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

Eligibility Criteria

• 1. Pre- or postmenopausal women or men.
• 2. 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.
• 3. Histological or cytological confirmation of ER+/HER2 - disease
• 4. No evidence of progression for at least 6 months on an AI/CDKi combination for advanced breast cancer.
• 5. 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.
• 6. Locally advanced or metastatic breast cancer with either measurable (according to RECIST 1.1) or non-measurable lesions.
• 7. 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.
• 8. Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1
• 9. Adequate organ function
• 10. Able to swallow tablets
• 11. Brain metastases are allowed only if the following 4 parameters hold:
• 1. Asymptomatic,
• 2. Definitively treated (e.g., radiotherapy, surgery),
• 3. Not requiring steroids up to 4 weeks before study treatment initiation, AND
• 4. Central nervous system disease stable for \>3 months prior to registration as documented by magnetic resonance imagining (MRI).
• 12. Able to understand and voluntarily sign a written informed consent before any screening procedures.
• 1. Lymphangitic carcinomatosis involving the lung.
• 2. History of Grade 3 or Grade 4 interstitial lung disease (ILD) on previous therapy.
• 3. Visceral crisis in need of cytotoxic chemotherapy as assessed by the investigator.
• 4. Prior progression of disease on abemaciclib, fulvestrant, or other selective estrogen receptor degrader (SERD) therapy.
• 5. Subjects with a known hypersensitivity to fulvestrant or to any of the excipients
• 6. 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).
• 7. 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.)
• 8. History of long QTc (Q-T interval corrected for heart rate) syndrome or a QTc of \>480 msec.
• 9. History of a pulmonary embolus (PE), deep vein thrombosis (DVT), or any known thrombophilia.
• 10. 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).
• 11. On concomitant strong CYP3A4 inhibitors.
• 12. On strong and moderate CYP3A4 inducers.
• 13. Any significant co-morbidity that would impact the study or the subject's safety, including subjects with significant malabsorption.
• 14. Active systemic bacterial or fungal infection (requiring intravenous \[IV\] antibiotics or antifungals at the time of initiating study treatment).
• 15. Known infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV).
• 16. 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.
• 17. Positive serum pregnancy test (only if premenopausal).
• 18. Sexually active premenopausal women and men unwilling to use double-barrier contraception.
• 19. Women who are breast feeding
• 20. History of non-compliance to medical regimens.
• 21. Unwilling or unable to comply with the protocol.
• 22. Current participation in any clinical research trial involving an investigational drug or device within the last 30 days.