Evaluation of Lasofoxifene Versus Fulvestrant in Advanced or Metastatic ER+/HER2- Breast Cancer With an ESR1 Mutation

Inclusion Criteria:

1. Pre- or postmenopausal.

   Postmenopausal women are defined as:
   1. ≥60 years of age with no vaginal bleeding over the prior year, or
   2. \<60 years with "premature menopause" or "premature ovarian failure" manifest itself with secondary amenorrhea for at least 1 year and follicle stimulating hormone (FSH) and estradiol levels in the postmenopausal range according to institutional standards, or
   3. surgical menopause with bilateral oophorectomy. Note: premenopausal women who meet all of the other entry criteria must be maintained on ovarian suppression (such as Lupron) during the study and subjects counseled to use appropriate contraception to prevent pregnancy.
2. If possible, a biopsy of metastatic breast cancer tissue will be obtained to provide histological or cytological confirmation of ER+ and HER2- disease as assessed by a local laboratory, according to the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines, using slides, paraffin blocks, or paraffin samples. If a biopsy is not possible, the ER and HER2 status from the tissue obtained at the time of the original diagnosis must confirm that the subject's cancer is ER+ and HER2-.
3. Locally advanced or metastatic breast cancer with radiological or clinical evidence of progression on an AI in combination with a CDK 4/6 inhibitor for advanced breast cancer with demonstrated prior sensitivity to endocrine therapy (recurrence or progression after at least 12 months of treatment in the metastatic setting).
4. Locally advanced or metastatic breast cancer with either measurable (according to RECIST 1.1) or non-measurable lesions.
5. At least one or more of the following point ESR1 mutations as assessed in cell-free circulating tumor DNA (ctDNA) obtained from a blood (plasma) or tissue sample: Y537S, Y537C, D538G, E380Q, S463P, V534E, P535H, L536H, L536P, L536R, L536Q, or Y537N. The ctDNA sample collection must be obtained within 30 days prior to randomization to determine eligibility and baseline. Note: a prior genomic test confirming that the subject has an ESR1 mutation can be used to determine eligibility; however, an ESR1 sample must also be collected within 30 days of randomization.
6. Subjects who have not received cytotoxic chemotherapy or those who have received one cytotoxic chemotherapy regimen in the neo-adjuvant or adjuvant setting prior to entry into the trial and/or no more than one chemotherapy regimen for metastatic breast cancer. Subjects must be free of all chemotherapy acute toxicity excluding alopecia and Grade II peripheral neuropathy before study entry.
7. ECOG performance score of 0 or 1.
8. Adequate organ function as shown by:

   1. absolute neutrophil count (ANC) \>/=1,500 cells/mm3
   2. platelet count ≤100,000 cells/mm3
   3. hemoglobin \>/=9.0 g/dl
   4. ALT and AST levels ≤2.5 upper limit of normal (ULN) or ≤5 in the presence of visceral metastasis
   5. total serum bilirubin ≤1.5 X ULN (≤ 3 X ULN for subjects known to have Gilbert Syndrome)
   6. alkaline phosphatase level ≤ 2.5 X ULN
   7. creatinine clearance of 40 ml/min or greater as calculated by the Cockcroft-Gault formula
   8. International normalized ratio (INR), activated partial thromboplastin (aPTT), or partial thromboplastin time (PTT) \<2.0 X ULN.
9. Able to swallow tablets.
10. Able to understand and voluntarily sign a written informed consent before any screening procedures.

Exclusion Criteria:

1. Prior use of everolimus or other mammalian target of rapamycin (mTOR) inhibitor or phosphoinositide 3-kinase inhibitor (PI3K) inhibitors is excluded unless discontinued to reasons other than disease progression.
2. Presence of brain metastasis.
3. Lymphangitic carcinomatosis involving the lung.
4. Impending visceral crisis in need of cytotoxic chemotherapy as assessed by the investigator.
5. Radiotherapy within 30 days prior to randomization except in case of localized radiotherapy for analgesic purposes or for lytic lesions at risk of fracture, which can then be completed within 7 days prior to randomization. Subjects must have recovered from radiotherapy toxicities prior to randomization.
6. History of long QTC syndrome or a QTC of \>480 ms.
7. History of a pulmonary embolus (PE) or deep vein thrombosis (DVT) within the last 6 months or any known thrombophilia. Subjects stable on anti-coagulants for maintenance are eligible as long as the DVT and/or PE occurred \>6 months prior to enrollment and there is no evidence for active thrombosis. The use of low dose ASA is permitted.
8. Any significant co-morbidity that would impact the study or the subject's safety.
9. History of a positive human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) at Screening. Subjects cured of hepatitis C (no viral load) are eligible.
10. History of malignancy within the past 5 years (excluding breast cancer), except basal cell or squamous cell carcinoma of the skin curatively treated by surgery, or early stage cervical cancer.
11. History of vaginal bleeding over the last year unless it is documented that the bleeding was due to non-uterine causes (e.g. vaginal atrophy).
12. Uncontrolled hypertension defined as sitting systolic pressure \>160 mm Hg or diastolic pressure \>100 mm Hg at Screening.
13. History of non-compliance to medical regimens.
14. Unwilling or unable to comply with the protocol.
15. Current participation in any clinical research trial involving an investigational drug or device within the last 30 days.