Researchers are gaining new insights into why resistance develops to daraxonrasib, a breakthrough targeted drug for advanced pancreatic cancer, a development that could inform strategies to extend patient survival. Daraxonrasib, approved in August, initially showed promise by doubling median survival times for patients with late-stage pancreatic cancer. However, like many targeted therapies, its effectiveness diminishes over time, with tumors often becoming resistant after approximately seven months.

This challenge was highlighted recently when former U.S. Senator Ben Sasse announced that his Stage 4 pancreatic cancer had stopped responding to daraxonrasib. Experts, including Dr. Andrew Aguirre of the Dana-Farber Cancer Institute, noted that such resistance is common among patients receiving the drug.

To better understand the mechanisms behind this resistance, a collaborative study involving Break Through Cancer, the Lustgarten Foundation, and Revolution Medicines—manufacturer of daraxonrasib—enrolled 66 patients with advanced pancreatic cancer who were participating in early-stage clinical trials of the drug. Researchers conducted tumor biopsies at three points: before treatment, about two weeks into therapy, and upon disease progression.

Initial biopsy results demonstrated that daraxonrasib rapidly reduced the tumor burden, halving cancer cell numbers within the first two weeks. However, the surviving cells showed notable differences from pre-treatment samples. Prior to therapy, cancer cells appeared aggressive and poorly differentiated. Two weeks later, the remaining cells resembled those typically responsive to chemotherapy, a finding that suggests combining daraxonrasib with chemotherapy might improve outcomes, according to Dr. Mark Goldsmith, CEO of Revolution Medicines.

Parallel analyses of blood samples from 44 patients provided additional clues. Investigators identified that over half of the resistant tumors bypassed the drug’s effects by overproducing KRAS protein, the very target of daraxonrasib. This overexpression enables cancer cells to continue growing despite treatment. Similar patterns were observed in tumor biopsies taken after resistance developed, reinforcing the significance of KRAS in tumor survival.

These findings have prompted consideration of using multiple KRAS inhibitors in tandem, as more than 90 such agents are currently in clinical trials, aiming to prevent or overcome resistance by targeting the protein through different mechanisms.

Nevertheless, not all mechanisms of resistance are fully understood. Dr. Aguirre noted that non-genetic factors, possibly involving the tumor microenvironment or cancer cell adaptations independent of genetic mutations, may also contribute to treatment failure.

The research is receiving renewed funding to explore how daraxonrasib may interact with other therapies. Tyler Jacks, president of Break Through Cancer and founding director of M.I.T.’s Koch Institute, emphasized the importance of combining KRAS inhibitors with complementary treatments, expressing optimism that ongoing patient-based research will eventually lead to curative approaches.