Dr. Manish Shah (Host): We have some terrific news and want to start with a brief and exciting note to our listeners. This following episode was recorded prior to the FDA approval of daraxonrasib, which was officially approved for previously treated pancreatic cancer on August 26, 2026. This approval is the first ever for a RAS targeted therapy in metastatic pancreatic cancer and is the only major new metastatic pancreatic cancer treatment approved this decade.

The science around this new molecule is astounding. It's a very exciting time in pancreatic cancer treatment, and we hope this episode provides listeners with more information about this oral medication now known as Rasonque.

We explore how daraxonrasib works and explain the clinical trial data presented at the ASCO 2026 conference that led to this FDA approval. We're very optimistic and hopeful for the future of pancreatic cancer treatment and research that builds on this breakthrough to continue to develop new treatment options for this aggressive disease. Please enjoy the show.

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 updates in pancreatic cancer treatment, an area which has gotten a lot of news and media attention lately.

Our guest today is Dr. Shubham Pant. Dr. Pant is a professor in the Department of Gastrointestinal Medical Oncology with a joint appointment in the Department of Investigational Cancer Therapeutics, the Phase 1 Center at the University of Texas MD Anderson Cancer Center.

Dr. Pant is an international expert in gastrointestinal cancers with an emphasis on pancreatic and biliary cancers and early phase clinical trials. His research focuses on novel immunotherapeutic approaches and developing targeted therapies in GI cancers. This includes devising novel ways to target the KRAS mutation, a mutation found in many cancers and in over 90% of patients with the most common form of pancreatic cancer, pancreatic adenocarcinoma.

He has been involved with several global practice-changing clinical trials and I'm looking forward to getting into that in more depth with our discussion today. Thank you, Dr. Pant, for being here.

Dr. Shubham Pant: Thank you so much, Dr. Shah. It's truly an honor for me to be here on this podcast.

Dr. Manish Shah: Wonderful. So, let's get into it. So, pancreatic cancer, it's a scary disease. Tell us a little bit about why it's so challenging to diagnose and treat.

Dr. Shubham Pant: So, pancreatic cancer, the challenge is that it lies deep inside the body, the pancreas. And the cancer develops, there's no screening test. So, there's no, like, colonoscopy or a mammogram that we can use. And it grows quietly. By the time it's detected, in majority of the cases, it's advanced disease. I's already metastasized. It's already stage IV disease, has gone to the liver, to the lungs. Patients get jaundice, weight loss or some back pain or abdominal pain.

The other problem is that it's very nonspecific, the symptoms. So, dyspepsia, you're not feeling well, you have abdominal pain. What happens is these patients sometimes get diagnosed a little bit late, about 80% of patients have advanced disease, either metastatic or something called locally advanced. That means we cannot resect the tumor out. So, truly a challenging disease.

Dr. Manish Shah: Absolutely. And I think what you said resonates with me as well. It's location, location, location. And it's right in the center. There are important structures, the celiac axis, the blood vessels. So, it makes it challenging. One thing that I learned a few years ago was that unlike other cancers, mutations in pancreatic cancer that lead to metastases happen early. Is that right?

Dr. Shubham Pant: That's exactly right. So, the KRAS mutation, which we are going to talk about a lot more, is in 90% of pancreatic cancer patients, and it really comes very early. When you think about it, it's not like a full flower, just like a bud. And even in the bud stage, the KRAS mutation comes in. So, it's a true driver mutation, as we say in pancreatic cancer.

Dr. Manish Shah: So, conceptually, there's early-stage disease where surgery would be considered. There's disease that is involving blood vessels, maybe becoming unresectable, that's locally advanced. And then, there's metastatic disease. Can you give us an idea of the percentage in each of these categories? And how do we manage patients that are in that category?

Dr. Shubham Pant: I'm going to start with resectable. So in pancreatic cancer, patients always ask me, "What's the stage of my disease?" And what I tell them is it's important to know if you're resectable or unresectable. That's the big thing. Staging, I think does matter if you're stage IV, but in practical terms, if you're resectable, unresectable or metastatic is what matters.

