Elacestrant Plus Everolimus Delivers 8.3-Month Median PFS After CDK4/6 Inhibitor Progression in the ELEVATE Umbrella Study

A 50-patient cohort built to look like the clinic

ELEVATE enrolled patients with ER-positive, HER2-negative advanced breast cancer who had received one or two lines of endocrine therapy combined with a CDK4/6 inhibitor and no chemotherapy for advanced disease. Prior fulvestrant and primary endocrine resistance were allowed, which matters because those groups are often screened out of endocrine-combination trials. The umbrella design assigns elacestrant to one of six partners: everolimus, alpelisib, capivasertib, abemaciclib, ribociclib or palbociclib. The Clinical Cancer Research paper, first-authored by Hope S. Rugo of City of Hope National Medical Center with Virginia Kaklamani of The University of Texas Health Science Center at San Antonio as senior author, reports only the everolimus arm.

The phase 1b portion treated 23 patients and settled on 345 mg of elacestrant, the labeled monotherapy dose, plus 7.5 mg of everolimus rather than the 10 mg used with exemestane in the drug's existing breast cancer indication. The phase 2 expansion then enrolled 50 patients. Nearly three-quarters had visceral disease and half had already progressed on fulvestrant, the injectable degrader elacestrant was designed to replace.

The PFS numbers and what sits inside the confidence intervals

Median PFS in the full phase 2 cohort was 8.3 months with a 95% confidence interval of 4.0 to 10.2 months. The mutation subgroups track the overall figure closely: 8.3 months in ESR1-mutant tumors, 9.0 months in ESR1 wild-type, 8.3 months in PIK3CA-mutant and 9.4 months in PIK3CA wild-type, where the upper bound was not reached. The lower bounds, between 3.5 and 4.2 months in every subgroup, reflect a cohort of 50 split roughly in half twice over, and the authors present the consistency across subgroups as the finding rather than any single median.

That consistency is the argument for the combination. Elacestrant's FDA approval in January 2023 was confined to ESR1-mutated disease, on the strength of the EMERALD trial, with a plasma ctDNA assay defining eligibility. The ELEVATE abstract reports that the everolimus pairing performed the same in the 58% of patients whose tumors were ESR1 wild-type, a population the single agent's label does not reach. The paper's conclusion states that the combination "showed a clinically meaningful PFS benefit across clinical/genomic subgroups, irrespective of ESR1 or PIK3CA-mutation status," and that elacestrant "has the potential to become an ET backbone" for PI3K/AKT/mTOR-pathway combinations.

Safety at the lower everolimus dose

The abstract describes adverse events as "consistent with known safety of everolimus plus SOC ET," with most events grade 1 or 2. Adverse events caused 6% of patients to stop treatment and 2% to reduce a dose. The 7.5 mg everolimus dose is a quarter below the 10 mg standard, and the abstract does not report stomatitis, hyperglycemia or pneumonitis rates individually. Only the abstract could be read for this article. The full text sits behind the journal's access controls and the per-event safety table, the data cut-off and any response-rate data were not available.

ADELA is already asking the randomized question

ELEVATE is single-arm, so the 8.3-month median has no internal comparator. ADELA, NCT06382948, is a randomized, double-blind, placebo-controlled Phase III sponsored by the Spanish academic group MedSIR that began enrolling on December 5, 2024. It assigns patients with ER-positive, HER2-negative, ESR1-mutant advanced breast cancer progressing on endocrine therapy plus a CDK4/6 inhibitor to elacestrant 345 mg with everolimus 7.5 mg or to elacestrant with matched placebo, with 300 patients planned. The doses are the ELEVATE recommended phase 2 doses, and the ClinicalTrials.gov record lists the study as recruiting. ADELA is restricted to ESR1-mutant tumors, so the wild-type activity reported here will need a separate randomized test.

Why This Matters to the APO|APE Reader

ADELA's ESR1-mutant-only entry criterion means the ctDNA ESR1 call that gates elacestrant monotherapy today will also gate the first randomized read on this combination, and the 42% ESR1-mutant rate in ELEVATE's phase 2 cohort is a fair estimate of how many post-CDK4/6 patients a liquid biopsy will qualify. The 50% PIK3CA-mutant rate in the same 50 patients is the more awkward figure: those patients already have alpelisib and capivasertib as labeled options, and an all-oral everolimus pairing that works irrespective of PIK3CA status will compete for them on tolerability and cost rather than on a biomarker. Molecular labs reporting ESR1 and PIK3CA together on one post-progression panel will be supplying the numbers that decide which arm of the umbrella a patient lands in.