This phase II/III trial compares the effect of the 3-drug chemotherapy combination of nab-paclitaxel, gemcitabine, plus cisplatin versus the 2-drug chemotherapy combination of nab-paclitaxel plus gemcitabine for the treatment of patients with pancreatic cancer that has spread to other places in the body (metastatic) and a known genetic mutation in the BRCA1, BRCA2, or PALB2 gene.

PRIMARY OBJECTIVES:

I. To evaluate and compare overall response rate (ORR) in patients with BRCA1/2 or PALB2 mutant pancreas cancer whose disease has progressed on front-line fluorouracil, irinotecan, leucovorin and oxaliplatin (FOLFIRINOX) treated with nab-paclitaxel, gemcitabine, and cisplatin (NABPLAGEM) = nab-paclitaxel, gemcitabine, and cisplatin (arm 1) versus nab-paclitaxel and gemcitabine (arm 2). (Phase II) II. To evaluate and compare overall survival (OS) time in patients with BRCA1/2 or PALB2 mutant whose disease has progressed on front-line FOLFIRINOX treated with 1) NABPLAGEM = nab-paclitaxel, gemcitabine, and cisplatin (arm 1) versus nab-paclitaxel and gemcitabine (arm 2). (Phase III)

SECONDARY OBJECTIVES:

I. To evaluate and compare progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) criteria between 2 treatment arms.

II. To evaluate and compare duration of response (DoR) between 2 treatment arms.

III. To evaluate and compare CA19-9 response (defined as patients with a baseline CA19-9 >= 2x upper limit of normal (ULN) who demonstrate a minimum 25% decrease in CA19-9 at any time point) between 2 treatment arms.

IV. To evaluate and compare toxicity profile as assessed by treating clinicians between 2 treatment arms.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive nab-paclitaxel intravenously (IV) over 30-40 minutes, gemcitabine IV over 30-40 minutes, and cisplatin IV over 30-60 minutes on days 1 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo magnetic resonance imaging (MRI) or computed tomography (CT) throughout the trial. Patients may optionally undergo blood sample collection at baseline and on study.

ARM II: Patients receive nab-paclitaxel IV over 30-40 minutes and gemcitabine IV over 30-40 minutes on days 1 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI or CT throughout the trial. Patients may optionally undergo blood sample collection at baseline and on study.

After completion of study treatment, patients are followed up within 30 days and then every 3 months for 2 years or until death, whichever comes first.

Inclusion Criteria:

• Metastatic pancreatic adenocarcinoma. Adenosquamous carcinoma, squamous carcinoma, acinar cell carcinoma, and carcinoma not otherwise specified are also acceptable

• BRCA1/2 or PALB2 mutation (somatic or germline) identified on any Clinical Laboratory Improvement Amendments (CLIA)-certified gene panel. Mutations must be considered pathogenic or likely pathogenic by a reference database such as ClinVar or OncoKb.org. (Submission of mutation report will be required)

• Measurable disease

• Potential trial participants should have recovered from clinically significant adverse events of their most recent therapy/intervention prior to enrollment

• Clinical or radiographic progression on first-line FOLFIRINOX (or nanoliposomal irinotecan, fluorouracil, leucovorin, and oxaliplatin [NALIRIFOX]) for metastatic disease

  • Patients whose front-line chemotherapy was required to be simplified due to toxicity associated with any of the constituent components of FOLFIRINOX/NALIRIFOX (e.g. simplified to leucovorin calcium, fluorouracil, and oxaliplatin [FOLFOX], leucovorin calcium, fluorouracil, and irinotecan [FOLFIRI], fluorouracil [5-FU] [including capecitabine]) will be eligible
  • Patients with progressive disease while on maintenance PARP inhibitor treatment after FOLFIRINOX (or NALIRIFOX), irrespective of how long ago they received FOLFIRINOX/NALIRIFOX, will also be eligible
  • Patients who develop metastatic disease during or within 6 months after completing FOLFIRINOX/NALIRIFOX in either the locally advanced or adjuvant/neoadjuvant settings will be eligible

• Patients may not have received prior cisplatin for their pancreatic cancer in any setting

  * Note: Patients may have previously received gemcitabine +/- nab-paclitaxel for resectable (neoadjuvant/adjuvant) or locally advanced disease if (1) treatment was completed > 1 year ago and (2) in the opinion of the treating provider, re-treatment with gemcitabine/nab-paclitaxel is appropriate

• Age >= 18 years

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (Karnofsky performance status >= 60)

• Absolute neutrophil count >= 1,500/mm^3

• Platelet count >= 100,000/mm^3

• Hemoglobin >= 8.0 g/dL

• Creatinine =< 1.8 x institutional upper limit of normal (ULN) or calculated creatinine clearance (Calc. CrCl) > 40 mL/min

• Total bilirubin =< 2.0 x institutional ULN

  * Any elevated bilirubin should be asymptomatic at enrollment (except for participants with documented Gilbert's syndrome who may only be included if the total bilirubin =< 3 x ULN or direct bilirubin =< 1.5 x ULN)

• Aspartate transaminase (AST)/alanine transaminase (ALT) =< 3 x institutional ULN

  * AST/ALT of =< 5 x ULN if liver metastases are present

• Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects

  * Therefore, for women of childbearing potential only, a negative pregnancy test done =< 14 days prior to registration is required

• Patients with > grade 2 peripheral sensory neuropathy are not eligible

• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial

• Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression for at least 8-weeks.

  * Patients with known, new or progressive brain metastases (active brain metastases) or leptomeningeal disease are ineligible

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load anytime within 6 months prior to registration are eligible for this trial

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

  * Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load

• Concomitant chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this study. Patients on strong CYP3A4 inhibitors must discontinue the drug for 14 days prior to registration on the study

• Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must discontinue the drug 14 days prior to the start of study treatment

Exclusion Criteria:

• N/A