Daraxonrasib, a targeted RAS inhibitor, showed early signs of activity against pancreatic adenocarcinoma in a Phase 1/2 study conducted at MD Anderson Cancer Center.
Trial results suggest longer survival than standard chemotherapy
The open‑label dose‑expansion enrolled 38 participants with RAS‑mutated disease, each receiving a 300 mg daily dose. The primary goal was safety, but efficacy signals emerged quickly.
Objective responses were recorded in 29 % of the cohort, and the median overall survival reached 15.6 months. Historical data for second‑line chemotherapy in this setting report survival of five to seven months, making the new figures noteworthy.
“This trial provides a really strong signal that this targeted therapy has the potential to extend the overall survival of these patients,” said Dr. David Hong, deputy chair of Investigational Cancer Therapeutics. “We saw rapid and durable responses, and the manageable overall safety profile supports the ongoing evaluation of daraxonrasib.”
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Adverse events were common, with 96 % of participants reporting any‑grade effects. Grade 3 or higher toxicities occurred in 30 % of cases, most often rash, diarrhea, oral inflammation and fatigue. Dose adjustments were required for half of those on the 300 mg regimen, yet no one stopped treatment because of side effects.
How daraxonrasib differs from earlier RAS‑targeted drugs
More than 90 % of pancreatic adenocarcinomas carry mutations that activate RAS proteins, primarily KRAS. Existing inhibitors such as KRAS G12C blockers focus on a less common mutation and bind the protein when it is inactive. Daraxonrasib, by contrast, can engage RAS in its active (“on”) state and targets several KRAS variants, expanding its potential applicability.
In the past, drugs that only addressed the “off” state have shown limited benefit for pancreatic disease, where the oncogenic driver is usually locked in the “on” configuration.
The ability to inhibit multiple RAS forms may explain the higher response rate seen in this early trial.
Regulatory attention followed the presentation of these data at the 2025 ASCO Gastrointestinal Cancers Symposium. The FDA granted orphan drug status to daraxonrasib, and a confirmatory Phase 3 study named RASolute is now recruiting.
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Pancreatic cancer remains one of the deadliest malignancies, largely because most cases are diagnosed at an advanced stage when standard therapies have limited impact. First‑line chemotherapy elicits responses in roughly a third of patients, and second‑line options succeed in fewer than ten percent. The new survival numbers, while still modest, push the median beyond the typical five‑month window for later‑line treatment.
Looking back, the field has struggled to translate RAS biology into effective drugs for pancreatic tumors. Earlier attempts focused on a single KRAS mutation that rarely appears in this cancer type, and they often required patients to tolerate high toxicity. Daraxonrasib’s broader activity and tolerable safety profile could represent a shift, though the modest sample size and lack of a control arm temper optimism.
No discontinuations due to toxicity were reported.
Future analysis will compare the ongoing Phase 3 results with standard chemotherapy benchmarks, and will explore whether combination approaches could further improve outcomes. For now, the Phase 1/2 data provide a measurable step forward in a disease that has seen few advances in recent years.
