, and we as investigators can speak with the companies that are developing these new drugs and try and come up with novel clinical research studies that will really help our patients.

Dr. Manish Shah: I couldn't agree more. I think that this is one of the seminal meetings that occur every year. And it brings together researchers, pharmaceutical companies, caregivers, and patient advocates. And over the last forty years, I would say, oncologic care has become more and more specialized.

There are many oncologists focused on GU cancers as you do, or GI cancers. But still, the vast majority of oncologists see a plethora of diseases. They see the gamut, from lung cancer to GI cancer to lymphoma. And it's a forum where these more general oncologists are able to, in one condensed setting, really get up-to-date information on how best to manage patients.

And one of the key things is that it really drives drug development. I think that, with the explosion of new drugs that are available or being tested, having an ability to talk to people about how best to do a trial, what are the toxicities. These things really can affect how drug development happens. So, ASCO is really an important meeting, and it's really wonderful to give this update every year on this podcast.

So, from your perspective, could you highlight two or three key abstracts that you found at this year's ASCO meeting?

Dr. David Nanus: So, the first I would like to discuss is what's called the PROTEUS trial. And this was presented in the plenary session. And for those who don't know, there's about five studies that are picked by the meeting organizers that highlight some of what we consider practice-changing trials.

Practice-changing meaning, something that will really almost from the time it's presented affect the way we as oncologists manage patients.

This particular trial had to do with early stage, but locally advanced or high-risk prostate cancer. So, one of the dilemmas we have in prostate cancer, is some men are diagnosed where the cancer has not spread, it's not metastatic, so that's good. It's still local in the prostate, but it has a high risk of recurrence for a variety of reasons. Maybe occupying most of the prostate, maybe poorly differentiated, meaning that it looks very aggressive under the microscope. We know historically those cancers are more likely to spread or maybe there's one or two lymph nodes involved.

In any case, the way those patients have been treated over the years are sometimes they'll undergo surgery and sometimes they'll undergo radiation with testosterone-lowering therapy or hormonal therapy. But unfortunately, many of those patients will relapse.

So, this study was based on a number of prior small trials, many of them coming out of Dana-Farber with Mary-Ellen Taplin, who was the lead investigator on this particular trial, the PROTEUS study.

And the concept was that if you give intensive hormonal therapy prior to surgery, and maybe after surgery, patients will do better and less likely to relapse. Now, this is not a new concept. Male hormone, or androgen and testosterone, stimulate prostate cancer to grow, so lowering testosterone, is a good strategy to kill the cancer, though frequently it's not curative.

In this particular trial, patients were randomized to getting testosterone-lowering therapy for six months, then having surgery, and then another six months of therapy. So, it's what we call perioperative. It could be before, and in this case before and after surgery. That's a strategy that's done in many different cancer types.

But this was a very large study. And the randomization was just one drug, which is testosterone-lowering therapy, and another drug, in this case it was apalutamide, which is one of a class of agents that inhibit other male hormones besides testosterone. So, other male hormones that stimulate your cancer via what's called the androgen receptors. But it's more intensive hormonal therapy to keep it very simple.

So, patients are randomized, six months treatment, either one drug or two drugs, then surgery, and then six more months. And we know from prior studies that this seemed to be a reasonable strategy, but it wasn't clear because it would be these small trials of 50, 60 patients. This was a very large, international trial of 2,000 patients, which makes it quite striking, and will lead to a lot more analysis.

But basically, what we saw was that there was a significant increase in the number of patients who had no evidence of cancer when their prostate’s removed. Still a low number, a little bit less than 10%, but much higher than previous studies. There was a 20% decreased risk of the cancer spreading, almost a 30% decrease, at this point, of dying of prostate cancer.

And I think what was the most striking to many of us, for those patients who did need treatment after surgery -- which sometimes happens if patients’ relapse -- it was three years longer in the treatment arm than in the control arm. Meaning that even if you did need surgery, it was three more years of life without any issues. And it's not that patients died, it's just that, then they went on to the next treatment.

So, this was really practice-changing. This is the first perioperative or treatment around surgery that has shown to significantly affect prognosis and how patients do. Obviously, it's early. This is the first presentation. But it immediately changes the concept of if a patient comes with high-risk prostate cancer and says, "Doc, I want to get my prostate out anyway." Then, we'd say, "Well, let's give you a little treatment before, a little treatment after, and we'll do the surgery in between. And you have a better chance of a really good outcome."

