Pancreatic ductal adenocarcinoma (PDAC) remains one of the most treatment-resistant malignancies, with limited benefit from existing cytotoxic regimens. Nearly 92% of PDACs harbor RAS mutations, making the pathway one of the most ubiquitous oncogenic drivers in human cancer.

Revolution Medicines’ daraxonrasib (RMC-6236)—a multi-selective RAS(ON) inhibitor—has emerged as one of the most promising new agents in this space. Following encouraging results from early-phase studies, the program is advancing into the pivotal RASolute 303 trial, which compares daraxonrasib as monotherapy and in combination with chemotherapy against standard first-line treatment.

To explore how this next-generation RAS inhibitor could redefine care for pancreatic cancer, OncoDaily spoke with Dr. Shiraj Sen, Principal Investigator of the RASolute 303 study and Director of NEXT Oncology–Dallas.

Dr. Shiraj Sen

Dr. Shiraj Sen Linkedin photo

Trial Design and Methods

RASolute 303 is a global, randomized Phase 3 study enrolling newly diagnosed metastatic PDAC patients (ECOG 0–1). Participants are randomized 1:1:1 to:

Daraxonrasib monotherapy (300 mg QD)
Daraxonrasib + gemcitabine/nab-paclitaxel (200 mg QD)
Standard gemcitabine/nab-paclitaxel (GnP)

Primary endpoints: PFS and OS (independent RECIST v1.1).
Secondary endpoints: ORR, DoR, DCR, safety, and patient-reported QoL.

Key Results of RASolute 303

Early clinical activity across trials shows:

Second-line PDAC: ORR 27–36%, DCR >90%, median PFS ~8.5 months, OS up to 15.6 months.
First-line monotherapy: ORR 47%, DCR 89%, with high dose intensity.
First-line combination (daraxonrasib + GnP): ORR 55%, DCR 90%, well tolerated.

Across studies, rash and mucositis remain the most common toxicities, with high treatment adherence and no discontinuations due to toxicity.

These data form the scientific basis for RASolute 303, aiming to compare targeted RAS(ON) inhibition—alone or with chemotherapy—against standard cytotoxic therapy.

Continuous RAS Suppression and Tumor Signaling

Dr. Sen explained that sustained RAS inhibition is already reshaping the therapeutic landscape of pancreatic cancer.

“Emerging data from the early phase studies of multi-selective RAS(ON) inhibitors, both as mono therapy and in combination with conventional chemotherapy, are demonstrating that durable responses are possible in individuals with metastatic, unresectable pancreatic cancer with a variety of RAS mutations. This is very encouraging as it is the first time that a targeted therapy has shown such promise in metastatic pancreatic cancer. Ongoing biomarker analyses will help elucidate how continuous RAS suppression is impacting RAS signaling at the tumor level, both when individuals are responding to treatment and at time of disease progression.”

Why a Three-Arm Trial Design Matters?

The RASolute 303 trial was built on insights from prior data that revealed strong efficacy both with daraxonrasib alone and when combined with chemotherapy. The global Phase 3 study will enroll patients with newly diagnosed metastatic PDAC and randomize them to receive daraxonrasib monotherapy, daraxonrasib plus gemcitabine/nab-paclitaxel, or standard chemotherapy.

Dr. Sen explained that this design was shaped by early clinical experience showing that daraxonrasib could deliver deep and durable responses in multiple treatment settings.

“Revolution Medicines has recently shared the data supporting this three-arm design from the early phase trials of daraxonrasib, both as a monotherapy and in combination with conventional chemotherapy, which we have been fortunate to participate in at NEXT Oncology. The data illustrate that in 38 individuals with newly metastatic pancreatic cancer harboring a RAS mutation that were treated with daraxonrasib at 300 mg as a monotherapy, the overall response rate was 47% and disease control rate was 89%.

This was with the RAS inhibitor alone, without any chemotherapy. In a separate trial, 31 individuals with newly metastatic pancreatic cancer harboring a RAS mutation were treated with daraxonrasib at 200 mg in combination with gemcitabine plus nab-paclitaxel. The ORR was 55% and DCR 90%. Given the efficacy of both regimens, it seems most appropriate to compare both a monotherapy and combination arm to the current standard of care in the RASolute 303 trial in the first line setting. The randomized approach will help clarify how daraxonrasib will may be most effectively utilized, as a monotherapy or in combination with chemotherapy.”

The primary endpoints are progression-free and overall survival, assessed independently using RECIST v1.1 criteria, with secondary endpoints including response durability, safety, and patient-reported quality-of-life outcomes.

Potential to Redefine the Cytotoxic Standard

For decades, treatment for advanced pancreatic cancer has relied on intensive cytotoxic regimens like FOLFIRINOX and gemcitabine/nab-paclitaxel. Daraxonrasib may signal the beginning of a shift toward non-cytotoxic, targeted therapy.

“Currently, the ongoing RASolute 302 trial is evaluating the efficacy of daraxonrasib compared to cytotoxic chemotherapy in the second line, metastatic setting. The readout of this trial may potentially redefine the established treatment sequence of metastatic pancreatic cancer since ~92% of pancreatic cancers harbor a RAS mutation. If this trial identifies that daraxonrasib is more effective than chemotherapy in the second line metastatic setting, this would introduce the first effective, non-cytotoxic treatment option for individuals with metastatic pancreatic cancer ever.”

Patient Experience at the Core

As the program advances, patient experience is becoming a critical focus. Dr. Sen underscored the value of daraxonrasib’s oral dosing and its potential to reduce treatment burden.

“Patient experience and quality of life are always at the forefront of our minds when we develop new treatment options against cancer. As a once-a-day oral treatment option, individuals may be able to spend more time with loved ones or doing what they love and less time in the infusion room or in their oncologist’s office. Recently, many individuals with metastatic pancreatic cancer are being diagnosed at a younger age and still working full-time, traveling, and on-the-go. It will be important to see how patient experience and quality of life differs in individuals getting daraxonrasib compared to chemotherapy.”

Extending RAS(ON) Inhibition Beyond Pancreatic Cancer

Because RAS mutations are also highly prevalent in colorectal and lung cancers, the lessons from pancreatic cancer may guide broader development of RAS(ON) inhibitors.

“Publicly available data already suggests efficacy of RAS(ON) inhibitors, both allele-specific as well as in a multi-selective fashion, in colorectal cancer and NSCLC, as well. As data emerges from the registrational RASolve 301 trial in NSCLC with daraxonrasib, we will be able to assess how these classes of drugs will work across different tumor types. This may help inform the development of the many multi/pan-(K)RAS inhibitors now being offered in the early phase clinical trials at centers like ours at NEXT Oncology.”

Outlook

With RASolute 303 now enrolling, daraxonrasib stands at the forefront of a long-awaited transformation in RAS-driven cancers. Durable responses, oral dosing, and potential synergy with chemotherapy may finally usher in a new era of targeted, patient-centered therapy in one of oncology’s most difficult frontiers.

RASolute 303-for-PDAC