Study of Pembrolizumab Plus Fulvestrant in Hormone Receptor Positive, HER-2 Negative Advanced/Metastatic Breast Cancer Patients

Inclusion Criteria: Subject must meet all of the following applicable inclusion criteria to participate in this study: * Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately. * Men \[29\] and women ≥ 18 years of age at the time of informed consent. NOTE: Both pre- and post-menopausal women are eligible. Patients who are premenopausal should either undergo bilateral oophorectomy or receive ovarian suppression according to institutional standards. Male patients will be treated as premenopausal females and receive a GnRH agonist. * ECOG Performance Status of 0 or 1 within 28 days prior to registration. * Histologic or cytologic diagnosis of metastatic breast cancer. * Has received no more than two lines of prior therapy for advanced non-resectable/metastatic disease. Prior lines can can be either chemotherapy or hormonal therapy. Prior or current fulvestrant is allowed. Combination therapy is considered as one regimen. * Tumor is estrogen receptor positive (ER+) and/or (PR+), HER-2 negative (HER2-). ER and PR positivity is defined as \>1%. HER-2 negative is defined as by IHC (0, 1+) or FISH. HER2 positive test result includes: Single-probe average HER2 copy number ≥6.0 signals/cell; Dual-probe HER2/CEP17 ratio ≥2.0 with an average HER2; copy number ≥4.0 signals/cell; Dual-probe HER2/CEP17 ratio ≥2.0 with an average HER2copy number \<4.0 signals/cell; or Dual-probe HER2/CEP17 ratio \< 2.0 with an average HER2 copy number ≥6.0 signals/cell. Equivocal findings for IHC as 2+ should be reflexed to FISH. Equivocal results by FISH may be considered with approval from the Sponsor-Investigator. * Measurable disease based on RECIST 1.1 within 28 days prior to registration. Except in patients with bone-only disease, in the absence of measurable disease, evaluable bone lesion is allowed. NOTE: Bone-only disease is the sole non-measurable disease site allowed and biopsy is required. Measurable disease is required in all other cases. * Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. NOTE: Subjects for whom newly-obtained fresh tissue samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the Sponsor-Investigator. * Normal cardiac function as determined by treating physician per institutional standards via echocardiogram (ECHO) performed within 28 days prior to registration. * Prior chemotherapy must be completed at least 28 days prior to registration or at least 14 days prior to registration for targeted therapy. * Prior hormonal therapy or radiation therapy must be completed at least 14 days prior to registration. If subject is currently receiving fulvestrant, it may continue without interruption as per standard of care. * The subject must have recovered from all reversible acute toxic effects of the regimen (other than alopecia) to ≤ Grade 1 or baseline. NOTE: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. NOTE: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to study registration, as determined by the enrolling physician. * Demonstrate adequate organ function as defined in the table below; all screening labs will be performed within 28 days of study registration. * Hematological * Absolute Neutrophil Count (ANC): ≥ 1500/mm3 * Platelets: ≥100,000 / mcL * Hemoglobin (Hgb): ≥ 9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (within 7 days of assessment) * Renal ---Serum creatinine OR Measured or calculateda creatinine clearance (GFR can also be used in place of creatinine or CrCl): ≤1.5 × upper limit of normal (ULN) OR ≥30 mL/min for subjects with creatinine levels \> 1.5 × institutional ULN * Hepatic * Serum total bilirubin: ≤ 1.5 X ULN OR * Direct bilirubin ≤ ULN for subjects with total bilirubin levels: \> 1.5 ULN * AST (SGOT) and ALT (SGPT): ≤ 2.5 × ULN * Albumin: \>2.5 mg/dL * Coagulation ---International Normalized Ratio (INR) or Prothrombin Time (PT) Activated Partial Thromboplastin Time (aPTT): ≤1.5 × ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants aCreatinine clearance will be calculated per institutional standard. * Females of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to study registration. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. NOTE: Females are considered of childbearing potential unless: they are postmenopausal; are surgically sterile; or they have a congenital or acquired condition that prevents childbearing. See the protocol for definitions. NOTE: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. * Females and males of reproductive potential must be willing to abstain from heterosexual activity which could result in pregnancy or agree to use an adequate method of contraception as outlined in the protocol. Hormonal contraceptives are contraindicated in this population and are not allowed. Contraception will begin from the time of informed consent through 120 days after the last dose of study drug(s). Exclusion Criteria: * Is currently receiving an investigational agent or has received an investigational agent or used an investigational device within 28 days of study registration. * Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to study registration. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger. NOTE: 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. * Has a known history of active TB (Bacillus Tuberculosis). NOTE: TB testing is not required. * Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). NOTE: HIV testing is not required. * Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected). NOTE: Hepatitis B and Hepatitis C testing is not required. * Hypersensitivity to pembrolizumab or any of its excipients. * Has received prior chemotherapy within 28 days prior to study registration or has received prior hormonal/targeted therapy within 14 days prior to study registration * More than two lines of chemotherapy or more than two lines of hormonal therapy excludes participation. * Has a known additional malignancy that is progressing or requires active treatment. 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. * Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability. * Has known history of non-infectious pneumonitis/interstitial lung disease that required steroids or has any evidence of active pneumonitis/interstitial lung disease. * Has known history of, or any evidence of active interstitial lung disease, Class II-IV congestive heart failure, or myocardial infarction within 6 months from randomization. * Active infection requiring systemic therapy. * Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. * Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. * Breastfeeding during the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment. NOTE: breast milk cannot be stored for future use while the mother is being treated on study. * Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent * Has received a live vaccine or live-attenuated vaccine within 30 days of study registration. Administration of killed vaccines is allowed.