Elacestrant (oral SERD) + capivasertib (AKT inhibitor) posts 11.3-mo mPFS in post-CDK4/6 ER+/HER2− ABC (Ph 1b)

Elacestrant is an oral selective estrogen receptor degrader (SERD) combined here with capivasertib, an oral AKT inhibitor, to address endocrine resistance driven by ESR1 mutations and PI3K/AKT/PTEN pathway alterations. In the ELEVATE Phase 1b/2 open-label umbrella study (NCT05563220), patients with ER+/HER2− advanced breast cancer after 1–2 prior lines of endocrine therapy ± CDK4/6 inhibitor (no chemo for ABC) received dose-escalated elacestrant (258–345mg QD) + capivasertib (320–400mg; intermittent schedule), with 31 patients treated as of the December 2025 cutoff; 90% had visceral metastases, 45% had ESR1 mutations, 94% had prior CDK4/6i, and 45% had prior fulvestrant. At the RP2D (elacestrant 345mg QD + capivasertib 320mg BID, 4-days-on/3-days-off), response-evaluable patients (n=9) had ORR 22% and CBR24wk 67% (1 CR, 1 PR, 6 SD) with median PFS 11.3 months at a 10.2-month median follow-up—numerically longer than the 7.2–7.3 month mPFS seen with capivasertib + fulvestrant in CAPItello-291 (overall and AKT-altered populations) and far above fulvestrant-alone control PFS (3.1–3.6 months) in that setting, albeit with cross-trial caveats and a much smaller n here. Safety looked consistent with capivasertib biology: common TEAEs were diarrhea 81% (6% grade 3), rash 61% (13% grade 3), nausea 74% (0% grade 3), fatigue 58% (3% grade 3), and hyperglycemia 29% (10% grade 3); no DLTs were observed, and the RP2D was selected based on tolerability and PK.