Background: CDK 4/6i has demonstrated benefit in progression free survival (PFS) and overall survival (OS) in pts with HR+, HER2- MBC when combined with endocrine therapy (ET). While observational data demonstrate a potential benefit of continuing CDK 4/6i and switching ET at progression, no prospective trials have evaluated this approach. We conducted a phase II, multi-center, randomized, trial to evaluate the efficacy of fulvestrant or exemestane +/- ribociclib in pts with HR+HER2- MBC whose cancer previously progressed on any CDK 4/6i + any ET. Methods: In this investigator-initiated, phase II, double-blind, placebo-controlled trial, men or women with measurable or non-measurable HR+/HER2- MBC whose cancer progressed during CDK 4/6i and ET were randomized 1:1 to fulvestrant or exemestane +/- ribociclib. Pts treated with prior fulvestrant received exemestane as ET in the randomization; if prior exemestane fulvestrant was the ET; if neither, fulvestrant or exemestane was per investigator discretion, though fulvestrant was encouraged. PFS was the primary endpoint, defined as time from randomization to progression of disease or death. A one-sided log-rank test with a sample size of 120 randomized and evaluable pts with a significance level alpha of 2.5%, achieves 80% power to detect an effect size (difference in PFS) of 3 months. Results: Of the 120 randomized evaluable pts, 1 pt was removed due to not taking ET along with ribociclib/placebo. All but 1 pt was female, the median age was 57.0 years, 88 pts (74%) were white, and 21 (17.6%) were Hispanic. For ET, 99 pts received fulvestrant (83%) and 20 pts exemestane (17%). In terms of prior CDK 4/6i, 100 pts previously received palbociclib (84%), 13 pribociclib (11%), 2 abemaciclib (2%), and 4 palbociclib and another CDK 4/6i (3%). There was a statistically significant PFS improvement for pts randomized to fulvestrant or exemestane + ribociclib [median: 5.33 months, 95% CI (Confidence Interval): 3.25–8.12 months] vs. placebo (median: 2.76 months, 95% CI: 2.66–3.25 months): Hazard Ratio (HR) = 0.56 (95% CI: 0.37-0.83), p = 0.004. Similar results were seen in the subset of pts treated with fulvestrant, with a median PFS for those randomized to ribociclib (5.29 months) vs. placebo (2.76 months), HR = 0.59 (95% CI: 0.38-0.91), p = 0.02. At 6 months, 42% were progression-free on the ribociclib arm vs. 24% on placebo. At 12 months, 25% were progression-free on the ribociclib arm vs. 7% on placebo. Additional endpoints will be reported, including overall response rate and safety. Conclusions: In this randomized, placebo-controlled trial, there was a significant PFS benefit for pts with HR+/HER2- MBC to switch ET and receive ribociclib after progression on CDK 4/6i. Clinical trial information: NCT02632045.