Niraparib in Combination With Osimertinib in EGFR-Mutated Advanced Lung Cancer

Inclusion Criteria: * Participants must have histologically or cytologically confirmed stage IV (AJCC 8th ed.) NSCLC with an activating EGFR mutation as identified in a CLIA-approved laboratory. * Presence of evaluable disease, either measure or non-measurable, in accordance with RECIST 1.1 criteria. * Participants must have had clinical progression on osimertinib at any prior time, i.e., intervening therapy between osimertinib and study enrollment is allowed. * Participants must have access to commercial osimertinib. * Participants must not have received any prior PARP inhibitor therapy. * Age minimum 18 years. * ECOG performance status ≤1 (Karnofsky ≥70%, see Appendix A). * Life expectancy of greater than 6 months. * Participants must have normal organ and marrow function as defined below: * absolute neutrophil count ≥1,500/mcL * platelets ≥100,000/mcL * hemoglobin ≥ 9 g/dL * bilirubin total bilirubin ≤ 1.5 x upper limit of normal (ULN) (≤2.0 in patients with known Gilberts syndrome or liver metastases) OR direct bilirubin ≤ 1 x ULN * AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal, unless liver metastases are present, in which case they must be ≤ 5 x ULN * creatinine ≤ 1.5 x institutional ULN OR * creatinine clearance ≥50 mL/min using the Cockcroft-Gault equation * Participants must have undergone a prior tumor biopsy upon clinical progression on osimertinib. If it was not feasible or medically safe to undergo a biopsy a patient may enroll with permission of the PI. * The effects of Niraparib on the developing human fetus are unknown but based on its mechanism of action Niraparib may cause fetal harm when administered to a pregnant woman. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry through 180 days after the last dose of study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of Niraparib administration. * Female participant must have a negative urine or serum pregnancy test within 7 days prior to taking study treatment if of childbearing potential, or is of nonchildbearing potential. Nonchildbearing 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 180 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. * Ability to take oral medications whole. * Participant receiving corticosteroids may continue as long as their dose is stable for least 4 weeks prior to initiating protocol therapy. * Participant must agree to not donate blood during the study or for 90 days after the last dose of study treatment * Participant must agree not to breastfeed during the study or for 180 days after the last dose of study treatment. * Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: * Participants must not be simultaneously enrolled in any interventional clinical trial. * Participants receiving any systemic standard of care or investigational therapy within 4 weeks from the last dose prior to planned study treatment, with the exception of osimertinib. This time frame may be shortened for participants depending on the characteristics of the individual therapy, after discussion with the Study PI. For investigational therapy, the time frame will not be shortened to less than at least 5 half-lives of the investigational agent. * Patients receiving radiation therapy encompassing \> 20% of the bone marrow by investigator's estimate within 14 days, or any radiation therapy within 7 days from the last treatment prior to planned study treatment. However, small volume palliative radiation therapy with no or little bone marrow exposure is allowed at the investigator's discretion. * Participants may receive a stable dose of bisphosphonates for bone metastases, before and during the study as long as these were started at least 4 weeks prior to treatment. * Participants who had any major surgery within the past 3 weeks (excluding vascular access placement, mediastinoscopy, or biopsies performed by an interventional service) and participant must have recovered from any surgical effects. * Participants with symptomatic uncontrolled brain or leptomeningeal metastases. Participants with brain metastases that have been treated with prior radiation therapy and are stable on a subsequent scan are allowed. Participants with untreated possible brain metastases that are ≤ 1 cm and asymptomatic are allowed. * Participants who received a transfusion (platelets, red blood cells) or hematopoetic growth factors within 4 weeks of study treatment. * Presence of any of the following cardiac criteria/factors: * Resting QT interval of \>470 msec. * Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG, such as complete left bundle branch block, third degree heart block, or second degree heart block. * Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first degree relatives, or any concomitant medication known to prolong the QT interval. * Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required corticosteroid treatment, or any evidence of clinically active interstitial lung disease. * Participants with known hypersensitivity to the components or excipients of niraparib or osimertinib. * Participants may not have received prior treatment with anti-PD1, -PDL1, or -CTLA4 inhibitors. * Participants with a second, clinically active, malignancy. Participants must not have known history or current diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, myocardial infarction, major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or psychiatric illness/social situations that would limit compliance with study requirements. * Participants must not have 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. * Participants must not have current evidence of any condition, therapy, or laboratory abnormality (including active or uncontrolled myelosuppression \[ie, anemia, leukopenia, neutropenia, thrombocytopenia\]) that might confound the results of the study or interfere with the patient's participation for the full duration of the study treatment or that makes it not in the best interest of the patient to participate in the opinion of the investigator or sponsor. * Patients must not have known, active hepatitis B/C. * Known disorder affecting gastrointestinal absorption. * Patients must not be pregnant or breastfeeding, or expecting to conceive children, within the projected duration of the study treatment, or for 180 days after the last dose of study treatment. * Known HIV-positive participants are ineligible because of the potential for pharmacokinetic interactions with Niraparib. In addition, these participants may be at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated, However, HIV testing is not required.