A new pancreatic cancer pill may be a game changer for patients

An experimental pancreatic cancer drug has ignited hope in a field desperate for new treatments.

Compared with traditional chemotherapy, a pill called daraxonrasib nearly doubled the survival time of people with advanced pancreatic cancer, scientists reported May 31 at the annual American Society of Clinical Oncology meeting in Chicago. Half of patients on the new drug lived 13 months or longer after treatment. In comparison, the median survival was less than seven months for those on chemo.

An extra six months of life might not sound like much, but “it’s a drastic improvement,” says Andrew Coveler, an oncologist who specializes in pancreatic cancer at Fred Hutchinson Cancer Center in Seattle and was not involved with the work. Survival time for people with cancer that’s spread beyond the pancreas is often less than a year. 

The new results are “a huge deal for so many reasons,” says Benjamin Musher, a gastrointestinal medical oncologist at Baylor College of Medicine in Houston who did not participate in the new study. Beyond how well daraxonrasib appears to work, it lays the foundation for future — and perhaps even more effective — therapies. “This is opening the door to a whole new world of research in pancreatic cancer,” he says.

Despite the excitement, which has been buzzing since the drug’s manufacturer released early results in April, Musher and other experts are careful to point out daraxonrasib’s limitations. “This is not a panacea,” says Anirban Maitra, a pancreatic cancer researcher at NYU Langone Health who was not part of the trial team. “We have not cured pancreas cancer. I cannot emphasize this enough.”

Though pancreatic cancer is relatively rare, with about 60,000 new cases diagnosed in the United States each year, it is infamously deadly. Diagnosis often comes late, after the disease has already advanced, and only 3 percent of people with advanced cases are still alive five years later. “It’s a truly devastating disease, and we haven’t had many therapy options,” says Shubham Pant, a medical oncologist at the University of Texas MD Anderson Cancer Center in Houston and one of the trial’s investigators.

Once the cancer has spread beyond the pancreas and weaseled its way into other tissues, it’s usually not possible to operate. An experimental mRNA cancer vaccine currently in the works might one day help, though it’s still in the early stages of testing. So doctors rely on chemotherapy, but that doesn’t extend patients’ lives much. The disease is somehow able to resist the medicine’s toxic effects.

Pancreatic cancer is commonly fueled by malfunctioning RAS proteins. These proteins typically act like a light switch, toggling on or off to promote cell growth or rest. But in pancreatic cancer, the switch is stuck in the “on” position. “It’s always telling the tumor cells to grow,” Pant says.

Scientists have been trying for decades to design drugs that target the pushy proteins. “It’s been a very hard nut to crack,” says Maitra, who participates in other cancer research involving the new pill. RAS proteins don’t have the kind of molecular grooves that make it easy for drugs to latch on, Coveler says. Imagine the smooth surface of a ball bearing, he says.

Daraxonrasib, made by the Redwood City, Calif., biotech company Revolution Medicines, skirts the issue by using a different strategy: It acts like a molecular glue. First, the drug sticks to cyclophilin A, a protein abundant in cells. Then the duo gloms onto RAS, blocking the protein’s grow-grow-grow command. Imagine the drug and its partner bear-hugging RAS, Maitra says, “like an embrace of death.”

In a Phase III clinical trial with 500 patients to evaluate how well the drug worked, researchers compared people given a daily daraxonrasib pill with those given standard intravenous chemotherapy. All patients had advanced disease and had undergone previous therapy. In addition to extending patients’ lives, daraxonrasib also helped some patients control their pain, Pant says. He remembers one man whose pain faded enough after treatment that he was able to start golfing again. “He had a great quality of life,” Pant says. “He was just out golfing all the time.”

Overall, daraxonrasib’s side effects tended to be less severe than what patients endured with chemotherapy. During the trial, only about 1 percent of patients on the drug stopped taking it due to side effects versus 11 percent on chemo, the team reported.

Side effects can include diarrhea, nausea, painful mouth inflammation and vomiting, researchers involved in an earlier trial reported May 6 in the New England Journal of Medicine. In the new trial, the most common severe side effect was a rash, which occurred in nearly 14 percent of patients.

Researchers had previously shown that roughly 90 percent of patients on daraxonrasib develop some form of rash. It “can range from quite mild to quite fierce,” says Musher, who is working on a separate clinical trial that combines daraxonrasib with chemotherapy. The rash typically starts on the face and can flare across the scalp, chest and back. A regimen of creams and pills can help prevent irritation and soothe angry skin — something clinicians will need to learn when the drug gets approved, Musher says. And for him, drug approval is a question of “when” not “if.”

The U.S. Food and Drug Administration has not yet given daraxonrasib its stamp of approval, but it has allowed Revolution Medicines to expand access to the drug beyond clinical trials, for seriously ill pancreatic cancer patients who have no other treatment options.

Maitra believes the drug is going to change how cancer doctors practice medicine. Daraxonrasib is “a major home run,” he says. “We haven’t won the World Series, but it’s a home run in a disease where there has been a series of strikeouts.”