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Targeting the Future of Pancreatic Cancer Care: RAS, Biomarkers, and Emerging Therapies

[00:00:00] Hello, and welcome to the Decera Clinical Education Oncology Podcast. Today's episode features three expert GI medical oncologists: Dr. Paul Oberstein out of NYU Langone Health, Dr. Efrat Dotan out of Penn Medicine, and Dr. Andrew Ko from the University of California, San Francisco. In this episode, our faculty discuss the current treatment landscape for pancreatic cancer, including the growing role of comprehensive molecular testing, the emergence of tumor-treating fields for locally advanced disease, and the latest advances in KRAS-targeted therapy, with a special focus on daranarib and the practical implications of the new data presented at ASCO 2026.

This episode is part of a larger educational program titled "The Art of Therapeutic Balance: Innovations in Pancreatic Cancer Care Across the Disease Continuum." For more information about our faculty and to access the full educational program, please visit the [00:01:00] show notes for this episode. With that, I will hand this over to Doctors Oberstein, Dotan, and Ko.

Thank you all for joining us today for this important discussion. Hello everyone. Welcome to this podcast where I'm joined by two really great colleagues for an encore presentation of discussion about pancreatic cancer.

My name is Paul Oberstein. I'm an associate professor of medicine and a GI medical oncologist at NYU Langone in New York, and I'm joined today by two colleagues to talk about some of the really exciting and innovative findings that have come out after ASCO in 2026.

Hi, everyone. My name's Andrew Ko. I'm a professor of, uh, medicine at the University of California, San Francisco, also a GI medical oncologist. Happy to be here. And I'm Ephrat Dotan. I'm a professor of medicine at University of Pennsylvania and also a GI medical [00:02:00] oncologist, and I'm excited to talk about pancreas cancer for the next 30 minutes.

Great. So before we dig into some of the really exciting new data, I think it's really important to start off, talk a little bit about where we currently are. Uh, you know, pancreatic cancer is, is one of the most common causes of death from cancer in the United States, and the current standard of care for metastatic patients really involves multi-agent chemotherapy, which can prolong survival and help patients but is, of course, limited in its scope.

I think, you know, as of today, I'm curious from the two of you, any- anything that you would say from a standard of care that we need to remind people of before we launch into s- some of the new things? Yeah, I'll, I'll start by saying that I, I agree, chemotherapy does remain the, the mainstay of treatment and, and we're quite familiar with, with using either a FOLFIRINOX or its sort of adjacent regimen, Nálarifox versus gemcitabine [00:03:00] nab-paclitaxel.

And there's been long discussions about how to select. Right now it's primarily on a clinical basis, although there might be some molecular features that might steer us one way or another. I think we're all excited about the possibility that chemo may ultimately be supplanted or certainly complemented by some of the novel targeted therapies that, uh, that came out of, uh, ASCO and that soon will shape our practice Yeah, I would also wanna add that I think we have all gained a lot of experience, um, with, you know, how to use these, uh, regimens, how to support patients, understanding how to, uh, manage toxicities adjust therapies based on, you know, risk of and, and potential side effects.

So, you know, despite all the excitement, I think we've come a long way with using chemotherapies and knowing how to maximize the benefit of them, and I don't think that we are [00:04:00] gonna give up on them completely yet. Yeah, I agree. I mean, I think one of the things, the disappointing thing about chemotherapy is that for most people it provides benefit for a short period of time, and usually measured in months.

But I, I do think for those months, for most people, we often get significant benefit, right? So patients get pain control often with chemo, often even functional status improves for a brief period of time. And so, you know, certainly for some people who need symptomatic relief, chemo has a huge role. It's just that it doesn't really last that long for most people.

You know, one of the big things that we're gonna talk about is how do we get things that, that are more persistent.

And Farah, I guess while we're talking about symptom control as well, you know, I think you have some insight into another novel therapy that, that might help with symptom control in locally advanced pancreas cancer. Can you tell us a little bit about that? Yeah. W- I think it's important to remember, we keep talking about metastatic disease, which is the bulk of our patients, but, uh, locally advanced disease are pretty not rare.

