The main purpose of this research study is to learn whether the investigational combination of olaparib, palbociclib, and fulvestrant is safe in patients with estrogen receptor-positive breast cancer and BRCA1 or BRCA2 mutations.

Inclusion Criteria:

• Females/males ≥ age 18

• Germline or somatic deleterious or suspected deleterious mutation in BRCA1 or BRCA2

• Metastatic or locally advanced unresectable breast cancer that is ER and/or PR positive (>1%) and HER2 nonamplified

• Prior treatment with 0-2 prior lines of chemotherapy for metastatic breast cancer

• Regarding prior platinum-based chemotherapy:

  1. Patients who received prior platinum-based chemotherapy in the adjuvant or neoadjuvant setting for breast cancer are eligible if treatment was completed at least 12 months prior to diagnosis of metastatic disease.
  2. Patients who received platinum for advanced breast cancer are eligible to enter the study provided there was no evidence of disease progression during the platinum chemotherapy.
  3. Patients who received prior platinum-based as a potentially curative treatment for a prior non-breast cancer (e.g., ovarian cancer) with no evidence of disease for 5 years or greater prior to study entry are permitted.

• Deemed a candidate for endocrine therapy (any prior endocrine therapy is permitted; no prior endocrine therapy is also permitted)

• Adequate organ and bone marrow function

• ECOG performance status 0-1

• At least one measurable disease or disease that can be assessed by CT or MRI

• Life expectancy ≥ 16 weeks

• Postmenopausal as defined below. Women who are on pharmacologic ovarian suppression must have two negative urine or serum pregnancy tests: one during screening (within 28 days prior to study treatment) and one within 7 days prior to commencing treatment.

Postmenopausal is defined as one of the below:

• Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments
• Follicle stimulating hormone (FSH) levels in the post-menopausal range for women under 50
• radiation-induced oophorectomy with last menses >1 year ago
• chemotherapy-induced menopause with >1 year interval since last menses
• bilateral oophorectomy or hysterectomy
• on luteinizing hormone-releasing hormone (LHRH) agonists according to current clinical practice standards as pharmacologic ovarian suppression
• Female patients of childbearing potential (not post-menopausal as defined above) must agree to the use of two highly effective forms of contraception in combination throughout the period of taking study treatment and for 1 month after last dose of study drug(s) to prevent pregnancy.
• Male patients and their sexual partners of childbearing potential must agree to the use of two highly effective forms of contraception in combination throughout the period of taking study treatment and for 3 months after last dose of study drug(s) to prevent pregnancy in a partner.
• Willing to comply with study requirements and procedures including use of appropriate contraception, willingness to discontinue herbal preparations / medications, and study biopsy if archival tissue is not available

Exclusion Criteria:

• Involvement in study planning or conduct

• Regarding prior olaparib or palbociclib,

  a) Phase II: Patients who previously progressed on olaparib or palbociclib for metastatic breast cancer treatment are excluded

• Participation in another clinical study with an investigational product during the last 3 weeks

• Systemic chemotherapy or radiotherapy (except palliative) within 3 weeks of start of study treatment

• Major surgery within 2 weeks of start of study treatment

• Other malignancy within the last 5 years with exceptions listed in the protocol

• Concomitant strong or moderate CYP3A inhibitors/ inducers

• Persistent toxicity of prior cancer therapy that is grade ≥ 2 except for alopecia or neuropathy

• MDS or features suggestive of MDS/AML

• Symptomatic uncontrolled brain metastases

• Patients considered to be at poor medical risk

• QTc >470 msec on 2 or more time points or a family history of long QT syndrome

• Unable to swallow or absorb oral medication

• Immunocompromised patients

• Pregnant or breast-feeding

• Hypersensitivity to olaparib, palbociclib, fulvestrant, or any excipients of these products

• Known active hepatitis

• Prior bone marrow transplant

• Whole blood transfusions 120 days prior to signing consent