Due to slow accruals

Patients can be prescreened for the study at the time of diagnosis of locally advanced or metastatic disease by determining presence of LOH high status and/or deleterious alterations in HR pathway genes in the most recent available tumor tissue sample or in blood if they are found to have germline mutations. Patients with either somatic or germline mutations will be allowed. At the time of disease progression, patients with high LOH or deleterious alterations in HR pathway genes and satisfying all other inclusion criteria will be enrolled on the study. Patients will be treated with niraparib (flat dose) orally every day for 28 days until disease progression, unacceptable side effects, withdrawal of consent, or death. CT of the chest/abdomen/pelvis will be performed every 2 months and response will be assessed by RECIST 1.1.

Inclusion Criteria:

1. Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.

2. Age ≥ 18 years at the time of consent.

3. ECOG Performance Status of 0-1 within 14 days prior to registration.

4. Locally advanced esophageal adenocarcinoma or proximal gastric adenocarcinoma or metastatic adenocarcinoma originating from esophagus, GE junction, or proximal stomach who progress/recur beyond 2 months of receiving a platinum- containing regimen

   NOTE: Patients can be pre-screened for study at any time including after surgical resection for locally advanced esophageal cancer, at presentation with metastatic disease and potentially during chemotherapy and radiation prior to surgery.

5. A subject with symptomatic brain metastasis may be considered if they have completed their treatment for brain metastasis at least 4 weeks prior to study registration, have been off of corticosteroids for ≥ 2 weeks, and are asymptomatic. Patients with asymptomatic brain mets that are untreated will be allowed.

6. Must not have received more than 1 prior line of chemotherapy in the metastatic setting (could have received immunotherapy, VEGF directed therapy, and/or trastuzumab which does not count as chemotherapy).

7. One of the following genetic results is required for eligibility:

   • High LOH in tissue OR
   • HR mutation in tissue OR
   • Germline mutation (blood)

   NOTE: Mutations, deletions or loss by fusions are the acceptable alterations in HR genes as long as they are deleterious. Patients are eligible if they have a mutation in pre-specified HR genes BRCA1/2, PALB2, ATM, BARD1, BRIP1, CDK12, CHEK2, FANCA, RAD51, RAD51B, RAD51C, RAD51D, RAD54L, NBN, ARID1A and GEN1. Deleterious mutations in HR genes are defined as those that have been previously characterized to be loss-of-function/pathogenic/or likely pathogenic as specified per the following databases: Clinvar, OncoKB, or BRCAExchange. Mutations or small insertions or deletions that results in truncation, frameshift, stop codon loss, or stop codon gain will also be considered deleterious irrespective of their presence in the aforementioned databases unless previously characterized to be benign. Copy number losses or disruption by fusion will also be considered deleterious irrespective of their presence in the aforementioned databases. Gene amplifications or variants of unknown significance will not be eligible for inclusion.

   NOTE: Genetic testing results from a CLIA certified lab that confirm one of the following: high LOH in tissue, HR mutation in tissue or germline mutation in blood are required and can be used to meet eligibility. Even if subject has met eligibility with one of the criteria above, results from the other analysis is required if available.

   If prior genetic results are not available, subject must have archival tissue or fresh tissue (by new biopsy) for testing. Both primary tumor tissue and metastatic site sample biopsies are allowed. Blood will also be required for germline mutation analyses. Central confirmation of all results will be performed but are not mandated for eligibility. If a subject has met eligibility with prior genetic results but does not have sufficient archival tissue for central confirmation, a biopsy is not required.

8. Presence of measurable disease by RECIST v1.1, defined as:

   • Tumor lesions that must be accurately measured in at least one dimension (longest diameter in the plane of measurement is to be recorded) with a minimum size of:

     • 10 mm by CT scan (CT scan slice thickness no greater than 5 mm)
     • 10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured with calipers should be recorded as non-measurable)
     • 20 mm by chest X-ray

   • Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed.

9. Prior cancer treatment must be completed at least 14 days prior to registration and the subject must have recovered from all reversible acute toxic effects of the regimen (other than alopecia) to ≤ Grade 1 or baseline.

10. Demonstrate adequate organ function as defined in the table below; all screening labs to be obtained within 14 days prior to registration.

    • Absolute Neutrophil Count (ANC) ≥ 1.5 K/mm3
    • Hemoglobin (Hgb) ≥ 9 g/dL
    • Platelet Count (Plt) ≥ 100 K/ mm3
    • Creatinine ≤ 1.5 X upper limit of normal (ULN)
    • Bilirubin ≤ 1.5× ULN ((≤2.0 in patients with known Gilberts syndrome))
    • Aspartate aminotransferase (AST) ≤ 2.5× ULN*
    • Alanine aminotransferase (ALT) ≤ 2.5 × ULN*

11. Females of childbearing potential must have a negative pregnancy test within 7 days prior to study treatment. Urine or serum βhCG if clinically appropriate. If a urine test is done and it is positive or cannot be confirmed as negative, a serum pregnancy test will be required. NOTE: Females are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months.

12. Females of childbearing potential must be willing to abstain from heterosexual intercourse or use adequate contraception as described in the protocol. Males must be willing to abstain from heterosexual intercourse or use adequate contraception as described in the protocol.

13. Participants must agree to not breastfeed during the study or for 30 days after the last dose of study treatment.

14. As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study.

15. Participant must agree to not donate blood during the study or for 90 days after the last dose of study treatment.

Exclusion Criteria:

1. Prior therapy with a PARP inhibitor
2. Disease progression during first 2 months of standard dose platinum-based chemotherapy (platinum refractory). This excludes low dose platinum based therapy that is given in a chemotherapy-radiation regimen for locally advanced esophageal cancer.
3. Participant must not be simultaneously enrolled in any other interventional clinical trial.
4. Participant must not have had major surgery ≤ 3 weeks prior to initiating protocol therapy and participant must have recovered from any surgical effects.
5. Participant must not have 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.
6. Participant has had 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.
7. Participant must not have a known hypersensitivity to niraparib components or excipients including tartrazine.
8. Participant must not have received a transfusion (platelets or red blood cells) ≤ 4 weeks prior to initiating protocol therapy.
9. Participant must not have received colony stimulating factors (e.g., granulocyte colony-stimulating factor, granulocyte macrophage colony stimulating factor, or recombinant erythropoietin) within 4 weeks prior initiating protocol therapy.
10. Participant has had any 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.
11. Participant must not have any known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).
12. Participant must not have a serious, uncontrolled medical disorder, nonmalignant systemic disease, or active, uncontrolled infection. 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.
13. No active secondary cancer