Why Scientists Thought Pancreatic Cancer Was 'Undruggable' — And What Changed

Hook

For decades, one of the most common mutations in pancreatic cancer sat in plain sight — and researchers could not effectively target it.

That mutation is called KRAS. It is present in more than 90% of pancreatic cancers, it drives tumour growth, and until recently it was widely described as nearly impossible to drug. The assumption was so entrenched that some scientists called it “undruggable.”

In May 2026, results from a large Phase 3 trial reported in the New England Journal of Medicine suggested that assumption may be changing. A drug called daraxonrasib, taken orally once daily, roughly doubled median overall survival compared with standard chemotherapy in patients with previously treated metastatic pancreatic cancer.

That does not mean pancreatic cancer is solved. But it represents a meaningful shift in the science — and for a disease that has seen limited treatment progress in decades, the scale of that shift matters.

Context

Pancreatic cancer and why advanced disease is so difficult to treat

Pancreatic cancer begins in the cells of the pancreas, a gland that sits behind the stomach and produces digestive enzymes and hormones including insulin. Most cases are pancreatic ductal adenocarcinoma (PDAC), a form that arises from the ducts that carry digestive fluid.

By the time most people are diagnosed, the cancer has often spread beyond the pancreas. Advanced or metastatic pancreatic cancer is one of the most difficult cancers to treat, partly because the pancreas is deep in the abdomen and symptoms tend to appear late, and partly because the tumour’s biology makes it resistant to many standard therapies.

According to the American Cancer Society and the National Cancer Institute, the five-year survival rate for pancreatic cancer remains low compared with many other cancers, and has improved only modestly over the past several decades. For people with metastatic disease — cancer that has spread to other organs — median survival on standard chemotherapy has typically been measured in months.

Current first-line chemotherapy regimens such as FOLFIRINOX and gemcitabine-based combinations have improved outcomes, but once those regimens stop working, there are limited options. That is the situation RASolute 302 was designed to address.

What KRAS is, and why it was hard to target

Cells communicate through signalling pathways — chains of molecular signals that tell a cell to grow, divide, or stop. KRAS is a protein that acts as a molecular switch in one of those pathways. When it is working normally, it switches on when growth signals arrive and switches off again when they are no longer needed.

In most pancreatic cancers, a mutation in the KRAS gene locks the switch in the “on” position permanently. The cell keeps receiving a signal to grow and divide, even when it should not. This uncontrolled signalling is a central driver of how the cancer grows and spreads.

The reason KRAS was historically difficult to drug comes down to its shape. For many decades, KRAS lacked an obvious binding pocket — a crevice where a drug molecule could dock and block its activity. Without that foothold, drug developers could not design a small molecule that would reliably interfere with it. Research into KRAS inhibitors stalled for years, and the protein earned its “undruggable” reputation.

What changed was structural biology: advances in understanding the precise shape of KRAS in its active state revealed binding sites that had not been recognised before, and allowed researchers to design molecules that could block the protein while it was switched on.

What Is Daraxonrasib?

Daraxonrasib (also referred to as RMC-6236) is an oral, multi-selective RAS(ON) inhibitor — a drug designed to block RAS proteins while they are in their active (“on”) state. It was developed by Revolution Medicines.

Unlike chemotherapy, which broadly targets rapidly dividing cells, daraxonrasib is designed to interfere with a specific protein involved in driving cancer cell growth. It is taken by mouth as a tablet, once daily.

Daraxonrasib is not standard care for any cancer. It is under investigation in clinical trials. In June 2025, the US Food and Drug Administration (FDA) granted it Breakthrough Therapy designation for previously treated metastatic pancreatic cancer, based on early trial results. As of June 2026, it has not received formal approval from the FDA or other major regulatory bodies, though an expanded access programme was initiated in the United States in May 2026 for eligible patients.

Whether and when daraxonrasib receives regulatory approval will depend on ongoing regulatory review.

What Did The Trial Report?

The results summarised below come from the RASolute 302 trial (NCT06625320), a global, randomised, open-label Phase 3 study conducted at 59 sites across North America, Europe, and Asia. The trial was sponsored by Revolution Medicines. Results were simultaneously published in the New England Journal of Medicine on May 31, 2026 and presented at the ASCO Annual Meeting 2026.

