Olaparib and Estradiol for the Treatment of Metastatic or Locally Recurrent ER+/HER2- Breast Cancer, PHOEBE Trial

Inclusion Criteria

• Women ≥ 18 years of age with metastatic ER+/HER2- breast cancer, or with locally recurrent ER+/HER2- disease not amenable to therapy for curative intent
• Patient must have been treated with an anti-estrogen-containing or aromatase inhibitor-containing regimen as their most recent line of therapy. All combination regimens that include a targeted agent are permitted (e.g., a CDK4/6 inhibitor, everolimus, alpelisib, or any biologics), and are considered to be a single anti-estrogen-based regimen * Any number of prior lines of systemic therapy is permissible, including anti-estrogens and chemotherapy
• Histologic documentation of strongly ER+ breast cancer by core needle biopsy, fine needle aspiration, incisional biopsy, or surgical biopsy of ≥ 1 site(s) of metastatic or locally recurrent disease performed as standard of care * Exceptions: patients with bone-dominant metastatic disease, or non-bone metastatic disease in whom a safe and accurate biopsy of recurrent/metastatic disease cannot be readily obtained, with a history of ER+ breast cancer are eligible, and biopsy is not required, providing their primary cancer is consistent with the ER criteria described below
• Strong ER+ status defined as ER staining by immunohistochemistry in ≥ 50% of malignant cell nuclei with an intensity ≥ 2+ on a scale of 0-3+. These criteria are equivalent to an Allred score ≥ 6. HER2-negative status is defined as immunohistochemistry score of 0-1+, or with a fluorescence in situ hybridization (FISH) ratio of < 2 if immunohistochemistry (IHC) is 2+ or if IHC has not been done. In cases of borderline or equivocal HER2 status, eligibility will be determined by the local principal investigator (PI)
• If available, archived tumor tissue may be requested for research purposes
• Patient must be a candidate for treatment with 17b-estradiol and olaparib
• Patient must be post-menopausal per National Comprehensive Cancer Network (NCCN) guidelines
• Baseline radiographic staging performed as standard of care, including specifically either PET/CT, or contrast CT (chest, abdomen, pelvis [CAP]) and bone scan
• Patient must be capable and willing to provide informed written consent for study participation
• Hemoglobin > 9 g/dL (within 28 days prior to initiation of study therapy)
• White blood cell (WBC) count (≥ 3,000/μL) (within 28 days prior to initiation of study therapy)
• Platelet count ≥ 100,000/μL (within 28 days prior to initiation of study therapy)
• Creatinine clearance > 50 mL/min by the Cockcroft-Gault method (within 28 days prior to initiation of study therapy)
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (within 28 days prior to initiation of study therapy)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x upper limits of normal (ULN) (within 28 days prior to initiation of study therapy) * Exception: in patients with liver metastasis, < 5 x upper limits of normal (ULN)

Exclusion Criteria

• During study treatment, no concurrent anti-cancer therapies are allowed with the following exceptions: anti-resorptive bone therapies (e.g., bisphosphonates, denosumab) permitted
• Any investigational cancer therapy or systemic chemotherapy in the last 3 weeks
• Any radiation therapy in the last 2 weeks
• Known central nervous system (CNS) disease, unless clinically stable for ≥ 3 months
• Concomitant use of known strong or moderate CYP3A inhibitors
• Persistent toxicities (≥ Common Terminology Criteria for Adverse Events [CTCAE] grade 2) caused by previous cancer therapy
• History of any of the following: * Deep venous thrombosis * Pulmonary embolism * Stroke * Acute myocardial infarction * Congestive heart failure * Previous malignancy not treated with curative intent, or with an estimated recurrence risk ≥ 30%
• Renal impairment (creatinine clearance ≤ 50 mL/min)