I mean, we see [00:05:00] them more and more. These are difficult tumors to manage, um, difficult to keep patients on chemotherapy for a long time. These patients suffer from significant pain and discomfort. And we do have a new device that has been approved by the FDA, which is called, uh, tumor.

 treating field and, um, was, uh, uh, shown to be beneficial by the PANOVA3 trial.

And the trial randomized patient to receive this tumor.

 treating field radiation device along with chemotherapy, and was able to show significant improvement in, pain-free survival, and since this

s- causes significant burden for patient, I think we should consider these treatment for the appropriate candidates. Great. Thanks for sharing. I think before we get into, you know, our discussion about KRAS and what we call the KRAS revolution, you know, so KRAS is, of course, a gene alteration or mutation.

And I'm curious of everyone's [00:06:00] practice. You know, in, in my clinic we refer every new pancreas cancer patient for both germline testing and tumor somatic testing. You know, often we don't have enough tissue to really do robust testing, and we send blood. I'm curious to hear your practices and, and what you think is really important to be done for metastatic patients.

Yeah. So I'm definitely doing the same, Paul, in terms of germline testing regardless of family history and now somatic testing, ideally on tumor biopsy specimen in our, our... both our interventional radiologists and, and gastroenterologists who are doing the endoscopic ultrasound guided tissue sampling, uh, understand now that getting a, a core biopsy as opposed to just an FNA is important in terms of adequate yield for doing next-generation sequencing.

And the good things I'm seeing out in the community, I think there's increasing awareness that, that this should be done. Now, in the past, I would s- you know, tell patients, "Well, it's always great to get this information," but that information is not always going to [00:07:00] be actionable, uh, in terms of finding therapeutic relevant, therapeutically relevant targets.

Uh, and, and the nice thing as we, uh, move into the, the RAS era is that uh, identifying not just the presence of a RAS mutation but the specific, uh, genotype, uh, is going to be very, uh, informative in terms of guiding our clinical practice. And so in the past, it was like, "Well, that should be done maybe down the road at some point after patient's already gone through chemotherapy and are looking for other options."

But now I, I just really wanna impress that it... this should be done at the time of original diagnosis. Get those results, uh, really early on, uh, to help, uh, shape your treatment plan for patients. Yeah, I would, I would take that even further. I wouldn't wait till patients are metastatic.

Patients were resected or, have enough tissue at diagnosis, I, I would get it upfront. We are gonna have more and more opportunities to use these targeted agent in the adjuvant setting or, um, [00:08:00] neoadjuvant setting, so, the earlier, the better. I also, you know, I'm really impressed. I remember when I started to send up blood, um, years ago and there were all these papers that there is not enough shedding of the pancreatic tumor into the blood, and we would never be able to detect cells.

Um, these assays that are available now are so sensitive, uh, that even if the tissue is not sufficient, which is a problem we run into often I quite often am able to get some data from peripheral blood, um, at least in terms if the patient has a KRAS mutation, and often they can tell which one. So yes, you really need to work hard to get the NGS testing.

And I would add one more thing. I think we'll talk about it a little bit towards the end of the podcast, but if you get NGS testing and you do not find a RAS mutation in pancreas cancer, that should be a big red flag in your mind to go and [00:09:00] dig deeper because there has to be something else driving this tumor.

And is it that we're not seeing the RAS mutation because there was not enough in that sample, you took blood and they weren't able to isolate enough cancer cells, or is it because the patient really has some other mechanism that drives the cancer? So don't stop there. Don't stop. I, I think that's really important.

I agree. And yeah, we do the same thing. I mean, I think when we don't see a RAS mutation, we always ask, "Did you see a different driver?" Right? If you see another driver, that explains it, NTRK or BRAF but, you know, sometimes we just, it's just not a sensitive enough test, right?

But I guess, you know, it's a great segue into our next, you know, segment, which is really, I'll call it the elephant in the room, but the RAS in the room. You know, ni- 90 to 95% of patients will have KRAS mutations in pancreas cancer. This is not news. We've known this for quite some time and been trying to target it, and we're about to hear some really, a summary of some great data.

