The majority of patients (pts) with breast cancer have hormone receptor positive (HR+) disease, and this holds true for pts with advanced breast cancer (ABC). Currently frontline therapy for pts with HR+ ABC is antihormonal therapy with an aromatase inhibitor or selective estrogen receptor degrader plus a CDK4/6i. The proposed trial is a randomized study to further evaluate the potential benefit of switching a frontline regimen at the time that a molecular signal, ctDNA, suggests progression prior to detection of clinical progression using standard methods. The purpose of this study is to determine whether switching treatment earlier in the disease process, based on molecular progression, will increase the amount of time that a patient's metastatic breast cancer is controlled compared to patients with metastatic breast cancer who receive treatment later based on diagnostic imaging results or other methods currently used in medical practice.

Inclusion Criteria:

1. Men or women age ≥ 18 years.

2. Patients with a diagnosis of ER+, human epidermal growth factor receptor 2 negative (HER2-) metastatic (Stage IV) breast cancer. Positivity status is defined as >10% staining for ER and immunohistochemistry (IHC) 0+ or IHC 1 or 2+ staining for HER-2, and fluorescence in situ hybridization (FISH) negative with standard pathology staining methods.

3. Patients with de novo metastatic disease at the Screening Visit must undergo a SOC diagnostic biopsy.

4. Archived tumor tissue available.

5. Women and men with proven locally advanced, locoregionally recurrent or metastatic disease adenocarcinoma of the breast not amenable to curative therapy. Note: patients relapsing while on adjuvant tamoxifen or AI are eligible for this study.

6. No prior systemic anticancer therapy for metastatic or advanced disease (chemotherapy targeted therapy or endocrine therapy (ET)).

   Note 1: prior endocrine therapy in the metastatic setting is not allowed unless initiated <30 days from study initiation or Cycle 1, Day 1 (C1D1).

   Note 2: prior initiation of luteinizing hormone-releasing hormone (LHRH) agonist or bone-directed agents, however, is allowed.

7. No visceral crisis. Visceral crisis is defined as advanced, symptomatic, visceral spread that is at risk of life-threatening complication in the short term and that requires chemotherapy.

8. Adequate organ and marrow function as defined below:

   • Hematological

     • Absolute neutrophil count (ANC) ≥1,500 cells/mm³
     • Platelets ≥100,000 cells/mm³
     • Hemoglobin ≥9.0 g/dL or ≥8.0 g/dL for patients with bone metastases and/or menstruating females with evidence of iron deficiency

   • Renal

     • Serum creatinine or Measured or calculated creatinine clearance (glomerular filtration rate (GFR) can also be used in place of creatinine or creatinine clearance (CrCl)) ≤ 1.5 x upper limit of normal (ULN) or CrCl ≥ 40 mL/min. CrCl should be calculated per institutional standard.

   • Hepatic

     • Serum total bilirubin < 1.0 ULN
     • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase (SGOT)) and alanine transaminase (ALT) (serum glutamic-pyruvic transaminase (SGPT)). Aminotransferase (AST and ALT) ≤ 2.5 x ULN or 5 X ULN for patients with liver metastases
     • Albumin ≥ 2.5 mg/dL

9. Measurable disease as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST V.1.1) or non-measurable disease that is evaluable.

10. Patients with an Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1.

11. Ability to understand and the willingness to sign a written informed consent document.

12. Life expectancy >3 months.

13. Postmenopausal women, women with suppressed ovarian function, or premenopausal women, provided they are being treated with monthly LHRH analogues and are willing to continue to receive LHRH agonist therapy for the duration of the trial. Menopausal patients or patients with suppressed ovarian function are defined as follows:

    • Women with bilateral oophorectomy

    • Postmenopausal women, as defined by any of the following criteria:

      • Age 60 or over
      • Age 50-59 years and meets the following criterion:
      • Amenorrhea for ≥12 months and follicle-stimulating hormone and estradiol levels within the postmenopausal range
      • Women with hysterectomy or chemotherapy-induced amenorrhea. Note: Patients with hysterectomy or chemotherapy-induced amenorrhea must display follicle stimulating hormone and estradiol levels within the postmenopausal range.

14. Resolution of all acute toxic effects from prior anticancer therapy or surgical procedures as defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) V 5.0 to grade 1 (except alopecia or other toxicities not considered a safety risk for the patient at Investigator's discretion)

Exclusion Criteria:

1. Patients who are currently receiving or have received treatment for a secondary cancer other than resected non-melanoma skin cancer lesions or in situ cancer within the past 24 months.
2. Prior exposure to CDK4/6i ≤12 months prior to enrollment.
3. Use of investigational drugs ≤28 days prior to study enrollment and during the study.
4. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or that makes participation in the trial to be not in the best interest of the patient in the opinion of the Investigator.
5. Locally advanced breast cancer or locoregional relapse amenable for any treatment with curative intent.
6. HER2+ or equivocal tumor status either on the primary or on the recurrent tumor defined as IHC 3+, FISH/chromogenic in situ hybridization (CISH) amplified or FISH/CISH equivocal according to the American Society of Clinical Oncologists (ASCO) 2015 criteria.
7. Prior endocrine therapy in the metastatic setting is not allowed unless initiated < 30 days from study initiation or Cycle 1, Day 1 (C1D1).
8. Prior treatment with any CDK 4/6 inhibitor in the metastatic setting is not allowed.
9. Any major surgery (defined as requiring general anesthesia) or significant traumatic injury within 4 weeks of treatment; however, surgical diagnostic procedure is allowed (even if under general anesthesia).
10. Known active, bleeding diathesis.
11. Any serious known concomitant systemic disorder incompatible with the study (at the discretion of the Investigator).
12. Patients unable to swallow tablets.
13. History of malabsorption syndrome or other condition that would interfere with enteral absorption.
14. Known active uncontrolled or symptomatic central nervous system (CNS) metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral edema and/or progressive growth. Patients with a history of CNS metastases or cord compression are eligible if they have been definitively treated with local therapy (e.g., radiotherapy, stereotactic surgery) and are clinically stable and off anticonvulsants and steroids for at least 4 weeks before treatment initiation.
15. Known hypersensitivity to letrozole, anastrozole, exemestane, fulvestrant, or CDK4/6i or any of their excipients.
16. Uncontrolled electrolyte disorders that can compound the effects of a corrected QT (QTc) interval prolonging drug (eg, hypocalcemia, hypokalemia, hypomagnesaemia).
17. Patients treated within the last 7 days prior to treatment start in the study with medications that are known to be cytochrome (CYP) CYP3A4 inhibitors or drugs that are known to be CYP3A4 inducers.
18. Patients requiring palliative radiation within the 30 days following C1D1 in Step 1.
19. Patients already included in another therapeutic trial evaluating an investigational medicinal product or having received an investigational medicinal product within 3 months.
20. Any stage II, III, or IV cancer within 5 years preceding patient enrollment in the trial; however, multiple breast cancers (contralateral/ipsilateral cancers/local relapses) are allowed pending all tumor masses were ER+.
21. Any history of hematologic malignancy.
22. Pregnancy or lactation period. Women of childbearing potential must implement adequate nonhormonal contraceptive measures (barrier methods, intrauterine contraceptive devices, sterilization; LHRH agonist cannot be considered as an efficient contraceptive measure) during study treatment and for 90 days after discontinuation. A serum pregnancy test must be negative in premenopausal women or women with amenorrhea of less than 12 months.