Daraxonrasib Approval Signals a New Era for RAS-Targeted Therapy in Pancreatic Cancer

The FDA approval of daraxonrasib (Rasonque), an oral RAS(ON) inhibitor employing a mechanism that has long been difficult to achieve, for patients with metastatic pancreatic adenocarcinoma provides a new treatment option after prior systemic therapy, as well as an option for patients who are not candidates for multi-agent systemic therapy, according to Benjamin Weinberg, MD.

The approval was supported by findings from the phase 3 RASolute 302 trial (NCT06625320), which randomly assigned 500 patients whose disease had progressed after 1 prior line of systemic therapy to receive daraxonrasib or standard-of-care chemotherapy.^1,2 In the overall population, the median overall survival (OS) was 13.2 months (95% CI, 10.0-not estimable) with daraxonrasib (n = 248) vs 6.7 months (95% CI, 5.8-8.0) with chemotherapy (n = 252; HR, 0.40; 95% CI, 0.30-0.53; P < .0001). The median progression-free survival values were 7.2 months (95% CI, 5.7-7.5) vs 3.6 months (95% CI, 2.9-4.2), respectively (HR, 0.49; 95% CI, 0.38-0.64; P < .0001). The respective objective response rates were 30% (95% CI, 25%-36%) vs 11% (95% CI, 7%-15%; P < .0001).

“The median OS was nearly doubled [with daraxonrasib], which is impressive in this population,” Weinberg said in an interview with OncLive^®.

In the interview, Weinberg discussed why he views the approval as a dramatic change in pancreatic cancer care. He also explained how daraxonrasib works, what to know about managing rash and other adverse effects associated with the agent, and how the results could inform future RAS-targeted combinations.

Weinberg is an associate professor of medicine and an attending physician at MedStar Health and an associate professor of medicine in the Division of Hematology and Oncology at the Lombardi Comprehensive Cancer Center at Georgetown University in Washington, DC.

OncLive: What is the significance of the FDA approval of daraxonrasib for patients with pancreatic cancer?

Weinberg: We throw around terms like ‘breakthrough’ and ‘sea change’ quite a bit, but this truly is a dramatic change in how we manage pancreatic cancer. We’ve been trying for 40-plus years to target RAS. KRAS mutations are seen in approximately 90% to 92% of pancreatic adenocarcinomas, and we’ve struggled to target them on a molecular level.

Daraxonrasib is a pan-RAS inhibitor, so it blocks all RAS signaling, both in RAS-mutated tumors and in RAS wild-type tumors. It doesn’t seem to matter what the specific molecular alteration in the tumor is. This [agent] works through a different mechanism and pathway than systemic chemotherapy, which is just killing rapidly dividing cells.

In the [RASolute 302] study that led to the drug’s approval, patients with metastatic pancreatic cancer who’d already received 1 prior line of systemic chemotherapy [achieved better outcomes] with this drug than with chemotherapy. Although the drug is associated with adverse effects [(AEs), it will make] a big difference in how we treat patients with this cancer, especially those who have already received chemotherapy.

The FDA[-approved indication also includes] patients who we don’t think would tolerate multi-agent systemic therapy. They can start with [daraxonrasib] instead of having to be exposed to chemotherapy first. This approval expands the treatment landscape for those patients as well.

What makes daraxonrasib’s mechanism of action unique?

The abnormality of RAS is that it is a GTPase that gets stuck in its GTP-bound, or ON, state. It cycles between that and its GDP-bound, or OFF, state. Other drugs have already been developed to target specific KRAS alleles like KRAS G12C, which is seen more commonly in lung cancer and, to a lesser extent, colorectal cancer. Those bind the [RAS] OFF state, and that specific allele tends to cycle back and forth in a predictable way.

With most of the KRAS mutations in pancreatic cancer [G12D, G12V, and G12R being the most common], we have to hit the ON state and hit it effectively. Daraxonrasib gets incorporated intracellularly and binds to cyclophilin A, which allows it to hit this molecular pocket and act as a glue, to dislodge the ON state and prevent it from signaling down signal-transduction pathways, mostly the MAPK pathway and, to a lesser extent, the PI3K/mTOR pathway. Doing so blocks RAS signaling in both RAS-mutated and RAS wild-type cells. There are associated AEs, in part because normal cells use this pathway as well. But [overall, this process is] what allows these tumors to be killed more preferentially than with chemotherapy.

What were the key efficacy findings from RASolute 302?

