Pancreatic cancer's best new drug works — then the cancer finds a way around it

For the first time in the history of pancreatic cancer treatment, a pill has nearly doubled how long patients with advanced disease survive. Now, months after that milestone, researchers are confronting the next hard truth: the cancer can find a way to fight back.

The drug is daraxonrasib, sold as Rasonque, made by Revolution Medicines. The FDA approved it on August 26, several months ahead of its expected decision deadline, for adults with metastatic pancreatic cancer who have already received at least one prior treatment. In a phase 3 trial of 500 patients, those taking the once-daily pill lived a median of 13.2 months, compared with 6.7 months for patients receiving standard chemotherapy. Median progression-free survival — the time before the cancer worsened — was 7.2 months on daraxonrasib versus 3.6 months on chemotherapy.

Ongoing analyses by Revolution Medicines and collaborators, including researchers at Dana-Farber, are examining how resistance to the drug may develop in patients. The findings, from ongoing analyses, do not diminish what the drug has already achieved. They define the next problem to solve.

I don't think that the news can be overstated. It's nothing short of a paradigm-shifting, historical approval.— Peter Hosein, medical oncologist and associate director for clinical research, Pancreatic Cancer Research Institute at Sylvester Comprehensive Cancer Center

Pancreatic cancer kills with particular efficiency. Only 13 percent of patients are alive five years after diagnosis. For decades, chemotherapy was essentially the only option, offering modest survival gains. The disease's central driver — a mutated protein called KRAS, present in more than 90 percent of the most common form of pancreatic cancer — was long considered beyond the reach of medicine. Scientists called it 'undruggable': flat and smooth, like, as some put it, a bowling ball with no holes, offering no pockets or crevices where a drug could get a grip.

It started as a way of antagonizing people — I started giving talks on 'drugging the undruggable' to force people not to capitulate.— Gregory Verdine, Harvard professor and entrepreneur who launched Warp Drive Bio, later acquired by Revolution Medicines

The scientific path to daraxonrasib ran through two distinct strategies. In 2008, Kevan Shokat, a chemical biologist at the University of California San Francisco and an investigator at the Howard Hughes Medical Institute, began working on KRAS despite the field's pessimism. His team focused on a specific mutation driving a fraction of lung cancer cases, using a form of KRAS bound to a molecule called GDP — functioning like an off switch. In 2013, they reported molecules that could stick to KRAS by revealing a previously hidden pocket. Two drugs using that approach have since been approved, but they target a mutation called KRAS G12C, which appears in only about 1 percent of pancreatic cancer cases.

Verdine took a different route. He looked to nature, finding that at least three small molecules produced by bacteria and fungi can't bind to their targets alone — but when they attach to a bystander protein, they form a larger complex that can lock onto the target. Revolution Medicines spent years engineering a drug that imitated this 'molecular glue' approach: a compound that could build a complex in the body to block KRAS without needing to target a specific mutation or find a pocket, and that worked against the active, switched-on form of the protein.

Evolution is telling you something you should pay attention to.— Gregory Verdine, Harvard professor and entrepreneur

That breadth is what makes daraxonrasib different from earlier targeted treatments. It is 'multiselective,' designed to block the active forms of several RAS proteins and mutations. The FDA's approval does not require patients to have any particular RAS mutation to receive it — a significant distinction in a disease where most previously approved targeted therapies applied to only small subsets of patients. Treatments targeting BRCA mutations, for example, apply to roughly 5 to 8 percent of pancreatic cancer patients; some other targeted options are relevant to fewer than 1 percent.

There's no doubt that this is the best available treatment for patients who've had previous chemo.— Peter Hosein, medical oncologist, Sylvester Comprehensive Cancer Center

The trial data showed benefits beyond survival. Patients on daraxonrasib went significantly longer before experiencing deterioration in pain and overall quality of life than those on chemotherapy. Severe adverse events — grade 3 or higher — occurred in 61.8 percent of daraxonrasib patients, compared with 69.6 percent of those receiving chemotherapy. Treatment-related side effects led 1.2 percent of daraxonrasib patients to discontinue treatment, versus 11.2 percent of chemotherapy patients. Common effects included rash, diarrhea, mouth inflammation, nausea, fatigue, vomiting, abdominal pain, swelling, decreased appetite, and bleeding.

For patients, the difference was tangible. Alyson Luck, an art educator from Westport, Connecticut, was 40 years old when she was diagnosed with Stage 4 pancreatic cancer in 2022, with the disease already spread to her liver. Her daughter, Olivia, was 5. Her son, Sam, was 7. After a dozen rounds of chemotherapy and other treatments, she joined the Revolution Medicines trial in early 2024. She died in 2025, but the year the drug gave her family was unlike the chemotherapy years.

I look at pictures from that year, versus the year and a half when she was doing chemo. They're so different. She was smiling. She could do things. Every day you got where she was able to function and feel like a human was a blessing.— Michael Shafrir, husband of trial participant Alyson Luck

The family took vacations to Disney World, to Spain, to the Jersey Shore.

Now the field's attention is turning to the resistance problem. Researchers say this points toward potential strategies: combining multiple KRAS inhibitors, or pairing daraxonrasib with chemotherapy, to delay or overcome resistance. Other resistance mechanisms remain under study.

The resistance findings also carry an unexpected implication. The cells that survive daraxonrasib often appear less aggressive or more sensitive to chemotherapy than the cells the drug killed — suggesting that the drug's selective pressure may, in some cases, leave behind a more treatable residual disease.

This is the news we've been waiting for. This is the breakthrough — it's been a long time coming.— Tyler Jacks, founding director, Koch Institute for Integrative Cancer Research at MIT

Daraxonrasib is not the only drug in this space. According to Olatunji Alese, an oncologist at Emory University's Winship Cancer Institute, more than 70 pancreatic cancer KRAS inhibitors are currently in the pipeline. Combination chemotherapy remains the standard first treatment for most patients healthy enough to tolerate it; daraxonrasib does not replace chemotherapy throughout the course of disease, but gives patients an alternative after their cancer progresses.

Not every bet in pancreatic cancer has paid off. FibroGen, a San Francisco biotech, recently confirmed that its drug pamrevlumab — which targeted connective tissue growth factor rather than KRAS — failed to improve overall survival in two separate trials: the PanCAN Precision Promise study in metastatic disease and the LAPIS trial in locally advanced, unresectable disease. The company announced plans to cut three-quarters of its workforce, and its shares fell 46 percent in premarket trading following the announcement. Chief executive Thane Wettig said he was 'deeply disappointed' by the outcome.

It's the start of a huge wave for this disease.— Eileen O'Reilly, gastrointestinal medical oncologist, Memorial Sloan Kettering Cancer Center

The next phase of research will test whether combining daraxonrasib with other agents — other KRAS inhibitors, chemotherapy, or both — can extend the window of benefit before resistance closes it. Andrew Ko, who led UCSF's trials of daraxonrasib, has been explaining the science and its implications for patients on the heels of the FDA approval. The answers will determine whether the 13-month median becomes a floor rather than a ceiling.

Why it matters — Daraxonrasib is the first drug to meaningfully extend survival for the broad population of advanced pancreatic cancer patients, but the near-universal emergence of resistance means the drug is a starting point — and the race to combine or sequence it with other treatments is now the central challenge in one of medicine's hardest problems.

Reported by nytimes.com, washingtonpost.com, seattletimes.com, nationalgeographic.com, newscientist.com, ucsf.edu, pharmaphorum.com