How Did Daraxonrasib Double Survival in Pretreated Metastatic Pancreatic Cancer?

The treatment landscape for pancreatic cancer has long been characterized by limited therapeutic options and a survival rate that has proven difficult to improve. However, data from the phase 3 RASolute 302 trial (NCT06284538), evaluating daraxonrasib in patients with previously treated metastatic pancreatic ductal adenocarcinoma (PDAC), have demonstrated a significant survival benefit for this population.¹ By targeting KRAS, investigators are opening a new frontier in precision oncology for a disease once considered “undruggable.”

In an interview with CancerNetwork®, Diane Simeone, MD, director of the Moores Cancer Center at UC San Diego Health, detailed the clinical significance of these findings, which showed a doubling of overall survival (OS) compared with standard-of-care chemotherapy. Beyond the survival metrics, Simeone discussed the unique chemistry of the agent, which utilizes cyclophilin A to target a previously inaccessible pocket of the KRAS protein. The discussion also addressed the practicalities of clinical implementation, including managing treatment-related toxicities such as rash and diarrhea, and the critical importance of universal germline testing and tumor sequencing.

As the oncology community looks toward the future, the focus is shifting toward moving these potent therapies into earlier stages of disease. Simeone emphasized that combining advanced therapeutics with robust early detection initiatives, such as the PRECEDE Consortium, represents the most viable path toward significantly increasing cure rates for patients with pancreatic cancer.

CancerNetwork: What were the OS findings from this trial, and why are they significant?

Simeone: Pancreas cancer has been a recalcitrant cancer to treat, and we have struggled to move the needle with novel therapeutics. In fact, we have not moved much beyond standard chemotherapy, in which we have 2 different combinations—FOLFIRINOX and gemcitabine plus nab-paclitaxel—that are the workhorses for patients. A couple of years ago, the [phase 3 POLO trial (NCT02184195)] showed that patients who have BRCA-mutant pancreas cancer can have outlier responses to platinum-containing regimens along with PARP inhibitors, but it has been a challenge to target KRAS in a meaningful way because it was previously thought to be an undruggable target.²

With smart chemistry and determination, there have been a number of new approaches to make novel KRAS-targeting drugs. With a new agent produced by Revolution Medicines, they have now shown the results of their phase 3 RASolute 302 clinical trial. Used in the second-line setting, patients who had already been treated with standard chemotherapy were given an oral pan-RAS therapeutic once a day and compared with standard-of-care chemotherapy. The results were significant; the therapy approximately doubled the OS rate in the second-line setting, reaching 13.2 months vs 6.7 months. This is a substantial benefit for patients with metastatic pancreas cancer, who represent about half of the patients we see. These findings are impactful for improving both the length and quality of life for patients.

When was the last time you remember seeing a result that represented such a significant leap in pancreatic cancer?

These are compelling results. Occasionally, we see similar results in patients with BRCA mutations who respond to platinum-containing agents and PARP inhibitors, but those are smaller subsets with outlier responses. This pan-RAS inhibitor can apply more broadly, as about 93% of patients with pancreatic cancer have an oncogenic KRAS mutation. While other agents in clinical trials target specific KRAS mutations, this is a pan-RAS inhibitor, which opens a new frontier. It is not curative, but we are seeing an explosion of new ways to target KRAS. This approach, and various combinations, will be used to further improve OS for patients.

What about this agent allows it to target KRAS?

It resulted from a nifty understanding of the 3-dimensional structure of KRAS. A natural product-based small molecule was used to remodel the surface of cyclophilin A. Research published in Science in 2003 outlined the chemistry around this, which utilized a very shallow pocket to develop a targetable approach. There are many interesting new chemistries and technologies rolling out, including novel degraders and glues. There’s a lot of interest in targeting KRAS, and of course pancreatic cancer has been the holy grail. But these developments are also important for subsets of patients with lung and colon cancer.

What toxicities emerge with daraxonrasib in this population?

Like many therapeutics, it is a balance of risk and benefit. We know the benefit; [it’s] the significant improvement in OS. These drugs are not without significant adverse effects [AEs}. There was a recent compelling interview in the New York Times with Ben Sasse, and I have to really applaud Ben for his bravery in speaking out because he showed visible evidence of the associated rash.³ As we advance this space with RAS therapeutics, we must enhance the performance of these agents while mitigating AEs so they are easier for patients to tolerate. That’s critically important.

I don’t think we’re ready to give RAS therapeutics in the drinking water yet. I’ve heard people say, “Well let’s just give it to everybody” and I think to espouse general use of these reagents is premature. We need to fully understand how they perform. You could see a leaning to try to push these into the earlier stages of cancer. Of course, that'll be important in both the neoadjuvant setting, where we have maybe about 15% or 20% of patients who are operative candidates, where we may want to shrink their tumors to make it more favorable to resect them. Or even in the adjuvant setting, where we resect a patient's tumor, and then if we want to make sure there are any cells lurking around that we can't see, to treat with RAS therapeutics.

What do conversations typically look like when an agent offers a significant leap in survival but potentially intense toxicity?

