The RASolute 302 study

In this video, Prof Dr Jeroen Dekervel (University Hospitals Leuven) & Dr Brian Wolpin (Dana Farber Cancer Institute) discuss the results of RASolute 302, a pivotal study evaluating the pan-RAS inhibitor daraxonrasib in patients with previously treated metastatic pancreatic ductal adenocarcinoma (PDAC). The study addressed a longstanding unmet need in pancreatic cancer, a disease for which therapeutic advances have remained limited and where chemotherapy continues to represent the backbone of treatment for most patients.

The rationale for the study was based on the central role of RAS signaling in pancreatic tumorigenesis. Approximately 90–95% of pancreatic cancers harbor RAS mutations, making aberrant RAS activation a key driver of disease initiation and progression. Daraxonrasib is an oral, multi-selective “RAS-on” inhibitor that targets the active GTP-bound form of RAS. Unlike mutation-specific inhibitors, the agent inhibits multiple RAS mutations and also demonstrates activity against wild-type RAS, providing a broader therapeutic approach to suppressing RAS-driven signaling. The investigators hypothesized that direct inhibition of RAS could provide superior clinical outcomes compared with standard chemotherapy in patients with previously treated metastatic disease.

The phase III trial enrolled patients with metastatic PDAC who had received one prior line of systemic therapy. Eligibility was independent of RAS mutational status, allowing enrollment of an all-comer population that included patients with RAS-mutant and RAS–wild-type tumors. Participants were randomized in a 1:1 ratio to receive either daraxonrasib 300 mg orally once daily or investigator’s choice of standard chemotherapy. Physicians and patients could select among four accepted chemotherapy regimens, with gemcitabine plus nab-paclitaxel and nanoliposomal irinotecan plus 5-fluorouracil/leucovorin being the most commonly chosen options. The study enrolled a total of 500 patients, with baseline demographic and clinical characteristics, including age, performance status, and prior treatment exposure, being well balanced between treatment arms.

The trial incorporated co-primary endpoints of overall survival (OS) and progression-free survival (PFS). Efficacy was first assessed in the predefined population of patients harboring a RAS^G12 mutation, after which these endpoints were assessed in the overall study population. This hierarchical strategy was designed to evaluate treatment benefit initially in a biologically homogeneous population before extending the analysis to the broader study cohort, including patients with less common RAS alterations and those without known RAS mutations.

The results demonstrated a substantial and statistically significant improvement in OS with daraxonrasib compared with chemotherapy in RAS^G12-mutated patients and overall study population. In the overall population, the median OS reached 13.2 months in the daraxonrasib arm as compared 6.7 months with chemotherapy, representing a clinically meaningful extension of survival in a disease historically associated with poor outcomes (HR[95%CI]: 0.40[0.30-0.53]). According to both experts, this magnitude of benefit observed is uncommon in pancreatic cancer and compares favorably with previous therapeutic advances in the field. Beyond the primary endpoint, statistically significant improvements were also reported for PFS, objective response rate, and patient-reported quality of life, indicating a consistent treatment effect across multiple efficacy measures. 

The safety profile of daraxonrasib was considered manageable. The most characteristic adverse events were rash and mucositis, with additional gastrointestinal toxicities including nausea and diarrhea. Gastrointestinal adverse events were generally controlled with standard supportive care measures such as antiemetics and antidiarrheal agents. Rash emerged as the principal toxicity requiring specific management strategies. Prophylactic treatment with tetracycline-class antibiotics and topical corticosteroids has become part of routine management, supplemented by additional interventions when necessary. Approximately 10% of patients experienced more severe rash, often requiring multidisciplinary input from dermatology specialists. Despite these challenges, treatment discontinuation due to adverse events occurred in only about 1% of patients, suggesting that toxicity was largely controllable and rarely necessitated permanent cessation of therapy.

Ongoing studies are evaluating daraxonrasib in earlier disease settings, including the first-line metastatic setting in the phase III RASolute 303 trial and the adjuvant setting in the RASolute 304 study. Beyond the development of daraxonrasib itself, the results reinforce the therapeutic potential of RAS inhibition as a strategy targeting the fundamental biological driver of pancreatic cancer. While further research is required to define the optimal use of these agents, the study represents a potentially transformative advance that may reshape treatment paradigms and reduce reliance on conventional chemotherapy in the years ahead