Niraparib and Dostarlimab for the Treatment of Germline or Somatic BRCA1/2 and PALB2 Mutated Metastatic Pancreatic Cancer

Presence of either a germline deleterious mutation or somatic deleterious mutation in any one of the genes in our proposed gene-panel as determined by any of the commercially available or institutional testing platforms. Note: The somatic mutation could be either on a tissue-based test or the circulating tumor DNA (ctDNA)-based assay. The 6 genes that would determine eligibility would be: BRCA1/2, PALB2, BARD1, RAD51c, RAD51d

Provide written informed consent

Histological/cytological confirmation of diagnosis of metastatic pancreatic ductal adenocarcinoma

At least one but no more than two prior lines of systemic therapy for metastatic disease (maintenance therapy is not considered a line of treatment)

* Note: Patients who have not had any prior chemotherapy can refuse chemotherapy and be considered eligible. This refusal and their reason for refusal would have to be documented

Received a platinum agent as part of first or second line treatment (unless contraindicated)

Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

Serum creatinine =\< 1.5 x upper limit of normal (ULN) or estimated glomerular filtration rate (eGFR) \>= 60 mL/min using the Cockcroft-Gault Equation (=\< 14 days prior to registration)

Hemoglobin \>= 9.0 g/dL (=\< 14 days prior to registration)

Absolute neutrophil count \>= 1500/uL (=\< 14 days prior to registration:)

Platelets \>= 100 x 10\^9/L (=\< 14 days prior to registration)

Total bilirubin =\< 1.5 x ULN, (2.0 x ULN for subjects with Gilbert's disease) (=\< 14 days prior to registration:)

Aspartate transaminase (AST) and alanine transaminase (ALT) =\< 2.5 x ULN (for subjects with hepatic metastases =\< 5 x ULN) (=\< 14 days prior to registration). Note: One time repeat testing to meet eligibility is allowed. If more testing is required, discuss with principal investigator (PI)

International normalized ratio (INR) or prothrombin time (PT) =\< 1.5 x ULN unless patient is receiving anticoagulant therapy as long as PT or partial thromboplastin (PTT) is within therapeutic range of intended use of anticoagulants. Activated partial thromboplastin time (aPTT) =\< 1.5 x ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (=\< 14 days prior to registration)

Evaluable or measurable disease per iRECIST

Life expectancy of \>= 3 months

Willingness to consent to translational studies

Willingness to undergo repeat biopsies of tumor lesions amenable to biopsy

* Note: While biopsies are mandatory, subjects are allowed to participate if no lesions are amenable to biopsy, or if biopsy is not possible due to safety

Willingness to not donate blood during the study or for 90 days after the last dose of study treatment

Willingness to not breastfeed during the study or for 90 days after the last dose of study treatment

Negative pregnancy test done =\< 7 days prior to registration, for persons of childbearing potential only

Received colony-stimulating factors (e.g., granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor, or recombinant erythropoietin) =\< 4 weeks prior to registration

Known grade 3 or 4 anemia, neutropenia or thrombocytopenia due to prior chemotherapy that persisted \> 4 weeks and was related to the most recent treatment

Known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML)

=\< 4 weeks since receiving treatment with another investigational drug, or anti-cancer therapy, or within a time interval less than at least 5 half-lives of the investigational agent (whichever is shorter), or insufficient recovery (to the judgement of the investigator) from adverse events due to such a previously administered agent, except for alopecia prior to initiating protocol therapy. Bisphosphonate therapy and receptor activator of nuclear factor kappa-Β ligand (RANKL) inhibitors are not considered anti-cancer therapy

Inadequate recovery from toxicity and/or complications from previous interventions, including due to major surgery to the judgement of the investigator. Minor surgery allowed up to 3 weeks from registration

Primary or secondary immunodeficiency, including immunosuppressive disease, and immunosuppressive doses of corticosteroids (e.g., prednisone \> 20 mg per day during 2 weeks prior to first study treatment) or other immunosuppressive medications at dose levels that to the judgement of the investigator would preclude participation within the past 4 weeks prior to registration. Subjects with human immunodeficiency virus (HIV) who are stable on highly active antiretroviral therapy (HAART) will not be excluded

Participant has known active hepatitis B (e.g., hepatitis B surface antigen \[HBsAg\] reactive) or hepatitis C (e.g., hepatitis C virus \[HCV\] ribonucleic acid \[qualitative\] is detected)

Pregnant or lactating

Clinically significant, active, bacterial infections that, to the judgement of the investigator makes it undesirable for the subject to participate in the study

Persons of childbearing potential (POCBP) or those capable of causing pregnancy whose sexual partners are POCBP who are unwilling or unable to use an effective method of contraception for at least 1 month prior to study entry, for the duration of the study, and for at least 180 days after the last dose of study drug. Non-childbearing potential is defined as follows (by other than medical reasons):

* \>= 45 years of age and has not had menses for \> 1 year

* Patients who have been amenorrhoeic for \< 2 years without history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation

* Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure, otherwise the patient must be willing to use an adequate barrier method throughout the study, starting with the screening visit through 180 days after the last dose of study treatment. Information must be captured appropriately within the site's source documents. Note: Abstinence is acceptable if this is the established and preferred contraception for the patient

History or active TB (Bacillus tuberculosis) that in the investigators opinion would preclude participation within the study

Any gastro-intestinal conditions that to the judgement of the investigator would interfere with the absorption of niraparib

Active, known or suspected unstable auto-immune disease, are excluded from this study. Exceptions to this criterion are all auto-immune disease that have remained stable within the past 3 months on corticosteroids (=\< prednisone 20 mg or equivalent) prior to first study treatment are allowed to enroll. Patients with autoimmune diseases that do not require active immunosuppression are also allowed to enroll

* Note: Paraneoplastic disease as a cause of auto-immune phenomenon will not be considered as auto-immune disease and are allowed to enroll

Evidence of serious uncontrolled medical disorder, active infection or mental disorder that, to the judgement of the investigator, makes it undesirable for the subject to participate in the study or that would jeopardize compliance with the protocol. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric disorder that prohibits obtaining informed consent

Prior malignancy which required active systemic treatment within 2 years prior to first study treatment. Exceptions are: successfully treated squamous cell carcinoma of the skin, superficial bladder cancer, and in situ carcinoma of the cervix. Since patients with BRCA 1/2 or PALB2 can have other tumors, as long as they have been definitively treated, it would not be considered an exclusion

What this study is about