For Margaret, a 68-year-old retired teacher from western Sydney, the third-line chemotherapy infusion marked the moment her oncologist had quietly run out of obvious next steps. Six months earlier, a CT scan had lit up with liver metastases from a pancreatic primary. By the time she began a clinical-trial protocol involving a once-daily pill called daraxonrasib, her cancer-related pain had become its own daily problem. Twelve months on, her disease is still measurable, but the trajectory everyone in the consulting room had quietly feared has bent in a different direction. Her case is composite, drawn from the patient profile of the RASolute 302 trial, but the pattern is real.
The shape of an "undruggable" target
To understand why Margaret's trajectory matters, start with a single amino-acid change in a single protein. KRAS is a small molecular switch that sits just inside the cell membrane, cycling between an active, GTP-bound form and an inactive, GDP-bound form [1]. When the gene acquires one of a handful of common mutations, most often at codons 12, 13 or 61, the switch sticks in the "on" position and the cell receives a constant, undimmed signal to grow [1]. Activating RAS mutations occur in more than 90% of pancreatic ductal adenocarcinomas (PDAC), the most common form of pancreatic cancer, making KRAS the dominant oncogenic driver in a disease that is unusually starved of treatment options [2].
For four decades, KRAS was considered "undruggable." The protein's surface is smooth, lacks the deep pockets that small molecules usually exploit, and was long thought to bind its substrates too loosely to interrupt. The first crack came with sotorasib and adagrasib, covalent inhibitors that trap the KRAS G12C mutant in its inactive, GDP-bound state [3]. Their success was real but narrow: KRAS G12C accounts for only about 15% of KRAS-mutated cancers, and the mutation is found in just 1-2% of pancreatic tumours, where G12D, G12V and G12R dominate [3]. For most patients with KRAS-driven disease, the 2021-2024 generation of targeted therapy simply was not an option.
A molecular glue for active RAS
Daraxonrasib (RMC-6236) takes a different tack entirely. It is a RAS(ON) inhibitor, meaning it does not try to lock RAS in the "off" position. Instead, it binds to the active, GTP-bound form and silences it there. To do that, the molecule recruits a small intracellular helper called cyclophilin A (CypA), forming a three-part "tri-complex" of CypA, the drug and active RAS [4]. The shape created by this ternary assembly blocks the surface that downstream signalling partners would normally use, shutting down the MAPK cascade the cancer depends on [4].
Two practical consequences follow. Because the binding pocket forms at the interface between CypA and RAS, it can accommodate the bulky amino-acid substitutions at codons 12, 13 and 61, which is why the same drug works across G12D, G12V, G12R, G12C and beyond [4]. And because daraxonrasib binds the active state, it can engage wild-type RAS proteins when tumours become dependent on them, a pattern of resistance that has blunted the G12C-selective drugs [5]. The drug is a macrocyclic, oral, once-daily tablet, with 300 mg selected as the Phase 3 dose [2].
What RASolute 302 showed
The pivotal data come from RASolute 302, a Phase 3 international trial that randomised 500 patients with previously treated metastatic PDAC: 248 to daraxonrasib, 252 to investigator's choice chemotherapy [6]. 91.8% of those enrolled carried a RAS G12 mutation [6].
In the primary analysis restricted to the RAS G12 population, median overall survival was 13.2 months on daraxonrasib compared with 6.6 months on chemotherapy, a hazard ratio of 0.40 (P<0.001) [6]. In plain language, the risk of death during follow-up was roughly 60% lower in the daraxonrasib arm, and median survival was effectively doubled. The same hazard ratio of 0.40 held in the overall intention-to-treat population (13.2 versus 6.7 months, P<0.001), and median progression-free survival in the G12 group improved from 3.5 to 7.3 months (HR 0.45, P<0.001) [6]. The Phase 1-2 work that preceded the Phase 3 trial pointed in the same direction: 26 patients with second-line RAS G12-mutant PDAC treated at 300 mg had a 35% objective response rate, a median duration of response of 8.2 months and a median overall survival of 13.1 months [2].
As the RASolute 302 investigators, O'Reilly and colleagues, concluded in their published paper:
"Among patients with previously treated mPDAC, treatment with daraxonrasib led to significantly longer overall survival and progression-free survival than chemotherapy" [6].
Safety held up. Grade 3 or higher events were less common with daraxonrasib (61.8%) than with chemotherapy (69.6%), and treatment-related discontinuations occurred in 1.2% of daraxonrasib patients versus 11.2% on chemotherapy, almost a tenfold reduction [6]. In the Phase 1-2 study, the most common toxicities were rash, diarrhoea, nausea, stomatitis, vomiting and fatigue [2]. Real symptoms, but the kind oncology teams are accustomed to supporting patients through.
Beyond the pancreas: where RAS mutations reach
Pancreatic cancer is among the most lethal common solid tumours, with a five-year survival of 14% in the US and roughly 552,700 deaths globally in 2023 [7]. But RAS-driven cancer is not a pancreas-only story. RAS mutations are estimated to drive roughly a quarter of all human cancers, including around 30% of colorectal cancers and 25% of lung cancers [5]. Revolution Medicines has Phase 3 programmes already under way in both non-small cell lung cancer and colorectal cancer [8].
Two caveats matter. KRAS-mutant non-small cell lung cancer develops brain metastases in around 30% of patients, and preclinical work suggests the ABCB1 transporter may pump daraxonrasib out at the blood-brain barrier [8]. Acquired resistance is also a real and soon-to-be-clinical problem. A May 2026 analysis of paired baseline and end-of-treatment samples from 40 daraxonrasib-treated patients found that 18 of 40 (45%) had acquired mutations that disrupt the tri-complex itself, the first clinical evidence of how this new class of drugs fails [9]. Designing the second-generation tri-complex inhibitor that escapes resistance is the next research question the field is already working on.
The Australian patient on Monday morning
For Australian readers, the immediate question is what these numbers mean at home. Cancer Council Australia estimated that 4,641 people were diagnosed with pancreatic cancer in 2024, with an average age at diagnosis of 72 and a lifetime risk of about one in 70 by age 85 [10]. The disease is the eighth most commonly diagnosed cancer in the country, and there is still no national screening program [10]. Risk factors include smoking, which roughly doubles or triples the odds, alongside obesity, type 2 diabetes, chronic pancreatitis and a strong family history [10][11].
Pancare Foundation, the principal Australian charity supporting people with upper gastrointestinal cancers, runs a nurse-led support line (1300 881 698, weekdays 9-5) and produces the My Care KIT patient guide [11]. For Australian patients with previously treated metastatic PDAC today, access to daraxonrasib runs through the Revolution Medicines clinical-trial programme at major metropolitan cancer centres, rather than through a Pharmaceutical Benefits Scheme listing. TGA evaluation has not yet completed, and Australian-specific mortality data could not be independently verified at the time of writing. Science is no longer the bottleneck. Logistics, getting the drug to the right patient on the right trial in the right city, now are.
For Margaret, and the thousands of Australians who share her diagnosis each year, the appearance of a once-daily pill that more than doubles median survival in a randomised trial is the first clear signal in two decades that the field has turned a corner on KRAS. There is more work to do on resistance, brain metastases and access, and on the many other cancers this mechanism could reach. But 13.2 months against 6.6 is the kind of result that, in oncology, you build a programme around.