A Study of Enzalutamide, Enzalutamide in Combination With Mifepristone, or Chemotherapy in People With Metastatic Breast Cancer

Inclusion Criteria:

Screening Cohort (non-MSK patients only):

* Age ≥18 years at time of consent
* signed the pre-screening informed consent document to allow for AR testing as part of study screening

Treatment Cohort:

* Female or male
* Pathologically confirmed invasive breast cancer that is unresectable, locally advanced, or metastatic
* TNBC (ER/PgR \<1%) or ER-low defined as:

  * ER and PgR 1-10%
  * HER2 negative per American Society of Clinical Oncology/College of American Pathologists guidelines
  * Local testing for ER/PgR and HER2 is acceptable for eligibility.
* Tumor must be AR positive. AR is considered positive by IHC if ≥10% of cell nuclei are immunoreactive.

  °AR testing performed locally must use protocol specified methodology to be acceptable for eligibility. Central testing is an option for those unable to perform local testing per this methodology. Please refer to the Section entitled "Treatment Plan" for AR testing methodology or refer to the laboratory manual.
* Evaluable or measurable disease per RECIST version 1.1; subjects with no evaluable AND no measurable disease (e.g., malignant effusions or bone marrow as the only manifestations of disease) are not eligible for enrollment.
* Eligible for one of the chemotherapy options listed as TPC (eribulin, capecitabine, paclitaxel, or carboplatin), as per investigator assessment.
* A representative, formalin-fixed, paraffin-embedded tumor specimen that enables the diagnosis of breast cancer, with adequate viable tumor cells in a tissue block (preferred) or 15 freshly cut unstained slides and 1 H\&E slide. Tissue from a metastatic site is preferred.

If not available, tissue from the primary site may be obtained.

* Patients may have received up to 2 prior lines of chemotherapy for metastatic breast cancer.

  * Patients with ER-low breast cancer may receive any number of lines of endocrine therapy +/- targeted therapy (i.e., CDK4/6 inhibitors, PI3K inhibitors).
  * Patients with PD-L1 positive breast cancer (CPS ≥ 10) should have received prior treatment with a checkpoint inhibitor setting unless there is a contraindication to checkpoint inhibitor therapy.
* Patients may receive bisphosphonate or denosumab.
* ECOG performance status 0-2.
* Age ≥18 years.
* Able to understand and the willingness to provide informed consent.
* Patients must not have another active malignancy that requires treatment.
* Women of child-bearing potential and men must agree to use 2 forms of adequate contraception (i.e., barrier contraception, abstinence, intrauterine device, or sterilization method) during study period and for 7 months following treatment end. Women must not breast feed while on study and for at least 3 months after final drug administration.
* Ability to swallow intact enzalutamide and mifepristone.
* Patient must be recovered from any recent major surgery. Radiation must have completed 14 days prior to study start. If treated in the second-line setting, the last chemotherapy or investigational anticancer therapy dose must be at least 14 days prior.
* Adequate organ and marrow function, as defined below:

  * ANC ≥1000, hemoglobin ≥9 g/dL, platelets ≥100,000
  * Total bilirubin ≤1.5x upper limit of normal (ULN), except for patients with known Gilbert syndrome; AST/ALT ≤3x ULN (≤5x ULN if liver metastases); creatinine ≤ 1.5x ULN.
  * Cortisol within normal limits
* Patients must agree to research biopsy at study entry until 40 patients randomized to Arm A and 40 patients randomized to Arm B and 20 patients randomized to Arm C have been biopsied.

  * Biopsy requirement may be waived in consultation with the study PI (Drs. Traina or Nanda) if not medically feasible.

Exclusion Criteria:

* Seizure disorder or any condition that may predispose to seizure (e.g., prior cortical stroke, significant brain trauma) at any time in the past. History of loss of consciousness or transient ischemic attack within 12 months.
* History of brain metastases or leptomeningeal disease.
* Prior antiandrogen therapy (AR antagonist or CYP17 inhibitors).
* Other concurrent investigational anticancer agents.
* Confirmed QT interval with Fridericia correction (QTcF) \> 480 msec.
* Any severe concurrent disease, infection, or comorbid condition that renders the patient inappropriate for enrollment in the opinion of the investigator or that interferes with the patient's ability to participate in the study requirements.
* Pregnant patients are not eligible for study.
* Women with a history of unexplained vaginal bleeding or with endometrial hyperplasia with atypia or endometrial carcinoma are excluded from study.
* An active gastrointestinal disorder affecting absorption (e.g., gastrectomy, uncontrolled celiac disease).
* Use of concurrent or chronic daily corticosteroid use. Topical or inhaled corticosteroids are permitted.
* Use of concurrent medications that are strong inducers/inhibitors or substrates of CYP3A4. Patients may be switched to alternative medications for eligibility purposes. A list of CYP3A4 substrates, inducers, and/or inhibitors
* Hypersensitivity reaction to the active pharmaceutical ingredient or any of the tablet components, including Labrasol, butylated hydroxyanisole, and butylated hydroxytoluene.