RAS Inhibitor Daraxonrasib Redefines Pancreatic Cancer Treatment After FDA Approval

Pancreatic ductal adenocarcinoma has long been one of the most lethal malignancies in medicine, with a five-year survival rate of approximately 13 percent, among the lowest of all cancers. The disease typically causes nonspecific symptoms, so most patients arrive at diagnosis with advanced disease already spread to the liver, lymph nodes, lungs, or peritoneum. Front-line treatment for metastatic disease has consisted of cytotoxic chemotherapy regimens—modified FOLFIRINOX, its liposomal irinotecan variant NALIRIFOX, or the combination of gemcitabine and nab-paclitaxel—yet median survival with these approaches remains under one year, and their considerable toxicity limits their use in frail and older patients. Now, a Perspective published in PLOS Medicine by Samuel P. Soff and Eileen M. O’Reilly of Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center argues that this chemotherapy-dominated era is ending, displaced by small molecules that finally target the RAS oncogene.

The pivot rests on the biology of RAS itself. Pancreatic ductal adenocarcinoma is characterized by alterations in the rat sarcoma mitogen-activated protein kinase pathway. In its normal state, the RAS enzyme cycles between an inactive guanosine diphosphate-bound “off” configuration and an active guanosine triphosphate-bound “on” state that promotes cell proliferation and survival. Mutations lock the protein into a constitutively active “on” state, driving tumor growth, survival, migration, and invasion in pancreatic, lung, and colorectal cancers. Mutations in the KRAS oncogene occur in 90 to 95 percent of pancreatic cancers, most commonly at codon 12: G12D accounts for roughly 40 percent of cases, G12V for about 30 percent, and G12R for approximately 15 percent. That near-universal prevalence has made KRAS the most compelling therapeutic target in the disease.

For decades, however, RAS was considered “undruggable,” because the protein offers few binding pockets for drugs and binds GTP with extremely high affinity. The first crack in that wall came from targeting the KRAS G12C subtype, which appears in only 1 to 2 percent of pancreatic cancers. The G12C inhibitor sotorasib demonstrated an overall response rate of 21 percent, a median progression-free survival of 4.0 months, and a median overall survival of 6.9 months in pancreatic cancer, while a second G12C inhibitor, adagrasib, showed a moderate survival benefit and response rate. Those results, though confined to a small slice of patients, established the clinical principle that RAS could be drugged at all.

The decisive shift came with daraxonrasib, known in development as RMC-6236, a novel tricomplex inhibitor that binds the active, GTP-bound RAS-ON state across multiple oncogenic RAS variants as well as wild-type forms. Because it does not depend on a single rare mutation, it potentially extends targeted therapy to nearly every patient with pancreatic ductal adenocarcinoma. In the phase 3 RASolute 302 trial, five hundred patients with previously treated metastatic disease—92 percent of whom had KRAS G12-mutated tumors—were randomized to daraxonrasib or to the best standard chemotherapy. In the G12-mutated population, daraxonrasib produced a median overall survival of 13.2 months versus 6.6 months for chemotherapy, and median progression-free survival of 7.3 months versus 3.5 months.

The tolerability data were equally striking. The most common side effects of daraxonrasib were rash, diarrhea, stomatitis, nausea, and vomiting, but the drug was generally tolerated more favorably than chemotherapy. Grade 3 or higher adverse events occurred in 61.8 percent of patients on daraxonrasib versus 69.6 percent on chemotherapy, and treatment-related discontinuation rates were 1.2 percent versus 11.2 percent. The Perspective’s authors describe these results as without precedent in pancreatic cancer, firmly discrediting the notion that RAS is undruggable and opening nonchemotherapy treatment paradigms that could include older and frailer patients previously excluded from intensive regimens. Daraxonrasib received approval from the US Food and Drug Administration in August 2026 and is under expedited review by global authorities.