I, I guess before [00:10:00] we get there, like philosophically or, or big picture, you know, why do we think we suddenly are more successful and have the first real, pan-RAS inhibitor? , In terms of understanding the the structure of the molecule, identifying a hidden pocket, the so-called switch II pocket that formed the basis for the original inhibitor, specifically for KRAS G12C mutations, uh, which definitely have a role in, in, especially in non-small cell lung cancer, but just isn't seen that commonly in, in, in pancreas cancer.

Um, but we sort of moved away from this idea of, oh, well, this is something that can't be targeted. In the past, because of, well, the thought that this has a very smooth surface, right? It doesn't have, uh, a lot of deep binding pockets, and it's kind of toggling between an on and off state. A-and just even at that nucleotide, uh, binding site it-- there's just such a, a tight affinity for GTP that, um, that it, it-- you c-- it was hard to develop competitive small molecule inhibitors for.

So with the development of deraxone rasib, this pan-RAS, uh, inhibitor [00:11:00] which inhibits RAS in its on state, which is mostly where RAS, uh, resides, toggling between on and off. Deraxone binds to this chaperone, a protein called cyclophilin A, which then forms this, this tri-complex inhibitor with RAS thereby preventing binding to downstream effectors like RAF.

And so ef-- essentially shuts off uh, RAS signaling, which is, uh, really responsible for, uh, the great clinical results, so aside from the, the terrific clinical results, I think the excitement is just because this has been sort of the holy grail in pancreas biology and developing novel drugs targeting this specific, um, uh, pathway, and I'm just really excited that we're, uh, finally there.

Yeah. I guess one maybe, Afraid, you can comment on this. I, I also think it's amazing how, you know, what you just described, Andrew, that it's a new mechanism, right? They found a new way essentially to have this, molecule be targeted. But it's also true that, you know, the direct RAS inhibitors and the off inhibitors are making [00:12:00] progress as well, right?

And we saw even at ASCO other drugs. So all of a sudden it seems like we're finding potentially multiple ways to, to drug what's been undruggable, and it's sort of like the floodgates have opened. And, uh, I don't actually know if, if it's a switch or we're just trying more and more things. Um, but our hope is that we'll see many more inhibitors, not, you know, not just one pathway, but many ways to block RAS. It feels like the floodgates have opened for many, many targets, and there are multiple targets that I, I don't think any of us have thought about as options for pancreas cancer that are now becoming options, including Claudin and, uh, MTAP.

I, I think we really are in the, in an era of better understanding of the biology, better understanding of the mutations that are driving these tumors and, um, going into a, a highly personalized treatment approach for these patients

Andrew, maybe you could summarize for us or share your [00:13:00] impressions of the deroxatramatub data from the Rasloot three O two. We know there was a standing ovation. I was in the room, which was exciting. Yeah. Yeah, I mean, I think a lot of us got...

who have been devoting large portion of our careers on research and caring for patients actually got kind of emotional seeing those Kaplan-Meier survival curves pop up on the screen. , the Phase 1, uh, data that already looked really promising, I was thinking, "Oh, well, if the Phase 3 trial can even anywhere near replicate those kinds of results, you know, it's gonna be, um, a home run."

I was almost gonna be disappointed if, well, it's, you know, the Phase 3 study was positive, but maybe the results weren't quite as transformative as, as sort of the early data would suggest. Uh, but, you know, this study, which was a big Phase 3 study, and again, specifically in the second-line setting. So this was for patients with metastatic disease, had previously received one line of chemotherapy and were now randomized either to get sort of standard second-line chemotherapy, depending on whether they started with a GEM or [00:14:00] fluoropyrimidine-based regimen.

So they were randomized to either get standard of care chemotherapy in that second-line setting or duraxonrasib three hundred milligrams daily. So the primary endpoint specifically focused on the majority of patients who had, uh, mutations in codon twelve. And, but then they also showed the data for all comers, including those with mutations at, uh, o-other spots in the RAS gene, and some even who, uh, who did not have a RAS mutation.

