A New Pill Could Transform How Pancreatic Cancer Is Treated

For decades, researchers struggled to develop drugs against RAS, a family of proteins involved in cell growth. Mutations in KRAS—one member of that family—drive more than 90 percent of the most common form of pancreatic cancer. Now, the FDA has approved the first RAS inhibitor for metastatic pancreatic cancer, marking a major shift in the treatment of one of the deadliest cancers.

The once-daily pill, known generically as daraxonrasib and sold as Rasonque is approved for adults whose cancer has spread and who have already received at least one systemic treatment, as well as patients who are not candidates for multi-drug therapy. In a phase 3 trial of 500 adults with previously treated metastatic disease, patients taking daraxonrasib lived a median of 13.2 months, compared with 6.7 months among those receiving standard chemotherapy.

“I don’t think that the news can be overstated,” says Peter Hosein, a medical oncologist and associate director for clinical research at the Pancreatic Cancer Research Institute at Sylvester Comprehensive Cancer Center, which participated in the trial. He calls it “nothing short of a paradigm-shifting, historical approval.”

How Scientists Finally Cracked RAS

The FDA approved Rasonque on August 26, several months ahead of its expected decision deadline. It is the first approved drug in a new class of medicines designed to block several forms of active RAS.

RAS refers to a family of proteins—including KRAS, NRAS, and HRAS—that help regulate cell growth. In pancreatic cancer, KRAS is by far the most important: Mutations can leave the protein permanently switched on, continually signaling cells to grow and divide. The cells “just keep dividing and growing and dividing until it practically snuffs out the life of the patient,” says Olatunji Alese, an oncologist at Emory University’s Winship Cancer Institute who specializes in gastrointestinal cancers.

Earlier inhibitors generally targeted one specific KRAS mutation. Daraxonrasib takes a broader approach. It is “multiselective,” meaning it was designed to block the active forms of several RAS proteins and mutations, including the KRAS mutations commonly found in pancreatic cancer. The FDA’s indication does not require patients to have a particular RAS mutation to receive it.

That breadth helps distinguish Rasonque from previously approved targeted treatments for pancreatic cancer, which apply only to small groups of patients with uncommon genetic features, says Hosein. Treatments targeting BRCA mutations, for example, may apply to roughly 5 to 8 percent of patients, while some other targeted options are relevant to fewer than one percent.

The approval was based on an international, randomized phase 3 trial involving 500 adults whose metastatic pancreatic cancer had previously been treated. Daraxonrasib was given by itself and compared with another course of chemotherapy. Median overall survival was 13.2 months with daraxonrasib and 6.7 months with chemotherapy. Median progression-free survival—the period before the cancer worsened—was 7.2 months and 3.6 months, respectively.

The benefit extended beyond survival. Patients receiving daraxonrasib went significantly longer before experiencing deterioration in pain and overall quality of life than those receiving chemotherapy, according to the published trial results.

“The impact is primarily improving survival, and that translates also into improved quality of life,” Hosein says. “In terms of the day-to-day management of these patients, we see pain improvement almost immediately.”

At Sylvester, he says, some patients also experienced declining cancer markers, renewed appetite, and regained weight. Those changes can alter how patients think about their immediate futures. “Now with this treatment, they can start thinking about plans for the future, travel, family,” Hosein says.

Adverse events rated grade 3 or higher—meaning severe or worse—occurred in 61.8 percent of patients taking daraxonrasib, compared with 69.6 percent receiving chemotherapy. Treatment-related side effects led 1.2 percent of daraxonrasib patients to discontinue treatment, compared with 11.2 percent of patients receiving chemotherapy. The most commonly reported effects included rash, diarrhea, mouth inflammation, nausea, fatigue, vomiting, abdominal pain, swelling, decreased appetite, and bleeding.

RAS mutations were first identified in human cancers in the early ’80s, but it wasn’t until more than three decades later, in 2013, that researchers identified a druggable pocket on one mutant form of the KRAS protein, known as KRAS G12C. Compounds could bind to that pocket and block the protein’s cancer-driving signals.

