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Precision Oncology in Pancreatic Cancer
Entering a New Era: Evolving Precision Oncology in Pancreatic Cancer

Released: July 29, 2026

Efrat Dotan
Efrat Dotan, MD, MTR
Andrew H. Ko
Andrew H. Ko, MD, FASCO
Paul E. Oberstein
Paul E. Oberstein, MD, MS
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Key Takeaways
  • Daraxonrasib is a multiselective RAS inhibitor for the treatment of metastatic PDAC that showed ground-breaking results in the RASolute-302 clinical trial that doubled both median PFS and OS compared with current standard of care second-line chemotherapy in the RASolute-302 clinical trial.
  • Comprehensive tumor molecular testing and germline testing will become key, as actionable alterations such as BRCA1/2, PALB2, MSI-high, and other emerging biomarkers continue to expand precision treatment options for patients with PDAC.
  • Innovations beyond targeted therapy such as tumor treating fields and strategies to proactively manage RAS inhibitor toxicities are helping improve both survival and quality of life in patients with pancreatic cancer.

In this commentary, experts review and discuss key questions related to evolving care strategies, management challenges, and new clinical trial results in pancreatic cancer with a focus on RAS inhibition and other targeted therapies. The discussion examines applying state-of-the-art targeted treatment advances and practical implications of integrating these approaches into real-world practice.

How does emerging data on KRAS inhibitors like daraxonrasib influence treatment sequencing in metastatic pancreatic ductal adenocarcinoma (PDAC)? 

Andrew Ko, MD, FASCO
For years, KRAS was considered 'undruggable,' making it one of the biggest challenges in drug development. That has changed dramatically over the past decade, and daraxonrasib represents one of the most exciting therapeutic advances we've ever seen in pancreatic cancer.

Unlike earlier allele-specific KRAS inhibitors (eg, KRAS G12C–specific drugs such as adagrasib and sotorasib), daraxonrasib is a multiselective RAS inhibitor that works by forming a tricomplex with the chaperone protein Cyclophilin A and activated RAS. This prevents RAS from interacting with downstream signaling molecules like RAF, effectively shutting down RAS signaling. Given that approximately 90% of pancreatic cancers harbor a KRAS mutation, this approach has the potential to benefit a large proportion of our patients.

The phase III RASolute-302 trial, which was a plenary presentation at the ASCO 2026 Annual Meeting and simultaneously published in the New England Journal of Medicine, evaluated daraxonrasib in the second-line setting after prior chemotherapy, comparing it with investigator's choice of standard chemotherapy. The primary endpoints were overall survival (OS) and progression-free survival (PFS) in patients with RAS G12X mutations, who comprised 91.8% of the study population. In this group, median OS was 13.2 months with daraxonrasib vs 6.6 months with chemotherapy (HR: 0.40), and median PFS was 7.3 months vs 3.5 months, respectively (HR: 0.45). Secondary analyses in the overall study population also met both endpoints, with a median OS of 13.2 months vs 6.7 months (HR: 0.40) and a median PFS of 7.2 months vs 3.6 months (HR: 0.49) for daraxonrasib and chemotherapy, respectively. These are extraordinary results that will undoubtedly transform clinical practice.

Because of that excitement, an Expanded Access Program is already available while the drug moves through the FDA review process. It requires some additional paperwork, but I would encourage healthcare professionals who treat pancreatic cancer to explore this option for eligible patients.

The success of RASolute-302 is also reshaping how we're thinking about treatment sequencing. Although the initial approval is expected in the second-line setting, preliminary data from the phase I/II RMC-6236-001 study suggest daraxonrasib may be even more active earlier in the disease course. Among previously untreated patients with metastatic PDAC, the objective response rate was 47%, exceeding what we typically see with frontline chemotherapy. Although those results aren't yet sufficient to replace standard first-line chemotherapy, they certainly justify evaluating the drug in earlier-line settings.

