For decades, small molecules could not directly target RAS, the primary oncogenic driver of pancreatic cancer. Tanios S. Bekaii-Saab, MD, opens this discussion on metastatic pancreatic ductal adenocarcinoma by asking what changed. Anne Noonan, MB BCh, PhD, credits the 2013 discovery of a drug-binding pocket on the surface of mutant RAS, known as the switch II pocket, which enabled the first preclinical RAS inhibitors. She explains that RAS proteins cycle between an inactive guanosine diphosphate-bound off state and an active guanosine triphosphate-bound on state, and that oncogenic mutations shift this equilibrium toward the on state. Paul E. Oberstein, MD, describes the tri-complex approach: the oral drug enters the cell, binds the chaperone protein cyclophilin A, and that complex then binds active RAS to block downstream signaling, using the cell's own machinery. Shiraj Sen, MD, PhD, shares how he explains this mechanism to patients, comparing the medicine to a Trojan horse that uses a chaperone protein to reach and block RAS.

Before daraxonrasib, second-line therapy for metastatic pancreatic cancer meant more chemotherapy with overlapping toxicities. Jonathan Lee, MD, describes telling patients that response was unlikely and focusing instead on limiting tumor growth and controlling symptoms. Shiraj Sen, MD, PhD, estimates that about half of patients reach second-line therapy and emphasizes offering clinical trials at every step. Tanios S. Bekaii-Saab, MD, notes that the approved indication covers patients with at least 1 prior systemic therapy and patients who are not candidates for multiagent therapy, although every trial participant had progressed on 1 prior line. Anne Noonan, MB BCh, PhD, sees a role for frail patients; however, she urges caution in defining frailty given the side effect profile. Paul E. Oberstein, MD, hopes the drug expands the pool of treated patients and advises giving chemotherapy first when patients can receive it, because the trial sequenced chemotherapy before RAS inhibition. Dr. Lee wants real-world evidence and stresses frank conversations, since first-line data remain limited.