Pancreatic

Histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas (as per American Joint Committee on Cancer 8th Edition [Chun et al 2018]).
Note 1: Prescreening for participants with suspected PDAC is allowed.
Note 2: Squamous, sarcomatoid, neuroendocrine (carcinoid, islet cell), and acinar pancreatic carcinoma are excluded.

Screening Inclusion Criteria
4. Documented KRAS G12D mutation in tumor tissue or blood (eg, ctDNA genetic testing). The following are acceptable:
a. Presence of KRAS G12D mutation documented in participant medical record as detected in tumor tissue or blood (eg, ctDNA genetic testing) based on a sponsor-approved assay (PCR- or NGS-based only).
b. Presence of KRAS G12D mutation determined prior to screening by local laboratory assay or sponsor-approved assay (PCR- or NGS-based only) qualified per national country regulations and performed on tumor tissue or blood using sponsor-permitted methods and laboratories.
5. No prior systemic treatment for metastatic PDAC.
Note: Participants who previously received therapy for nonmetastatic disease may enroll if no systemic treatment was administered within 6 months before randomization into the study.
6. Radiographically measurable disease (based on local site investigator/radiology evaluation) per RECIST v1.1 criteria, evidenced by available baseline imaging.
Note 1: Target lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
Note 2: Tumor lesions that have been biopsied should not be selected as target lesions unless postbiopsy imaging confirms that they still qualify as RECIST-defined measurable lesions.

3. Confirmed histologic or cytologic diagnosis of PDAC (note: mixed histologies, other histologies, neuroendocrine, acinar, and ampullary cancers are not eligible).
4. Initial diagnosis of metastatic disease (according to the eighth edition of the American Joint Committee on Cancer [AJCC] Staging Manual) must have occurred ≤ 9 weeks prior to enrollment in the study.
5. Life expectancy of ≥ 3 months
6. Radiographic confirmation of metastatic disease (per AJCC Cancer Staging Manual 8th edition) with at least 1 distant tumor metastasis measurable on radiology imaging per RECIST version 1.1 criteria (eg, distant / non-regional lymph nodes that are not considered appropriate for resection, or distant solid organ metastases). Note: Standard multiphasic (pancreas) protocols should be used for all radiographic tumor assessments. The exact same image acquisition and processing parameters should be used throughout the study.
7. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1. Patients with a rapid deterioration of performance status during Screening are not eligible.
8. Able to understand and provide informed consent for participation in the study and comply with protocol requirements.
9. Able to swallow and retain oral medication and does not have uncontrolled emesis.
10. Has adequate gastrointestinal absorption.
a. Patients diagnosed with exocrine pancreatic insufficiency (EPI) must be taking pancreatic enzyme replacement therapy (PERT) for ≥ 1 week prior to C1D1 and expected to maintain PERT throughout the treatment period. Patients with malabsorption-related symptoms (eg, appetite loss, weight loss, steatorrhea, diarrhea, fat-soluble vitamin deficiencies, excessive flatulence, bloating, and abdominal discomfort) must be assessed for EPI per American Gastroenterological Association (AGA) guidelines (Whitcomb 2023).
b. If the patient has undergone gastric bypass surgery and/or surgery of gastrointestinal or hepatobiliary tract, the patient must demonstrate adequate absorption as evidenced by albumin ≥ 3.0 g/dL, controlled EPI (if present), and lack of evidence of malabsorption.
11. Received no prior systemic anticancer therapy to treat metastatic PDAC. Treatment of PDAC with a single agent RAS inhibitor is permitted if the last dose of the RAS inhibitor was taken no more than 8 weeks prior to C1D1 on this study.
12. If a patient received prior treatment of PDAC with chemotherapy in the adjuvant setting (see also Exclusion Criterion #3), he/she is eligible only if disease progression occurred > 12 months after completing the last dose and no persistent treatment-related toxicities are present.

4. Disease histology. Patient has definitive histologically or cytologically confirmed pancreatic adenocarcinoma, that has not been previously treated in the metastatic setting.
a. The definitive diagnosis of metastatic PDAC should be made by integrating the histopathology data with clinical and radiographic data. Initial diagnosis of metastatic disease must have occurred ≤ 6 weeks prior to screening.
5. Measurable disease per RECIST v1.1. Assessed by computed tomography (CT) or magnetic resonance imaging (MRI) scans per RECIST v1.1 based on local assessment.
a. Previously radiated lesions are not considered measurable unless they have progressed after radiation.
6. Documented KRAS G12D mutation. 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 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.