ASTX727 and Talazoparib for the Treatment of Triple Negative or Hormone Resistant/HER2-Negative Metastatic Breast Cancer

Inclusion Criteria

• >= 18 years old at the time of informed consent
• Ability to provide written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization
• Locally recurrent (not amenable to local therapy with curative intent) or metastatic breast cancer * Patients with triple negative breast cancer (estrogen receptor [ER] and progesterone [PR], =< 5% weakly staining) must have received at least one prior chemotherapy regimen for metastatic disease. * Patients with hormone-positive, HER2-negative disease (as defined by American Society of Clinical Oncology and College of American Pathologists [ASCO and CAP]) must have received treatment with and progressed on at least one prior endocrine therapy including a CDK4/6 inhibitor in the metastatic setting
• Measurable or evaluable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• Only subjects who have disease amenable to biopsy will be asked to consent to serial tumor biopsies. Consent for biopsy is not required for participation * NOTE: If no amenable disease is present at the time of second biopsy, subjects may continue participation in the study and further study specific biopsies will not be required
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
• Patients with treated, asymptomatic central nervous system (CNS) disease may participate if the patient is > 4 weeks from completion of CNS therapy (radiation and/or surgery), is clinically stable at the time of study entry, and is receiving a stable or decreasing dose of corticosteroid therapy. Brain magnetic resonance imaging (MRI) or head computed tomography (CT) is required at screening for patients with known brain metastases
• Total bilirubin =< upper limit of normal (ULN) (except in patients with documented Gilbert’s disease, who must have a total bilirubin =< 3.0 mg/dL)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 x ULN (=< 1.5-3.0 x baseline if baseline is abnormal)
• Calculated creatinine clearance of >= 60 mL/min using the Cockcroft-Gault formula
• Absolute neutrophil count (ANC) >= 1.5 K/mm^3
• Platelets >= 100 K/ mm^3
• Hemoglobin (Hgb) >= 9.0 g/dL
• Women of childbearing potential must have a negative pregnancy test within 14 days of protocol registration. Women are considered to have childbearing potential (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) unless they meet one of the following criteria: * Has undergone a hysterectomy or bilateral oophorectomy; or * Has been naturally amenorrheic for at least 24 consecutive months
• Women of childbearing potential and men must agree to use effective contraception throughout the study and for 7 months after the last study treatment. * Note: Acceptable methods of birth control include abstinence, partner with previous vasectomy, placement of an intrauterine device (IUD), condom with spermicidal foam/gel/film/cream/suppository, diaphragm or cervical vault cap, or hormonal birth control (pills or injections)

Exclusion Criteria

• Prior treatment with decitabine, guadecitabine or other known DNMT inhibitor (DNMTi)
• Prior treatment with talazoparib or other known PARP inhibitor (PARPi)
• Known deleterious BRCA mutation. Patients with BRCA variants of unknown significance (VUS) or who have not had germline genetic testing may participate
• Active or symptomatic CNS disease
• Patients with HER2+ disease * HER2 will be considered positive if scored 3+ by immunohistochemistry (IHC) or 2+ by IHC associated with a fluorescence in situ hybridization (FISH) ratio of > 2.0 or > 6 total HER2 gene copies per cell
• Patients with active malignancy other than breast cancer. Patients with prior malignancies without recurrence after standard treatment will not be excluded
• Chemotherapy within 3 weeks of registration
• Radiation therapy within 2 weeks of registration
• Hormone therapy within 2 weeks of registration
• Patients requiring ongoing therapy with strong P-glycoprotein (P-gp) inhibitors