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Background Cyclin dependent kinase 4 and 6 inhibitors (CDK4/6i), including palbociclib and ribociclib (R), have demonstrated remarkable benefit in progression free survival (PFS) in patients (pts) with hormone receptor positive (HR+), HER2- metastatic breast cancer (MBC) when combined with anti-estrogen therapy. Switching between anti-estrogen therapies at disease progression is standard of care in the treatment of HR+ MBC. We evaluate the strategy of switching anti-estrogen therapy to fulvestrant (F) and maintaining CDK4/6 inhibition with R in pts with HR+, HER2- MBC who have progressed on an aromatase inhibitor (AI) + CDK4/6i. Trial Design Phase II, multi-center, randomized, double-blind, placebo-controlled trial to evaluate F +/- R in pts with HR+, HER2- MBC who have previously progressed on any AI + CDK4/6i. Pts can be screened and registered at two different time points: Scenario 1: Before receiving any CDK4/6i Scenario 2: At the time of progression of disease (POD) while being treated with an AI + CDK4/6i In scenario 1, the study will provide pts with letrozole + R, but pts will not be randomized until they demonstrate POD. At randomization, pts will be assigned 1:1 to either a) F + R or b) F + placebo, with treatment given in 4-week cycles. F will be given as a 500 mg dose intramuscularly every 2 weeks for 3 times and then every 4 weeks, as per standard of care. R or placebo will be given orally at 600 mg daily, 3 weeks on/1 week off. CT scans and bone scan are to be performed prior to every third cycle. Serum and whole blood samples and optional tissue biopsies for biomarker assessment will be performed prior to study treatment (scenario 1), prior to randomization to R +/- F, and when the patient goes off study. Main Eligibility Criteria: 1. Age ≥ 18 years with unresectable or metastatic BC 2. Estrogen and/or progesterone receptor positive, HER2 negative, as per ASCO-CAP 3. Postmenopausal status or receiving ovarian suppression 4. Measurable or unmeasurable disease; stable CNS disease allowed 5. No clinically significant cardiac disease 6. No concomitant CYP3A4/5 inducer or inhibitor Specific Aims Primary: Progression free survival (PFS), defined as the time from randomization to POD or death. Secondary: Objective response rate (ORR), clinical benefit rate (CBR = ORR + stable disease rate), overall survival (OS), and duration of response. Pts in scenario 1 will also be assessed for PFS, OS, CBR, and safety while receiving AI + R (pre-randomization). Biomarker assessment will include amplification of cyclin D1 and cyclin E, phosphoRb and TK1 expression, Rb1 and p16 loss, and ctDNA for ESR1 and PIK3CA mutations. Target Accrual 132 pts accrued from 11 academic medical centers in the U.S, with a goal of completing accrual in two years (∼60 to 72 pts in each scenario). Statistical Methods Assuming a median PFS of 3.8 months with F alone, we predict that F + R will lead to a median PFS of at least 6.5 months. A one-sided log-rank test with a sample size of N=120 and alpha=0.025, achieves 80% power to detect a difference in PFS of 2.7 months. N=132 pts allows for a 10% drop-out rate. Citation Format: Mundi PS, Codruta C, Accordino MK, Sparano J, Andreopoulou E, Vadhat LT, Tiersten A, Esteva F, O'Regan R, Jain S, Mayer I, Forero A, Crew KD, Hershman DL, Kalinsky KM. A randomized phase II trial of fulvestrant with or without ribociclib after progression on aromatase inhibition plus cyclin-dependent kinase 4/6 inhibition in patients with unresectable or metastatic hormone receptor positive, HER2 negative breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-01-19.