Trial design

500 patients with metastatic pancreatic ductal adenocarcinoma (PDAC)
All had received one prior line of chemotherapy for metastatic disease
More than 91% of enrolled patients had a KRAS mutation in their tumour
Patients were randomly assigned 1:1 to receive either daraxonrasib (300 mg orally, once daily) or investigator’s choice of one of four standard-of-care chemotherapy regimens given intravenously

Efficacy results

According to results published in the New England Journal of Medicine:

Median overall survival (OS):

Daraxonrasib: 13.2 months
Chemotherapy: 6.7 months
Hazard ratio (HR): 0.40 — reflecting a 60% reduction in the risk of death with daraxonrasib
P-value: < 0.0001

Median progression-free survival (PFS):

Daraxonrasib: 7.2 months
Chemotherapy: 3.6 months

Objective response rate (ORR) — proportion of patients whose tumour measurably shrank:

Daraxonrasib: 31.6%
Chemotherapy: 11.2%

In the subgroup of patients with RAS G12 mutations (the most common RAS mutation in pancreatic cancer), the response rate with daraxonrasib was 33.2% versus 11.8% with chemotherapy.

Safety

The most commonly reported side effects with daraxonrasib were:

Rash: approximately 86% of patients (severe in around 14%)
Stomatitis (mouth inflammation/sores): approximately 54% of patients (severe in around 12%)
Nausea and diarrhoea were also reported

One important comparator: approximately 1% of patients on daraxonrasib discontinued treatment due to severe side effects, compared with approximately 11% of patients on chemotherapy in this trial. No unexpected safety findings were reported by the investigators.

Limitations

The trial’s primary focus was on patients with KRAS mutations, which drove the enrolment criteria. The number of patients enrolled who did not have a KRAS mutation was small, meaning the drug’s benefit in RAS-wild-type pancreatic cancer remains uncertain and requires further study.

The trial compared daraxonrasib against second-line chemotherapy in a previously treated population. It does not yet establish how the drug performs in the first-line setting or in combination with other agents.

These were results from a single Phase 3 trial. Regulatory decisions will involve independent review of the full data package.

Why This Matters

Decades of limited progress

Pancreatic cancer has been among the most resistant to targeted therapy of any solid tumour. KRAS was identified as a driver mutation in pancreatic cancer in the 1980s. The fact that, more than 40 years later, there is now a randomised Phase 3 trial showing meaningful benefit from a drug that directly targets RAS signalling represents a substantial shift — not just in outcomes, but in the underlying science.

The scale of the OS benefit

In metastatic pancreatic cancer, a doubling of median overall survival versus the current standard of care would, if confirmed through regulatory review, be a clinically significant result. Prior second-line therapies have typically extended survival by weeks to a few months in this setting. A hazard ratio of 0.40 (60% reduction in risk of death) in a randomised controlled trial is a substantial finding.

Implications beyond pancreatic cancer

KRAS mutations are found in multiple cancers beyond pancreatic: they drive a large proportion of colorectal cancers and lung adenocarcinomas. The development of effective RAS(ON) inhibitors has potential implications across oncology, not only for pancreatic cancer. Early research into daraxonrasib is ongoing in other tumour types.

A proof of concept for a historically hard target

The scientific significance of this result is not only in the numbers. It demonstrates that RAS — long described as resistant to small-molecule inhibition — can be meaningfully targeted in a clinically relevant way. That opens a line of research that has been constrained for decades.

What This Does Not Mean

It is worth being explicit about what this trial does not establish.

It does not mean pancreatic cancer is cured. Median overall survival of 13.2 months reflects that many patients still face a serious prognosis. The drug extends life meaningfully in this population; it does not eliminate the disease.

It does not mean daraxonrasib is suitable for every patient with pancreatic cancer. The trial enrolled patients with previously treated metastatic disease and KRAS mutations. It does not cover early-stage disease, patients who have not yet received chemotherapy, or patients whose tumours do not carry RAS mutations.

It does not mean people should stop current treatment or defer chemotherapy. Daraxonrasib is not approved. For most patients, standard treatment guidelines remain the appropriate guide.

