This phase II trial studies how well olaparib works in treating patients with stage IV pancreatic cancer. Olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To determine the efficacy of olaparib monotherapy in stage IV pancreatic ductal adenocarcinoma (PDAC) with breast cancer, early onset (BRCA)ness.

SECONDARY OBJECTIVES:

I. To further determine the efficacy of olaparib in the study population.

SAFETY OBJECTIVES:

I. To assess the safety and tolerability of olaparib.

EXPLORATORY OBJECTIVES:

I. To identify tissue based biomarkers of defective homologous recombination repair (HRD).

OUTLINE:

Patients receive olaparib orally (PO) twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 8 weeks thereafter.

Inclusion Criteria:

• Patients with histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas
• Family history: one or more close blood relative with ovarian carcinoma at any age or breast cancer age 50 or younger or two relatives with breast, pancreatic or prostate cancer (Gleason 7 or higher) at any age, or patients with Ashkenazi Jewish ancestry; however, patients with previously identified genetic aberrations that are associated with homologous recombination deficiency (HRD) will be eligible even in the absence of family history (e.g. somatic BRCA mutation, Fanconi anemia gene, ATM or RAD51 mutations)
• Patients must be germline BRCA 1 or 2 negative; (Note: if BRCA status was previously determined, that result is acceptable but documentation of status must be available; subjects with unknown status will be referred to genetic counselling for BRCA testing as per standard of care) and/or patients with previously identified genetic aberrations that are associated with HRD will be eligible even in the absence of family history (e.g. somatic BRCA mutation, Fanconi Anemia gene, ATM or RAD51 mutations)
• Patients must have received at least one prior therapy for metastatic disease to be eligible
• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan
• All treated patients have the option to undergo pre-treatment biopsy (liver, omentum, lung or lymph node) to be eligible
• Patients with prior malignancy and treated with no evidence of active disease, and more than 2 years from initial diagnosis are eligible
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Karnofsky > 70)
• Leukocytes >= 3,000 cells/mm^3
• Absolute neutrophil count >= 1,500 cells/mm^3
• Platelets >= 75,000 cells/mm^3
• Hemoglobin >= 9 g/dl (no blood transfusions within 4 weeks prior to enrollment)
• Total bilirubin < 1.5 x institutional upper limit of normal (IULN)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x IULN without liver metastasis; =< 5 x IULN for patients with liver metastasis
• Creatinine not greater than upper institutional limits OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
• International normalized ratio (INR) < 1.5
• Women of childbearing potential (defined as not post-menopausal for 12 months or no previous surgical sterilization) and fertile men must agree to use two highly effective forms of contraception while they are receiving study treatment and for 30 days after last dose of study drug; male subjects must agree to refrain from sperm donation during the study and for 30 days after the last dose of study drugs
• Ability to understand and the willingness to sign a written informed consent document; signed informed consent form must be obtained prior to initiation of study evaluations and/or activities

Exclusion Criteria:

• Uncontrolled intercurrent illness including symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia and myocardial infarction (MI) within 3 months of initiation of therapy
• Patients whose tumors are deemed to be platinum-refractory will be excluded from the trial
• Pregnancy or lactation
• Patient has active and uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy
• Patient has undergone major surgical resection within 4 weeks prior to enrollment
• Patient received radiotherapy, surgery, chemotherapy, or an investigational therapy within 2 weeks prior to study entry
• Patient has serious medical risk factors involving any of the major organ systems such that the investigator considers it unsafe for the patient to receive an experimental research drug
• Serious psychiatric or medical conditions that could interfere with treatment
• Major bleeding in the last 4 weeks prior to study entry
• Concomitant use of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitors
• Resting electrocardiogram (ECG) with corrected QT interval (QTc) > 470 msec (Fridericia's scale)

5 years, 8 months