So, resectable means, it's not the size of the lesion, pancreatic cancer, it's in relation to the blood vessels. So just as you said with celiac axis, with superior mesenteric artery, SMA, some other blood vessels, if it's wrapped around it, it's called locally advanced. If it's away from it, it's called resectable. There's kind of an intermediate stage called borderline resectable, but I'm just going to keep it to resectable or locally advanced disease. That means involvement of the vessels and no involvement of the vessels essentially.

And, about 20% of patients are resectable. So, those are the ones that are found a little bit early, but small minority. About 25 to 30% are locally advanced, and about 50% plus are metastatic at diagnosis. So, a majority are stage IV at diagnosis.

Dr. Manish Shah: And so, if you're resectable, the approach is to go to surgery. Do we think about chemo beforehand or afterwards for that category?

Dr. Shubham Pant: So, in resectable disease, there are two different ways to take it, and both are considered appropriate. One is the surgeon takes the tumor out, and we give patients adjuvant therapy. That means therapy to kill the micrometastatic disease. So, it's like the little seeds which could exist. We've pulled out the main tree. But then, there are little seeds which have been scattered around that we're trying to kill with chemotherapy.

However, in certain centers, including ours at MD Anderson, we tend to treat patients with something called neoadjuvant therapy. So, we give them chemotherapy before resection. We think it helps us identify tumor biology. If some patients are metastatic, even at the time of resection, it helps identify those patients.

So, it's different philosophies. I think both are appropriate. Different centers, mostly depending on the surgeons, use different philosophies. Neoadjuvant therapy, surgery, followed by some adjuvant therapy. Or surgery followed by adjuvant therapy after that.

Dr. Manish Shah: And then, for the locally advanced, so these are tumors that haven't spread yet, but they're involving blood vessels and they're not resectable. What's our approach?

Dr. Shubham Pant: So, for those patients we give chemotherapy first, called induction chemotherapy. And then, we tend to either put them on maintenance therapy kind of after six months, lighten the chemotherapy, try to preserve the quality of life, or sometimes we refer patients out to our radiation oncology colleagues to maybe give radiation to the locally advanced tumor, and then we can deescalate their chemotherapy after that. Obviously, individual patients are different, but that's the way we normally treat these patients with locally advanced disease.

Dr. Manish Shah: And then, of course, for metastatic patients where the cancer has spread beyond the pancreas, we're focused on treatment throughout the body such as chemotherapy. One thing that always comes up is genetic testing. One thing we know about is BRCA, but there are other genes as well. Who should get genetic testing for pancreatic cancer?

Dr. Shubham Pant: I think everybody should genetic testing and that reflects in our guidelines, the NCCN guidelines, ASCO cancer guidelines that we talk about. And the reason is exactly what you were saying, about 5, 10% patients have a BRCA1, BRCA2 gene, just like breast cancer and ovarian cancer, high risk for pancreatic cancer. There can also be a gene called PALB2, which is also important, because the choice of chemotherapy depends on that genetic mutation.

So, there are two benefits for it. One is obviously for family members to know if they carry the gene, so they can be followed up with in a high-risk clinic. We have one such clinic at Anderson, and there are others at other centers. And the second thing is, if you have a BRCA1, BRCA2, a PALB2 mutation, we think that you should get platinum, which is called oxaliplatin or cisplatin as part of your treatment. There's also a drug approved for the maintenance setting called olaparib for patients who have BRCA1 or BRCA2 mutations. So, it's very important to have the germline testing upfront for our patients with pancreatic cancer.

Dr. Manish Shah: This can sometimes be confusing to patients. There's a difference between tumor testing and then testing a patient's blood, not the tumor, the germline. Why are we focused on germline testing for these genes?

Dr. Shubham Pant: I'll make it a little bit more complicated. There are three different kinds of tests. So, one is a germline, which is a blood test or a swab test, mouth swab, which is that concept of passing maybe these genetic changes to your children that you might have inherited.

The second one is tumor testing. Just like we all have different fingerprints, every tumor has different fingerprints. But that is not something you can genetically pass on to your children. It's essentially the way your tumor is. So, that's called genomic testing.