So, I think this was a very well-received study. It's based on prior knowledge. It already has changed the way we discuss with these patients what's the best approach.

Dr. Manish Shah: That’s incredible. I was amazed by the study. But the discussant mentioned something that made me think a little bit, and I think he’s right. Not only is there tangible benefits, as you pointed out, to having an event progression or something like that.

The discussant mentioned two things. One is this other idea of the time to next treatment, which was something like three years extended with the combination therapy. And then, the other thing was the delay relating to anxiety relating to biochemical failure. If you can delay that, even that’s important.

Dr. David Nanus: And the other thing about this trial which makes it very current is when they started the study, because you can imagine it took them many years, they were using standard imaging, CAT scans and bone scans. But early on in the study, they changed to using PSMA PET scans, which are more sensitive. And that really impacts the trial. It makes it more real world or current, because that's how we typically will diagnose patients when they recur. So, the fact that they're looking at if patients recur by PET scan and they're not seeing it in the treatment arm is very encouraging, and speaks to a long-term benefit of this approach.

Dr. Manish Shah: That's incredible. Was there another trial you wanted to mention?

Dr. David Nanus: One I think is worth mentioning because it comes out of a lot of work at Weill Cornell. It's not quite yet a practice-changing trial. But it includes a drug that was actually developed at Cornell by my colleague Neil Bander. In fact, when I first came to Cornell, one of the reasons I did come was to help perform clinical trials for this drug. It's called monoclonal antibody J591. The trial was called CONVERGE-01. And it's a study of this drug which is now called rosopatamab tetraxetan. It's a study for patients with advanced prostate cancer who've gone through many different treatments including radioimmunotherapy, where you link radioisotopes, usually lutetium with a drug called Pluvicto, to target cancer. And this one uses a different radioisotope. So, these are patients that have been heavily pretreated. And this comes on the back of phase II studies that we did at Weill Cornell with my colleagues Scott Tagawa and with Dr. Neil Bander, myself and others.

And basically, this drug was taken over by this company. And we're seeing very good early results, very encouraging, which really just confirms what we've seen in the past at our own institution.

But I think in the future, this will be one of the drugs that patients will be using. It's adding to the armamentarium of how we treat patients with refractory prostate cancer. So, it's exciting. It's exciting to see a study that was developed internally make it to the world stage. And we're very excited about this in the future.

Dr. Manish Shah: Those are really incredible advances in GU cancers. So, there was a video of a standing ovation from the plenary session at ASCO that went viral. And that was in response to the RASolute study, which is a study that uses daraxonrasib, which is a pan-KRAS inhibitor in pancreatic cancer. So, KRAS is one of the key proteins in many cancers. If there's a mutation in KRAS, it activates a signaling cascade that gives the cancer cell advantages with regard to survival. It's an anti-death signal. It increases the ability of the cancer to spread.

And for 25 years, it's been a target that we called undruggable, meaning that there wasn't a way to figure out how to block that target. But then, recently, in the last three or four years, there's actually been several new drugs, some approved and some in development that are targeting that. There was a drug in lung cancer, which is a KRAS G12C inhibitor, that has changed practice.

So, daraxonrasib is what we call a pan-KRAS inhibitor. It means that it targets many different mutations in KRAS. And the RASolute study was a randomized study in the second-line setting of daraxonrasib versus chemotherapy. And this was in pancreatic cancer. It's a tough disease. Most patients don't have an extended survival. And in the second-line setting, survival is, in fact, quite limited. And in this randomized study, the one-year survival in patients who received daraxonrasib was over 50% versus around 19% with the standard of care chemotherapy arm.

So, that was really quite remarkable, I think in part because, in pancreatic cancer, drug development has been challenging. There haven't been new targeted agents being developed or approved, and this is likely to be the first one. So, that was quite amazing at the plenary session.

Dr. David Nanus: I would agree, Manish. That was clearly one of the buzz discussions, I would say, at ASCO. Finally, a drug that seems to work better in pancreatic cancer, which all of us -- doctors and patients and people across the world -- know of someone who's been diagnosed with pancreatic cancer.

And unfortunately, it's universally fatal in almost everybody. So, having a drug that actually works leads to new strategies, new approaches. And RAS has been around a long time. When I first started my career, my research actually was looking at the RAS oncogene and these different types of RAS proteins. At that time, it was just seeing which ones were mutated in cancer. And it was discovered way back then that it was highly mutated in pancreatic cancer. And now, for years, investigators have been trying to target that mutation. Finally, it's been successful.

