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For years, treatment for metastatic pancreatic cancer has relied on highly toxic chemotherapy regimens that offer survival gains typically measured in months. Most patients diagnosed with advanced disease do not survive beyond a year.

That math — and the treatment strategy — is now starting to change. KRAS, the mutation driving more than 90% of pancreatic tumors and long considered undruggable, has become the focal point for two emerging therapeutic strategies: inhibition and degradation.

In April, drugmaker Revolution Medicines reported that its oral KRAS inhibitor, daraxonrasib, nearly doubled median survival in patients with previously treated metastatic pancreatic ductal adenocarcinoma. In the phase 3 RASolute 302 trial, patients receiving daraxonrasib lived a median of 13.2 months vs 6.7 months with investigator’s choice of chemotherapy. The benefit held across patients with a range of KRAS mutations.

Weeks earlier, a separate KRAS-directed program reached its own milestone. Setidegrasib (ASP3082), a first-in-class KRAS G12D-targeted protein degrader, became the first KRAS-directed degrader to advance toward a phase 3 trial. Phase 1 data, published in late March, showed the drug produced tumor responses in 24% of heavily pretreated patients with metastatic pancreatic cancer and reported a median overall survival of 10.3 months.

The emergence of two mechanistically distinct RAS-directed strategies may mark an inflection point for pancreatic cancer, especially in the second-line setting where objective response rates to second-line chemotherapy have historically been low, with median overall survival often ranging from 5 to 7 months.

“I can’t remember the last time I saw such a leap forward in pancreatic cancer,” said Mark A. Lewis, MD, director of gastrointestinal oncology at Intermountain Healthcare in Murray, Utah.

These promising options also raise an important question for oncologists: which strategy to use, for which patient, and when.

A Tale of Two Strategies

KRAS belongs to a family of three closely related RAS proteins that act as molecular switches, relaying growth signals from cell surface receptors to MAPK and other pathways that regulate cell division and survival. In healthy cells, the switch toggles between active and inactive states: KRAS turns on, then off, allowing the signal to pulse, then quiet.

Cancer-associated mutations disrupt this control mechanism, leaving the switch stuck on. Downstream signaling never quiets, and cells proliferate.

In pancreatic ductal adenocarcinoma, more than 90% of tumors harbor a KRAS mutation. The disease is dominated by G12D, G12V, and G12R variants, rather than G12C, which is the target of the first approved KRAS inhibitors — sotorasib and adagrasib. These agents, approved for certain lung and colorectal cancers, inhibit KRAS G12C by locking the mutant protein in its inactive state. Still, no KRAS-targeted therapy has been approved for pancreatic cancer.

“G12C is the easy one — the light switch is off,” Lewis explained. “The much larger problem is that the vast majority of pancreatic cancer has a KRAS mutation where the light switch is stuck on.”

That’s where the latest drugs come in.

Daraxonrasib does not try to turn the switch off. Instead, the oral drug binds the chaperone protein cyclophilin A, and the resulting complex binds the active form of RAS, blocking downstream signaling. Daraxonrasib does not discriminate by mutation type. It can target a broad range of RAS variants in their active state, including wild-type RAS.

“If the light switch is stuck on, let’s just cut the wires that run to the light,” Lewis said. “It is an incredibly effective, but also less selective approach.”

Setidegrasib takes a different path. Rather than blocking the protein, it tags KRAS G12D for destruction by the cell’s own disposal machinery — the same system that clears damaged proteins under normal conditions. The drug then dissociates and binds another KRAS molecule, triggering a catalytic mechanism.

The trade-offs of the two drugs follow from the mechanism. Daraxonrasib casts a much wider net across KRAS-mutated disease, which covers most patients, but that broader reach comes with greater toxicity. Setidegrasib targets fewer patients — only the roughly 40% of patients whose tumors carry KRAS G12D mutations — but comes with fewer side effects.

It’s essentially a shotgun vs sniper approach, explained Wungki Park, MD, MS, a gastrointestinal medical oncologist at Memorial Sloan Kettering Cancer Center (MSKCC) in New York City and lead author of setidegrasib’s phase 1 study.

The shotgun approach for daraxonrasib “is not as clean. It will hit a lot,” while setidegrasib’s sniper approach will just target G12D, Park said.

