Revolution Medicines has initiated RASolute 305 (NCT07621718), a global Phase 3 trial of zoldonrasib plus chemotherapy in first‑line metastatic pancreatic cancer with RAS G12D mutations, aiming to improve survival and quality of life in a disease with <3% five‑year survival.
Written By: Farha Farheen, PharmD
Reviewed By: Pharmacally Editorial Team
Revolution Medicines has initiated patient treatment in RASolute 305 (NCT07621718), a global, randomized, double-blind, placebo-controlled Phase 3 trial evaluating zoldonrasib in combination with standard-of-care chemotherapy for patients with previously untreated metastatic RAS G12D pancreatic ductal adenocarcinoma (PDAC).
The trial compares zoldonrasib plus chemotherapy with placebo plus chemotherapy. Investigators may select either modified FOLFIRINOX or gemcitabine plus nab-paclitaxel, two widely used first-line treatment regimens for metastatic PDAC.
The study’s co-primary endpoints are progression-free survival (PFS) and overall survival (OS). Secondary endpoints include objective response rate, duration of response, disease control rate, safety, tolerability, and patient-reported outcomes.
Building on Emerging RAS(ON) Evidence
According to Dr. Alan Sandler, Chief Development Officer of Revolution Medicines, recent clinical findings with daraxonrasib demonstrated improvements in survival, disease control, response rates, and quality-of-life measures compared with chemotherapy in previously treated metastatic pancreatic cancer patients. Those results provided clinical support for advancing RAS(ON)-targeted therapies into earlier treatment settings.
Sandler also noted that early clinical studies of zoldonrasib have shown encouraging antitumor activity and safety, supporting its evaluation in a pivotal first-line trial.
Targeting the Most Common RAS Mutation
Pancreatic ductal adenocarcinoma remains one of the deadliest cancers, with most patients diagnosed after the disease has already spread. More than 90% of PDAC tumors harbor RAS mutations, making the pathway a major driver of tumor growth and progression.
RAS G12D is the most common RAS mutation subtype in pancreatic cancer, occurring in approximately 40% of patients and often associated with poor clinical outcomes. Despite its prevalence, no targeted therapies have been approved specifically for RAS G12D-mutated cancers.
Zoldonrasib is an oral tri-complex inhibitor that selectively targets the active RAS(ON) G12D protein through interaction with cyclophilin A. Beyond pancreatic cancer, RAS G12D is found across several solid tumors and accounts for an estimated 29% of all RAS-driven cancers.
Expanding the Pancreatic Cancer Portfolio
The launch of RASolute 305 expands Revolution Medicines’ late-stage pancreatic cancer program alongside the ongoing Phase 3 RASolute 303 trials evaluating daraxonrasib in the first-line metastatic setting.
Together, the studies are exploring complementary approaches to RAS inhibition, with zoldonrasib targeting the specific G12D mutation and daraxonrasib providing broader multi-selective RAS(ON) inhibition.
What This Means for Patients
Patients with metastatic RAS G12D pancreatic cancer currently rely on chemotherapy and face poor long-term survival outcomes. RASolute 305 will determine whether adding a mutation-specific RAS inhibitor to standard treatment can improve survival, delay disease progression, and maintain quality of life. A positive outcome could establish the first targeted therapy for the most common RAS mutation in pancreatic cancer and expand precision medicine options in a disease with substantial unmet need.
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About the Writer
Farha Farheen, PharmD (LinkedIn) is a pharmacy professional with a strong interest in pharmacovigilance and clinical research. She has completed her Doctor of Pharmacy (Pharm.D) along with her internship as a Clinical Pharmacist. She has hands-on experience in adverse drug reaction (ADR) reporting, safety data documentation, and pharmacovigilance workflows, and is proficient in using VigiFlow. She is also a patent holder for an antibacterial formulation enriched with bioactive substances, granted by the German Patent and Trademark Office.