So, it's very optimistic outlook, I think, for patients with this disease, because here's the first drug. As we've seen along the way, when someone gets successful targeting in a mutation, usually more drugs, better drugs tend to follow. So, I think for patients and their family members that have pancreatic cancer, this really raises some optimism.

Dr. Manish Shah: Absolutely. And then, in the plenary session, the other study that was in lung cancer that was really quite exciting was the evaluation of selpercatinib, which is a drug that targets RET, which is mutated in less than 3% of lung cancer. So, this study examined stage IB to III non-small cell lung cancer that had a RET gene fusion. And patients received adjuvant therapy with selpercatinib, and there was a significant improvement in event-free survival. So at three years, 80% of patients didn't have an event with the RET infusion versus 50% with standard of care. The hazard ratio -- I haven't seen something this low -- zero point one seven, meaning, nearly 82% of patients had benefit with the RET inhibitor in the adjuvant setting.

If you have a target, the earlier you attack that target, this is true in many different cancers, the better the outcomes. Meaning that in the second or third-line setting, the target shows some efficacy. If you bring it into the first-line setting, the patient benefit is even more. And here, in the adjuvant setting, meaning after surgery, you could still use the target and prevent recurrences. And so, that's quite remarkable.

Dr. David Nanus: I think what that speaks to is some of these mutations may not be that common, but frequently they're driving the cancer. And early on, they're really the main driver of cancer. But over time and treatments, other mutations, secondary mutations, sometimes these driving mutations even become backseat mutations. And so, when you target them, you don't get the same benefit. So, I think you're right, that moving things earlier sometimes has a dramatic benefit.

I think the other thing it speaks to, is the concept of getting your tumor sequenced. It should be done in almost every cancer. Not every, but just about every cancer, because sometimes there are these rare mutations. This particular mutation in lung cancer is quite rare. But if you have it, it changes your treatment, improves your outcomes. And so, it is important to advocate for yourself and say, "Doctor, did you sequence my tumor?" And I think that's become the standard of care for many different disease types. But in the reality, it's not done as often as it should be.

We know even in prostate cancer, which is a common disease, less than half the time the tumors get sequenced or genetic testing for inherited mutations get performed. So, it's still a big problem out there in the real world. And we, as academics push for it, and we think it's important that patients self-advocate to get this done.

Dr. Manish Shah: That has been a theme that, in the current era, of targeted therapies, the more information we have about the cancer in terms of molecular testing and sequencing, the better we can tailor treatment to the patient. And importantly, the earlier we tailor this therapy, the better. And I think that's come through time and time again.

The other technology that came out at ASCO, which was very interesting, there was a study in renal cell, the KEYNOTE-564 study with ctDNA. That was an important study. There was a study of ctDNA in colon cancer that also showed important benefits.

Dr. David Nanus: The concept is “can you predict by looking at circulating tumor DNA, which patients will benefit through treatment, more commonly adjuvant treatment?” I think it's most well developed in my world in bladder cancer. And the idea being that if you have a complete response and you have no evidence of circulating tumor DNA, then maybe that's it, you're one and done.

So, bladder cancer specifically, we know patients almost always, if it's locally advanced, get preoperative therapy with chemotherapy, typically with enfortumab vedotin and pembrolizumab, which is immunotherapy and an antibody drug conjugate. And the idea is that if you have a great response, meaning a complete response, which happens in over half the patients in the bladder, and you have no circulating tumor DNA, maybe you don't need any more treatment. There's some studies ongoing in that realm.

In kidney cancer, similarly, there was a positive outcome with pembrolizumab, looking at whether or not you had ctDNA. It is a little prognostic, perhaps predictive. But in kidney cancer, we're not quite there yet. These are more hypothesis-generating and require bigger studies.

Where I would say, in bladder cancer, we're already almost there. Doctors are using it to try and help them guide therapy. In fact, I think one of the assays was recently FDA approved for that. I know in colon cancer, this is a big deal for years, and you guys are ahead of us in this area.

Dr. Manish Shah: So, the CIRCULATE study was presented at ASCO. And ctDNA, circulating tumor DNA, you take a blood sample, and you look for specific alterations or mutations, or something called methylation, which is another way that the DNA can be altered in the blood. And these alterations are specific for cancer, so we say that they indicate that there's evidence of DNA fragments that must be from cancer.

And one concept that people I think are very comfortable with now is something called minimal residual disease, which is that the CAT scans or PET scans are negative. They don't identify any evidence of cancer. But the blood test might show that the tumor marker is elevated, and you think that there's some indicator of disease.

