For roughly forty years, oncologists have treated pancreatic cancer with the grim arithmetic of months gained, not years. A new drug called daraxonrasib appears ready to rewrite that math. In late-stage trial data, patients who added it to chemotherapy lived roughly twice as long as those on chemo alone – an outcome doctors caring for this disease describe as the biggest news in their field in over a decade.
Key Takeaways:
- Daraxonrasib roughly doubled overall survival when paired with chemotherapy in advanced pancreatic cancer trials, with the FDA already granting expanded access outside formal studies.
- The drug binds RAS – a cancer-driving protein considered untargetable for decades – by hijacking a second protein, cyclophilin A, to lock onto it.
- Phase 3 results suggest patients without the typical KRAS mutation may also benefit, opening the door to broader use across pancreatic, colorectal and lung cancers.
Revolution Medicines, the company developing daraxonrasib, has already secured a Fast Track designation from the U.S. Food and Drug Administration. Last week the agency went a step further, allowing the company to provide the drug to patients outside its clinical trials through an expanded access program – a rare nod to how badly the field needs new options.
The early signals arrived in April, when Revolution Medicines reported preliminary findings from its Phase 3 trial. Patients who received daraxonrasib alongside chemotherapy survived roughly twice as long as those receiving chemotherapy by itself.
On Wednesday, the New England Journal of Medicine published earlier-phase results that filled in the picture. Among patients whose cancer had spread to other organs, daraxonrasib held tumors in check for more than eight months and kept patients alive for close to a year and a half.
To grasp why those numbers matter, consider the baseline. Pancreatic cancer is usually diagnosed only after it has already migrated, often to the liver or lungs. Even with aggressive chemotherapy, most patients do not survive a year past diagnosis. Only 3% of people with metastatic pancreatic cancer are alive five years later, the American Cancer Society reports.
“We have been desperately working very hard trying to find other ways to treat the cancer,” said Dr. Brian Wolpin, who led the new daraxonrasib research and runs the Hale Family Center for Pancreatic Cancer Research at Dana-Farber Cancer Institute in Boston. “This really feels like a watershed moment. It's going to shift how we think about treatment for pancreatic cancer overall.”
Cracking an “undruggable” protein
The drug goes after RAS, a protein that controls how cells grow. More than 90% of pancreatic cancers carry a mutation in the RAS gene that locks the protein in the “on” position, telling cells to multiply without brakes. For years, RAS earned a reputation as untargetable – attempt after attempt to block it failed.
Daraxonrasib gets around the problem by recruiting a partner. Inside the cell, it binds to a protein called cyclophilin A. Together the two act as what Wolpin describes as a “molecular glue,” sticking onto RAS and shutting it down.
The findings published Wednesday come from a Phase 1/2 trial designed to test safety and dosing. All 168 enrolled patients had advanced disease that had already spread, mostly to the lungs and liver, and all had previously received standard chemotherapy. At the highest dose, progression-free survival – the time before tumors started growing again – averaged about 8.1 months. Overall survival reached roughly 15.6 months.
Side effects: tolerable, but not gentle
The drug is not free of consequences. The most common side effects included a blistering rash resembling a severe sunburn, sores in the mouth and throat, vomiting and diarrhea. Former Sen. Ben Sasse, R-Neb., who joined a clinical trial after his Stage 4 diagnosis last year, called the rash “nuclear” on a New York Times podcast last month. He also said his tumors have shrunk substantially since starting the drug.
Wolpin said some patients had to pause the drug “to let the rash calm down.” Most side effects were managed with antibiotics, topical creams and anti-diarrheal medication. About 30% of patients experienced severe reactions, and eight people withdrew from the trial because of them.
Even so, Wolpin argued the trade-off favors the new pill. The drug is “much more tolerable than chemo. Most patients greatly prefer the ability to take a pill every day rather than do all of those infusions,” he said.
The Phase 3 numbers, and a wider audience
Phase 3 results, scheduled for presentation later this month at the American Society of Clinical Oncology's annual meeting, sharpen the case. Overall survival for patients on chemotherapy alone was 6.7 months. For those receiving the combination, it climbed to 13.2 months. The Phase 3 cohort also included patients without the KRAS mutation, hinting that the benefit may stretch beyond the genetically defined group most researchers expected.
“I think we're going to stop thinking of chemotherapy as something that you have to give to everyone,” Wolpin said.
That sentiment is finding echoes among physicians who normally guard against hype.
“Those of us who take care of this disease are, frankly, a little cynical about new data that comes out, especially data that gets a lot of press in the general media, because most of the time it is overhyped,” said Dr. Reza Nazemzadeh, a gastrointestinal medical oncologist at Atrium Health Levine Cancer in Charlotte, North Carolina. “But this is a big deal. This drug is the most exciting thing in pancreas cancer in over a decade.”
Nazemzadeh did not work on the daraxonrasib trials but has had patients enrolled. Anecdotally, he said those patients fared well and gained more time with their families than they likely would have on existing therapies.
“I don't use the word 'groundbreaking' lightly,” said Dr. Sekhar Padmanabhan, a surgical oncologist and director of robotic liver, pancreas and bile duct surgery at Vanderbilt University Medical Center. “This is going to have a significant impact on how we take care of our patients.”
Why the urgency
The American Cancer Society projects more than 67,000 new pancreatic cancer diagnoses in the United States this year and over 52,000 deaths from the disease. There is no routine screening, and early symptoms are vague enough that 80% of patients are diagnosed at later stages, when treatment options narrow sharply.
Dr. Dae Won Kim, a gastrointestinal medical oncologist at Moffitt Cancer Center in Tampa, Florida, who was not involved in the research, expects the FDA to act quickly on approval.
The drug's reach may extend further still. RAS mutations show up in colorectal and lung cancers as well, and researchers are testing daraxonrasib in those settings too. Two smaller studies presented at the American Association for Cancer Research meeting in April suggested benefits when the drug is given as part of first-line therapy, before or alongside chemo, rather than after.
“That's the direction that the field is going,” Padmanabhan said. “It brings hope to a disease that for decades we didn't really have much to offer beyond first-line therapies that haven't prolonged life very much. This has the capacity to do that.”
Written by Vytautas Valinskas