Evaluation of Lasofoxifene Combined With Abemaciclib Compared With Fulvestrant Combined With Abemaciclib in Locally Advanced or Metastatic ER+/HER2- Breast Cancer With an ESR1 Mutation

Inclusion criteria

• Pre- or postmenopausal women or men.
• Locally advanced and/or metastatic ER+ breast cancer with radiological or clinical evidence of progression on an AI in combination with either palbociclib or ribociclib as their first hormonal treatment for metastatic disease.
• Histological or cytological confirmation of ER+/HER2 - disease
• No evidence of progression for at least 6 months on an AI/CDKi combination for advanced breast cancer.
• At least 1 or more ESR1 point mutations in the ESR1 ligand binding domain as assessed in cell- free ctDNA obtained from a blood or breast cancer tissue.
• Locally advanced or metastatic breast cancer with at least 1 measurable (according to RECIST 1.1) lesion with or without non-measurable lesions.
• Subjects may have received 1 cytotoxic chemotherapy regimen in the metastatic disease setting prior to study entry, but must have recovered from chemotherapy acute toxicity excluding alopecia and Grade 2 peripheral neuropathy.
• Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1
• Adequate organ function
• Able to swallow tablets
• Brain metastases are allowed only if the following 4 parameters hold:

• Asymptomatic,
• Definitively treated (e.g., radiotherapy, surgery),
• Not requiring steroids up to 4 weeks before study treatment initiation, AND
• Central nervous system disease stable for >3 months prior to registration as documented by magnetic resonance imagining (MRI).
• Able to understand and voluntarily sign a written informed consent before any screening procedures.
• Every attempt should be made to obtain a biopsy of metastatic breast cancer tissue, when safe and feasible, to provide histological or cytological confirmation of ER+/HER2- disease as assessed by a local laboratory, according to American Society of Clinical Oncology/College of American Pathologists guidelines, using slides, paraffin blocks, or paraffin samples. If a biopsy is done, it may undergo genomic testing at some point to assess for ESR1 mutations and correlation with ctDNA results. If a biopsy is not possible or inappropriate from a clinical standpoint, the ER and HER2 status from the subject's most recent biopsy must confirm that the subject is ER+ and HER2

Exclusion criteria

• Lymphangitic carcinomatosis involving the lung.
• History of Grade 3 or Grade 4 interstitial lung disease (ILD) on previous therapy.
• Visceral crisis in need of cytotoxic chemotherapy as assessed by the investigator.
• Prior progression of disease on abemaciclib, fulvestrant, or other selective estrogen receptor degrader (SERD) therapy.
• Subjects with a known hypersensitivity to fulvestrant or to any of the excipients
• Radiotherapy within 30 days prior to Visit 0 (Day 1) 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 Visit 0 (Day 1). Subjects must have recovered from radiotherapy toxicities prior to Visit 0 (Day 1).
• Known RB1 mutations or deletions that in the opinion of the investigator confer resistance to CDK4/6i. (Screening for RB1 mutation is not required for entry.)
• History of long QTc (Q-T interval corrected for heart rate) syndrome or a QTc of >480 msec.
• History of a pulmonary embolus (PE), deep vein thrombosis (DVT), or any known thrombophilia, unless the event occurred greater than 6 months prior to screening and the subject is treated with chronic anticoagulant therapy such as apixaban (Eliquis) or rivaroxaban (Xarelto).
• Lasofoxifene is not recommended for use in subjects with conditions that place them at increased risk for VTEs (such as severe congestive heart failure [CHF] or prolonged immobilization).
• On concomitant strong CYP3A4 inhibitors.
• On strong and moderate CYP3A4 inducers.
• Any significant co-morbidity that would impact the study or the subject's safety, including subjects with significant malabsorption.
• Active systemic bacterial or fungal infection (requiring intravenous [IV] antibiotics or antifungals at the time of initiating study treatment).
• Known infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV).
• 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.
• Positive serum pregnancy test (only if premenopausal).
• Sexually active premenopausal women and men unwilling to use double-barrier contraception.
• Women who are breast feeding
• History of non-compliance to medical regimens.
• Unwilling or unable to comply with the protocol.
• Current participation in any clinical research trial involving an investigational drug or device within the last 30 days.
• Subjects with a history of familial hypertriglyceridemia or fasting triglyceride levels >880 mg/dL at screening.
• Fasting triglyceride level >300 mg/dL and ≤880 mg/dL at screening. Subjects may be retested and enrolled if they have a repeat fasting triglyceride level less than or equal to 300 mg/dL prior to enrollment (e.g., after adjustment with diet and/or treatment).
• Fasting cholesterol level >400 mg/dL at screening. Subjects may be retested and enrolled if they have a repeat fasting cholesterol level less than or equal to 400 mg/dL prior to enrollment (e.g., after adjustment with diet and/or treatment).