Phase 3 Randomized Trial of Daraxonrasib Monotherapy or Daraxonrasib + Gemcitabine/Nab‑Paclitaxel vs Gemcitabine/Nab‑Paclitaxel in First‑Line Metastatic Pancreatic Cancer

The primary objective is to compare daraxonrasib monotherapy and daraxonrasib combined with gemcitabine‑nab‑paclitaxel versus gemcitabine‑nab‑paclitaxel alone with respect to progression‑free survival and overall survival in patients with metastatic pancreatic adenocarcinoma. Secondary objectives include evaluation of objective response and duration of response, assessment of safety and tolerability, characterization of the pharmacokinetics of daraxonrasib as monotherapy and in combination, and comparison of impact on health‑related quality of life.

The trial enrolled 563 participants diagnosed with metastatic pancreatic adenocarcinoma. Eligible subjects were adults ≥18 years of age, encompassing both female and male patients, and included individuals classified as vulnerable. Enrollment required an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, histologic or cytologic confirmation of pancreatic adenocarcinoma with measurable disease per RECIST v1.1, and documented RAS mutation status (mutant or wild‑type). Participants had to have a confirmed diagnosis of metastatic disease within six weeks prior to consent, adequate bone‑marrow, hepatic, renal, and coagulation function, and the ability to ingest oral medication. The population reflected a broad adult age range and overall good functional status as defined by the inclusion criteria.

The study is a Phase 3, global, multicenter, open‑label, randomized 1:1:1 trial evaluating daraxonrasib monotherapy, daraxonrasib combined with gemcitabine and nab‑paclitaxel, and gemcitabine plus nab‑paclitaxel as first‑line therapy for metastatic pancreatic adenocarcinoma. Eligible participants undergo a screening visit to confirm diagnosis, RAS mutation status, organ function, and performance status (ECOG 0‑1). After successful screening, participants are randomized on Day 1 of Cycle 1 and receive treatment in 28‑day cycles: oral daraxonrasib 300 mg daily (arms A and B) and intravenous gemcitabine 1000 mg/m² plus nab‑paclitaxel 125 mg/m² on Days 1 and 8 (arm B and the comparator arm). On‑treatment visits occur at the start of each cycle for safety assessments, vital signs, laboratory tests, and adverse event monitoring; pharmacokinetic blood samples for daraxonrasib are collected up to Cycle 5 Day 1. Radiologic tumor assessments using RECIST v1.1 are performed every 8 weeks to evaluate disease status. Participants remain in the trial until disease progression, unacceptable toxicity, withdrawal of consent, protocol non‑compliance, or completion of the planned follow‑up period, which extends up to approximately 2 years from randomization. The primary endpoints, Progression free survival and overall survival, are measured from randomization to the respective events within this timeframe, with secondary endpoints including objective response rate, duration of response, quality‑of‑life scores, and incidence of adverse events.

The experimental agent, DARAXONRASIB (RMC-6236), is supplied as a tablet for oral administration containing 300 mg of the active compound. Each tablet is taken according to the study dosing schedule, and compliance is assessed through patient‑reported dosing diaries and pill count verification at each study visit.

The comparator chemotherapy includes albumin‑bound paclitaxel supplied as a 5 mg/mL powder for dispersion for infusion (Abraxane). The product is reconstituted and administered intravenously at a dose of 125 mg/m² per infusion, with infusion records maintained to document administration and monitor adherence.

Gemcitabine is provided as a concentrate for infusion (available from HEXAL and Hikma) at a concentration of 40 mg/mL or 38 mg/mL, respectively. The drug is administered intravenously at 1000 mg/m² per infusion. Infusion logs are used to confirm dosing accuracy and to track participant compliance with the scheduled treatment cycles.

Efficacy will be evaluated using both primary and secondary endpoints. The primary efficacy parameters are progression free survival (PFS) and overall survival (OS), each defined as the time from randomization to disease progression or death from any cause, and to death from any cause, respectively. Disease progression is determined according to RECIST v1.1 criteria by the investigator, with follow‑up extending up to approximately two years.

Secondary efficacy assessments include objective response rate (ORR), defined as the proportion of patients achieving a partial or complete response per RECIST v1.1, and duration of response (DOR), measured from the first documented response to subsequent progression or death. Pharmacokinetic exposure is characterized by pre‑dose trough and post‑dose blood concentrations of daraxonrasib collected at selected visits through Cycle 5 Day 1 (each cycle = 28 days). Health‑related outcomes are captured by changes from baseline in the EORTC QLQ‑PAN26 pain scale and the EORTC QLQ‑C30 global health status, both assessed at scheduled intervals throughout the study period. Safety‑related efficacy signals are monitored through the incidence of adverse events graded by CTCAE v5, as well as longitudinal changes in vital signs and clinical laboratory values, all compared to baseline over the approximately two‑year observation window.