1069 Background: Endocrine therapy (ET) + CDK4/6i is the mainstay in 1st-line ER+/HER2- mBC; however, resistance to ET arises. De novo resistance mechanisms include alterations in the PI3K/AKT/mTOR or cell cycle pathways; acquired resistance mechanisms include ESR1-mut during ET in mBC. In EMERALD, single-agent elacestrant significantly improved PFS vs SOC ET and was associated with manageable safety in pts with ER+/HER2-, ESR1-mut mBC previously treated with ET+CDK4/6i, leading to the first oral SERD approved. Pts had a 45% reduction in risk of progression or death with elacestrant vs SOC (HR = 0.55; 95% CI, 0.39-0.77; p = 0.0005) (Bidard 2022). In pts with ≥12 mo prior ET+CDK4/6i, mPFS with elacestrant was 8.6 mo vs 1.9 mo with SOC (SABCS 2022). To address other resistance mechanisms and enable oral-oral combinations, ELEVATE (NCT05563220) is evaluating elacestrant in combination with everolimus, alpelisib, ribociclib, palbociclib, or abemaciclib. Methods: Eligible pts have ER+/HER2− mBC. Phase 1b objective is to identify the recommended phase 2 dose (RP2D) of each combination. The RP2D of elacestrant + abemaciclib is being determined in ELECTRA (NCT05386108). Results: As of January 2024, 12 pts have been enrolled in the elacestrant (86-172 mg) + ribociclib (400 mg) cohorts. Most common (≥30%) all-grade (Gr) AEs were decreased neutrophils/neutropenia (n=6, 50%; Gr3+ n=4, 33%). No diarrhea or QT prolongation observed. In the elacestrant (258-345 mg) + palbociclib (100 mg) cohorts, 8 pts have been enrolled. Most common all-Gr AEs were nausea (n=3, 38%; Gr3+ n=0) and decreased neutrophils/neutropenia (n=3, 38%; Gr3+ n=2, 25%). In the elacestrant (258-345 mg) + everolimus (5-10 mg) cohorts, 15 pts have been enrolled. Most common all-Gr AEs were nausea, fatigue, diarrhea, (for each: n=6, 40%; Gr3+ n=1, 7%), and stomatitis and back pain (n=5, 33%; Gr3+ n=1, 7% back pain only). No hyperglycemia or Gr3+ elevated transaminases were observed. In the elacestrant (258-345 mg) + alpelisib (200-250 mg) cohorts, 9 pts have been enrolled. Most common all-Gr AEs were nausea (n=7, 78%; Gr3+ n=1, 11%), rash (n=5, 56%; Gr3+ n=3, 33%), fatigue and stomatitis (n=4, 44%; Gr3+ n=0), diarrhea, dizziness, and hyperglycemia/type 2 diabetes (n=3, 33%; Gr3+ n=1, 11% hyperglycemia only). To date, up to 6 cycles with ribociclib, 7 with palbociclib, 8 with alpelisib, and 12 with everolimus have been administered. Updated safety, PK, and preliminary efficacy will be reported. Conclusions: The combinations evaluated are consistent with the known safety profiles of everolimus, alpelisib, ribociclib and palbociclib with standard of care endocrine therapy, demonstrating the potential of elacestrant to be combined with targeted therapies, enabling all oral regimens. Clinical trial information: NCT05563220 .