This [trial enrolled] patients with metastatic pancreatic cancer [and treated them] in the second-line setting. The focus was on those with KRAS G12–mutated tumors, but the trial also evaluated the overall population [regardless of RAS mutational status], and it turned out there wasn’t a significant difference [in daraxonrasib efficacy between the KRAS G12–mutated population and the overall population].

The chemotherapy arm did what we expected, with a median OS of approximately 6 to 7 months [across subpopulations]. With daraxonrasib, we saw a median OS of approximately 12 to 13 months, depending on which subpopulation you’re looking at. That’s a near doubling in median OS. There are patients who have been [receiving daraxonrasib] for longer than 1 year with stable disease or responses.

[Daraxonrasib has shown] a higher response rate and greater durability of response [vs chemotherapy]. But at the end of the day, what really matters, aside from toxicity, is survival.

What is important to know about daraxonrasib’s safety profile?

The rash is real, and most patients get it. It tends to affect the head, neck, and trunk. If anyone has seen interviews with Ben Sasse, the former United States senator who [was a patient] on the study, you can see the evolution of his rash [mitigation] over time, likely due to more effective management and perhaps dose modification.

We recommend starting prophylaxis [before patients start daraxonrasib]. Similar to EGFR-directed antibody–associated rashes, I tend to give patients a tetracycline antibiotic, usually minocycline, twice a day. It’s also recommended that you prescribe 2 different topical corticosteroids, 1 for the face and 1 for the neck and trunk, applied twice a day, along with an antiseptic and sunscreen. It’s a lot of skin care and maintenance that we need to become more comfortable with and spend time working through with our patients. By doing this, a lot of the rash can be mitigated.

Another [AE] risk is stomatitis, or mouth sores. It’s recommended to avoid alcohol, alcoholic mouth rinses, and even foods like chips that have sharp edges and could damage the mucosa. We also need to watch for diarrhea, nausea, vomiting, and fatigue. But the big, unique AEs are the skin effects and stomatitis.

We all worry about the rash, but in reality, few patients had to come off the drug due to toxicity. [The daraxonrasib discontinuation rate was] 1.2%, whereas 11.2% of patients on the chemotherapy arm had to come off the trial due to toxicity.

What did the patient-reported outcomes show in RASolute 302?

The study collected patient questionnaires about pain and general quality of life. What we saw was a significant prolongation in time to deterioration for both pain and overall quality of life in the daraxonrasib arm vs the chemotherapy arm. Anecdotally, patients can sometimes see quick relief of some symptoms, especially pain, after starting daraxonrasib, which we don’t see as often with chemotherapy.

What could the FDA approval of daraxonrasib mean for future RAS-targeted treatment?

It’s an exciting time, but in many ways, this is the first shot on goal. We’re happy that it succeeded so dramatically. Coming down the pipeline are more targeted agents that don’t hit all of RAS but hit common alleles like KRAS G12D. Emerging data suggest that combining, for example, a KRAS G12D inhibitor with a pan-RAS inhibitor may have synergistic effects.

Findings from an earlier phase 1/2 study [NCT05379985] involving patients [with previously treated, advanced RAS-mutated solid tumors, including pancreatic cancer] treated with daraxonrasib at different dose levels suggested that when patients have disease progression, which everyone tends to at some point, it’s not necessarily a new RAS mutation, but amplification of the existing KRAS mutation or KRAS amplification more generally. There’s a lot of expectation that [using] pan-RAS [inhibitors] and [inhibitors targeted at certain] alleles together could create synergy.

There’s also interest in combining these drugs with chemotherapy, especially the more targeted inhibitors, which might be a little safer and easier to combine than a pan-RAS inhibitor. We have a lot of interest in combining them with immunotherapy because there seems to be a way to give immune cells more time to go after the tumor and maybe disrupt some of the stromal issues that have impaired immunotherapy’s effectiveness in this disease.

There’s a lot of potential for combinations. Now that we know more about these resistance mechanisms, if resistance isn’t [occurring] through the RAS/MAPK pathway, there may be other pathways we can target. We’re already seeing next lines of treatment lining up for when resistance develops.

References

• FDA approves daraxonrasib for metastatic pancreatic adenocarcinoma.FDA. August 26, 2026. Accessed September 25, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daraxonrasib-metastatic-pancreatic-adenocarcinoma
• O’Reilly EM, Wainberg ZA, Hendifar AE, et al. Daraxonrasib or chemotherapy in previously treated metastatic pancreatic cancer. N Engl J Med. 2026;395(4):325-337. doi:10.1056/NEJMoa2605555