Targeting the PAM50 Her2-Enriched Phenotype With Enzalutamide in Hormone Receptor-Positive/Her2-Negative Metastatic BC

Inclusion Criteria: * Written informed consent for all study procedures according to local regulatory requirements prior to beginning specific protocol procedures. * Subjects with progression on or following at least 1 prior standard of care systemic anti-cancer therapy. * Female and male patients. * Performance status of 0-2. * Age ≥18 years. * Pre/peri-menopausal and post-menopausal women are allowed; menopausal status is relevant for the requirement of goserelin, triptorelin or leuprolide to be used concomitantly with enzalutamide. Post-menopausal status is defined either by: * Prior bilateral oophorectomy or * Age ≥60 or * Age \< 60 and amenorrhea for ≥ 12 months (in the absence of chemotherapy, tamoxifen, toremifen, or ovarian suppression) and FSH and estradiol in the post-menopausal range per local standards. * If a patient is taking tamoxifen or toremifene and is aged \< 60, then FSH and plasma estradiol levels should be in post-menopausal range per local values. * For women with therapy-induced amenorrhea, measurement of FSH and/or estradiol are needed to ensure menopausal status. * Life expectancy ≥ 12 weeks. * Locally advanced or metastatic breast cancer not amenable to curative intent. * Histologically confirmed HR-positive/HER2-negative disease based on the most recent biopsy before signing the informed consent. * HER2 negativity is defined as either of the following by local laboratory assessment: IHC 0, IHC 1+ or IHC2+/in situ hybridisation (ISH/FISH) negative as per American Society of Clinical Oncology (ASCO)-College of American Pathologists Guideline (CAP) guideline(73). * ER and/or PR positivity are defined as \>1% of cells expressing HR via IHC analysis as per ASCO-CAP guideline (74) * Patients must have a site of disease amenable to safely perform a biopsy, as per Investigator's assessment, and be a candidate for tumor biopsy according to the treating institution's guidelines. * Possibility of performing a biopsy prior to the start of treatment and its repetition after 2 weeks (14-21 days) on the same location. It will be provided formalin-fixed paraffin-embedded (FFPE) tumor block. The tumor tissue should be of good quality based on total and viable tumor content and must be evaluated centrally for PAM50 analysis prior to enrollment. Patients whose tumor tissue is not evaluable for central testing are not eligible. It is recommended to send the biopsy directly to the central lab after confirming the existence of a tumor, so as not to delay the inclusion, without the need to carry out IHC studies in the same. * Acceptable samples include core needle biopsies for deep tumor tissue or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions or biopsies from bone metastases. * Fine needle aspiration, brushing, cell pellet from pleural effusion and lavage samples are not acceptable. * Patient must be willing to provide biopsy prior to the start of treatment and its repetition after 2 weeks (14-21 days) on the same location. * The following subtypes identified in the pre-treatment tumor biopsy, as assessed by PAM50 assay at the Central Laboratory: * HER2-E (Cohort A) * Luminal A and Luminal B (Cohort B). * No more than 4 prior lines of chemotherapy regimens for recurrent, locally advanced or metastatic breast cancer. * Endocrine resistant disease, defined as the presence of disease recurrence while receiving adjuvant endocrine therapy for early stage breast cancer or disease progression of locally advanced/metastatic BC under ongoing endocrine therapy. There is no limit of previous received hormonal agents. * Measurable and non-measurable (but evaluable) disease per RECIST 1.1 criteria. * Adequate organ function, as determined by the following laboratory tests, within 28 days prior to enrollment: * Absolute neutrophil count (ANC) ≥ 1.5 x 109/L. * Hemoglobin (Hb) ≥ 9 g/dL (red blood cell transfusion and/or erythropoietin allowed 7 days before study treatment). * Platelets ≥ 75,000/mm3. * International normalized ratio (INR) or prothrombin time (PT) ≤1.5 × ULN and activated partial thromboplastin time (aPTT) within therapeutic range * Serum creatinine ≤ 1.5x upper limit of normal (ULN) * AST or ALT ≤ 3 x ULN. * Serum bilirubin ≤ 1.5 upper limit of normal (ULN) unless the patient has documented non-malignant disease (e.g. Gilbert´s syndrome). * Ability to swallow study drug and comply with study requirements. * Resolution of all acute toxic effects of prior therapy or surgical procedures to baseline or Grade ≤ 1 (except alopecia or other toxicities not considered to be a safety risk for the patient) according to NCI CTCAE version 5.0. Exclusion Criteria: * History of current or previously treated CNS metastases or leptomeningeal disease. Testing for CNS metastasis is not mandatory. * History of seizure or any condition that may predispose to seizure. * Clinically significant cardiovascular disease within 6 months prior to enrolment defined as: * Myocardial infarction. * Inadequately controlled angina or serious cardiac arrhythmia not controlled by adequate medication. * Congestive heart failure (CHF) New York Health Association (NYHA) Class ≥ II. * History of clinically significant ventricular arrhythmias (eg, ventricular tachycardia, ventricular fibrillation, torsade de pointes). * History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place. * Hypotension as indicated by systolic blood pressure \< 86 millimeters of mercury (mmHg) on 2 consecutive measurements at the screening visit. * Bradycardia as indicated by a heart rate of \< 50 beats per minute on the screening electrocardiogram (ECG) recording. * Uncontrolled hypertension as indicated by systolic blood pressure \> 170 mmHg or diastolic blood pressure \> 105 mmHg on 2 consecutive measurements at the screening visit. * Inability to swallow tablets, extensive reduction surgery of the stomach or small bowel or any active gastrointestinal disorder which may impair the absorption of the trial treatment (e.g. active peptic ulcer disease; uncontrolled celiac disease). * Major surgical procedure within 4 weeks prior to allocation or anticipation of the need for major surgery during the course of study treatment. * Use of medications that could reduce seizure threshold or concomitant treatment with potent CYP3A4 inducers. * Treatment with warfarin and coumarin-like anticoagulants. Prophylactic use of low molecular weight heparin (LMWH) is allowed. * Fructose intolerance. * Treatment with any anticancer commercially available or investigational drug within 14 days prior to commencing trial treatment. * Hypersensitivity reaction to the active pharmaceutical ingredient or any of the capsule components, including Labrasol, butylated hydroxyanisole, and butylated hydroxytoluene. * Current severe disease, infection, or systemic condition that renders the patient inappropriate for enrollment in the opinion of the investigator. * Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial. * Has a known history of Human Immunodeficiency Virus (HIV). * Has a known history of Hepatitis B (defined as Hepatitis B surface antigen \[HBsAg\] reactive) or known active Hepatitis C virus (defined as HCV RNA \[qualitative\] is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority. * Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. * Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of enzalutamide. * Treatment with any approved or investigational agent that blocks androgen synthesis or targets the AR (eg, abiraterone acetate, ARN-509, bicalutamide, enzalutamide, ODM-201, TAK-448, TAK-683, TAK-700); or patients who progressed on Exemestane in adjuvant/advanced setting are not allowed; patients who received treatment for \< 28 days or placebo on an investigational study are acceptable