Niraparib + Dostarlimab + RT in Pancreatic Cancer

Inclusion Criteria:

* Histologically or cytologically confirmed metastatic adenocarcinoma of pancreatic origin.
* Age \> 18 years.
* ECOG performance status ≤ 1.
* Life expectancy of greater than 3 months.
* Participants must have normal organ and marrow function as defined below:

  * leukocytes ≥ 2,000/mcL
  * absolute neutrophil count ≥ 1,500/mcL
  * platelets ≥ 100,000/mcL
  * hemoglobin ≥ 9 g/dL
  * AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal(subjects with liver metastases can have an AST (SGOT) ≤ 5 x ULN
  * creatinine ≤ 1.5 x ULN OR
  * creatinine clearance\* ≥ 60 mL/min (if using the Cockcroft-Gault formula)
  * total bilirubin ≤ 1.5 x ULN (subjects with Gilbert Syndrome can have a total bilirubin \< 3 x ULN)
  * INR, PT, aPTT ≤ 1.5 x ULN (subjects receiving anticoagulant therapy must have PT or PTT within therapeutic range) \*Creatinine clearance should be calculated per the following: CrCl (mL/min) = (140 - age \[years\]) x weight \[kg\] x 1.23 (x 0.85 if female)/ Serum creatinine (micromol/L)
* Women of childbearing potential (WoCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 7 days prior to initiating protocol therapy.

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 2 adequate barrier methods throughout the study, starting with the screening visit through 150 days after the last dose of study treatment. See Section 4.4 for a list of acceptable birth control methods. 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.

  * Women of childbearing potential must agree to use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 6 months (30 days plus the time required for niraparib to undergo five half-lives/150 days) after the last dose of investigational drug.
  * Women must not be breastfeeding during the study or for 150 days after the last dose of investigational drug.
  * Men who are sexually active with WoCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving protocol therapy and who are sexually active with WoCBP will be instructed to adhere to contraception for a period of 6 months (150 days) after the last dose of investigational product. (Women who are not of childbearing potential, i.e. are postmenopausal as defined in the eligibility criteria or surgically sterile, as well as azoospermic men do not require contraception.) Ability to understand and the willingness to sign a written informed consent document
  * If applicable, stable dose of dexamethasone of 10mg or less for 4 weeks prior to initiation of investigational protocol therapy. Regimen must be completed \>14 days prior to treatment start.
  * One previously unirradiated lesion amenable to radiotherapy at a dose of 8 Gy x 3 and can meet dose constraints, and another unirradiated measurable lesion \> 1 cm in size outside the radiation field that can be used as measurable disease.
  * Patients must have had at least one line of prior treatment. Any prior line of treatment is permitted, including adjuvant.

Exclusion Criteria:

Participants who meet any of the following criteria will be excluded:

* Systemic anticancer or biological therapy including prior chemotherapy, immunotherapy, targeted small molecule therapy within 14 days prior to investigational agent, or those who have not recovered (i.e., ≤ grade 1 or at baseline) from adverse events due to agents administered more than 2 weeks earlier. Participants with ≤ grade 2 neuropathy are an exception to these criteria and may qualify for the study. If the participant received major surgery, then they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
* Received investigational therapy ≥ 4 weeks, or within a time interval less than at least 5 half-lives of the investigational agent, whichever is shorter, prior initiating protocol therapy.
* Major surgery ≤ 3 weeks prior to initiating protocol therapy and/or not recovered from any surgical effects.
* Received radiation therapy encompassing \>20% of the bone marrow within 2 weeks; or any radiation therapy within 1 week prior to day 1 of protocol therapy.
* Received a transfusion (platelets or red blood cells) ≤ 4 weeks prior to initiating protocol therapy
* Received colony-stimulating factors (e.g., granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor, or recombinant erythropoietin) within 4 weeks prior to initiating protocol therapy. Known history of 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).
* Active, known or suspected autoimmune disease that has required systemic treatment within the past 2 years other than vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
* Any condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Participants are permitted to use topical, ocular, intraarticular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if \> 10 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted.
* Known history of active TB (Bacillus Tuberculosis). Testing is not required for eligibility purposes.
* Known hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection. Testing is not required for eligibility purposes.
* Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). These participants are at increased risk of lethal infections when treated with marrow suppressive therapy. Testing is not required for eligibility purposes.
* Known ≥ Grade 3 immune-related AE with prior immunotherapy, with the exception of non-clinically significant lab abnormalities.
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, recent (within 90 days) myocardial infarction or psychiatric illness/social situations that would limit compliance with study requirements.
* Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
* Known additional malignancy diagnosed, detected or treated ≤ 2 years prior to initiation of protocol therapy . Exceptions include basal cell carcinoma of the skin and squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
* Known history of, or any evidence of active, non-infectious pneumonitis or interstitial lung disease.
* Active infection requiring systemic therapy
* Has received a live vaccine within 30 days of planned start of study therapy. Note:

Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

* Known hypersensitivity to niraparib and dostarlimab components or excipients.
* History of severe hypersensitivity reaction to any monoclonal antibody
* Participants with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.

Further imaging is not required for eligibility purposes.