So, pretty clearly, across many cancers, colon cancer, bladder cancer, breast cancer, if you have a positive ctDNA in the setting where the cancer's been resected, then that does indicate that you have a higher risk of recurrence because you might have some residual cancer remaining in the body.

Now, the field, though, has been waiting on data to say, "Well, let's act on this. Let's treat based on a positive ctDNA." And the study that was presented at ASCO was the CIRCULATE study. It came out of Germany. Basically, patients with stage II colon cancer, who had ctDNA positivity, they were randomized to observation, which is the standard of care, or chemotherapy. And this is a tough study to do because there's a lot of anxiety that you might imagine with this.

And very clearly, patients who received chemotherapy based on the ctDNA positivity, they appeared to have better outcomes. It's a hard study to do because they had to screen 1,400 patients to get sixty to get randomized. So, I think it was a little bit underpowered. But there's enough evidence emerging, as you were saying in bladder cancer, where we may be able to act on this and not just do more frequent scans, but actually treat patients based on a positive MRD test.

Dr. David Nanus: Solid tumor is a little behind in this area because MRD and leukemia and myeloma have been around for a while. And, and more recently in lymphoma, some trials are actually going to use ctDNA to help manage treatment.

Historically, they would use PET scans. And now, the concept is if your PET scan's negative and your ctDNA is negative, can you give less chemotherapy, instead of the typical six cycles, like for instance in Hodgkin's or non-Hodgkin's lymphoma?

So, the advances we're making by using technology are pretty incredible from when you and I started, where we just had CAT scans and bone scans. Sometimes, because the blood markers we would use in our respective diseases were going up, we knew something was going on, but we just sort of waited for it to present on a scan. We couldn't treat a number.

I think what's changed is, one, more sensitive imaging. But I think more importantly, the concept that we'll probably be going to where we can treat a number, meaning a rising marker with clear circulating tumor DNA in the blood, because we know what's going to happen. But more importantly, we know if we intercede early, we maybe can cure some of these patients.

Dr. Manish Shah: Absolutely. And you talked about advances in technology and advances in the drug development. I was struck by the advances in drug development that are occurring globally. And in particular, many drugs are coming out of China. And at this ASCO in particular, there were several drugs that originated in China, maybe licensed out, and had positive results and made it to key abstracts. What were your thoughts on that?

Dr. David Nanus: I think myself and my colleagues were shocked or surprised at how many of the studies that were presented came directly out of China and were done in China. Obviously, there's a big population. So, they unfortunately have a number of patients who have cancer that can be studied.

Most of these drugs, interestingly enough, were not new drugs, but they were almost like a copy or a similar drug to what we studied here. And my understanding is some of the drugs that we develop are difficult to get into China or expensive in China. So, they've developed similar drugs for the same indications, and they're not compared head-to-head, but seemingly work just as well and will be used in China. So, some of the agents that we're using, we'll use. Some of the agents they've developed, they'll use.

I think, though, this is just step one. And, I know in China they're developing new and novel agents, which will ultimately be used there and here. And to me, it speaks a little bit to, unfortunately, the cut in research funding that's happened in the last few years that really is impacting our ability in the United States, to develop new drugs.

I mean, drug development is expensive. Most drug development occurs in academic labs based on grant funding that is then spun off into a small company that's then taken over by a large company. And then, you have these 2,000 people or 1,000 patient trials, and that brings it to market.

So, we’re falling behind. I think it’s unfortunate. Hopefully, this will change and Congress will designate more money for cancer research funding. And I encourage all our listeners to reach out to their congresspeople to tell them and reinforce how important cancer research funding is.

Dr. Manish Shah: Yeah, I couldn’t agree more. And on one hand, I think that it's really incredible to have a global imprint on drug development. For years, it has felt that it's been dominated by North America and Europe, but I think more and more work coming out of Japan and China is really quite good. I think that their ability to develop new agents building on the previous success, as you mentioned, has been quite amazing.

One drug that came out of China is a drug called Iza-bren. It's a bispecific antibody, Izalontamab brengitecan. So essentially, it's an antibody-drug conjugate targeting HER2. And it was examined in esophageal squamous cell cancer, and it was a positive study done entirely in China and now is licensed to a U.S.-based company and being developed further. And that's just one example.

But this leads me to two other points. One is that we do need to do better. I think there's lots of regulation around clinical trials that actually hamper our ability to do rapid clinical trials. And places like China may have an advantage. But then, there's another thing, that good ideas can still develop into practice-changing studies.

