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:

1. Pre- or postmenopausal women or men.

2. Locally advanced and/or metastatic ER+ breast cancer with radiological or clinicalevidence of progression on an AI in combination with either palbociclib orribociclib 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 foradvanced breast cancer.

5. At least 1 or more ESR1 point mutations in the ESR1 ligand binding domain asassessed in cell- free ctDNA obtained from a blood or breast cancer tissue.

6. Locally advanced or metastatic breast cancer with either measurable (according toRECIST 1.1) or non-measurable lesions.

7. Subjects may have received 1 cytotoxic chemotherapy regimen in the metastaticdisease setting prior to study entry, but must have recovered from chemotherapyacute 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:

12. Asymptomatic,

13. Definitively treated (e.g., radiotherapy, surgery),

14. Not requiring steroids up to 4 weeks before study treatment initiation, AND

15. Central nervous system disease stable for >3 months prior to registration asdocumented by magnetic resonance imagining (MRI).

16. Able to understand and voluntarily sign a written informed consent before anyscreening procedures.

17. Every attempt should be made to obtain a biopsy of metastatic breast cancer tissue,when safe and feasible, to provide histological or cytological confirmation ofER+/HER2- disease as assessed by a local laboratory, according to American Societyof Clinical Oncology/College of American Pathologists guidelines, using slides,paraffin blocks, or paraffin samples. If a biopsy is done, it may undergo genomictesting at some point to assess for ESR1 mutations and correlation with ctDNAresults. 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 thesubject is ER+ and HER2

Exclusion Criteria:

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 selectiveestrogen 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 localizedradiotherapy for analgesic purposes or for lytic lesions at risk of fracture, whichcan then be completed within 7 days prior to Visit 0 (Day 1). Subjects must haverecovered from radiotherapy toxicities prior to Visit 0 (Day 1).

7. Known RB1 mutations or deletions that in the opinion of the investigator conferresistance 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 knownthrombophilia, unless the event occurred greater than 6 months prior to screeningand the subject is treated with chronic anticoagulant therapy such as apixaban (Eliquis) or rivaroxaban (Xarelto).

10. Lasofoxifene is not recommended for use in subjects with conditions that place themat increased risk for VTEs (such as severe congestive heart failure [CHF] orprolonged 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), orhepatitis C virus (HCV).

16. History of malignancy within the past 5 years (excluding breast cancer), exceptbasal 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-barriercontraception.

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 investigationaldrug or device within the last 30 days.