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Those discoveries accelerated the race to develop medicines capable of targeting RAS-driven cancers. The first KRAS inhibitor was approved by the FDA in 2021 for lung cancer, but it targets a mutation called KRAS G12C, which is relatively uncommon in pancreatic cancer.

Daraxonrasib may be leading this new wave, but it’s far from the only drug in testing. “By the last count, [there were] more than 70 [pancreatic cancer KRAS inhibitors] in the pipeline,” Alese says.

Expanding the Treatment Landscape

Combination chemotherapy remains the standard first treatment for most patients healthy enough to tolerate it. Rasonque does not replace chemotherapy throughout the course of the disease, but it now gives many patients an alternative to another chemotherapy regimen after their cancer progresses.

“There’s no doubt that this is the best available treatment for patients who’ve had previous chemo,” Hosein says.

The pill may also reduce some of the logistical burden of treatment. “You don’t have to come in for IV infusions or wear a pump at home that delivers the chemo,” Wolpin explains. “It is, I think, more convenient.”

But the approval has important limits. The pivotal trial included patients with stage IV pancreatic cancer who had already received systemic treatment. It did not establish the drug as the preferred first treatment for most patients, nor did it test the drug in earlier-stage disease.

The FDA indication does, however, allow patients who are not candidates for multi-drug therapy to receive Rasonque. That could permit some patients to take it as their first treatment, even as researchers continue studying its broader use.

An ongoing phase 3 trial is evaluating daraxonrasib by itself and in combination with chemotherapy among patients with previously untreated metastatic disease. Other trials are investigating whether it could help prevent recurrence after surgery and chemotherapy. Its use in patients whose tumors remain localized but cannot initially be removed surgically is also of interest, Hosein says, but has not been established.

“It definitely is a huge breakthrough, but these are the caveats,” he says. Hosein expects researchers to learn over the next several years whether daraxonrasib should move into frontline treatment, either by itself or alongside chemotherapy, and whether it could eventually benefit patients with earlier-stage disease.

Separately, researchers are studying other ways to expand the pancreatic cancer treatment arsenal, including personalized mRNA vaccines, though those remain much further from widespread use.

Of the eight patients whose immune systems responded to the vaccine, seven were still alive four to six years after surgery. But some researchers have hesitations about how likely it is that mRNA vaccines will become a leading treatment for such a deadly cancer: “The idea that the first effective cancer vaccine is going to be against pancreas cancer—strange believability,” says Robert Eil, a surgical oncologist and immunotherapy researcher at Oregon Health & Science University.

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If not a leading treatment, vaccines like these could become a weapon in a doctor’s growing arsenal of pancreatic cancer treatments, and would likely be most effective before the cancer is very advanced, Alese says. In the case of pancreatic cancer, it’s rarely diagnosed that early.

Unlike breast or colorectal cancer, there is no routine pancreatic cancer screening recommended for the general population. There are also few early warning signs, and the disease can spread early. The combination of these factors is why most pancreatic cancer patients are first diagnosed at stage IV. At that point, the disease has already metastasized, and the five-year survival rate is only 3 percent.

“You need to find it earlier, and you need to have more effective ways to treat it,” Wolpin says. “You put those two things together, and we would hope we would be able to cure a lot more people if we could do that.”

Rasonque is not a cure. Even patients who respond well can eventually develop resistance, and researchers do not yet know why some remain on the drug far longer than others. At Sylvester, Hosein says, several trial participants were still taking daraxonrasib more than a year after beginning treatment—considerably longer than the trial’s median progression-free survival.

“On an individual basis, it could be a lot longer than seven months, and that’s usually what we try to explain to people,” he says.

Researchers are now investigating why resistance develops and whether it can be delayed, prevented, or overcome. They are also studying more selective drugs aimed at individual KRAS mutations, including G12D and G12V.

“This is a first step in this new world of RAS inhibitors,” Hosein says. “It’s a breakthrough, but still a lot of work to be done.”