We are the trusted partner to the patient, so we must be open and honest, share the data, and help them make an informed decision. We work with other specialties to effectively treat, and as we continue to use these therapies, we learn to mitigate some of the AE profiles through nuanced dosing. I think [Ben Sasse’s] interview was telling because every month of life is important, especially if it is a high-quality month that gives people time to interact with their children, to see somebody graduate, to see someone get married. Time is the most precious thing we have.

What is the process of managing the supply and distribution of this therapy once it becomes available?

I'm not treating patients with cancer myself right now, but when we opened this trial at my previous institution before I came here to be the director at Morris Cancer Center 2 years ago, we were one of the first sites and patients, they’re lining up around the corner to have access to this. The good thing is that [Revolution Medicines] is not alone in making these drugs. There are now at least 15 or 20 companies that are bringing new RAS therapeutics into the clinical arena, and the quicker and sooner that we can get these agents available for patients, that's going to be important.

Just like any [disease], we have many therapeutics in the pancreatic cancer space, and we don't see cures with this treatment. We're also going to need to know what to do next with patients after they receive the benefit from this therapy: if their tumor starts to outsmart the therapy. What are the next combinations? What other kinds of therapies are out there besides this class of therapies? There are lots of novel therapeutics going after pancreatic cancer and other categories. Certainly, we're still trying to turn this cold, immune-resistant tumor to an immune-responsive tumor. There's a lot of work in that space. There are also precision oncology therapies that we talked about. There are certain portfolios mutations in pancreas cancer that may be uniquely responses to certain classes of drugs. As we work across the landscape, an important thing is to make sure all patients with pancreatic cancer get germline testing and tumor sequencing, because we don't really give patients the opportunity to have access to a clinical trial on might what might be a groundbreaking therapy for them. That's on us as a field.

We work very hard here at the Morris Cancer Center to make sure every patient has tumor sequencing, but if you look across the US, there's still lots of patients that don't get their tumor sequenced. They may not know what might be the best therapy that is within their grasp. That's important messaging for us to get out there, too. For all the doctors that are seeing patients with cancer, push to make sure you get germline testing and tumor sequencing on every single patient.

What are the logistical obstacles to increasing genetic testing for more patients?

Awareness of national standards is the first step. I refer to the NCCN guidelines…. I am a strong believer in germline testing for cancer risk, where we still are incomplete on identifying who is at elevated cancer risk across the US—and now germline testing is recommended for many patients with cancer. And then tumor sequencing. That’s just making sure that not only physicians, but patients should be their own advocates and ask their doctors about these options. We always recommend getting a second opinion at a comprehensive cancer center where a multidisciplinary team can guide them.

What do these findings mean for the future landscape of pancreatic ductal adenocarcinoma development?

This has been a holy grail type of thing, where people have been wanting to target KRAS but it’s been a challenge. This has been a breakthrough. I’ve been beating the drum that all drugs work better if we are treating smaller, earlier-stage tumors. While the effect is dramatic in patients with metastatic cancer—and unfortunately that’s still half of patients who walk in the door with pancreatic cancer—applying this therapy to stage I cancer could be even more profound and drive cures. Investment in early detection, partnered with these advances in therapeutics, is where we will see the most significant progress in increasing survival rates.

How do initiatives like the PRECEDE Consortium pair with these developments to push the field forward?

Investments need to happen in parallel. Only 6% to 8% of all cancer funding is dedicated to early detection and prevention. If we find stage I pancreas cancers and resect them, the cure rate is at least 83%. The PRECEDE study is the largest longitudinal study of individuals at high risk for pancreas cancer, with 12,000 individuals at 65 centers worldwide.⁴ This platform helps determine which early detection tools work best. If I can find a stage I cancer, it might be that it doesn't need any treatment, and that's the best option. But if we find a stage II cancer and we resect it, then we can do a follow-up, short treatment with a KRAS inhibitor. That could also become a highly curative situation, where we go from a 40% survival with stage II to a 90% survival rate. Those 2 things sprinting in parallel, that's what we need for this disease.

Is there anything else you would like to add about this development or the field in general?

I want to recognize the patients who put their trust in us. They are the unsung heroes who participate in these trials and manage extra visits. We also recognize the families of patients who have passed from pancreas cancer. This is a disease that requires significant resources and increased effort to address, and these findings are an important piece of the puzzle.

References

1. Daraxonrasib demonstrates unprecedented overall survival benefit in pivotal phase 3 RASolute 302 clinical trial in patients with metastatic pancreatic cancer. News release. Revolution Medicines Inc. April 13, 2026. Accessed April 20, 2026. https://tinyurl.com/44t5vh5d
2. Kindler HL, Hammel P, Reni M, et al. Overall survival results from the POLO Trial: a phase III study of active maintenance olaparib versus placebo for germline BRCA-mutated metastatic pancreatic cancer. J Clin Oncol. 2022;40(34):3929-3939. doi:10.1200/JCO.21.01604
3. Douthat R, Chamberlin V. How Ben Sasse is living now that he Is dying. New York Times. April 9, 2026. Accessed April 20, 2026. https://tinyurl.com/5n8f9w7s
4. Pancreatic Cancer Early Detection Consortium (PRECEDE). ClinicalTrials.gov. Updated January 28. 2026. Accessed April 20, 2026. https://tinyurl.com/mwtxk2nj