Pancreatic Cancer's 'Undruggable' Gene Has Finally Been Cracked

13.2 months versus 6.7 months. A 60% reduction in the risk of death. A once-daily pill instead of intravenous chemotherapy.

For metastatic pancreatic cancer — where the five-year survival rate sits at 3% and meaningful treatment advances have been virtually nonexistent for four decades — these numbers have oncologists reaching for language they normally avoid. “Earth-shattering,” said a Stanford oncologist. “Truly transformational,” said a researcher at MD Anderson.

The results, announced last week, come from a Phase 3 trial of daraxonrasib by Revolution Medicines. Earlier-stage first-line data was presented at this week’s AACR conference in San Diego. A separate drug, elraglusib, from Actuate Therapeutics, doubled survival in a Phase 2 trial published the same week. Together, they represent the most significant pancreatic cancer advance in a generation.

The Numbers

In the RASolute 302 trial, patients whose metastatic cancer had progressed on chemotherapy received either daraxonrasib or standard chemotherapy. Median survival: 13.2 months versus 6.7 months. The hazard ratio of 0.40 (p < 0.0001) translates to a 60% reduction in the risk of death.

No drug has matched this in a Phase 3 pancreatic cancer trial. “In the patient population that was being evaluated, six months is huge,” Matthew Katz, a surgical oncologist at MD Anderson, told National Geographic. “It is a definite win.”

Elraglusib, given intravenously, reduced the risk of death by 38% in a Phase 2 trial and added roughly three months of survival when combined with chemotherapy in newly diagnosed patients.

Why Pancreatic Cancer Resists Everything

Pancreatic cancer is the third-leading cause of cancer death globally, projected to overtake all but lung cancer in developed countries within years. In the US, roughly 60,000 people are diagnosed annually and about 50,000 die. There is no screening test. About 80% of patients are diagnosed at an advanced stage, when the disease has already spread.

The tumors resist nearly every weapon in modern oncology. Immunotherapies and targeted treatments that revolutionized outcomes in melanoma and lung cancer have largely failed here. Dense fibrotic tissue surrounds pancreatic tumors, blocking immune cells from reaching them. As researcher Patrick Mehlen of France’s Léon Bérard cancer centre told AFP, there has been essentially no medical progress in 40 years.

Cracking the ‘Undruggable’ Gene

More than 90% of pancreatic tumors carry mutations in RAS, genes that regulate cell growth. KRAS, the most common variant, was the first cancer-causing gene identified, discovered in the early 1980s. For three decades, it was considered undruggable — the protein lacked an obvious binding pocket for a compound to attach.

In 2013, researchers demonstrated that inhibitory compounds could bind to mutant RAS and block its signals. Amgen’s Lumakras, approved for lung cancer in 2021, became the first KRAS drug to reach patients. But pancreatic cancer requires more complete suppression than lung cancer, and Lumakras wasn’t potent enough.

Daraxonrasib uses a fundamentally different mechanism. Rather than slotting into the protein, it acts as molecular glue, binding mutant RAS to another protein called cyclophilin A — which disables the growth signal. Crucially, it works across multiple RAS variants, not just one. Alan Sandler, Revolution Medicines’ chief development officer, told Fierce Biotech the Phase 3 results are just “the tip of the iceberg.”

Gains, Not Cures

Nobody is claiming victory. “We are not curing patients, unfortunately, but patients are living longer,” Devalingam Mahalingam of Northwestern University, lead author of the elraglusib study, told Time.

The side effects are real. Former US Senator Ben Sasse, diagnosed with stage-four pancreatic cancer in late 2025 and told he had months to live, told The New York Times that daraxonrasib shrank his tumors by 76%. The drug also left his face peeling and bloody from a severe rash. Revolution Medicines says rash is a known but manageable side effect; according to Dr. Shubham Pant, an MD Anderson oncologist involved in the trials, fewer than 10% of patients developed a severe rash.

