Late-Breaking HOPA News: RASolute 302 Breakthrough in Metastatic Pancreatic Adenocarcinoma

Background

Pancreatic cancer ranks as one of the deadliest forms of cancer, with an estimated 53,000 deaths occurring in the United States in 2026, falling behind only lung/bronchus cancers and colorectal cancer. This is despite ranking outside the top 10 malignancies in annual new diagnoses. Nearly half of newly diagnosed cases are metastatic, and to correlate, the 5-year overall survival rate for metastatic patients is a bleak 3.4%.¹ Traditional cytotoxic chemotherapy is the standard front-line treatment option for these patients, often deciding between modified FOLFIRINOX, gemcitabine plus nab-paclitaxel, or NALIRIFOX.² Unfortunately, there are a limited number of subsequent lines of therapy following progression or recurrence of disease.

There are few targeted therapy medications approved in the pancreatic cancer space, however many of these targetable mutations are rarely present drivers for active malignancy (BRAF 4%, NTRK 1%, RET 1%, NRG1 0.5%).³ The most common mutations present for these malignancies are RAS mutations at over 90%, and in particular KRAS G12 variant mutations are present in over 80% of pancreatic cancer cases.⁴ While KRAS G12C inhibitors exist, this specific mutation is only present in 1-2% of pancreatic cancer cases.³ This leaves a large opportunity gap in therapy options to target other RAS mutations that are present in this malignancy.

RASolute 302⁵

The RASolute 302 (NCT06625320) trial is a phase 3, international, open-label, randomized trial that evaluated daraxonrasib versus the investigator’s choice chemotherapy in patients with previously treated metastatic pancreatic ductal adenocarcinoma (mPDAC). Patients were randomized to receive either daraxonrasib at 300 mg orally daily or the investigator’s choice of chemotherapy (gemcitabine plus nab-paclitaxel, modified FOLFIRINOX, FOLFOX, or liposomal irinotecan plus fluorouracil). There were 500 patients enrolled in the study with 248 randomized to the daraxonrasib arm and 252 to the chemotherapy arm. Of note, over 90% of patients in each cohort had a RAS mutation present, and over 85% of RAS mutations were G12D or G12V mutations.

The primary endpoints evaluated were overall survival and progression-free survival in the RAS G12 population. Daraxonrasib outperformed chemotherapy in both endpoints with a median overall survival of 13.2 months compared to 6.6 months (HR 0.40; P<0.001) and a progression-free survival of 7.3 months compared to 3.5 months (HR 0.45; P<0.001). These trends continued when evaluating the overall population, including patients with non-RAS G12 mutations or no mutations present at all.

Other endpoints evaluated included objective response rate, time to deterioration, and adverse effect profile. In the RAS G12 mutated population, the objective response rate was 33.2% with daraxonrasib and 11.8% with chemotherapy (p<0.001). The median time to deterioration was 9.0 months for daraxonrasib and 3.7 months for chemotherapy (HR 0.51; P<0.001). Adverse events that led to treatment discontinuation occurred in only 1.2% of the daraxonrasib cohort, while the chemotherapy cohort had 11.2% of therapies discontinued due to adverse effects. The adverse effect profile of the daraxonrasib is most notable for rash (85.5% any grade, 13.7% grade ³ 3), diarrhea (58.1% any grade, 5.4% grade ³ 3), stomatitis (53.1% any grade, 12.0% grade ³ 3), and nausea (46.5% any grade, 2.1% grade ³ 3).

Discussion

Daraxonrasib is a RAS(ON) multiselective inhibitor for both mutant and wild-type RAS.⁵ Mechanistically, daraxonrasib works in a variety of ways that allow for its efficacy. RAS can sit in a GTP-bound state (on state) or a GDP-bound state (off state); similar concept to the on/off switch for a light. The GTP-bound state is when signals are being sent to tell cancer cells to grow. Daraxonrasib is working to inhibit this “on state” and ultimately the signaling of cancer cell growth.⁶ Because daraxonrasib is a multiselective inhibitor, it allows for inhibition at a variety of mutational states. This includes the more common G12 mutations, but also the less common G13 and Q61 mutations. Uniquely, this also allows for activity when wild-type RAS is present without mutations.⁶ Since almost all pancreas cancers signal via the RAS and MAPK pathways, this makes daraxonrasib a useful drug for these populations. This differs from agents such as adagrasib or sotorasib that are specific the KRAS G12C mutations only. Lastly, daraxonrasib can also be considered a tri-complex inhibitor that binds to cyclophiln A and attaches it to RAS. This binding helps prevent RAS from engaging with other targets and thereby prevents downstream signaling.⁶

These results from the RASolute 302 trial are very encouraging and one of the largest breakthroughs for pancreatic cancer in the last 20 years. Daraxonrasib not only improved overall and progression-free survival compared to traditional chemotherapy options, but also roughly doubled both. For a patient population with limited overall survival and rarely reaching the 5-year mark, this is a significant improvement in outcomes. Because RAS G12 mutations are present in the vast majority of patients with pancreatic cancer, daraxonrasib should be a viable option for a large portion of patients who previously had no targetable therapy options available. However, given the survival data in the overall population that included non-RAS G12 mutations and patients without mutations, daraxonrasib may be an option for all patients who previously received treatment for their metastatic disease.

The adverse effect profile of daraxonrasib seems to be as tolerable as traditional chemotherapy options, if not better. This is supported by the extremely low percentage of patients who had to discontinue daraxonrasib therapy due to adverse effects. The notable adverse effect has been a rash that has been characterized as similar to that of an EGFR inhibitors. As such, the prevention and management recommendations for the rash remain the same: oral tetracycline therapy and topical steroid treatment.⁶ The inclusion and involvement of dermatology professionals have also been encouraged. The other prominent adverse effects observed in the study included stomatitis, diarrhea, and nausea/vomiting. Treatment and prevention for these side effects have largely followed standard management with magic mouthwash, antidiarrheals, and antiemetics.⁶

While these results likely show a practice-changing therapy in daraxonrasib, there are still questions that need to be answered. There are ongoing studies evaluating the use of daraxonrasib in the first-line setting, prior to receiving traditional chemotherapy. There are also studies evaluating the use of daraxonrasib in combination with other agents for the treatment of mPDAC. Ultimately the sequencing of daraxonrasib still needs investigation, but the results of the RASolute 302 trial highlight a new therapy that help fill a gap in the treatment of mPDAC. Currently access to daraxonrasib is limited to the drug company’s extended access program (EAP). While there is pending FDA approval for daraxonrasib, there is not a projected timeframe for this approval to take place.