Niraparib, Dostarlimab, and Radiation Therapy for the Treatment Metastatic PD-L1 Negative or Immunotherapy-Refractory Triple Negative Breast Cancer, the NADiR Study

Inclusion Criteria

• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• Histologically or cytologically-confirmed TNBC (estrogen receptor [ER] < 1%, progesterone receptor [PR] < 1%, HER-2-neu 0-1+ by immunohistochemistry [IHC] or non-fluorescence in situ hybridization [FISH]-amplified. * Patients must be PD-L1 negative, have progressed on or after ICI, or be PD-L1 positive but refuse cytotoxic chemotherapy for their metastatic disease. ** Note: PD-L1 status may be determined on tissues from either primary or metastatic sites. PD-L1 status must be determined by an Food and Drug Administration (FDA)-approved assay approved for breast cancer, such as PharmDx immunohistochemistry (IHC) (22C3) for pembrolizumab, Ventana (SP142) for atezolizumab, or other PD-L1 testing by a Clinical Laboratory Improvement Act (CLIA)-approved lab
• Metastatic or recurrent TNBC
• Radiation is clinically indicated for local control or palliation
• At least one tumor for which RT is considered clinically appropriate. New brain and dural-based metastases are included, so long as RT is considered clinically appropriate and may be treated with the suggested dose regimen (24 Gy/3 fractions or 30 Gy/5 fractions)
• At least one radiographically-confirmed metastases index lesion that will not undergo RT and is measurable based on RECIST v1.1
• Prior therapy with targeted agents or other forms of immunotherapy is allowed
• Prior RT is permitted, provided the treating radiation oncologist deems that study RT treatment planning guidelines can be achieved
• Available archived tumor tissue of a metastatic tumor * Note: There is no time interval over which biopsy of a metastatic tumor must have been performed prior to study registration
• Absolute neutrophil count (ANC) >= 1500/mm^3 (assessed within 8 days prior to initiation of protocol treatment, unless otherwise indicated)
• Platelet count >= 100,000/mm^3 (assessed within 8 days prior to initiation of protocol treatment, unless otherwise indicated)
• Hemoglobin >= 9.0 g/dL (assessed within 8 days prior to initiation of protocol treatment, unless otherwise indicated)
• Serum creatinine =< 3 x upper limit of normal (ULN) or measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 30 mL/min for participant with creatinine levels > 1.5 X ULN (assessed within 8 days prior to initiation of protocol treatment, unless otherwise indicated) * Creatinine clearance should be calculated per institutional standard
• Total bilirubin =< 1.5 ULN (direct bilirubin =< ULN for participants with total bilirubin levels > 1.5 ULN) (assessed within 8 days prior to initiation of protocol treatment, unless otherwise indicated)
• International normalized ratio (INR), prothrombin time (PT), activated partial thromboplastin time (aPTT) =< 1.5 x ULN (participants receiving anticoagulant therapy must have PT or PTT within therapeutic range) (assessed within 8 days prior to initiation of protocol treatment, unless otherwise indicated)
• Albumin >= 2.5 mg/dL (assessed within 8 days prior to initiation of protocol treatment, unless otherwise indicated)
• Aspartate aminotransferase (AST) =< 2.5 x ULN (assessed within 8 days prior to initiation of protocol treatment, unless otherwise indicated) * Participants with liver metastases may have AST and/or alanine aminotransferase (ALT) =< 5 x ULN
• Alanine aminotransferase (ALT) =< 2.5 x ULN (assessed within 8 days prior to initiation of protocol treatment, unless otherwise indicated) * Participants with liver metastases may have AST and/or ALT =< 5 x ULN
• Female participant has a negative urine or serum pregnancy test within 7 days prior to study registration if a woman of child-bearing potential and agrees to abstain from activities that could result in pregnancy from screening through 180 days after the last dose of study treatment or is of non-childbearing potential. * Note: If the screening pregnancy test was completed > 72 hours prior to C1D1, it will be repeated within 72 hours of treatment initiation 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
• Women of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 180 days after the last dose of study medication. Participants of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year * Note: Abstinence is acceptable if this is the established and preferred contraception for the patient
• Male participant agrees to use an adequate method of contraception starting with the first dose of study treatment through 90 days after the last dose of study treatment * Note: Abstinence is acceptable if this is the established and preferred contraception for the patient
• Male subjects must not donate sperm starting with the first dose of study drug through 90 days after the last dose of study drug
• Participant must agree not to breastfeed during the study or for 30 days after the last dose of study treatment
• Participant must agree to not donate blood during the study or for 90 days after the last dose of study treatment
• Ability to swallow (whole) and retain oral medications
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

• Known germline or somatic BRCA mutation-positive status
• Known active LMD (leptomeningeal disease). However, documented, previously treated and stable brain metastases are permitted. New, untreated brain metastases are permitted if they will be irradiated with the study regimen (24 Gy/3 fractions or 30 Gy/5 fractions)
• Known additional malignancy that progressed or required treatment in the last 2 years. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
• Prior treatment with either a PARP inhibitor or ICI is permitted, however, prior receipt of both therapies is excluded
• Hypersensitivity to niraparib or dostarlimab components or its excipients.
• Participation in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks (or at least 5 half-lives from previous therapy) of the first dose of study treatment
• Receipt of prior cytotoxic therapy or targeted small molecule therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., > grade 1 or at baseline) from adverse events due to a previously administered agent * Note: Participants with alopecia and =< grade 2 neuropathy are an exception to this criterion and may qualify for the study
• Patients who have undergone any major surgery within 3 weeks prior to study entry: patients must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
• Active autoimmune disease receiving systemic treatment within 7 days prior to the first dose of trial treatment (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Use of local corticosteroid injections (e.g. intra-articular injections), inhaled, intranasal, ophthalmic, and topical corticosteroids, and subjects requiring corticosteroid pre-medication for hypersensitivity reactions (e.g. CT scan pre-medication) are allowed
• Known history of/active, non-infectious pneumonitis requiring treatment with steroids or has history of/active interstitial lung disease
• Active infection requiring systemic therapy
• History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient’s participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator
• Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Participant has 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
• Pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 180 days after the last dose of trial treatment
• Known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML)
• Patients with a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies) may be included on a selective basis. As per FDA guidance, participants with known history of HIV infection are excluded, with the exception of participants who are positive for HIV and meet all of the following criteria:. * Is receiving a stable regimen of highly active anti-retroviral therapy (HAART); * Has no requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections; and * Has a CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard pCR-based tests
• Known active hepatitis B (e.g., hepatitis B surface antigen [HbsAg] reactive or HepB core+) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
• Known history of active TB (Bacillus Tuberculosis)
• Receipt of a live vaccine within 14 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
• Participant must not have received a transfusion (platelets or red blood cells) =< 4 weeks prior to initiating protocol therapy
• 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
• 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
• Patient experienced >= grade 3 immune-related adverse event (AE) with prior immunotherapy, with the exception of non-clinically significant lab abnormalities