And the third kind of testing we do sometimes is called circulating tumor DNA or ctDNA testing. And what that means is the tumor, especially stage IV cancer, it can shed this little DNA off the tumors into the blood. So, sometimes we are not able to get those fingerprints in the tumor. So, maybe we can just extract it from the blood, and we can devise maybe a targeted therapy for the patient based on that testing. So, you have the somatic testing, which is the genomic testing, ctDNA testing, and the other side is the germline testing.

Dr. Manish Shah: Well, this is really a wonderful primer. And now, we're going to shift gears a little bit and get into the meat of what is the excitement around here. Pancreatic cancer, I would say is maybe now joining the party for biomarker-driven treatment.

And we've had lots of discussion on biomarkers and how it's important to identify the biomarkers so we can treat them. BRCA 1 and 2, PALB2, these are biomarkers. But let's talk about KRAS, which is the elephant in the room. It's a biomarker, but what made it so difficult to target?

Dr. Shubham Pant: Yeah. So KRAS, it's been around 40 years, a journey which has taken a lot of scientists. One thing for the podcast listeners is just science takes time. But once we start breaking that dam of resistance, then a lot of things start happening together. So, the KRAS mutation was identified about 40 years ago.

And then, over 30 years, we tried to target it, but there's a few challenges with KRAS. So first of all, it's mostly in the GTP phase. And what that means is think about it like a light switch, which should be turned off in the cancer cell, but it's turned on. And it's just giving growth signals for the cancer to grow all the time. And it's not only on, it's stuck in the on position with like Gorilla Glue or something. So, it's stuck in the on position. You cannot flip that switch off. And most of your cancer cells lie in that “on” state. So, it just consistently keeps on giving signals for the cell to grow.

The other thing, as you know, in drug development, scientists design or chemists design drugs to attach onto the surface of mutations, proteins, which are caused through these mutations. And the issue with the KRAS mutation and the KRAS protein is, think about it like a soccer ball, but very shiny, metallic soccer ball. Anything that we try to stick on it just slid off it essentially. It was very, very hard to target. But over time, really smart folks figured out how to target it. And now, we have all these new therapies which are coming up.

Dr. Manish Shah: That's really terrific, and that's a great analogy. So, KRAS is a protein. It's commonly mutated in pancreatic cancer. Over 90% of the tumors have a mutation. The mutation changes the protein function so that it's always delivering a downstream signal, and the downstream signal is a pro-survival signal. It's an anti-kill signal, meaning that the cancer cell stays alive. And it also is a signal that tells the cancer it should spread. If you're a cancer cell, everything you want to do -- not die, grow, divide, spread -- is driven by this pathway. So, it's really an important pathway and the ability to target it is so critical. But there are different mutations, and I think this will be important not only for this drug, but other drugs. Can you tell us do these mutations matter?

Dr. Shubham Pant: For the KRAS mutation, now, it's 90% of pancreatic cancer patients. It's also there in colorectal cancer, lung cancer. So, it's in other cancers also. But specifically for pancreatic cancer, now we have to take the pie, and we have to start dividing it, because it's not good enough to just know that there's a whole pie of KRAS. That means the main mutant alleles of KRAS are something called KRAS G12D, as in delta, which is in 40% of patients with pancreatic cancer; V as in Victor, which is 30% of patients with pancreatic cancer; and R as in Romeo, which is about 15% of patients with pancreatic cancer. Then, we have other mutations called KRAS G12C, which is there only in about 1% to 2% of pancreatic cancer, and KRAS Q61, which is about 5%.

And why it's important to distinguish these is because we have different therapies. We have one pan-RAS therapy that we'll talk about, but then we are also developing allele-specific therapies. So, there are inhibitors of KRAS G12D coming out. There are inhibitors of KRAS G21V. There's already inhibitors of KRAS G12C, which have been approved in other tumor types.

So, it's Pandora's box, but in a good way. This toolbox which is kind of opening up to treat our patients with pancreatic cancer, a disease which used to be universally devastating.

Dr. Manish Shah: That's incredible. So, coming back to these different mutation subtypes. Sotorasib, which is the G12C inhibitor, that's approved in lung cancer. It's very interesting. Only in the last few years has there been some biology that suggests that these different specific mutations actually carry different significance for the cancer.