What Comes Next

Revolution Medicines plans to seek FDA approval on an accelerated timeline under the agency’s National Priority Voucher program. It is already testing daraxonrasib in newly diagnosed patients, and at AACR presented data showing a 47% response rate as a first-line treatment, rising to 58% when paired with chemotherapy.

More than 70 KRAS inhibitors are now in development worldwide. The next frontier is combination therapy — pairing KRAS inhibitors with drugs that weaken tumor defenses, or with experimental mRNA vaccines. A small BioNTech-Genentech trial found that among patients whose immune systems responded to an mRNA vaccine, seven of eight were still alive six years later.

Brian Wolpin, an oncologist at Dana-Farber Cancer Institute and a trial investigator, put it plainly: “We’ve wanted to be able to do this for several decades, but have not had the tools.”

Now they do.

Sources

Daraxonrasib Demonstrates Unprecedented Overall Survival Benefit in Pivotal Phase 3 RASolute 302 Clinical Trial — Revolution Medicines
Two New Drugs Offer Hope for Pancreatic Cancer — Time Magazine
This might be the biggest breakthrough in pancreatic cancer in decades — National Geographic
Pancreatic cancer drug daraxonrasib from Revolution Medicines succeeds in trial — CNBC
New drugs raise hopes of pancreatic cancer breakthrough — France 24 (AFP)
AACR: Revolution rolls on in pancreatic cancer as RAS wave rises — Fierce Biotech

Discussion (9)

vkrishnan

The significance of this really can't be overstated. KRAS was first identified as an oncogene in 1982, and for three decades the protein was considered essentially untouchable. The breakthrough came from Kevan Shokat's lab at UCSF in 2013 (Ostrem et al., Nature) when they found a pocket on the KRAS G12C mutant that small molecules could exploit. But G12C is common in lung cancer — pancreatic tumors mostly carry G12D and G12V mutations. What's different about daraxonrasib is that it targets multiple RAS variants, not just one specific mutation. That's a fundamentally harder problem and is why this is genuinely new territory.

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jenny_k

My mom was diagnosed with stage 4 pancreatic cancer in March 2024. She made it 9 months. I keep reading articles like this hoping something will change for other families and it always feels like '5 years away.' Seeing actual Phase 3 numbers that aren't just marginal improvements... I don't know. This one hits different.

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Mike T.

Lost my dad to it in 2019. Nine months from diagnosis to the end. You're right — this does hit different. I'm glad your comment is near the top.

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frank_d

60% reduction in risk of death is insane for a cancer that's been essentially a death sentence. Even 13 months isn't enough but it's a real start.

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ConcernedPatriot

Notice how they always announce 'breakthroughs' right before asking for more funding. 40 years and NOW suddenly they figure it out? My neighbor's brother had pancreatic cancer and the doctors basically told him to get his affairs in order. That was 2 years ago. Probably had something like this sitting in a drawer the whole time. Follow the money.

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Linda M. Rojas

A few clarifications for anyone reading. The 13.2 vs 6.7 month comparison is in patients who had already been through chemotherapy and whose cancer had progressed. That's important context — these were very sick patients with limited options, which makes the results even more notable. Also worth noting that elraglusib is still Phase 2, so those numbers are more preliminary. The daraxonrasib Phase 3 data is the stronger evidence base right now.

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RealClear2024

So is this available now or what? My brother in law was just diagnosed and we need options fast. Article doesn't say when it gets approved.

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realpolitik_rc

The National Priority Voucher program Revolution Medicines is using was established under the 21st Century Cures Act amendments. It's designed specifically for drugs targeting diseases with high unmet need where no adequate therapies exist. The voucher gets you a 6-month reduction in FDA review time — normally 10 months for a standard review, so you're looking at ~4 months. Given the p < 0.0001 on the primary endpoint and the magnitude of the survival benefit, I'd expect a fairly smooth advisory committee meeting. Real question is what happens with the label indication — will it be second-line only initially or could they push for first-line based on the AACR data?

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donna_in_sd

Ben Sasse had pancreatic cancer?? since when

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