At least 18 years of age (or age greater than or equal to regionally approved age of consent for participation in investigational clinical studies) at the time of signing informed consent form (ICF).
Capable of giving signed informed consent as described in the protocol (which includes compliance with the requirements and restrictions listed in the ICF and in the protocol) at the time of signing the ICF.
ECOG performance status (ECOG performance status) 0 or 1.
Definitive histologically or cytologically confirmed pancreatic adenocarcinoma, including adenosquamous carcinoma, that has not been previously treated in the metastatic setting.
Initial diagnosis of metastatic disease occurring ≤ 6 weeks prior to informed consent.
No prior treatment of pancreatic adenocarcinoma in the locally advanced unresectable or metastatic setting with systemic anticancer therapy, including chemotherapy, targeted therapy, antibody-drug conjugate therapy, or investigational therapy.
Prior treatment with systemic anticancer therapy given in the neoadjuvant or adjuvant setting, if given in combination with surgical resection, is allowed if completed ≥ 6 months prior to diagnosis of metastatic disease and the systemic therapy was a standard chemotherapy regimen (eg, modified FOLFIRINOX, gemcitabine and capecitabine, GnP, gemcitabine and S-1, S-1 monotherapy, gemcitabine monotherapy).
Measurable metastatic disease assessed by computed tomography (CT) or positron emission tomography (PET)/CT scans with contrast or magnetic resonance imaging (MRI) scans with contrast (unless patient is allergic to contrast media, per RECIST v1.1 by Investigator assessment. Previously radiated lesions may not be considered target lesions for the purpose of the study.
KRAS G12D mutation (defined by a substitution of aspartic acid for glycine at codon 12 in KRAS) previously identified by an analytically validated assay on circulating tumor DNA (ctDNA), fresh tumor biopsy, or archival tumor tissue (obtained within 5 years of randomization), performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified (USA) or equivalently certified laboratory per local regulation (eg International Organization for Standardization, UK: CE-Mark/UKCA test) using next generation sequencing or polymerase chain reaction (PCR) methods. For patients without mutation test results available, formalin-fixed paraffin-embedded tumor tissue can be submitted to determine KRAS G12D mutation status by a Sponsor designated central test laboratory.
For sites in the EU, Switzerland, Turkey (and other countries may apply as required by local health authorities): Only archival tissue can be used to determine mutation status and must be collected prior to consent (independent of this study).
Confirmed availability of protocol-specified tumor tissue. Refer to Table 1 for additional information.
Adequate organ function.
Mutation status with previously known driver mutations for which there are approved targeted therapies (eg, BRCA1/BRCA2, microsatellite-instability high/mismatch repair deficient, and NTRK gene fusion).
Patients with acinar cell carcinoma, tumors involving islet cells, islet cell neoplasms, and neuroendocrine tumors are excluded. Other rare cancers: cystadenocarcinoma, ampullary cancers, pancreatic pseudopapillary, pancreatic neuroendocrine tumors, nonadenocarcinoma pancreatic cancers, pancreaticobiliary (adenocarcinomas originating from biliary tree), poorly differentiated, and adenosquamous histology if the predominant cell type cannot be characterized.
Patients with locally advanced unresectable or borderline resectable pancreatic adenocarcinoma are excluded.
Radical or definitive radiotherapy or any radiotherapy exceeding a total dose of 25 Gy for the treatment of metastatic pancreatic adenocarcinoma is prohibited. Localized, palliative radiotherapy (eg stereotactic radiotherapy) given within 2 weeks prior to randomization and exceeding 25 Gy is prohibited.
Prior therapy with a MAPK-pathway targeted therapy (eg, direct RAS-, BRAF-, or epidermal growth factor receptor-targeted therapy including degraders and/or inhibitors) is prohibited.
Prior administration of a RAS-targeted vaccine (including any boosters) is prohibited unless given ≥ 12 months prior to the occurrence of metastatic disease.
Use of bisphosphonates or denosumab for bone metastases, with the exception of a stable dose that was initiated ≥ 2 weeks prior to starting study treatment.
Active or known history of untreated central nervous system (CNS) metastatic or leptomeningeal disease. Treated CNS metastases are allowed if radiologically stable, asymptomatic with no ongoing requirement for corticosteroids as therapy for CNS disease.
Diagnosed or treated for cancers other than pancreatic adenocarcinoma ≤ 3 years prior to randomization, except:
Cancers for which no systemic anticancer treatment is required and may have been treated with successful definitive clear margin resection (eg, non-melanoma skin cancer, carcinoma in situ of the breast or cervix, basal or squamous cell skin cancer or other in situ cancers are eligible).
Cancers that have been treated with curative intent, with no evidence of disease recurrence within 2 years of initiation of curative therapy and judged by the Investigator to be at low risk for recurrence (ie, < 5% risk of recurrence within 5 years).
Uncontrolled pleural effusion, pericardial effusion, or clinically significant ascites defined as requiring monthly or more frequent paracentesis, drainage, diuretics and/or symptomatic effusions.
