Sapanisertib in Combination With Fulvestrant in Women With Advanced or Metastatic Breast Cancer After Aromatase Inhibitor Therapy

Inclusion Criteria

• Female participants aged 18 years or older who are postmenopausal.
• Histologically proven diagnosis of breast cancer with evidence of metastatic disease or locoregional recurrence.
• Histological confirmation and documentation of estrogen receptor (ER)-positive status (≥1% positive stained cells).
• Histological or cytological confirmation and documentation of human epidermal growth factor receptor-2 (HER2)-negative status by local laboratory testing using criteria in the American Society of Oncology (ASCO)/College of American Pathologists (CAP) Clinical Practice Guideline update.
• Measurable disease defined as either of the following:
• At least 1 extra-osseous lesion that could be accurately measured in at least 1 dimension.
• The lesion must have measured ≥20 mm with conventional imaging techniques or ≥10 mm with spiral CT or MRI. Lymph nodes must be ≥1.5 cm in the short axis to be considered measurable.
• Bone lesions (lytic or mixed [lytic plus sclerotic]) in the absence of measurable disease as defined above. Note: Participants with sclerotic/osteoblastic bone lesions only, in the absence of measurable disease, were not eligible.
• Progressive Disease (PD) during prior aromatase inhibitor (AI) therapy.
• Have a history of brain metastasis provided that all of the following criteria are met:
• Brain metastases have been treated.
• No evidence of PD for ≥3 months before the first dose of study drug.
• No hemorrhage after treatment.
• Off dexamethasone treatment for ≥4 weeks before the first dose of study drug.
• No ongoing requirement for dexamethasone or anti-epileptic drugs.
• Eastern cooperative oncology group (ECOG) performance status of 0 or 1.
• Clinical laboratory values as specified below within 4 weeks before the first dose of study drug:
• Bone marrow reserve consistent with absolute neutrophil count (ANC) ≥1.5*10^9/L; platelet count ≥100*10^9/L; hemoglobin (Hgb) ≥9 g/dL.
• Total bilirubin ≤1.5*the upper limit of the normal range (ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5*ULN (≤5*ULN if liver metastases are present).
• Creatinine clearance ≥40 mL/min based on Cockcroft-Gault estimate or based on a 12- or 24-hour urine collection.
• Fasting serum glucose ≤130 mg/dL and fasting triglycerides ≤300 mg/dL.

Exclusion Criteria

• Prior therapy with mechanistic target of rapamycin (mTOR), phosphoinositide-3-kinase (PI3K), or dual PI3K-mTOR inhibitors, serine/threonine-specific protein kinase (AKT) inhibitors, or fulvestrant.
• Prior treatment with >1 line of chemotherapy for metastatic breast cancer or for locoregional recurrence that was not amenable to resection or radiation therapy with curative intent.
• Experienced PD on >2 endocrine therapies for metastatic breast cancer or for locoregional recurrence that was not amenable to resection or radiation therapy with curative intent.
• Life-threatening metastatic visceral disease (defined as extensive hepatic involvement or symptomatic pulmonary lymphangitic spread).
• Poorly controlled diabetes mellitus defined as hemoglobin A1c (glycosylated hemoglobin; HbA1c) >7%; participants with a history of transient glucose intolerance due to corticosteroid administration may be eligible if all other inclusion/exclusion criteria are met.