And that leads me to the study of abemaciclib in dedifferentiated liposarcoma. This was in the plenary section. This was led by a friend of mine, Mark Dickson from Memorial Sloan Kettering, in sarcoma. So, this kind of sarcoma, dedifferentiated sarcoma, is very rare. Three thousand patients a year get it.

He identified 15 years ago that these sarcomas, over 80% of them overexpress CDK4 and 6. These are cell cycle proteins that can aid the cancer in cell division. And abemaciclib is a very specific CDK4/6 inhibitor.

And he did investigator-initiated trials. That means these were his own idea. He went to the drug company, asked for the drug, did the trial himself. And you and I, we've built our careers on these investigator-initiated trials.

This is a success story because the first trial was published in 2013 with palbociclib. The next one was published in 2017 with abemaciclib. That led to a phase III study, which led to a plenary session at ASCO this year. It was a randomized study of abemaciclib versus placebo. And patients who received abemaciclib actually had a significant improvement in survival versus the other standard of care. So, it shows that although there is a global imprint on drug development, good ideas can surface to the top.

Dr. David Nanus: Yeah. And that's based on science, research in his laboratory, and looking at pathways and so forth. What we can accomplish is unlimited. And today, with AI, God knows what we'll be able to do in the future. But it does require human, hard work, support from the government and from foundations to allow us to continue to do our research.

And I am optimistic that we'll do better and continue on this journey. Every year at ASCO, we see improvements in many different diseases, and people are living longer with cancer, which is great. And the cure for many cancers is probably not so far away. The harder we work and more successful we are, the better the outcomes will be for our patients and their families and society in general.

Dr. Manish Shah: Oh, absolutely. And thank you for those final thoughts. I couldn't agree more. I think that things have changed a lot in the last 30 years. We are smarter about characterizing the tumor. We are smarter about how to figure out where the tumor is, what the burden of the disease is. We are smarter about which drugs and how to deliver therapy. And it's really a time for optimism. Do you have any other abstracts you'd like to discuss?

Dr. David Nanus: There's some smaller studies, just as like a rapid fire.

There was one trial that looked at proton therapy for prostate cancer versus photon, different types. People have heard about proton. And the bottom line was they were the same. So either one is good.

There was another study looking at different androgen receptor antagonists, which one works better. They were similar. One may be a little bit better, darolutamide, in terms of causing cognitive dysfunction, which I think is something that's important for clinicians to know in terms of when they prescribe.

There were some other studies in adjuvant kidney cancer that pretty much confirm what we know, that high-risk patients should get some sort of therapy. And then, finally in bladder cancer, just confirming again the combination I discussed earlier.

So, I would say the biggest bang for the buck with this year and ASCO was related to prostate cancer, which I discussed. And then some of the other studies that you discussed I think were practice-changing and that all patients and their physicians should be aware of.

Dr. Manish Shah: I'll end on just two different abstracts. One was a large observational study. Normally, we don't think of them as practice-changing, but this was really quite remarkable. So, this was a study that looked at 111,000 patients in the Penn Medicine electronic medical record.

And they looked at women with a BMI of 25 or higher, and they found that, if you follow them over time, they had a 2.3% chance of getting a breast cancer. But if they were on a GLP-1 agonist, so these are drugs that have incredible effects on weight loss and diabetes management, women who were on a GLP-1 agonist had a 30% lower risk of developing breast cancer in the future. So, it really speaks to our body metabolism and cancer development.

Dr. David Nanus: What it also speaks to, Manish, is what obesity does. Obesity results in inflammation, and we know that the inflamed fat cells release certain substances, cytokines into your bloodstream, which can help propel cancer. So whether these drugs are clearly anti-inflammatory is being studied, but certainly even weight loss alone, we know since there's so many cancers associated with obesity, including breast cancer, may have an impact. This is certainly hypothesis-generating that it does have an impact on the risk of developing a cancer.

Dr. Manish Shah: Yeah, absolutely. And then, for malignant heme, there was a study of selinexor, which is a selective inhibitor of nuclear export. It blocks a protein called XPO. And this was examined with a JAK inhibitor versus a JAK inhibitor in MPN, myeloproliferative disorder, and it did show an improvement.

So, ASCO is for everybody, not just solid tumors. It was an incredible meeting. David, thank you for your time here.

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That's it for CancerCast: Conversations about New Developments in Medicine, Cancer Care, and Research. I'm Dr. Manish Shah. Thanks for listening.

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