This phase II trial studies the side effects and how well niraparib and panitumumab work in treating patients with colorectal cancer that has spread to other places in the body. Niraparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as panitumumab, may help the body's immune system attack the cancer and may interfere with the ability of tumor cells to grow and spread. Giving niraparib and panitumumab may work better in treating patients with colorectal cancer.

PRIMARY OBJECTIVE:

I. Evaluate the activity of the combination of niraparib with epidermal growth factor receptor (EGFR) inhibitor panitumumab in previously treated patients with rat sarcoma gene (RAS) wild type (WT) metastatic colorectal cancer.

SECONDARY OBJECTIVES:

I. Define the toxicity profile of the combination of niraparib and panitumumab.

II. Evaluate the activity of the combination of niraparib and panitumumab in previously treated patients with metastatic colorectal cancer.

OUTLINE:

Patients receive niraparib orally (PO) once daily (QD) on days 1-28 and panitumumab intravenously (IV) over 60-90 minutes on days 1 and 15. Cycles 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, every 6 months for 2 years, and then annually for up to 5 years.

Inclusion Criteria:

• Participant must have advanced, metastatic RAS wildtype colorectal cancer and must have received at least one line of systemic therapy. Both microsatellite (MSI) high and stable (MSS) patients are eligible
• Participants may have been intolerant of, progressed on, or failed at least one line of systemic chemotherapy. Patients who are currently on first line Oxaliplatin-containing chemotherapy regimen are allowed on the trial if they have remained stable or better ([partial response]PR or [complete response]CR) for at least 4 months on that line of treatment and are being considered for maintenance therapy as standard of care
• Histologic or cytologic diagnosis of colorectal cancer
• Participant must have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1
• Absolute neutrophil count ≥ 1,500/µL
• Platelets ≥ 100,000/µL
• Hemoglobin ≥ 9 g/dL
• Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault equation
• Total bilirubin ≤ 1.5 x ULN (≤ 2.0 in patients with known Gilberts syndrome) OR direct bilirubin ≤ 1 x ULN
• Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x ULN unless liver metastases are present, in which case they must be ≤ 5 x ULN
• Participant must agree to not donate blood during the study or for 90 days after the last dose of study treatment
• Female participant has a negative urine or serum pregnancy test within 7 days prior to taking study treatment if of childbearing potential and agrees to abstain from activities that could result in pregnancy from screening through 180 days after the last dose of study
• Male participant agrees to use an adequate method of contraception starting with the first dose of study treatment through 180 days after the last dose of study treatment
• Participant must be able to provide written informed consent

Exclusion Criteria:

• Participant must not be simultaneously enrolled in any interventional clinical trial
• Prior therapy with poly ADP (adenosine diphosphate) ribose polymerase (PARP) inhibitors or with EGFR inhibitors approved for the treatment of colorectal cancer (cetuximab or panitumumab)
• Patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis during screening
• Inability to take oral medications
• 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
• Participant must not have a known hypersensitivity to components or excipients of niraparib or panitumumab
• 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
• Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
• Participant must not have had diagnosis, detection, or treatment of another type of cancer ≤ 2 years prior to initiating protocol therapy (except basal or squamous cell carcinoma of the skin and cervical cancer that has been definitively treated)
• Participant must not have known active, symptomatic brain or leptomeningeal metastases.