So if you look at the overall survival results for the, uh, the primary endpoint, overall survival for that G12, uh, population, you saw a hazard ratio for survival of zero point four zero. We've, we rarely see anything like that in, in pancreas cancer studies. Uh, this was just a, a really terrific magnitude of benefit with duraxonrasib compared to chemotherapy.

And I'll say chemotherapy matched what we see historically, a median survival of about six and a half months or so. That's, that's what all prior studies had, had shown. Whereas folks getting [00:15:00] duraxonrasib had a median survival of upwards of thirteen months. So it's thirteen point two versus six point six months.

And then even the secondary endpoint, looking at the overall population, kind of irrespective of what type of RAS mutation, also basically matched that with hazard ratio of point four zero. And then there were improvements in all, all the other relevant clinical, um, endpoints that we typically look at for these types of studies.

Progression-free survival was better. Uh, objective response rate was better. This is clearly something that once it gets, uh, a-approved and, well, as all of us know who are trying to get this, uh, early access program available for our, our patients, this is going to completely change the way we treat patients.

Starting in the second-line setting, but I can only imagine the, that we're gonna be looking at it, we're going to be using this, uh, in earlier line settings and in earlier stage disease probably sooner rather than later.

I have to echo what Andrew was saying, that listening to that presentation in the room and [00:16:00] experiencing that standing ovation was probably the most emotional event in my whole career, and I'm sure you guys agree. It was just... You know, I, I saw images of the many, many, many pancreatic cancer patients that I've had over my career who could have benefited from this, and I, I think this is just such a advancement to the field and just the beginning.

As Andrew said, this is, um, you know, really opening up such hope for our patients, so it's just amazing. I agree. That room was incredible. And I think not... I mean, uh, like you said, for patients, but I think I f- I was thinking of all the people who've done trials, who've gone...

who plugged at it and designed these. You know, it's, it's just an incredible achievement. To, to me, I mean, Andrew, you mentioned the hazard ratio. I think what was so incredible was that it wasn't so selective, right? Meaning, we've seen some very s- narrow trials where you take [00:17:00] a subset of patients and you target them, and you're like, "We can get very good efficacy in those patients."

But here it was, it was in essentially all patients, right? And those hazard ratios and that benefit was seen both in the primary cohort of G12-mutated patients, but also all comers. And it was just amazing that this is something that might be relevant for everybody. Curious, I think, you know, what, what, what have you thought since then, right?

It's been three weeks since we saw that presentation. A lot of questions have come up. Everyone's trying to ask what happens next. And I think one of the biggest questions is, you know, what's next in terms of therapy, in terms of who becomes resistant to, to roxainrasib, right?

And can we identify them, and what do we do next? I think, any thoughts on, on that? Yeah. I mean, before we go there, which is a great question, Paul, you know, the-- I think this is going to beg the question since it seems to be effective almost irrespective of RAS mutation as well. Do you actually need to do testing?

Do you need to ascertain the RAS mutational status before actually giving diraxin rasib if it really is [00:18:00] effective even in potentially in RAS wild type or in, in non-G twelve patients? It-- I feel pretty strongly, and I think you guys would agree, that actually doing the testing, and Efrah, you'll probably do a little bit deeper dive into talking, or you already mentioned some of the, the other targets there.

I I still think it's gonna be really important for us to do that next-gen sequencing on patients. I-in part because, as folks have alluded to, there are some allele-specific, um, KRAS inhibitors coming down the pike, including, and particularly for G twelve D, which is the most common, uh, mutation seen in, in pancreas cancer.

And it may have some advantages, uh, especially in terms of toxicity compared to the pan-RAS inhibitors. So I do think that doing that testing is important and probably doing testing at the point when patients do develop resistance, you know, which hopefully is pushed way down the road.

But just because there-- it looks like there are [00:19:00] many different mechanisms that may explain the eventual development of resistance to RAS mutations. Some of them are genetic, and some of them may even be completely non-genetic and, and just sort of histologic transformation possibly. Or, uh, sometimes there might be just upregulation of, of MAP kinase signaling or even possibly HER2, um, overexpression or, or any number of potential resistance mechanisms.

