Background: The phase 3 EMERALD trial reported significantly prolonged progression-free survival (PFS) and a manageable safety profile with oral elacestrant (Ela) vs standard of care ET (SoC) in patients (pts) with ER+/HER2− mBC following progression on prior endocrine and CDK4/6i therapy. Duration of prior CDK4/6i was shown to be a potential predictor of efficacy in pts with ESR1 mutations (ESR1m) receiving elacestrant. Median PFS (mPFS) for pts with ESR1m receiving <6 mos of prior CDK4/6i was 1.87 mos (Ela) vs 1.87 mos (SoC), compared with 4.14 mos (Ela) vs 1.87 mos (SoC) for pts receiving CDK4/6i ≥6 mos and 8.61 mos (Ela) vs 1.91 mos (SoC) for pts receiving ≥12 mos of prior CDK4/6i. Understanding the clinical activity of Elacestrant in ESR1 non-detected (ESR1nd) ER+/HER2- mBC is still needed. Preclinical ER+ PDX models suggest that elacestrant is equally active in ESR1 wild-type (ESR1wt) and ESR1m. In the PDX model ST3932 (ESR1wt), derived from a pt treated with palbociclib plus aromatase inhibitor (AI) that was resistant to palbociclib in vivo, elacestrant demonstrated statistically significant single-agent antitumor activity (Patel, 2019). Methods: Pts with ER+/HER2- advanced or mBC who previously had 1-2 lines of ET, mandatory CDK4/6i, and ≤1 chemotherapy were randomized, 1:1 to receive oral elacestrant or SoC (investigator’s choice of AI or fulvestrant). An ad hoc subgroup analysis was performed on pts with ESR1nd by prior duration of CDK4/6i plus ET (<6 mos, ≥6 mos, ≥12 mos) in the advanced or metastatic setting. Results: Among the 478 pts enrolled, 250 (n=124, Ela; n=126, SoC) did not have a detectable ESR1m. Interestingly, in 41 pts with ESR1nd (n=20, Ela; n=21, SoC) that rapidly progressed on prior CDK4/6i plus ET (<6 mos), treatment with elacestrant was associated with prolonged mPFS vs SoC (5.32 mos vs 1.87 mos, respectively) (HR=0.518 [95% CI 0.216-1.165]), compared with a mPFS of 1.91 mos (Ela) vs 1.97 mos (SoC) for pts who were on CDK4/6i for ≥6 mos (HR=0.911 [95% CI 0.640-1.298]) and 2.33 mos (Ela) vs 2.04 mos (SoC) for pts who were on CDK4/6i for ≥12 mos (HR=0.886 [95% CI 0.586 - 1.337]). In these 41 pts, mean time to chemotherapy was 137.7 days for elacestrant vs 75.5 days for SoC. Safety results were consistent with previously reported data. Specific pt characteristic information will be provided in the presentation. Conclusions: In this post-hoc analysis, oral elacestrant delayed disease progression and time to subsequent chemotherapy in pts who did not have a detectable ESR1m and rapidly progressed within 6 months of CDK4/6i plus ET before study entry. Preclinical data support these findings. While caution needs to be exerted given small numbers, the results highlight the potential role of elacestrant in ESR1wt tumors, and more research is warranted. Clinical trial information: NCT03778931.