New treatments that directly target a genetic mutation found in more than nine out of ten pancreatic tumours are offering patients a genuine chance of extra months of life, according to clinical trial data that experts have described as a “gamechanger” and a “grand slam”.
The experimental oral drug daraxonrasib has been shown in a Phase 3 trial involving 500 patients with advanced pancreatic cancer that had already spread to other organs to nearly double median survival when compared with standard chemotherapy. Patients who received daraxonrasib lived for a median of 13.2 months, almost twice the 6.6 months seen in those given chemotherapy.
Although the drug did not significantly extend the time before the disease progressed — median progression-free survival was 7.3 months on daraxonrasib against 7.2 months on chemotherapy — it produced substantially fewer and less severe side effects. Severe adverse events occurred in 43.6% of patients on the new drug, compared with 57.5% on chemotherapy, and only 1.2% of daraxonrasib patients stopped treatment because of side effects, versus 11.2% in the chemotherapy arm.
Daraxonrasib belongs to a new class of medicines called Ras(On) multi-selective inhibitors. It works by binding directly to the mutated form of the KRAS gene, blocking the protein that instructs cancer cells to grow and divide uncontrollably. For decades, KRAS mutations were considered an “undruggable” target because the protein’s smooth surface made it extremely difficult for drugs to lock on to. Recent advances in drug design have finally allowed researchers to crack that barrier.
The KRAS mutation: a near-universal driver of pancreatic cancer
KRAS mutations are present in more than 90% of pancreatic tumours and are regarded as the primary genetic engine driving the disease’s rapid, aggressive growth. Understanding the specific variant of the mutation matters because different subtypes respond differently to treatments. In pancreatic cancer, the most common variants are G12D (found in 39.2% of cases), G12V (32.5%) and G12R (17.1%). The G12C variant, by contrast, is rare, occurring in only 1–2% of cases.
The rarity of G12C explains why existing KRAS inhibitors such as KRAZATI (adagrasib) and LUMAKRAS (sotorasib) — which are already approved for use in lung and colorectal cancers — can only be prescribed off-label for the tiny minority of pancreatic cancer patients who carry that specific mutation. Daraxonrasib, however, has been designed to hit a broader range of KRAS variants, making it relevant to the vast majority of patients with the disease.
Although these drugs represent a major breakthrough, resistance to KRAS inhibitors can still emerge over time. Researchers are already investigating combination strategies — pairing daraxonrasib with other agents — to prevent or overcome resistance. Additionally, work at the Mayo Clinic suggests that detecting mutant KRAS circulating tumour DNA (ctDNA) in a patient’s blood or peritoneal fluid could serve as a powerful biomarker to predict metastasis and survival, enabling doctors to tailor treatment more precisely. Other studies indicate that certain variants, such as G12D, may be linked to worse survival and a weaker immune response to immunotherapy, further underlining the need for personalised approaches.
Charity welcomes ‘most exciting developments in a generation’
Anna Jewell, director of services, research and innovation at Pancreatic Cancer UK, said the new wave of KRAS-targeting treatments represented “some of the most exciting developments we have seen in pancreatic cancer for a very long time”. She said patients were being given “months more precious time with their loved ones”.
Her reaction was echoed by senior clinicians at the American Society of Clinical Oncology (Asco). Dr Julie Gralow, Asco’s chief medical officer and executive vice-president, called the study a “gamechanger” and a “grand slam”. Rachna Shroff, chief of the division of haematology/oncology at the University of Arizona Cancer Centre, described the results as “landscape-changing for metastatic pancreatic cancer patients with a KRAS mutation”.
Daraxonrasib is not yet approved anywhere in the world. Final results from the Phase 3 trial are expected soon. If the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) grants a licence, the National Institute for Health and Care Excellence (NICE) will then need to issue a positive assessment before the drug becomes available on the NHS. Charity advocates believe that, under an optimised timetable, patients could see access in late 2026 or early 2027. Pancreatic Cancer UK is pressing for clinical trials of daraxonrasib to be set up in the UK and for regulators to fast-track its approval.
Pancreatic cancer, which claimed the lives of actors Alan Rickman and Patrick Swayze, remains one of the deadliest malignancies because it is often diagnosed at an advanced stage when surgery is no longer possible. Several patient support organisations — including Pancreatic Cancer UK, Pancreatic Cancer Action, Cancer Research UK and Macmillan Cancer Support — offer information, helplines and clinical trial finders to help patients and families navigate available options.