Combination strategies are also advancing: protein arginine methyltransferase 5 inhibitors, which disrupt gene splicing and cellular signaling and specifically target methylthioadenosine phosphorylase-deleted tumors present in roughly 20 to 30 percent of pancreatic cancers, showed in preclinical testing that combining them with daraxonrasib, the G12D inhibitor MRTX1133, or adagrasib reduced cell division and caused tumor regression more than either drug alone.

Early clinical combination data are encouraging but preliminary. An ongoing phase 1/2 trial of a PRMT5 inhibitor plus daraxonrasib demonstrated a 92 percent overall response rate, 90 percent progression-free survival at six months, and a 100 percent disease control rate, supporting a planned phase 3 trial. Separately, allele-specific agents are closing in on G12D, the most prevalent KRAS mutation in the disease. Setidegrasib, a G12D protein degrader, achieved objective tumor shrinkage in 24 percent of patients, with median progression-free survival of 3 months and overall survival of 10.3 months—notably, 67 percent of those patients received the drug as third-line treatment. HRS-4642, another G12D-specific inhibitor combined with gemcitabine and nab-paclitaxel, demonstrated 63.3 percent tumor shrinkage as first-line therapy in metastatic disease.

The implications reach beyond the pancreas. KRAS mutations drive substantial fractions of non-small-cell lung cancer and colorectal cancer, and G12C inhibitors including adagrasib, sotorasib, and olomorasib have been applied in both, as has setidegrasib in lung cancer. First-generation G12C inhibitors achieved overall response rates of 30 to 40 percent with progression-free survival of 6 to 8 months in those tumor types, mirroring their pancreatic results. Second-generation inhibitors such as olomorasib have improved on those numbers, with response rates of 45 to 55 percent and longer progression-free survival. Daraxonrasib has also shown promise in lung cancer: the phase 1/2 NCT05379985 trial demonstrated a 37 percent overall response rate in previously treated advanced RAS-mutant non-small-cell lung cancer.

Substantial obstacles remain, chief among them treatment resistance. Among patients with G12C-mutated lung or colorectal cancer treated with adagrasib or sotorasib, 45 percent developed mechanisms of resistance during treatment, and 18 percent showed multiple coinciding mechanisms. These include additional KRAS alterations, oncogenic fusions, and loss-of-function mutations. Resistance to the broader approach has also emerged: among pancreatic cancer patients treated with daraxonrasib, 59 percent had treatment-emergent genomic alterations in the RAS signaling pathway, along with alterations in other pathways such as receptor tyrosine kinase signaling. To counter this, combination strategies are under investigation that target both de novo and acquired resistance—daraxonrasib paired with agents targeting DNA damage response, receptor tyrosine kinases, or a second RAS inhibitor such as zoldonrasib decreased resistance in preclinical models.

Immune-directed combinations add another dimension. KRAS inhibitors can remodel the tumor microenvironment by reducing immunosuppressive cytokines, creating synergy with PD1/PDL1 checkpoint blockade; such combinations have improved responses and delayed resistance in studies that may guide future clinical investigation in RAS-mutated malignancies. The Perspective concludes that pancreatic cancer treatment is undergoing a paradigm shift—from chemotherapy for all to targeted RAS inhibition for all—underscored by the recent FDA approval of daraxonrasib. The next steps its authors identify are evaluating RAS inhibitors as first-line treatments and in neoadjuvant and adjuvant settings, addressing acquired resistance, and defining optimal combination strategies across pancreatic and other RAS-driven cancers.

Subject of Research: RAS-targeted small molecule inhibitors for pancreatic ductal adenocarcinoma

Article Title: Pancreatic cancer: The RAS paradigm shift

Article References: Soff, S. P., & O’Reilly, E. M. (2026). Pancreatic cancer: The RAS paradigm shift. PLOS Medicine, 23(10), e1005283. https://doi.org/10.1371/journal.pmed.1005283

Image Credits: AI Generated

DOI: 10.1371/journal.pmed.1005283

Keywords: pancreatic cancer, KRAS, daraxonrasib, RASolute 302, targeted therapy, drug resistance, clinical trials, oncology, G12D, precision medicine, FDA approval, non-small-cell lung cancer