Phase 3 Study of Daraxonrasib (RMC-6236) in Patients With Previously Treated Metastatic Pancreatic Ductal Adenocarcinoma (PDAC)

The purpose of this study is to evaluate the safety and efficacy of a novel RAS(ON) inhibitor compared to standard(s) of care (SOC) treatment.

This is a global, randomized, open-label, Phase 3 study designed to evaluate whether treatment with RMC-6236 will improve progression free survival (PFS) or overall survival (OS) compared to Investigator's choice of standard of care chemotherapy in patients with metastatic PDAC who were previously treated with one prior line of therapy with 5-fluorouracil (5-FU) based or gemcitabine-based regimen. Patients will be randomized in a 1:1 ratio to receive RMC-6236 (Arm A) or Investigator's choice of standard of care chemotherapy (Arm B).

Drug: RMC-6236. Oral Tablets

Drug: Gemcitabine. intravenous (IV) infusion

Drug: nab-paclitaxel. IV infusion

Drug: Irinotecan. IV infusion

Drug: Liposomal irinotecan. IV infusion

Drug: 5-fluorouracil. IV infusion

Drug: leucovorin. IV infusion

Drug: Oxaliplatin. IV infusion

RMC-6236 (experimental): Study drug

Investigator's choice of standard of care therapy (active comparator): Patients randomized to Investigator's choice of standard of care chemotherapy will receive one of the following four treatments: * Gemcitabine and nab-paclitaxel (GnP) * Oxaliplatin, leucovorin, irinotecan, and 5-FU (Modified FOLFIRINOX: mFOLFIRINOX) * Liposomal irinotecan (Nal-IRI + 5-FU/LV) * Oxaliplatin, leucovorin and 5-FU IV (FOLFOX)

Progression free survival (PFS) in the RAS G12-mutant population. PFS is defined as the time from randomization until disease progression or death from any cause, whichever occurs first. Progression is per response evaluation criteria in solid tumors (RECIST) v1.1 and as assessed by blinded independent central review (BICR) Time frame: Up to approximately 3 years.

Overall survival (OS) in the RAS G12-mutant population. OS is defined as the time from randomization until death from any cause. Time frame: Up to approximately 3 years.

PFS in the all-patient population. Time frame: Up to approximately 3 years.

OS in the all-patient population. Time frame: Up to approximately 3 years.

Objective response in the RAS G12 and all-patient populations. Time frame: Up to approximately 3 years.

Time to deterioration (TTD) in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Pancreatic Cancer Module (EORTC QLQ-PAN26) in the RAS G12 and all-patient populations. Time frame: Up to approximately 3 years.

Time to deterioration (TTD) in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) in the RAS G12 and all-patient populations. Time frame: Up to approximately 3 years.

Objective response per investigator in RAS G12 and all- patient populations. Time frame: Up to approximately 3 years.

Inclusion Criteria: * At least 18 years old and has provided informed consent. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. * Histologically or cytologically confirmed PDAC with metastatic disease. * Measurable disease per RECIST 1.1. * Adequate organ function (bone marrow, liver, kidney, coagulation) * Documented RAS mutation status, either mutant or wild-type. RAS mutations defined as nonsynonymous mutations in KRAS, NRAS, or HRAS at codons 12, 13, or 61 (G12, G13, or Q61). * Able to take oral medications. Exclusion Criteria: * Prior therapy with direct RAS-targeted therapy (eg. degraders and/or inhibitors). * History of or known central nervous system metastatic disease. * Any conditions that may affect the ability to take or absorb study treatment * Major surgery within 4 weeks prior to randomization. * Patient is unable or unwilling to comply with protocol-required study visits or procedures

Enrollment: 500 participants (actual).