Niraparib and Dostarlimab for Patients With MMR-D/MSI-H Colorectal Cancers

Inclusion Criteria: 1. Histologically confirmed mismatch repair deficient or microsatellite instability high advanced stage colorectal cancer 2. Measurable disease per RECIST v1.1 3. ECOG 0 to 2 4. Age ≥ 18 years 5. Able to swallow oral medication (tablets). 6. Progression on prior anti-PD1 ± anti-CTLA4 therapy. 7. Adequate organ function based on the following lab assessments: 1. ANC must be ≥ 1500/mm3. 2. Platelet count must be ≥ 100,000/mm3. 3. WBC count ≥ 2.5 × 109 /L 4. Hemoglobin must be ≥ 9 g/dL. 5. Alkaline phosphatase ≤ 2.5× upper limit of normal (ULN) with the exception of patients with documented liver or bone metastases who should have ALP ≤ 5.0× ULN. 6. AST and ALT≤ 2.5× ULN with the exception of patients with documented liver metastases who may have AST and/or ALT ≤ 5.0× ULN. 7. International normalized ratio (INR) ≤ 1.5 x ULN and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless receiving treatment with therapeutic anticoagulation. 8. Total bilirubin ≤ 1.5× ULN (≤3× ULN if Gilbert syndrome present) 9. Serum albumin ≥ 2.8 g/dL or 28 g/L 10. Creatinine clearance ≥ 60 mL/min using the Cockcroft-Gault equation. 8. Patient who experienced progression of disease on prior anti-PD1 ± Anti-CTLA in the adjuvant and neoadjuvant settings are eligible to be enrolled in this trial without requirement of a second line of immunotherapy for advanced stage disease. 9. Women of childbearing potentials must use a contraceptive method that is highly effective (with a failure rate of \<1% per year), from the screening visit through at least 120 days after the last dose of study treatment and agree not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. 10. Men must agree to use adequate contraception for the duration of trial participation and for 4 months after the last dose of study drugs. Men must also agree to not donate sperm. Men must agree to use adequate contraception for the duration of trial participation and for 4 months after the last dose of study drugs. Men must also agree to not donate sperm. Exclusion Criteria: 1. More than 2 lines of systemic therapy (excluding adjuvant therapy) 2. Prior oxaliplatin based chemotherapy for metastatic disease. This excludes adjuvant oxaliplatin. Patients who received oxaliplatin based chemotherapy for metastatic disease before determination of MMR-D/MSI-H status (due to test turn-around time) can be enrolled if they received 4 or less cycle of oxaliplatin treatment (each cycle is one dose). 3. More than 1 line of anti-PD1 based therapy. 4. History of severe hypersensitivity to anti-PD1 monoclonal antibodies 5. Prior PARPi 6. Progression on platinum-based chemotherapy 7. Active autoimmune disease requiring immune suppression except following conditions: 1. Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone without an active complication are eligible for the study. 2. Patients with well controlled Type 1 diabetes mellitus who are actively on an insulin regimen are eligible for the study. 3. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met: * Disease is well controlled at baseline and requires only topical corticosteroids. - No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months. 8. Active untreated brain metastasis (patients treated brain metastasis within 4 weeks can be enrolled) 9. Any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach and/or bowels. 10. Received colony-stimulating factors (e.g., granulocyte macrophage colony-stimulating factor or recombinant erythropoietin) within 4 weeks. 11. Previously or are currently participating in a treatment study of an investigational agent within 4 weeks of the first dose of therapy preceding the study. 12. Received live vaccine within 30 days of planned start of study randomization. Study patients can be vaccinated against Corona virus disease 2019 (COVID-19) using vaccines authorized via the appropriate regulatory mechanisms. Note: messenger ribonucleic acid (mRNA) and adenoviral-based COVID-19 vaccines are considered nonlive. If COVID-19 vaccine is administered at any time, the date, name of the COVID-19 vaccine anatomic location, must be entered in the eCRF. 13. Hypersensitivity to the components of niraparib or the formulation excipients. 14. Undergone major surgery within 4 weeks of starting the first dose of study treatment or have not recovered from any effects of any major surgery. 15. Have a second primary malignancy. Exceptions are the following: 1. Adequately treated nonmelanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS) of the breast, Stage I Grade 1 endometrial carcinoma 2. Other solid tumors and lymphomas (without bone marrow involvement) diagnosed ≥5 years prior to randomization and treated with no evidence of disease recurrence and for whom no more than 1 line of chemotherapy was applied. 16. Current active pneumonitis or any history of pneumonitis requiring steroids (any dose) or immunomodulatory treatment within 90 days of planned start of the study. 17. Any clinically significant concomitant disease or condition (such as transfusion-dependent anemia or thrombocytopenia) that could interfere with, or for which the treatment might interfere with, the conduct of the study or that would, in the opinion of the Investigator, pose an unacceptable risk to the patients in this study. 18. Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study requirements and/or follow-up procedures. Those conditions should be discussed with the patients before study entry. 19. High medical risk due to a serious, uncontrolled medical disorder; nonmalignant systemic disease; or active, uncontrolled infection (including COVID-19). 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, active uncontrolled coagulopathy, bleeding disorder, or any psychiatric disorder that prohibits obtaining informed consent. 20. Uncontrolled hypertension defined as SBP\>180 and DBP\>100 should receive antihypertensive medical therapy for blood pressure control (to achieve SBP\<160 and DBP \<90) before being enrolled in the study. 21. Is pregnant, breastfeeding, or expecting to conceive children while receiving study treatment and/or for up to 180 days after the last dose of study treatment. 22. Presence of hepatitis B surface antigen or a positive hepatitis C virus (HCV) antibody test result at Screening or within 3 months prior to first dose of study treatment. Patients with presence of hepatitis B core antibody should also be excluded. 1. NOTE: Patients with chronic hepatitis B virus (HBV) infection, who meet the criteria for anti-HBV therapy may be eligible if the participant is on a suppressive antiviral therapy prior to initiation of cancer therapy. 2. NOTE: Patients with positive HCV antibody due to prior resolved disease can be enrolled only if a confirmatory negative HCV RNA PCR is obtained. Also, patients with a history of HCV infection may be eligible if they have both: completed curative therapy, have an HCV viral load \<quantifiable limit. 23. Known history of MDS or AML 24. Are immunocompromised. Patients with splenectomy are allowed. Patients with known human immunodeficiency virus (HIV) are allowed if they meet the following criteria: 1. Cluster of differentiation 4 ≥350/µL and viral load \<400 copies/mL 2. No history of acquired immunodeficiency syndrome-defining opportunistic infections within 12 months prior to enrollment. 3. No history of HIV-associated malignancy for the past 5 years. Concurrent antiretroviral therapy as per the most current National Institutes of Health (NIH) Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV \[NIH, 2021\] started \>4 weeks prior to study enrollment. 25. Prior immunotherapy toxicities (until resolution to Grade 1 or better)