Approval is not automatic. Regulatory bodies review full data packages independently. The timeline and outcome of regulatory submissions is not yet determined.

Side effects are real. Rash and oral inflammation affected the majority of patients, and in some cases were severe. Managing these side effects is part of the clinical reality of this drug.

Resistance may develop. As with other targeted therapies, cancer cells can evolve mechanisms to work around drug blockade over time. The durability of benefit remains an open question.

Your Take

This is a story about decades of incremental science eventually making a difficult target reachable.

KRAS was identified as a driver in pancreatic cancer in the 1980s. The protein resisted drugging for so long that “undruggable” became a shorthand — not a statement of permanent impossibility, but of how hard the problem was with the tools available at the time. Structural biology improved. Computational drug design improved. Researchers found binding pockets that had not been apparent before. And a long-standing barrier began, slowly, to yield.

The RASolute 302 result is the clearest clinical evidence yet that targeting RAS in a meaningful way is possible.

It is reasonable to be genuinely encouraged by that. It is also reasonable to hold the result with appropriate care. One Phase 3 trial, in a specific second-line population, with results not yet through regulatory review, is the beginning of a new chapter for pancreatic cancer treatment — not the conclusion.

What has changed is the scientific basis for optimism. The target that was supposed to be unreachable has been reached, at least enough to produce a statistically significant, clinically meaningful survival benefit in a randomised trial. That is worth understanding clearly.

FAQ

What is pancreatic cancer? Pancreatic cancer starts in the cells of the pancreas, a gland behind the stomach. Most pancreatic cancers are pancreatic ductal adenocarcinoma (PDAC). It is often diagnosed late, and advanced disease is difficult to treat, with limited survival improvements over decades.

What is KRAS? KRAS is a gene that encodes a protein acting as a molecular switch in cell signalling pathways. In more than 90% of pancreatic cancers, a mutation in KRAS locks this switch in the “on” position permanently, telling cells to keep dividing. Historically, the shape of the KRAS protein made it very hard to block with a drug molecule.

What is daraxonrasib? Daraxonrasib (RMC-6236) is an oral, once-daily tablet developed by Revolution Medicines. It is a RAS(ON) inhibitor — designed to block the RAS protein while it is in its active state. It is being studied in clinical trials for pancreatic cancer and other RAS-mutated cancers. It is not yet approved by the FDA or other major regulators.

Does daraxonrasib cure pancreatic cancer? No. In the RASolute 302 Phase 3 trial, the median overall survival in patients receiving daraxonrasib was 13.2 months, compared with 6.7 months for chemotherapy. This is a meaningful improvement in survival, but it is not a cure. Most patients still face a serious prognosis.

Who might benefit from daraxonrasib? The RASolute 302 trial enrolled patients with metastatic pancreatic cancer who had already received one prior line of chemotherapy and whose tumours carried RAS mutations (>91% of enrolled patients). Whether daraxonrasib benefits patients in other settings — earlier disease, different tumour types, or first-line therapy — is the subject of ongoing research.

Is daraxonrasib approved? Not yet. As of June 2026, daraxonrasib has not received FDA approval or approval from other major regulatory agencies. It holds FDA Breakthrough Therapy designation for previously treated metastatic pancreatic cancer. An expanded access programme has been initiated in the US for eligible patients. Standard treatment guidelines remain the appropriate guide for most patients.

Why is this trial considered significant? KRAS was identified as a driver of pancreatic cancer in the 1980s but resisted drug targeting for decades. A Phase 3 randomised controlled trial showing a 60% reduction in risk of death (HR 0.40, p < 0.0001) compared with chemotherapy, simultaneously published in the New England Journal of Medicine, represents the clearest clinical evidence yet that RAS can be targeted meaningfully in pancreatic cancer. The scientific and clinical significance lies in both the magnitude of benefit and the demonstration that a historically “undruggable” target can be blocked effectively.

Could daraxonrasib help other cancers? Possibly. KRAS and RAS mutations are found in multiple cancer types, including lung and colorectal cancer. Early-phase research is ongoing. But the RASolute 302 results apply specifically to the second-line metastatic pancreatic cancer population studied in that trial. Effects in other cancers require their own evidence.