So I think the NGS testing up front and then ideally at the point of developing resistance, because that may then inform later lines of treatment in terms of targeted therapies. Yeah I think the question is gonna become even more complicated because we're going to have all these newer inhibitors coming through.

A G12D specific inhibitor for example. Would you use that first and then use a pan-RAS? Would you use that after? How would we sequence these [00:20:00] therapies? Would you combine them? What about other targets? I mean, I think we're gonna be in a situation where we're just gonna really have to understand resistant mechanism and, and what actually happens in the protein level to guide how we're you know, sequencing the treatments per se.

So- Yeah. Or even a fra- like you mentioned, MTAP, uh, loss- Yeah ... which is not uncommon. You know, you see that in maybe 20, 30% of- Pancreas ... pancreas cancer. So there are studies that are looking at combining RAS inhibitors with PRMT5, uh, inhibitors. So whether it makes sense to combine them up front, whether it makes sense to do them in sequence.

Um, so there's a lot of, lot of interesting directions to be able to, to go in, in terms of sequencing and combination strategies. And chemo, right? So we don't know- And yeah, chemo too. So there are ongoing studies with chemo, obviously. Sequencing questions earlier, as you said, there's this adjuvant study, right, of [00:21:00] maintenance deroxatramucib after chemo.

So really I'd say a ton of studies, but also really a lot of these questions that might help us understand resistance. One last question on, on deroxatramucib. You know, our, our hope, of course, is that this will rapidly be approved.

We don't exactly know what the approval will say. But everyone's eager to get this drug, everyone with pancreas cancer and hopefully will soon. There were toxicities seen with the, with the drug. It's definitely a new drug. It's something that we haven't quite targeted before for most patients, and rash was the big and very noticeable toxicity, though there were other ones.

Uh, I guess question is, what do we think or any thoughts on what's gonna happen when this starts getting adopted very broadly in community centers and places where they don't have prior experience, and how we can manage some of that side effects? Yeah, I think the training is gonna be important because, you know, there's perhaps some overlap with, for example, EGFR-associated rash, but it's not quite identical.

So that... stomatitis, diarrhea, those are the three sort [00:22:00] of most common side effects.

And in, in cases where it's refractory, it is very important to be friends with your, uh, local dermatologist because there's some additional tricks that are sort of beyond the scope or knowledge of us non-dermatologists. Um, so I, I do think, thankfully, for the most part, the rash is manageable, and because of the short half-life of the drug if you hold the drug for just, say, up to a week, those types of side effects generally subside to the point where you can restart drug, whether at the same dose or perhaps at a, a slightly lower dose.

But, you know, there are parts of the country, parts of the world where you don't have good access to a dermatologist. And so I think really it's the education piece and sort of what to expect, um, so people aren't thrown a curveball and, and sort of shy away from using duraxan rasib at the first sign of sort of a grade three rash.

Yeah, I think patients with pancreas cancer are willing to endure a lot of things. But [00:23:00] it is our job to make sure that we, uh, proactively manage that symptoms and keep them on the drug, curious if either of you have thought of other things besides KRAS, besides the one.

You know, I- you mentioned, Andrew, and, and Efrat as well, MTAP deletion, which I, I do think is a big target. I mean, it's almost a third, 20, 30% of patients, and there are really cool drugs coming out for that. So I'm excited to see where that goes, both in combination and alone. Anything else that stuck out or jumped out from the conference?

Well, I, I think, um, as I said earlier, RAS wild type, we have to look for a target. So, um, and there were studies showing that in these RAS wild type, albeit very small percentage of patient, you can find, um, NTRK fusions, you can find BRAF mutations, you can find NRG1 fusions, RET fusions, and all of these targets have specific treatments that are all FDA-approved and could really benefit the patient.

And then the other target is, [00:24:00] uh, claudin, which is becoming more and more studied in various ways, whether it's through antibody, like zolbetuximab. Uh, there are studies involving CAR T targets targeting claudin, uh, bispecific antibodies, ADCs.

