Daraxonrasib: The New Pancreatic Cancer Drug Patients Can Access Now through Clinical Trial Showing Promising Results

Introduction

Pancreatic cancer accounts for about 3% of cancer diagnoses in the United States with about 95% of cases being pancreatic ductal adenocarcinoma (PDAC).  In that pool, half of pancreatic cancers are diagnosed after they have already metastasized. The 5-year relative survival rate for metastatic pancreatic cancer is about 3% [1] 

Few therapies are available for patients with previously treated metastatic pancreatic ductal adenocarcinoma (mPDAC), and these treatment regimens have a questionable risk versus benefit ratio.  Activating mutations in the RAS signaling pathway have represented a therapeutic challenge in cancer management for a long time, particularly in mPDAC, where effective targeted therapies remain limited. These aberrant mutations in the RAS pathway drive the pathogenesis of PDAC and account for over 90% of the cases. Daraxonrasib has created a paradigm shift in targeting RAS-driven malignancies and has generated considerable excitement in early-phase clinical trials. 

At the ASCO 2026 annual meeting, the RASolute 302 clinical trial discussed at the plenary session gained attention in the management of metastatic pancreatic ductal adenocarcinoma (mPDAC). The RASolute 302 trial was designed to assess the efficacy of a RAS(ON) multi-selective inhibitor as second-line therapy in patients with metastatic pancreatic cancer, with the goal of establishing a more effective and less toxic alternative to existing chemotherapy regimens.

 RASolute 302 Clinical Trial Overview

RASolute 302 is a global, randomized, open-label, Phase 3 study in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). The study included 500 people with mPDAC who had previously received treatment. 500 participants from North America, Europe, and Asia were randomized to daraxonrasib (248) and currently available chemotherapy regimen (252). Participants had to have an ECOG Performance Status score of 0 or 1, meaning they were able to carry out most of their usual activities. About half were men and half were women, and their median age was 66. There are inclusion exclusion criteria for the trial is as follows:

Inclusion Criteria [2]:

• At least 18 years old and has provided informed consent.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

• Histologically or cytologically confirmed PDAC with metastatic disease.

• Measurable disease per RECIST 1.1.

• Adequate organ function 

• Documented RAS mutation status, either mutant or wild-type. 

• Able to take oral medications.

Exclusion Criteria [2]:

• Prior treatment with direct RAS-targeted therapy

• History of or known central nervous system metastatic disease.

• Any conditions that may affect the ability to take or absorb drug being studied.

• Major surgery within 4 weeks prior to randomization.

• Patient is unable or unwilling to comply with protocol-required study visits or procedures

Daraxonrasib, an oral RAS(ON) multiselective inhibitor, is an effective therapy for patients with previously treated RAS-mutated mPDAC. This agent forms an intracellular tri-complex with cyclophilin A and GTP-bound RAS, thereby inhibiting RAS–effector interactions and robustly suppressing downstream signaling pathways, while demonstrating activity against wild-type KRAS, HRAS, and NRAS. Patients in the other arm received one of the following four intravenous treatments: Gemcitabine and nab-paclitaxel; Oxaliplatin, leucovorin, irinotecan, and 5-FU; Liposomal irinotecan; Oxaliplatin, leucovorin and 5-FU.

Key Findings and Comparison with Standard of Care

• Outcomes measures included primary outcomes like progression free survival (PFS) and overall survival (OS) in the RAS G12–mutant population, and secondary outcome measures like PFS and OS in the all-patient population, time to deterioration (TTD) in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) in the RAS G12 and all-patient populations, percentage of patients with adverse events (AEs), duration of response (DOR), time to response (TTR),  and pharmacokinetics in RAS G12 and all-patient populations [2].

• Results from the first phase 3 trial of a RAS(ON) multi-selective inhibitor showed that daraxonrasib is effective for RAS-mutant and RAS-wild-type metastatic pancreatic ductal adenocarcinoma (mPDAC) [3]. 

• At a median follow-up of 8.5 months, median overall survival (OS) was 13.2 months in the daraxonrasib and 6.6 in the chemotherapy group. Daraxonrasib nearly doubles survival with fewer side effects compared to chemotherapy [3].

• In people who had received daraxonrasib, median progression-free survival (PFS) was 7.3 months for those with a RAS G12 variant and 7.2 months for the overall group whereas, in people getting chemotherapy, median PFS was 3.5 months for those with a RAS G12 variant and 3.6 months for the whole group [3].

• For participants in the daraxonrasib group, the objective response rate (ORR) was 33.2% for those with a RAS G12 variant and 31.6% for the overall group. For participants in the chemotherapy group, the ORR was 11.8% for those with a RAS G12 variant and 11.2% for the overall group [3]. 

• Grade 3 or higher adverse events occurred in 43.6% of the daraxonrasib group and 57.5% of the chemotherapy groups. Treatment discontinuation due to toxicity was also substantially lower with daraxonrasib (1.2% vs 11.2%) [3].

