Determine the safety and recommended Phase II dose of olaparib in combination with 17b-estradiol in post-menopausal patients with advanced ER+/HER2- breast cancer.

Patients with endocrine-resistant ER+/HER2- breast cancer are eligible. Patients will be treated with the combination of 17b-estradiol and olaparib for 2 cycles, and then treated with single-agent 17b-estradiol until disease progression. Clinical benefit, progression-free survival, objective response, tumor metabolic response, and toxicity will be determined.

Inclusion Criteria:

• Post-menopausal women with ER+/HER2- breast cancer.
• Metastatic or locoregional recurrence not amenable to treatment with curative intent.
• Received ≥1 prior line of endocrine-based therapy in the advanced/metastatic setting.

Exclusion Criteria:

• During study treatment, no concurrent anti-cancer therapies are allowed with the following exceptions:

  o 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 CNS disease, unless clinically stable for ≥ 3 months.

• Concomitant use of known strong or moderate CYP3A inhibitors.

• Persistent toxicities (≥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%
  • Severe renal impairment (creatinine clearance ≤ 30 mL/min).