Toxicity associated with prior anticancer therapy (eg, in the adjuvant or neoadjuvant setting) in the opinion of the Investigator that has not recovered to Grade ≤ 1, including ongoing Grade ≥ 2 peripheral neuropathy according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0, except for: a) alopecia; b) endocrine disorder, stably maintained with appropriate replacement therapy.
Significant cardiovascular disease defined as:
Medically uncontrolled hypertension (≥ 160 mmHg systolic blood pressure or ≥ 100 mmHg diastolic blood pressure) based on an average of 3 consecutive readings.
Acute coronary syndrome (eg, unstable angina, myocardial infarction) within 6 months of randomization.
Symptomatic congestive heart failure (New York Heart Association Class II to IV) within 4
weeks of randomization.
Significant cardiac conduction abnormalities:
Corrected QT interval (QTc) > 470 msec, using the screening clinic electrocardiogram (ECG) machine-derived QT interval corrected by Fridericia’s formula (QTcF) value.
Any clinically significant abnormalities, based on Investigator assessment, in rhythm, conduction, or morphology of resting ECG (eg, second-degree heart block, third-degree heart block, complete left bundle branch block, PR interval > 250 msec).
Patients who have pacemakers to control atrial arrhythmias are candidates for the study.
Patients with medically controlled atrial fibrillation > 1 month before initiation of study treatment are eligible.
History of interstitial lung disease, pneumonitis, pulmonary fibrosis, or radiation pneumonitis within 8 weeks of randomization, or any evidence of ongoing inflammation or active interstitial lung disease on screening imaging.
Any conditions that may affect the ability to take or absorb study treatment including but not limited to, inability to take oral medication, refractory nausea and/or vomiting, malabsorption, significant bowel resection or uncontrolled inflammatory GI disease (eg, Crohn disease or ulcerative colitis). Note: Patients with a prior Whipple procedure are eligible
Patients with the following active viral infections will be excluded if any of the following conditions are met:
For patients with known HIV infection:
CD4+ T-cell counts < 350 cells/µL or a history of AIDS-defining opportunistic infections in the preceding 12 months prior to randomization.
If CD4+ T-cell counts ≥ 350 cells/µL, enrollment may be considered if the patient is on established antiretroviral therapy for ≥ 4 weeks prior to randomization and treatment regimen does not conflict with other study restrictions, and patient has a viral load of < 400 copies/mL prior to randomization.
For patients positive for hepatitis B core antibody at Screening:
Positive for hepatitis C virus RNA by PCR test at Screening
Any uncontrolled, active systemic infection including any infection requiring systemic intravenous (IV) treatment which was completed ≤ 7 days prior to randomization.
Any serious medical or psychiatric condition (eg, bleeding diatheses) or organ system dysfunction, that, in the Investigator’s opinion, could compromise the patient’s safety or put the study outcomes at undue risk.
Women who have a positive pregnancy test at Screening or C1D1; are pregnant or breastfeeding; or are planning to become pregnant or breastfeed during treatment and ≥ 30 days after the last dose of daraxonrasib, ≥ 6 months after the last dose of zoldonrasib, and/or ≥ 6 months after the last dose of gemcitabine or nab-paclitaxel (depending on treatment arm assignment).
Women of childbearing or reproductive potential or men of reproductive potential unwilling to use highly effective forms of contraception or avoid intercourse during treatment and for the following durations after the last dose of study treatment (depending on treatment arm assignment):
For women of childbearing or reproductive potential, ≥ 30 days after the last dose of daraxonrasib, ≥ 6 months after the last dose of zoldonrasib, and/or ≥ 6 months after the last dose of gemcitabine or nab-paclitaxel (or per local label for gemcitabine or nab-paclitaxel).
For men of reproductive potential, ≥ 1 week after the last dose of daraxonrasib, ≥ 3 months after the last dose of zoldonrasib, and/or ≥ 3 months after the last dose of gemcitabine or nab-paclitaxel (or per local label for gemcitabine or nab-paclitaxel).
Women unwilling to abstain from donating eggs during treatment and for ≥ 30 days after the last dose of daraxonrasib, ≥ 6 months after the last dose of zoldonrasib, and/or ≥ 6 months after the last dose of gemcitabine or nab-paclitaxel (or per local label for gemcitabine or nab-paclitaxel). Men unwilling to abstain from donating sperm during treatment and for ≥ 1 week after the last dose of daraxonrasib, ≥ 3 months after the last dose of zoldonrasib, and/or ≥ 3 months after the last dose of gemcitabine or nabpaclitaxel (or per local label for gemcitabine or nab-paclitaxel).
History of allergy or known hypersensitivity to any of the study treatments or any of their excipients, or contraindication to any of the study treatments as outlined in the local prescribing information (eg, US Package Insert or EU Summary of Product Characteristics [SmPC]).
Major surgery ≤ 28 days of randomization, with the exception of placement of central venous access catheter(s) (eg, port or similar device), staging laparoscopy, and/or placement of biliary stent/tube.
Participation in clinical studies within 6 months prior to signing of the informed consent.
Patient is incapacitated, regardless of possession of legal representative, or committed to an institution by virtue of an order by a court or governmental authority.