At least in colon cancer, it seems that G12D, which is the one that's more common in pancreas cancer, makes the colon cancer more aggressive. Is there any data like that in pancreatic cancer?

Dr. Shubham Pant: Yeah. So, we did a retrospective analysis of our patients in MD Anderson, and what we found was that these alleles behave differently. So, if you have a KRAS G12R, the signaling pathway is a little bit different than the traditional RAS, RAF, MEK, ERK pathway—so if you have a KRAS G12R, you have a better prognosis than normal in pancreatic cancer. So, the pancreatic cancer, let's say before all these targeted agents, it's about 12 months median survival in most clinical trials. But in KRAS G12R, we found that the median survival could reach as much as 24 months. If you have a KRAS G12D and V, it kind of lies in that 12-month range. And if you have a KRAS Q61, that's actually very aggressive. So, that's a poor prognostic marker. Again, this is retrospective analysis, more are coming out. But R and Q61 seem to be a little bit different than what we see with KRAS D and V.

Now, one small, interesting point is about 10% of patients are KRAS wild type. So, they do not have a KRAS mutation, but those patients seem to have a much better prognosis than patients who are KRAS mutant. So, they actually have a prognosis which is maybe similar to the KRAS G12R. So, it's very interesting. And wild type is a different area where about 30% to 40% have fusions called NRG1 fusion or NTRK fusions, which can be targeted by other drugs which have been approved. So, that's a completely different subset. But you're right, 90% is KRAS. We're figuring out they're behaving a little differently.

Dr. Manish Shah: It's great that you mentioned the 10% that don't have a KRAS mutation. It's really important for patients to get their tumor tested, and get the sequencing done. Because you don't know what mutations you have that we can target. And even things that are very rare, they may be present in your tumor and there may be a drug available for you.

So, let's talk about daraxonrasib. So, this is a very exciting time. At the ASCO meeting that we had just a few months ago, there was a standing ovation for this clinical trial that was presented, the RASolute 302 study. Do you want to talk us through that study?

Dr. Shubham Pant: Super exciting time for our patients with pancreatic cancer. So, we saw early activities of this agent in the phase 1 trial that we did. And in that, the patients' response rate normally with chemotherapy is about 10% to 15%. We saw a doubling of response rates, about 33%.

So, this went to a phase 3 trial, the RASolute 302, and that trial was in patients who had received frontline chemotherapy for metastatic pancreatic cancer. And the patients had progressed on the frontline chemotherapy, and we randomized the patients to standard of care chemotherapy, and investigators could pick and choose. They could choose a 5-FU-based therapy if they got gemcitabine frontline or a gemcitabine-based therapy if they got 5-FU frontline. So, dealer's choice.

And on the other side, they got daraxonrasib at a dose of 300 milligrams a day, which is the pill that we're talking about. And the pill is given daily. So essentially, daily pill versus chemotherapy. And there were 500 patients randomized, and this was one of the fastest accruals I've ever seen to any trial that I've run. And I've run quite a few trials in pancreatic cancer.

Literally, we opened it, and we just had a number of patients, who were coming in to get on the trial. And I think in a remarkable fast time, we got the results back. So, the results were, in the patients who received daraxonrasib versus standard of care therapy, they’d almost doubled their survival. So, it was 6.7 months for patients on standard of care and 13.2 months in patients with daraxonrasib. And that’s one part of it.

The other part of it is when you look at the graph which was presented, the Kaplan-Meier curve as we call it, 57% of these patients who got daraxonrasib were alive at one year. And that’s not what we see in pancreatic cancer. In the chemotherapy arm, it was 16%, made it to one year. As you and I know, those patients, unfortunately, their performance status gets worse, and they overall feel bad. So, I think that was remarkable.

The other thing which was interesting was, one is the duration of lifespan, which is very important, obviously. The second thing is quality of life. I don’t think drugs have a lot of meaning if people are not getting quality of life, if they’re not spending time, quality time with their families, if they’re just in bed all the time because of the side effects of therapy.

Interestingly, the quality of life was much improved, statistically improved, in the patients who received daraxonrasib versus chemotherapy. And the reason was because pancreatic cancer gives you a lot of pain, makes you lose weight, decrease appetite. So, all these parameters, not only patients were living longer, they were feeling better when they were on the drug. So, that stood out for me.