Several phase III trials are already underway. RASolute-303 (NCT07491445) is evaluating daraxonrasib for patients with newly diagnosed metastatic disease, both in combination with gemcitabine/nab-paclitaxel and as monotherapy, and RASolute-304 (NCT07252232) is studying adjuvant daraxonrasib in patients with resected pancreatic cancer following surgery and perioperative chemotherapy.

Although we are not yet at the point where we can replace chemotherapy with an oral targeted therapy, that's clearly the direction the field is moving. If these ongoing studies are positive, daraxonrasib has the potential to transform treatment across multiple stages of pancreatic cancer, not just in the second-line setting.

What type of adverse event management can be expected with daraxonrasib?

Paul E. Oberstein, MD
One of the most common questions has been what rash management will look like once daraxonrasib is widely used in the community. In the early phase trials of daraxonrasib, rash occurred in more than 90% of patients, but no patients discontinued treatment because of this toxicity. Instead, supportive dermatologic care, dose interruptions, and dose modifications allowed patients to remain on therapy.

Those same management strategies were successfully built into the phase III RASolute-302 trial, giving us greater confidence that rash can be managed effectively in routine practice. Any-grade rash was reported in 85% (grade ≥3, 13.7%) of patients receiving daraxonrasib; however, only 36% of patients required a dose reduction and only 1.2% discontinued treatment, both lower rates compared to the modifications required for toxicity in the control chemotherapy arm.

For patients with more severe skin toxicity after treatment with daraxonrasib, close collaboration with dermatologists will be essential. Some cases may require specialized therapies that are typically managed by dermatology. The goal is to recognize these adverse events early, intervene promptly, and keep patients on what appears to be a highly effective treatment whenever possible.

Other common adverse events include oral sensitivity and mouth sores, which can often be prevented or managed with dexamethasone mouth rinse, as well as gastrointestinal side effects such as diarrhea. Of importance, daraxonrasib does not cause many of the toxicities we associate with traditional chemotherapy, including neuropathy, alopecia, or significant immunosuppression.

What other RAS-targeting therapies are you watching, and are there any data for a role in managing resistance in this setting?

Andrew Ko, MD, FASCO
Absolutely. Daraxonrasib may be the first major breakthrough, but the sky is the limit when it comes to the rapidly expanding RAS-targeting landscape.

Overall, the pipeline is remarkably robust, with agents targeting RAS through multiple mechanisms and different activation states. There is no doubt that we are entering a transformative period in pancreatic cancer treatment. For the time being, these therapies will be used primarily for chemotherapy-refractory disease, but I can easily envision them moving earlier in patients’ treatment journeys. In the future, I anticipate RAS inhibitors being used in the frontline, adjuvant, neoadjuvant, and/or maintenance settings, as well as in combination with chemotherapy, other targeted therapies, or immunotherapy where there may be the potential for synergistic activity.

In addition to pan-RAS and pan-KRAS inhibitors, allele-specific RAS inhibitors, such as those targeting G12D and G12V, are being developed and studied in clinical trials. Although these drugs apply to smaller subsets of patients with pancreatic cancer, they may offer a more favorable safety profile. Early data with G12D-specific inhibitors, including zoldonrasib and INC161734, have shown encouraging response rates with potentially less toxicity than broader RAS inhibitors.

Several other approaches in development include KRAS degraders, or PROTACs, which harness the cell's own protein degradation machinery to eliminate mutant RAS, as well as RAS-targeted vaccines, which are primarily being evaluated in the adjuvant setting to reduce the risk of recurrence after surgery.

Resistance will be another critical area to watch as these therapies become more widely used. Although the results with daraxonrasib and other RAS inhibitors are very encouraging, most patients will eventually develop resistance. We've already started to learn about several resistance mechanisms from both the daraxonrasib experience and earlier studies of KRAS G12C inhibitors in pancreatic and lung cancer. Some are nongenetic, such as epithelial-to-mesenchymal transition or even histologic transformation. Others involve new genetic alterations, including KRAS amplification, secondary RAS mutations, changes in upstream and downstream signaling pathways like the MAPK pathway, and even HER2 amplification. As we learn more, technologies like circulating tumor DNA and postprogression biopsies will be increasingly important for identifying these resistance mechanisms and helping guide subsequent treatment strategies. This is still an emerging area of research, but understanding why resistance develops will be essential to optimizing the next generation of RAS-targeted therapies and combinatorial approaches.

