Daraxonrasib cut the risk of death by 60% and delivered the strongest late-stage results yet against metastatic pancreatic cancer, prompting emotional scenes at the world's largest cancer meeting.
The unveiling of phase 3 data for the experimental oral drug daraxonrasib sparked an extraordinary response at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting.
Thousands of delegates rose to their feet for a standing ovation that lasted nearly a minute after investigators revealed the treatment had nearly doubled survival in metastatic pancreatic cancer.
Presenting the results during ASCO’s plenary session in Chicago on May 31, lead investigator Dr Brian M. Wolpin of the Dana-Farber Cancer Institute revealed that daraxonrasib had achieved a median overall survival of 13.2 months in previously treated metastatic pancreatic ductal adenocarcinoma (mPDAC), compared with 6.6 months for standard chemotherapy.
The treatment reduced the risk of death by 60%, producing a hazard ratio of 0.40, one of the largest survival benefits reported in a phase 3 pancreatic cancer trial.
When the survival curve appeared on screen, the packed auditorium erupted in applause. After waiting for the ovation to subside, Dr Wolpin joked: “That time was not built into my talk”.
The results support daraxonrasib as a potential “new standard of care for patients with previously treated mPDAC, ushering in a new era of RAS-targeted therapy in this disease”, he said.
“For many patients, second line chemotherapy provides modest benefits, and new treatments delivering more durable tumour control have been urgently needed,” Dr Wolpin said.
“In this global randomised trial, daraxonrasib, an oral RAS(ON) inhibitor, doubled median overall survival compared to standard of care chemotherapy for patients with previously treated metastatic pancreatic cancer. Importantly, this survival benefit was achieved with a generally manageable safety profile, highlighted by the low rate of treatment discontinuation due to treatment-related side effects.
“These results will change how scientists, clinicians, and patients think about treatment for pancreatic cancer, and support a new paradigm where RAS(ON) inhibition enters standard of care for patients with previously treated metastatic pancreatic adenocarcinoma.”
The reaction from the ASCO audience reflected decades of frustration in a disease where meaningful therapeutic advances have been rare.
Dr Jennifer Knox, of the University of Toronto and the Princess Margaret Cancer Centre in Toronto, offered her perspective as discussant at the plenary.
“This trial represents the first glimpse of the power of targeting RAS in PDAC. The benefit shown with daraxonrasib, a first-in-class agent, is a remarkable breakthrough,” she said.
“To double the median OS against standard-of-care chemotherapy is absolutely unprecedented in PDAC trials.”
Pancreatic ductal adenocarcinoma remains one of the deadliest malignancies worldwide. Most patients present with advanced disease, and survival outcomes after first-line treatment remain poor.
In previously treated metastatic disease, standard chemotherapy regimens typically deliver median progression-free survival of three to four months and median overall survival of six to seven months.
The biological rationale behind daraxonrasib targets what many cancer researchers have regarded as the central engine of pancreatic cancer.
More than 90% of pancreatic tumours harbour activating mutations in the RAS pathway, most commonly KRAS codon 12 alterations. These mutations drive uncontrolled cellular proliferation and tumour growth.
Daraxonrasib represents a new generation of RAS-targeted therapy. The drug is described as a RAS(ON) multiselective tri-complex inhibitor that targets the active guanosine triphosphate-bound state of both mutant and wild-type RAS proteins.
Unlike mutation-specific KRAS inhibitors currently available for small patient subsets, daraxonrasib was designed to inhibit signalling across multiple KRAS, NRAS, and HRAS variants, including G12, G13, and Q61 mutations.
Preclinical studies also suggested activity in tumours dependent on RAS signalling even when a RAS mutation is not detected.
Results of the pivotal RASolute 302 trial were published simultaneously in the New England Journal of Medicine.
The study enrolled 500 patients across 59 sites in six countries between October 2024 and November 2025.
Eligible patients had metastatic pancreatic ductal adenocarcinoma that had progressed following one prior line of systemic treatment.
Participants were randomised to receive either daraxonrasib 300mg orally once daily or investigator’s choice of chemotherapy, including gemcitabine plus nab-paclitaxel, liposomal irinotecan combinations, modified FOLFIRINOX (fluorouracil, irinotecan, leucovorin, and oxaliplatin) or FOLFOX (fluorouracil, leucovorin, and oxaliplatin).
Of the enrolled population, 91.8% harboured RAS G12 mutations, reflecting the real-world molecular epidemiology of pancreatic cancer.
The trial’s dual primary endpoints were overall survival and progression-free survival in this molecularly defined population.
