Are the RASolute 302 Results Overstated for Daraxonrasib in PDAC?

The RASolute 302 trial (NCT06625320) in pancreatic cancer has received a lot of attention. The study randomized 500 patients with previously treated metastatic pancreatic ductal adenocarcinoma (mPDAC) to either chemotherapy or the RAS(ON) inhibitor daraxonrasib. The results showed that daraxonrasib approximately doubled both median progression-free survival (3.6 months vs 7.2 months) and median overall survival (6.7 months vs 13.2 months) compared with chemotherapy.¹

The FDA is currently reviewing the new drug application for daraxonrasib and has also allowed an expanded access program. In fact, many of my partners who treat patients with pancreatic cancer are trying to access the drug for their patients using this expanded access program.

While no one would argue that second-line chemotherapy for metastatic pancreatic cancer is effective or that improving outcomes for these patients is critically important, I will point out that the RASolute 302 trial design and conduct suffered from a high rate of unbalanced informative censoring due to patient disappointment at being randomized to the control arm and that such unbalanced informative censoring could lead to an overestimate of the benefit of daraxonrasib as compared with chemotherapy.

Specifically, figure 1 of the paper indicates that 38 (15.1%) of the 252 patients assigned to chemotherapy withdrew from the study without receiving the assigned treatment, whereas only 7 (2.8%) of the 248 patients assigned to daraxonrasib did not receive the assigned treatment.¹ This phenomenon can compromise open-label trials in which participating patients (and perhaps investigators) have a preconceived notion of a potential benefit of the investigational arm, leading to disappointment at their treatment assignment and subsequent withdrawal from the study to pursue other options.

Other trials in oncology that have suffered from high rates of patient dropout in the control arm due to disappointment include the VISION trial (NCT03511664) in prostate cancer and the KEYNOTE-177 trial (NCT02563002) in colorectal cancer. In VISION, patients with metastatic prostate cancer were randomly assigned to receive either lutetium-177-PSMA-617 (Pluvicto) or an investigator’s choice of standard care regimens, which excluded chemotherapy and radium-223 (Xofigo).² Of the 280 patients randomly assigned to standard therapy, 79 (28%) did not receive the assigned treatment. In KEYNOTE-177, patients with microsatellite instability–high colorectal cancer were randomly assigned to receive pembrolizumab or chemotherapy.³ Of 154 patients assigned to receive chemotherapy, 11 (7%) did not receive it, in contrast to 0 patients assigned to pembrolizumab who did not receive it.

Such imbalances in informative censoring can lead to overestimates of differences of both progression-free and overall survival outcomes between arms of a trial. If healthier patients withdraw from a control arm to pursue experimental treatments elsewhere and are censored, then the trial winds up comparing healthier patients in the experimental arm with sicker patients in the control arm.⁴ In addition, if patients on a control arm do not receive treatment, their overall survival could be adversely impacted.

I am not arguing that daraxonrasib is not valuable for patients with pancreatic cancer, but I am questioning whether its benefits compared with conventional chemotherapy are overstated. I am not sure of the answer to this question, but I hope smart statisticians somewhere are working to figure it out.

John Burke, MD, is a hematologist, medical oncologist, and blood cancer specialist at Rocky Mountain Cancer Centers.

References

1. O’Reilly EM, Wainberg ZA, Hendifar AE, Borad MJ, Pietrantonio F, Pant S, et al. Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer. N Engl J Med. 2026 Jul 22;395(4):325-37. doi:10.1056/NEJMoa2605555

2. Sartor O, Bono J de, Chi KN, Fizazi K, Herrmann K, Rahbar K, et al. Lutetium-177–PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2021 Sep 15;385(12):1091-103. doi:10.1056/NEJMoa2107322

3. André T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, et al. Pembrolizumab in Microsatellite Instability–High Advanced Colorectal Cancer. N Engl J Med. 2020 Dec 2;383(23):2207-18. doi:10.1056/NEJMoa2017699

4. Mittal A, Kim MS, Dunn S, Wright K, Gyawali B. Frequently asked questions on surrogate endpoints in oncology-opportunities, pitfalls, and the way forward. EClinicalMedicine. 2024 Oct;76:102824. doi:10.1016/j.eclinm.2024.102824 PubMed PMID: 39764569; PubMed Central PMCID: PMC11701476.