Other than RAS therapy, what biomarkers and targeted therapies are important for pancreatic cancer care?

Efrat Dotan, MD, MTR
RAS inhibitors are generating the most excitement in pancreatic cancer right now, but they're far from the only targeted therapies advancing the field. We're seeing a rapidly expanding list of actionable biomarkers, and it's becoming increasingly important to perform comprehensive tumor molecular testing and germline for every patient whenever possible.

Germline BRCA mutations occur in approximately 5% of patients with pancreatic cancer, which is why current guidelines recommend germline testing for all patients. The phase III POLO trial established maintenance olaparib as a standard option for patients with germline BRCA-mutated metastatic pancreatic cancer whose disease remains stable after platinum-based chemotherapy. By transitioning to a PARP inhibitor, we can often maintain disease control while allowing patients a break from chemotherapy.

The field continues to evolve beyond POLO. The ongoing APOLLO (EA2192 NCT04858334) trial is investigating adjuvant olaparib after surgery and chemotherapy for patients with germline BRCA1/2 or PALB2 mutations.

Immunotherapy also has an important but limited role in selected patients. Microsatellite instability–high pancreatic cancer is very rare, occurring in approximately 1% of patients. These tumors can respond remarkably well to immune checkpoint inhibitors, but should only be considered when this biomarker is identified.

Beyond these established approaches, the pipeline is growing rapidly. Performing comprehensive molecular testing on tumors will allow for identification of the rarer patients with pancreatic cancer whose tumors do not carry a KRAS mutation. These tumors will likely present with other targetable alterations such as NTRK fusions, RET fusions, and NRG fusions, opening treatment options. Investigators are also exploring therapies targeting p53, Claudin 18.2, and the MTAP pathway, as well as cancer vaccines, gene-based therapies, and novel immunotherapy strategies. Many of these remain investigational, but they highlight just how quickly precision medicine is expanding in pancreatic cancer.

The key takeaway is that molecular testing has never been more important. Whether through tissue-based sequencing or circulating tumor DNA, identifying actionable alterations is becoming increasingly critical as more targeted therapies move into clinical practice. We are entering an era where treatment decisions are being driven mainly by the unique biology of each patient's tumor.

What is the evidence supporting TTFields combined with chemotherapy in locally advanced or metastatic PDAC?

Efrat Dotan, MD, MTR
I want to wrap up by talking about supportive care. Pancreatic cancer is a challenging disease and pain control is a major concern for patients with locally advanced pancreatic cancer. Tumor treating fields (TTFields) is a novel noninvasive therapy that uses a low-intensity electric field to disrupt cellular processes crucial for tumor progression and cancer cell viability.

One of the recent advances in locally advanced pancreatic cancer is the PANOVA-3 trial where TTFields were combined with gemcitabine and nab-paclitaxel. This is an important study because we have relatively few dedicated studies for patients with locally advanced disease. These patients present different therapeutic challenges with tumors causing significant pain and discomfort locally.

In PANOVA-3, patients received standard chemotherapy with or without TTFields. The device in the study was worn for at least 18 hours per day. The addition of TTFields improved OS from 14.2 to 16.2 months (HR: 0.82; P = .039) and nearly doubled pain-free survival, extending it from 9.1 to 15.2 months (HR: 0.74; P = .027). Interestingly, the use of TTFields also improved distant PFS from 11.5 to 13.9 months (HR: 0.74; P =.022).

I think these findings are particularly meaningful. For patients who are willing and able to wear the device, I think these data are compelling and make TTFields a reasonable option to consider alongside chemotherapy in locally advanced disease.

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