Dr. Manish Shah: Let’s unpack this a little bit. So, when Dr. Pant was talking about the average survival, the median survival, and the one-year survival. So, it’s kind of like a bell curve. So, there are some people that live longer, some people that live less. It’s an aggressive disease. On average, if you are receiving daraxonrasib, the bell curve for surviving cancer is shifted to the right, meaning shifted longer. More people are alive at six months than with chemotherapy. More people are alive at one year than with chemotherapy.

But one thing looking at these survival curves that struck me is that we compare them. One group getting the investigational drug, in this case, daraxonrasib, the other group getting the standard of care. The curves, they split very early within months, and it kept getting wider. It was amazing, I thought.

Dr. Shubham Pant: What struck me, Manish, in that is maybe we're changing the biology of the disease. That means maybe the tenor of the disease, we're slowing it down a little bit. And so, this curve starts separating very early in the disease, and they keep on separating and keep on growing.

You're exactly right. I think we joked saying you can drive a truck through the two curves and everything. I feel like we might be changing the biology of the disease. And I mean, there's so much research to come about why does this happen? And is there some change in the tumor microenvironment which is causing these changes? So, it's just a great time, I think.

Dr. Manish Shah: Absolutely. Let's come back to that changing the biology of the disease. So, when we think of biomarkers, we think of an alteration that we can take advantage of with a drug. And there are some alterations that occur later in the disease after many other alterations accumulate, and it could still be a biomarker, but maybe it has less of an impact because there are so many other mutations that developed earlier.

KRAS is an early mutation in pancreatic cancer. Almost 90% of cancers, but almost all the cells have the same mutation. And it's such a key and important driver. Maybe it begs the question that it's such a critical protein for the cancer, hitting it with a drug that attacks it, it could have profound effects on how the cancer behaves moving forward. That's what you mean by biology of the cancer, right?

Dr. Shubham Pant: Yes. How it behaves, how it's going to grow and everything, you're exactly right.

Dr. Manish Shah: I never thought of it that way. That's really quite exciting. So, let's talk about the pill. Daraxonrasib, it's a pill, you take it every day. What are the side effects? Do you reduce the dose if you have side effects? What do you do?

Dr. Shubham Pant: So, we should never forget about the side effects of drugs. And just like any drug, this also has side effects. So, the first thing is what we see early on when they start taking it, we see some diarrhea, and that could be for two or three days.

So, what I talk to my patients is we give them Imodium, kind of start taking it. So, that diarrhea actually settles down, but it's interesting that it happens mostly in the first few days. Patients can get delayed diarrhea also, but I think they should have Imodium at hand before they start the medication. So, that's important.

The main side effect that we see is a rash. And this rash is in 90% of patients who get on the drug, and about 15% get a grade 3 or 4 rash. That means a rash which covers quite a lot of their body. And this is based on inflammation. So, this rash, it just changes the inflammatory milieu of the skin because the MAP kinase pathway is important for that.

So, we give doxycycline or minocycline, not for its antibiotic effect, interestingly, because of an anti-inflammatory effect. So, that can damp down the inflammation. So, we give that as prophylaxis. We give hydrocortisone cream, also as prophylaxis, which patients can put on their face. So, the rash comes mostly in the face, neck, upper part of the body, though it can be anywhere. If the rash gets worse on what we are doing, then sometimes we do have to hold the therapy. It takes, in my experience, about two weeks, one to two weeks, it does get better.

In some patients, we can continue the same. We have a great dermatology department who's been dealing with these rashes for the last three years. And we're learning from each other, right? I've heard of cyclosporine creams, which could be used. Some of our dermatologists have used Accutane. It's just like acne, right? Just dries it up, decreases the inflammation. So, that can be used. And in some cases, they still keep on getting the rash. And so, we have to dose reduce them. So, we go from 300 milligrams to 200 milligrams in these patients if they're getting too much of a rash.

The other side effects that patients and physicians—because very few physicians have actually given patients this drug—need to know is stomatitis. So, you can get mouth sores, and sometimes dexamethasone mouthwashes have helped in those patients. And then, you can also sometimes get a little bit of paronychia, which is inflammation of the nail beds, but that comes later. So, we use, like, vinegar soaks and everything for those patients.