The Numbers That Matter

The daraxonrasib numbers signal a meaningful advance.

The phase 3 RASolute 302 trial randomly assigned patients with previously treated metastatic pancreatic cancer to daraxonrasib 300 mg orally once daily vs investigator’s choice of chemotherapy. The intent-to-treat population — covering G12, G13, Q61, and wild-type RAS tumors — produced the headline 13.2-month median overall survival vs 6.7 months for chemotherapy. The full primary analysis goes to plenary at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting later this week.

“The data looked so promising from the phase 1/2 that it allowed us to try to recapitulate that, and now prove it, in a phase 3 trial,” said Brian Wolpin, MD, MPH, the trial’s principal investigator and director of the Hale Family Center for Pancreatic Cancer Research at Dana-Farber Cancer Institute in Boston.

That phase 1/2 data, published online on May 6, demonstrated an objective response in 29% of 38 patients with a RAS mutation who received daraxonrasib 300 mg as second-line therapy. The disease control rate was 95%, the median progression-free survival was 8.1 months, and the median overall survival was 15.6 months.

Recent first-line has also pushed the daraxonrasib picture earlier. Daraxonrasib daily plus gemcitabine and nab-paclitaxel produced an objective response rate of 58% in 40 previously untreated patients, with 6-month progression-free and overall survival rates of 84% and 90%, according to phase 1/2 data presented at the AACR Annual Meeting 2026 in April. Another study from the meeting also found that first-line monotherapy achieved a 47% response rate.

Eileen M. O’Reilly, MD, a gastrointestinal medical oncologist at MSKCC and lead author on the monotherapy study, finds the possibility of an oral, targeted therapy “very compelling,” especially for patients who can’t tolerate or chose to forgo chemotherapy.

Kanwal Raghav, MD, a gastrointestinal medical oncologist at The University of Texas MD Anderson Cancer Center in Houston, is interested to see whether combining daraxonrasib with chemotherapy has an additive or synergistic effect compared to daraxonrasib monotherapy.

He did caution, however, that response rates from small, early studies tend to drop in larger trials, which “still means there’s about 50% of patients that don’t respond.”

A phase 3 first-line trial, RASolute 303, is now enrolling.

Setidegrasib’s dataset is smaller and earlier, but its biological readout is striking. The phase 1 study enrolled 203 patients with KRAS G12D-mutated solid tumors across 28 centers in five countries. Among 21 patients with metastatic pancreatic cancer who received the recommended 600-mg dose intravenously once weekly as second- or third-line treatment, 24% achieved a confirmed partial response, with median progression-free survival of 3.0 months and median overall survival of 10.3 months.

The pharmacodynamic readout went further. In paired tumor biopsies obtained before and after one cycle of treatment, the median KRAS G12D protein reduction at the 600-mg dose was 95.5% in the pancreatic cancer cohort. In responders, the median greatest reduction in circulating tumor DNA (ctDNA) exceeded 91%.

Although 95% “is really good,” it may not be enough, said Park. “It’s not always the case that if you have full degradation, it will translate into shutdown of the MAPK pathway. But it’s very meaningful.”

A phase 3 trial evaluating setidegrasib as first-line therapy in KRAS G12D-mutated metastatic pancreatic cancer is underway.

The Tolerability Bargain

The conversations these drugs require in the clinic are not interchangeable.

Daraxonrasib is oral, taken daily, and produces a side-effect profile that flows from its breadth. Among 83 patients who received the 300-mg dose in the phase 1/2 study, 34% had treatment-related adverse events of grade 3 or higher. Rash, the dominant toxicity, affected 90% of patients at any grade, followed by stomatitis or mucositis in 54%, diarrhea in 52%, and nausea in 39%.

Treatment-related adverse events led to dose modifications in nearly half of the patients, but no patient discontinued therapy because of them. The trial investigators recommended prophylaxis in future studies to limit grade 3 adverse events.

The benefits and costs have a public face. Former Sen. Ben Sasse disclosed his metastatic pancreatic cancer diagnosis in December and treatment with daraxonrasib through a clinical trial. In an interview with CBS News program 60 Minutes, Sasse reported a 76% reduction in tumor volume. He also appeared on camera with a serious facial rash.

