An experimental pancreatic cancer drug has sparked hope in an area 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 meeting of the American Society of Clinical Oncology in Chicago. Half of the patients taking the new drug lived 13 months or more after treatment. In comparison, median survival was less than seven months for people receiving chemotherapy.
Six additional months of life may not seem like much, but “it’s a drastic improvement,” says Andrew Coveler, an oncologist who specializes in pancreatic cancer at the Fred Hutchinson Cancer Center in Seattle and was not involved in the work. The survival time for people with cancer that extends beyond the pancreas is often less than a year.
The new findings are “a huge deal for many reasons,” says Benjamin Musher, a gastrointestinal medical oncologist at Baylor College of Medicine in Houston, who was not involved in the new study. Beyond daraxonrasib’s apparent effectiveness, it lays the foundation for future – and perhaps even more effective – therapies. “This opens the door to a whole new world of pancreatic cancer research,” he says.
Despite the excitement that has reigned since the the drug manufacturer has published the first results in April, Musher and other experts are careful to point out the limitations of daraxonrasib. “It’s 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 pancreatic cancer. I cannot stress that enough.”
Although pancreatic cancer is relatively rare, with approximately 60,000 new cases diagnosed each year in the United States, it is notoriously deadly. The diagnosis is often made late, when the disease has already progressed, and only 3% of people with an advanced case are still alive five years later. “It’s a really devastating disease, and we haven’t had a lot of treatment options,” says Shubham Pant, a medical oncologist at the University of Texas MD Anderson Cancer Center at Houston and one of the trial investigators.
Once the cancer has spread beyond the pancreas and spread to other tissues, it is usually no longer possible to operate on it. A experimental mRNA cancer vaccine currently in the works could one day help, although it is still in the early stages of testing. So doctors rely on chemotherapy, but it doesn’t extend patients’ lives much. The disease is somehow able to resist the toxic effects of the drug.
Pancreatic cancer is typically fueled by dysfunction of RAS proteins. These proteins generally act like a switch, turning on or off to encourage cells to grow or rest. But in pancreatic cancer, the switch is stuck in the “on” position. “This always signals the tumor cells to grow,” says Pant.
Scientists have been trying for decades to design drugs that target insistent proteins. “This was very difficult to resolve,” says Maitra, who is involved in other cancer research involving the new pill. RAS proteins don’t have the kind of molecular grooves that make it easier for drugs to stick, Coveler says. Imagine the smooth surface of a ball bearing, he says.
Daraxonrasib, made by the biotechnology company Revolution Medicines of Redwood City, Calif., gets around the problem by using a different strategy: It acts like molecular glue. First, the drug sticks to cyclophilin A, a protein abundant in cells. Next, the duo heads to RAS, blocking the protein’s grow-grow-grow drive. Imagine the drug and its partner RAS entwined, Maitra says, “like an embrace of death.”
In a Phase III clinical trial of 500 patients to evaluate the drug’s effectiveness, researchers compared people receiving a daily pill of daraxonrasib to those receiving standard intravenous chemotherapy. All patients had advanced disease and had previously received treatment. In addition to prolonging patients’ lives, daraxonrasib also helped some patients control their pain, Pant says. He remembers one man whose pain subsided enough after treatment that he could start playing golf again. “He had an excellent quality of life,” Pant says. “He played golf all the time.”
Overall, daraxonrasib’s side effects tended to be less severe than those endured by patients receiving chemotherapy. During the trial, only about 1 percent of patients on treatment stopped taking it due to side effects, compared to 11 percent on chemotherapy, the team reported.
Side effects may include diarrhea, nausea, painful inflammation of the mouth and vomitingresearchers involved in an earlier trial reported May 6 in the New England Journal of Medicine. In the new trial, the most common serious side effect was rash, occurring in nearly 14 percent of patients.
Researchers had previously shown that about 90 percent of patients taking daraxonrasib developed some form of rash. It “can range from very mild to very violent,” says Musher, who is working on a separate clinical trial that combines daraxonrasib with chemotherapy. The rash usually starts on the face and may spread to 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 is 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 approval to daraxonrasib, 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 will change the way oncologists practice medicine. Daraxonrasib is “a major home run,” he says. “We didn’t win the World Series, but it’s a home run in a disease where there’s been a string of strikeouts.”
