For more than three decades, oncologists have watched the same story play out with pancreatic cancer. A patient’s tumor is sequenced. A KRAS mutation is found, as it is in roughly 90 percent of pancreatic ductal adenocarcinomas. And then, because no approved drug could block that mutation, the finding changes nothing about treatment. The protein was too smooth, too featureless for a small molecule to grab onto. Researchers called it “undruggable.” Patients lived with the consequences.
A phase 1/2 clinical trial published in the New England Journal of Medicine in May 2026 offers the strongest evidence yet that the undruggable era may be ending. The trial tested daraxonrasib, a multi-selective RAS inhibitor, in patients with advanced RAS-mutated pancreatic cancer who had already failed at least one prior line of therapy. In the dose-expansion cohort, the drug achieved a disease control rate of 61 percent and a confirmed objective response rate of 20 percent. Median progression-free survival reached 5.5 months, and median overall survival was 8.3 months.
Those numbers may sound modest in isolation. They are not. In second-line pancreatic cancer, existing chemotherapy regimens typically deliver median overall survival in the range of six months, and objective response rates in the single digits. A targeted agent producing tumor shrinkage in one out of five patients, and disease control in more than three out of five, in a population that had already progressed on prior treatment represents a meaningful shift.
Why RAS was considered undruggable, and what changed
KRAS mutations drive the majority of pancreatic cancers by locking a signaling protein into its active, or “ON,” state, which tells cells to grow and divide without stopping. For years, drug developers tried and failed to find a binding pocket on the protein’s surface. The first breakthrough came with sotorasib and adagrasib, which target a single variant called KRAS G12C. But G12C accounts for only about 1 to 2 percent of pancreatic cancers. The dominant mutations in PDAC are G12D, G12V, and G12R, and those remained out of reach.
Daraxonrasib takes a different approach. Rather than locking onto one specific mutant form, it inhibits multiple active-state RAS proteins across several mutation subtypes. An accompanying editorial in the NEJM described this multi-selective RAS(ON) inhibition as a potential inflection point, arguing that the drug’s broader targeting profile directly addresses the diversity of RAS mutations that has stymied earlier, narrower inhibitors.
What the trial showed
The study, registered as NCT05379985, used a standard dose-escalation and dose-expansion design. Researchers first tested increasing doses in small groups to identify tolerable levels, then enrolled larger cohorts at selected doses to measure antitumor activity. All patients had confirmed RAS mutations and had received at least one prior systemic therapy for advanced disease.
The prespecified endpoints covered the metrics oncologists use to judge whether a drug is working: objective response rate (measurable tumor shrinkage), disease control rate (shrinkage plus stabilization), duration of response, progression-free survival, and overall survival. The results across these endpoints were strong enough to prompt regulatory action well before the trial was complete.
The FDA granted daraxonrasib Breakthrough Therapy designation, a status reserved for drugs that show substantial improvement over existing options for serious conditions. The agency also awarded Orphan Drug designation, reflecting the severity and limited treatment landscape of pancreatic cancer. Most recently, the FDA authorized expanded access for patients with previously treated metastatic PDAC who lack satisfactory alternatives, allowing the drug to be administered outside the formal trial under defined conditions. In Europe, the European Medicines Agency has granted its own orphan designation, making two major regulators treating the compound as a development priority.
What the data cannot yet answer
The trial’s results are early-phase, and several critical questions remain open.
Durability of response. Follow-up in phase 1/2 trials is inherently limited. Whether daraxonrasib can keep tumors in check for many months, or whether resistance develops quickly, is not yet fully characterized. Resistance to targeted therapies is common in oncology. Tumors frequently find bypass pathways around a blocked signal, and whether combination strategies will be needed to delay that escape is an active area of investigation.
Detailed safety profile. The FDA’s expanded-access authorization signals that regulators judged the risk-benefit balance acceptable. But granular data on severe adverse events by dose level, rates of treatment interruption, and dose reductions due to toxicity are contained in the NEJM publication and regulatory submissions, not in a freely searchable public format. For patients and oncologists weighing expanded access, this creates a practical gap.
Patient selection. Public regulatory filings do not break down the trial population by age, performance status, number of prior treatment lines, or distribution of specific RAS mutation subtypes. These variables matter. A drug that performs well in relatively fit patients with limited prior treatment may behave differently in older individuals, those with poorer functional status, or patients whose tumors carry rarer RAS variants.
Path to approval. No public documents yet outline a definitive regulatory strategy or timeline for a marketing application. The FDA has generally required randomized evidence for full approval in solid tumors, particularly when overall survival is a key endpoint. Whether the agency would consider accelerated approval based on single-arm phase 1/2 data, potentially supplemented by real-world evidence from expanded access, remains an open question.
Where daraxonrasib fits in the treatment landscape
Pancreatic cancer remains one of the deadliest malignancies. The five-year survival rate for all stages combined is approximately 13 percent, according to the American Cancer Society. For patients with metastatic disease, the figure drops into the low single digits. First-line treatment typically involves combination chemotherapy regimens such as FOLFIRINOX or gemcitabine plus nab-paclitaxel. When those fail, second-line options are limited and offer incremental benefit at best.
Daraxonrasib is not yet approved and has not been tested head-to-head against any standard regimen. Cross-trial comparisons are unreliable because patient populations, eligibility criteria, and endpoints differ. Still, the disease control and response rates from the phase 1/2 data are notable in a setting where most second-line chemotherapy produces objective responses in fewer than 10 percent of patients.
The NEJM editorial’s framing of the drug as a conceptual advance reflects genuine enthusiasm in the oncology community, but enthusiasm is not the same as proof of superiority. Full validation will require longer follow-up, potential randomized trials comparing daraxonrasib to standard chemotherapy or combination approaches, and real-world data from a broader patient population.
What patients and oncologists should do now
For patients with advanced RAS-mutated pancreatic cancer who have progressed on at least one prior therapy, the immediate step is a conversation with their oncology team about eligibility for the ongoing clinical trial or the FDA’s expanded-access program. Expanded access requires coordination between the treating physician, an institutional review board, and the drug’s sponsor. It is not automatic, and not every patient will qualify.
That conversation should be specific. Patients and families should ask what the current data show about response rates and survival, what is known about side effects at the dose being offered, and how daraxonrasib fits alongside or instead of remaining chemotherapy options. The evidence is promising but incomplete, and informed decision-making depends on understanding both what the drug has demonstrated and what it has not.
For oncologists, the challenge is balancing warranted optimism with honesty about the limits of early-phase data. Targeting RAS directly in pancreatic cancer is no longer theoretical. It is happening in clinic, producing measurable responses in a cancer type long defined by therapeutic dead ends. But mature survival data, broader safety experience, and randomized comparisons are still ahead. Until those arrive, daraxonrasib is best understood as the most promising lead in a field that has had painfully few of them.
More from Morning Overview
*This article was researched with the help of AI, with human editors creating the final content.