“I really admire him because he’s gone on public television with a fairly disfiguring, bleeding rash,” but “he’s getting longer survival,” Lewis said. “He’s showing both sides of it.”

Wolpin emphasized that managing toxicity is possible but requires practice change. “We have had other drugs that cause these similar side effects, including EGFR [epidermal growth factor receptor] antibodies,” he said. “We’ve learned you have to give prophylactic medicines, and you have to treat it early.”

Setidegrasib’s side-effect profile is narrower and largely limited to transient infusion-related reactions. Among 76 patients who received the 600-mg dose, 80% experienced an infusion-related reaction, though none reached grade 3. The reactions occurred predominantly during the first infusion and declined substantially with subsequent infusions, managed with antihistamines, infusion-rate modification, and temporary interruption. Treatment-related grade 3 or higher adverse events occurred in 9% of patients, with no grade 3 or higher gastrointestinal or dermatologic toxicities.

For Park, the cleaner profile carries strategic implications. “If your drug has a lot of side effects, it’s a lot harder to combine,” he said. “When it’s very clean and works with that sniper approach, then it’s easier to combine.”

From Trials to Clinic

The arrival of meaningful KRAS therapies is already reshaping the decisions oncologists make. The first is what to test for and when.

“We are very close to it being considered malpractice not to know what KRAS mutation is driving pancreatic cancer,” Lewis said. “That’s how forcefully I would put it.”

The infrastructure to make that testing routine is in place. Liquid biopsy panels that detect ctDNA can identify the relevant mutations in about 2 weeks from a blood draw, taking advantage of the very high shed rate of tumor DNA into the bloodstream.

Then comes access. On May 1, the FDA issued a “safe to proceed” letter allowing an expanded access program for daraxonrasib in patients with previously treated metastatic pancreatic cancer. But expanded access is not approval. The program requires that patients have exhausted all available standard chemotherapy, and even then, their oncologist must apply directly through Revolution Medicines, a process that may not be familiar to everyone.

Despite limited access now, Lewis and Wolpin both see a major payoff coming further upstream, particularly for adjuvant therapy after curative surgery where most patients ultimately relapse.

“It’s one thing to treat someone in the metastatic setting,” Lewis said. “It’s unfortunately very unlikely that we’ll see cures there. The bigger question is, if there’s less cancer to treat, maybe a pill like this is exactly what those patients need.”

O’Reilly sees the current moment as foundational. “To me, it’s like the emergence of immunotherapy for melanoma,” said O’Reilly, a principal investigator on RASolute 302 and RASolute 304, which is investigating adjuvant daraxonrasib following curative surgery. “It’s the start of something big in this disease.”

Resistance will emerge. Revolution Medicines has published preliminary data showing KRAS amplification as the dominant resistance mechanism to daraxonrasib in 35% of evaluable patients.

Setidegrasib’s resistance profile remains largely uncharacterized given its earlier development stage.

For Raghav, the picture is the start of a familiar arc rather than the end of a story. “By no stretch of imagination do I think any of these inhibitors by themselves will be a home run,” he said. “It’s the first step.”

But for the first time in three decades, the question oncologists treating pancreatic cancer face is not whether progress is possible, but how much more progress can be made.

“The mutation that was once the classically undruggable mutation is now druggable,” Lewis said. “We have now completely dispelled the notion that this is a fruitless avenue of research and practice.”

For Wolpin, who has spent more than a decade chasing this target, the moment registers personally. “I think we’re absolutely at an inflection point,” Wolpin said. Ultimately, these drugs are “going to dramatically change how we treat the cancer for our patients.”

Wolpin reported receiving research funding from and having consulting relationships with Revolution Medicines and other companies. Park reported receiving research funding from and having consulting relationships with Astellas Pharma and other companies. O’Reilly reported receiving research funding from and having consulting relationships with Revolution Medicines, Astellas Pharma, and other companies. Lewis and Raghav reported having no relevant disclosures related to the products discussed. Raghav has presented data on elironrasib, a separate KRAS G12C agent. Astellas Pharma funded the setidegrasib phase 1 trial. Revolution Medicines funded the daraxonrasib trials.