So, unlike chemotherapy, these targeted therapies have separate side effects. It reminds me of when cetuximab came out. And then, patients started to get a rash, and everybody's trying to scramble what to do. When capecitabine came out and we had hand-foot syndrome, we were trying to figure out. But I think as a scientific community, as an oncology community, there's a lot of conversation, and I'm sure folks are trying out a lot of different things.

And I've become a little bit of a dermatologist, but it's good. I'm enjoying trying to figure out what's going on, how to manage our patients. Because I think in the end, a lot of the community physicians don't have access to dermatologists like me and you do. So, I think we'll have to learn more as oncologists, to learn about what's happening. But obviously, we have great dermatology colleagues when we need them.

Dr. Manish Shah: So when bevacizumab came out, I became a cardiologist because the main side effect is hypertension. And then, cetuximab, it was dermatology. We're all immunologists now. And we adapt. That's what we do.

A couple quick questions. Daraxonrasib is a pan-RAS inhibitor. So, do you recommend that we don't even get tested, we just give the drug?

Dr. Shubham Pant: So, in the clinical trial the impact was seen across all subsets. So, the primary endpoint was for KRAS G12, which is DVR, which is in the about 80% to 85% of pancreatic cancers. But when you looked at the impact, it seemed to be even for patients who were KRAS wild type, G13, Q61.

But honestly, that subset was small, so you don't know if the big wave lifted all tides. So, we don't know if that's the case here. Interestingly, KRAS wild type, about 50% of it also is driven through the MAP kinase pathway.

So, there is some kind of data that it could be also impacting those cancers. The data in overall survival was doubled both in patients with G12 disease, primary endpoint, and the secondary endpoint, which was for the whole group. But the whole group was about 8% of patients, a smaller group, and I'm guessing KRAS wild type was less than that.

I think with the KRAS wild type, if we have an actionable alteration, like an NTRK NRG1, we would probably want to think about using that on patients first, because we just have more data in that setting with those agents.

Dr. Manish Shah: Yeah. And maybe more specific to that mutation. Pancreatic cancer is a scary disease. And it's a tough diagnosis. The drug is very exciting. What's preventing me if I'm newly diagnosed and untreated to get the drug?

Dr. Shubham Pant: The first thing is we don't have a lot of data. Chemotherapy is still the standard of care for frontline metastatic cancer because chemotherapies like FOLFIRINOX, NALIRIFOX, Gem-Abraxane, I think do give a meaningful benefit.

And if patients are progressing on it, then I think daraxonrasib can add onto it. We don't have data saying you just give daraxonrasib frontline to really improve the survival. It might, it might not. We hope it might.

That's why we started a trial called RASolute-303, in which we are randomizing patients to daraxonrasib as a single agent, daraxonrasib with gem nab-paclitaxel, which is a chemotherapy, versus gem nab-paclitaxel. So, I would encourage patients to seek out the clinical trial, because we really don’t have any data in that setting. So, we would really encourage them to go on the clinical trial.

If somebody had told me like three years ago that we would be designing a trial to give a pill for pancreatic cancer in the treatment-naive setting, I would've thought they were crazy. And it's just amazing how fast this field has progressed that we are able to offer such a clinical trial to our patients.

Dr. Manish Shah: I think, that's a good segue to a brief discussion on clinical trials. So, for our listeners, clinical trials are not random ideas that people come up with. There are actually criteria based on international guidelines and committees. There's something called the Helsinki Accord. And there are other Office of Human Protection guidelines that really inform how clinical trials are done. A trial should be based on science. A trial should ask a question and answer a question. A patient should have informed consent. They should have the opportunity not to do the trial and still get care. These are all key tenets of a trial.

And just having had ASCO and having the results of this study is a reminder of how important clinical trials are. If you participate in trials, you advance science, and can get the drug to millions of people because you played a role in this development.

Dr. Shubham Pant: That's very important. I think, Manish, one of the things patients worry about is, "Am I getting a placebo?" It's rare to just get a placebo on a clinical trial. That's important.