Comparison with Prior Trials

RASolute-302	Phase III; Daraxonrasib (RAS(ON) inhibitor) vs chemotherapy	Previously treated mPDAC	13.2 vs 6.6 months	~7.2 vs 3.6 months
NAPOLI-1 [4]	Phase III; Liposomal irinotecan + 5-FU/LV	2L mPDAC post-gemcitabine	~ 6.1 months	~3.1 months
CON [5]	Phase III; OFF (Oxaliplatin + 5-FU/LV)	Gemcitabine-refractory mPDAC	~ 5.9 vs 3.3 months	—
PANCREOX [6]	Phase III; FOLFOX vs 5-FU/LV	2L mPDAC	~6.1 vs 9.9 mo	—
Early KRAS-targeted trials [7]	Phase I/II; Sotorasib, Adagrasib	KRAS G12C (~1–2% PDAC)	Limited	Limited

Patient Perspective / Plain-Language Summary

In the RASOLUTE-302 Trial, about 500 patients were randomly assigned to receive either daraxonrasib or intravenous standard chemotherapy. The goal was to see if this new drug could help patients live longer and delay cancer progression. Daraxonrasib works differently from traditional chemotherapy. It targets RAS, which is abnormal in about 90% pancreatic cancer. The results were promising. Patients taking daraxonrasib lived significantly longer, about 13 months on average compared to 6–7 months with chemotherapy, and their cancer stayed controlled for a longer period. Additionally, fewer patients experienced severe side effects. Overall, this trial suggests that daraxonrasib could become a more effective and better-tolerated treatment option for patients with advanced pancreatic cancer.

Next Steps 

Although daraxonrasib is investigational, it is available to patients with previously treated mPDAC, regardless of RAS mutation status, through a US Food and Drug Administration (FDA) expanded access treatment protocol (EAP) while the drug undergoes regulatory review by the FDA. Ongoing studies are further evaluating daraxonrasib as a first-line therapy for mPDAC and in other RAS-driven malignancies. Future research is also focused on evaluating mechanisms of resistance and identifying synergistic combination strategies to enhance therapeutic outcomes.

FAQs

What is the trial drug?
Daraxonrasib is a new oral medication that targets the RAS protein, a key driver in about 90% of cases.

Who is eligible?
Adults with metastatic pancreatic cancer who have already received prior treatment and have a good performance status with ECOG of 0 or 1.

How does it compare to standard treatments?
Daraxonrasib nearly doubled survival (~13 vs 6–7 months). Serious side effects were less common with daraxonrasib as compared to chemotherapy.

Is the new drug available?
Yes. While still under review, daraxonrasib is available through clinical trials and US FDA expanded access treatment protocol.

References

1. Multi-Selective RAS(ON) Inhibitor Nearly Doubles Survival Time in People With Metastatic Pancreatic Cancer - ASCO

2. Study Details | NCT06625320 | Phase 3 Study of Daraxonrasib (RMC-6236) in Patients With Previously Treated Metastatic Pancreatic Ductal Adenocarcinoma (PDAC) | ClinicalTrials.gov

3. Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer | New England Journal of Medicine

4. Wang-Gillam A, Hubner RA, Siveke JT, Von Hoff DD, Belanger B, de Jong FA, Mirakhur B, Chen LT. NAPOLI-1 phase 3 study of liposomal irinotecan in metastatic pancreatic cancer: Final overall survival analysis and characteristics of long-term survivors. Eur J Cancer. 2019 Feb;108:78-87. doi: 10.1016/j.ejca.2018.12.007. Epub 2019 Jan 14. PMID: 30654298.

5. Giacchetti S, Perpoint B, Zidani R, Le Bail N, Faggiuolo R, Focan C, Chollet P, Llory JF, Letourneau Y, Coudert B, Bertheaut-Cvitkovic F, Larregain-Fournier D, Le Rol A, Walter S, Adam R, Misset JL, Lévi F. Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2000 Jan;18(1):136-47. doi: 10.1200/JCO.2000.18.1.136. PMID: 10623704.

6. Gill S, Ko YJ, Cripps C, Beaudoin A, Dhesy-Thind S, Zulfiqar M, Zalewski P, Do T, Cano P, Lam WYH, Dowden S, Grassin H, Stewart J, Moore M. PANCREOX: A Randomized Phase III Study of Fluorouracil/Leucovorin With or Without Oxaliplatin for Second-Line Advanced Pancreatic Cancer in Patients Who Have Received Gemcitabine-Based Chemotherapy. J Clin Oncol. 2016 Nov 10;34(32):3914-3920. doi: 10.1200/JCO.2016.68.5776. Epub 2016 Sep 30. PMID: 27621395.

7. DOI: 10.1056/NEJMoa1917239