The efficacy results exceeded expectations. Median overall survival reached 13.2 months in the daraxonrasib arm compared with 6.6 months in the chemotherapy arm among patients with RAS G12 mutations.
The benefit was maintained across the overall study population, where median survival was 13.2 months versus 6.7 months respectively. Investigators reported a hazard ratio of 0.40 in both analyses, representing a 60% reduction in mortality risk.
Progression-free survival findings were similarly striking. Patients receiving daraxonrasib experienced a median progression-free survival of 7.3 months compared with 3.5 months for chemotherapy in the RAS G12 subgroup. Across the overall study population, median progression-free survival was 7.2 months versus 3.6 months, corresponding to hazard ratios of 0.45 and 0.49 respectively.
Tumour responses were substantially more frequent with the experimental agent. Objective responses occurred in 33.2% of patients receiving daraxonrasib compared with 11.8% of those receiving chemotherapy in the RAS G12 population. In the overall population, response rates were 31.6% and 11.2% respectively.
The trial also demonstrated significant improvements in patient-reported outcomes. Median time to pain deterioration was 9.0 months with daraxonrasib compared with 3.7 months with chemotherapy.
Global health status and quality-of-life measures similarly favoured the oral therapy, with patients maintaining quality of life for more than twice as long as those receiving chemotherapy.
The researchers noted that the survival benefit observed with daraxonrasib compared favourably even with outcomes reported in pivotal first-line pancreatic cancer studies.
The median overall survival of 13.2 months achieved in previously treated patients exceeded the survival reported in several landmark first-line studies evaluating FOLFIRINOX, gemcitabine plus nab-paclitaxel and NALIRIFOX (liposomal irinotecan, fluorouracil, leucovorin, and oxaliplatin).
The safety profile has also attracted positive attention. Although adverse events were reported in nearly all patients, treatment-related grade 3 or higher adverse events occurred less frequently with daraxonrasib than with chemotherapy, affecting 43.6% and 57.5% of patients respectively. Serious treatment-related adverse events were also less common with the oral therapy.
The most frequently reported toxicities associated with daraxonrasib were rash, diarrhoea, stomatitis, nausea, and vomiting. Grade 3 toxicities were dominated by rash and stomatitis.
By contrast, chemotherapy produced higher rates of neutropenia, anaemia, thrombocytopenia, and peripheral neuropathy. Hospitalisations due to infections and haematologic toxicities were more common in the chemotherapy arm.
Treatment discontinuation due to treatment-related adverse events occurred in only 1.2% of patients receiving daraxonrasib compared with 11.2% of patients receiving chemotherapy.
The researchers reported that most adverse events could be managed through supportive care measures and dose modification.
“In the RASolute 302 trial, once-daily treatment with oral daraxonrasib resulted in significantly longer overall survival and progression-free survival than standard cytotoxic chemotherapy among patients with previously treated mPDAC, more than 90% of whom had RAS G12 mutations,” they concluded.
“Overall survival results were largely consistent across patient subgroups, and patient-reported end points favoured daraxonrasib. The results of this trial support daraxonrasib as a clinically meaningful advance in the treatment of patients with previously treated mPDAC.”
Related
Regulatory momentum is already building. The US Food and Drug Administration (FDA) has granted daraxonrasib Breakthrough Therapy Designation and Orphan Drug Designation for the treatment of patients with previously treated metastatic pancreatic ductal adenocarcinoma (PDAC) harbouring G12 mutations.
In addition, daraxonrasib was selected for the FDA Commissioner’s National Priority Voucher pilot program, which is intended to accelerate the development and review of therapies aligned with US national health priorities.
Expanded access programs are also being established for eligible patients while regulatory assessment proceeds.
Attention is now turning to earlier disease settings. Ongoing studies are evaluating daraxonrasib in first-line pancreatic cancer, in combination with chemotherapy, and across other RAS-driven malignancies including colorectal, lung, and ovarian cancers.
Daraxonrasib has been developed by Revolution Medicines, a late-stage clinical oncology company developing targeted therapies for patients with RAS-addicted cancers.
Dr Mark Goldsmith, chief executive officer and chairman of Revolution Medicines, welcomed the trial results.
“Daraxonrasib significantly elevates the survival bar in the treatment of one of the deadliest human cancers, while better preserving quality of life compared to chemotherapy,” he said.
“These striking results firmly support daraxonrasib as the new standard of care for patients with previously treated metastatic pancreatic cancer, and usher in a new era of RAS-targeted therapy for patients living with this disease.”