Sometimes you might get a placebo with chemotherapy. So, we have these KRAS G12D trials. So, the D agents seem to be better tolerated or easily combinable with chemotherapy. So, we have trials in which it's chemotherapy with or without the D agent. And that might be a placebo-controlled trial, but you're still getting chemotherapy. You're not getting sugared water. So, that's important for patients to know.

And you're exactly right. I think we just need to follow the data, and be agnostic to the results, whether we've had a hand in from phase 1 to phase 3. I've probably had more negative trials in pancreatic cancer than I can count. But we follow the data. We looked at what the science was, tried our best to design a trial. And then, if it affords benefit, it affords benefit. If it does not, then, we move on and see how we can use other targets or other pathways to further outcomes, further survival for our patients. So, we just need to be agnostic in the results and just follow the data and report it out. You're exactly right.

Dr. Manish Shah: It's so, so critical. Well, as we kind of come to a close, what other things excite you about pancreatic cancer? What's on the horizon? What should we be looking out for? And when will we see you on the podium next?

Dr. Shubham Pant: It's just good to be part of the journey. Honestly, my clinical team, they were like, "Dr. Pant, it's amazing.” I have now more patients living longer in my practice, which was not the case, and it's just an amazing time to just see these patients who would have a survival of a few months.

I had a patient on RASolute 302 who was on the daraxonrasib. He's still on the daraxonrasib, crossed a year, about 14 months out. So, just truly amazing to see that for our patients.

But the future is truly bright in pancreatic cancer. So, I could drone on for an hour on this, Manish. But I'll just take like two more minutes of your time.

So, we have four phase 3 trials which are underway or will be underway this year. One is called the RASolute 305, which is chemotherapy with or without a D agent called zoldonrasib. We have another trial called DAWN-303, which is chemotherapy again with a drug called INCB734, which is a KRAS on and off inhibitor. So, it binds to KRAS in the on state, the light switch, and binds to it in the off state. So, very interesting drug. And we have a trial coming up called RASolute 309, which is a novel, novel. So it combines daraxonrasib, the pill that we are talking about, RAS inhibitor, with the KRAS G12D inhibitor zoldonrasib. So, I think that's a beginning of a beautiful relationship. And then, the fourth one is PROTAC, which is protein degrader called setidegrasib with or without chemotherapy.

And the last one I'll say is 20% of pancreatic cancer patients have something called an MTAP loss. And if you have an MTAP loss, there is something called PRMT5 inhibitors, which exploit that redundancy in the cancer cell essentially. So, we have trials with PRMT5 inhibitors called vopimetostat and navlimetostat, making that as complicated as they can for us, in combination with chemotherapy and with targeted agents like daraxonrasib.

So, I could drone on and on, but really excited for the next few years, decades for developing these drugs for our patients with pancreatic cancer.

Dr. Manish Shah: The pace of drug discovery and drug development has really been quite amazing. So, it is a time of optimism.

Well, thank you so much for your time today. This was really a great conversation. You can download, subscribe, rate, and review CancerCast on Apple Podcasts,

Spotify, YouTube, or online at weillcornell.org. We also encourage you to write to us at cancercast@med.cornell.edu with questions, comments, and topics you'd like to hear us cover in the future. That's it for CancerCast: Conversations about New Developments in Medicine, Cancer Care, and Research. I'm Dr. Manish Shah. Thank you for listening.

disclaimer: All information contained in this podcast is intended for informational and educational purposes. The information is not intended nor suited to be a replacement or substitute for professional medical treatment or for professional medical advice relative to a specific medical question or condition. We urge you to always seek the advice of your physician or medical professional with respect to your medical condition or questions. Weill Cornell Medicine makes no warranty, guarantee, or representation as to the accuracy or sufficiency of the information featured in this podcast, and any reliance on such information is done at your own risk.

Participants may have consulting, equity, board membership, or other relationships with pharmaceutical, biotech, or device companies unrelated to their role in this podcast. No payments have been made by any company to endorse any treatments, devices, or procedures. And Weill Cornell Medicine does not endorse, approve, or recommend any product, service, or entity mentioned in this podcast.

Opinions expressed in this podcast are those of the speaker, and do not represent the perspectives of Weill Cornell Medicine as an institution.