‘Grand Slam’ in Pancreatic Cancer: Novel Pill Doubles Survival

CHICAGO — RASolute 302 trial results were hailed as a game-changing breakthrough in the treatment of pancreatic cancer.

The phase III study showed that second-line daraxonrasib, an investigational oral RAS(ON) multi-selective inhibitor, doubled overall survival (OS) and progression-free survival (PFS) in patients with previously treated metastatic pancreatic ductal adenocarcinoma.

In the primary endpoint population of patients with RAS G12 mutations, median OS reached 13.2 months with daraxonrasib versus 6.6 months with investigator’s choice of chemotherapy (HR 0.40, 95% CI 0.30-0.54, P<0.001), reported Brian Wolpin, MD, MPH, of the Dana-Farber Cancer Institute in Boston.

PFS (the second primary endpoint) reached a median 7.3 months with daraxonrasib versus 3.5 months with chemotherapy (HR 0.45, 95% CI 0.34-0.59, P<0.001), according to findings detailed at the American Society of Clinical Oncology (ASCO) annual meeting and published simultaneously in the New England Journal of Medicine.

“These results support daraxonrasib as the new standard of care for patients with previously treated metastatic pancreatic cancer,” Wolpin said at a press briefing.

The magnitude of OS and PFS benefit was similar in the study’s overall population, which also included patients with less common RAS mutations.

ASCO discussant Rachna Shroff, MD, MS, of the University of Arizona Cancer Center in Tucson, said the study is “a proof of principle that targeting the RAS signaling pathway is critical in the treatment of pancreatic cancer.”

“RASolute 302 literally checks all of the boxes when we think about relevant and important and meaningful clinical outcomes,” that were “never seen in previously treated pancreatic cancer,” she said. “This is such an incredibly impactful study for our patients.”

“I’ve heard this study described as a home run,” said ASCO’s chief medical officer Julie Gralow, MD. “I would actually say it’s a grand slam.”

In early May, the FDA greenlighted daraxonrasib’s maker to initiate an expanded access program in collaboration with licensed prescribers.

Pancreatic cancer remains a very challenging and lethal malignancy, Wolpin said. “Standard chemotherapy in the second-line setting … really does not work as well as we would like.”

More than 90% of pancreatic cancer cases involve a mutation in KRAS.

“Most often, that’s KRAS G12D, G12V, and G12R. Because of this, excessive signaling through RAS drives the tumor to grow, and that’s true when there’s a RAS mutation and also happens to be true when there’s not a RAS mutation,” said Wolpin. “RAS signaling is still very important to pancreatic cancer growth. We’ve known this for quite some time. However, there have been no approved therapies that target RAS that can be used … for patients with pancreatic cancer.”

Wolpin explained that daraxonrasib binds to and blocks wild-type and mutant RAS, including the mutations at the codons commonly seen in pancreatic cancer.

The 500 patients in RASolute 302 had previously treated metastatic pancreatic ductal adenocarcinoma. Median patient age in the overall population was around 65, most were male, about a quarter underwent a Whipple procedure, and the liver was the most common site of metastases. Roughly 85% had received first-line systemic therapy, with the remaining having quickly progressed to metastatic disease following neoadjuvant or adjuvant treatment.

Participants were randomized from October 2024 to November 2025 to oral daraxonrasib (300 mg once daily) or investigator’s choice of chemotherapy: gemcitabine plus nab-paclitaxel (Abraxane), modified FOLFIRINOX (fluorouracil, irinotecan, leucovorin, oxaliplatin), FOLFOX (fluorouracil,
leucovorin, oxaliplatin), or liposomal irinotecan plus fluorouracil and leucovorin.

Median duration of follow-up was 8.5 months. The median duration of treatment was 6.2 months with daraxonrasib and 1.5 to 3.2 months with chemotherapy, depending on the regimen.

Objective response rates were 33.2% with daraxonrasib and 11.8% with chemotherapy in the RAS G12 population and 31.6% and 11.2%, respectively, in the overall population.

Wolpin said that the time to deterioration, as assessed on the basis of pain and patient-reported quality of life, was significantly longer with daraxonrasib than with chemotherapy in both populations.

Regarding safety, treatment-related adverse events (TRAEs) occurred in over 90% of both arms; the most common TRAE with daraxonrasib was rash (85.5%). The most frequent grade ≥3 TRAEs with daraxonrasib were rash (13.7%) and stomatitis (12%). TRAEs leading to treatment discontinuation occurred in 1.2% of the daraxonrasib arm and 11.2% of the chemotherapy arm.

“While there have been questions around the safety profile of daraxonrasib in targeting RAS specifically, I think the other important takeaway … is that the safety profile is relatively predictable and really did not lead to a significant amount of discontinuation,” Shroff observed. “We see that in how patients stayed on this treatment because it was providing a durable and meaningful benefit to them. And the patient-reported outcomes … support that as well.”

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