And, uh, MTAP, you mentioned, in about 20 to 30% of patients, um, using the PRMT5 inhibitors, and there are multiple ongoing trials comparing chemo alone to chemotherapy plus these, these, uh, inhibitors, with some preliminary data showing very good response rates. So, I think, you know, what, what our audience should take away is that there are gonna be a lot of new advances in pancreas cancer, but let's encourage patients to go on studies to participate in these trials, especially if you find a very unique target, um, and help us get the data faster so we can get these drugs out to patients faster.

Yeah. [00:25:00] I've, I've had my first couple patients Efrat, with, uh, NRG1 fusions, which are very rare. But since we have now- Yeah ... zenocutuzumab, uh- Exactly ... and by specifically, uh, targeting, uh, this, th- you know, it's actually a well-tolerated and quite effective drug for that very small subgroup of patients. And just to your point, for those KRAS wild type tumors, some of these, uh, alterations are really better picked up by RNA sequencing than DNA.

So- Mm-hmm ... thankfully a lot of the commercial platforms, um, give you that option. So, so be sure to, to do RNA sequencing for patients if you're not picking up a KRAS mutation. Great. I, I just wanna mention, you know, we keep saying there's new information coming, obviously a new therapy and toxicity and managing the rash.

Um, I wanna give a shout-out to PanCAN who have this, you know, Pancreatic Cancer Action Network, have a great patient services, uh, phone number they have. It's a website. They've got all kinds of resources, and certainly there are many others like that are there to help our patients navigate this new [00:26:00] landscape.

I think just to close it up with one question I'm not sure which what question, but I, I guess, I guess, w-what are you... Either, either of you, both of you, I guess, what do you think is gonna look different in your practice in 12 months because of this data that's coming out? Okay, I've thought about this.

And so for sure, let's say duraxanrasib gets its approval, well, hopefully as soon as possible, . I'm going to initially use it sort of as it's specifically approved, meaning after folks have received chemotherapy. Now, I think there's gonna be a lot of end-arounds and, and people are gonna have...

come up with excuses to stop patients, uh, short on chemotherapy just so that they can switch over to duraxanrasib. And I, I understand that. I guess maybe I'm a bit of a purist and, and would want folks to sort of max out on their benefit or tolerability of chemotherapy before shifting gears to, um, durax- to duraxanrasib.

There are first-line studies that will accrue very rapidly and will give us that answer in terms of for front-line treatment. [00:27:00] Can duraxanrasib as a monotherapy, is it going to be as good or better than chemo? Is combining chemo with duraxanrasib gonna be, uh, the way to go? And again, there are other chemo plus other RAS inhibitor studies going.

So I'm, I'm not quite ready to say we're gonna give this to upfront patients. I don't think that's what we should be doing until we have a little more data in that uh, front-line setting to inform that decision. But there's no question that ideally every patient at some point during their disease journey will be able to receive a RAS inhibitor.

I think that would be probably the, the wholesale change that I, I anticipate adopting.

I agree with Andrew 100%. I think that the main thing is gonna, that's gonna change is that my clinic or my patient panel is gonna grow even more. Because I think our patients are gonna live longer, enjoy life, not getting chemo. That... [00:28:00] It's, it's a dream.

So I guess, uh- Amen ... I don't know, maybe I should recruit another GI oncologist. Yeah. I, I think that's the message. I mean, it's a good message. We're gonna get busier. Exactly. We need more oncologists, yes. But our management of these patients is gonna be different than the...

'cause there are different side effects than chemotherapy. So- Mm-hmm ... and it might be less frequent visits, but, learning how to manage rash and these other things I'd say a good problem- Collaborating with dermatology and yeah. Yeah. It's great problems to have.

Thank you, Doctors Oberstein, Dotan, and Ko. And many thanks to you, our listeners, for joining us. As a reminder, to view the full program, "The Art of Therapeutic Balance: Innovations in Pancreatic Cancer Across the Disease Continuum," please click the link in the show notes, and be sure to check back regularly for more episodes on important oncology topics.