In a Phase 1b/2 study of palazestrant plus ribociclib in ER+/HER2- advanced or metastatic breast cancer, the 120 mg palazestrant cohort achieved a median progression-free survival of 15.5 months across all patients with more than 19 months of follow-up. Among patients previously treated with a CDK4/6 inhibitor, median PFS was 12.2 months, splitting to 13.8 months in ESR1-mutant tumors and 9.2 months in ESR1 wild-type tumors. Safety remained favorable with mostly grade 1–2 events, no new signals, and no apparent drug-drug interaction with ribociclib.
The update, presented at ESMO 2025, covers 72 patients treated with ribociclib 600 mg plus palazestrant at 120 mg (n=56) or 90 mg (n=16). Sixty-three percent had prior CDK4/6 inhibitor exposure in the advanced setting. Median PFS in the 90 mg cohort was not reached at a median follow-up of 10.8 months. Olema has already moved the combination into Phase 3 with OPERA-02 in the frontline setting, alongside OPERA-01 testing palazestrant monotherapy.
Strategically, Olema is positioning palazestrant as a backbone endocrine partner to CDK4/6 inhibitors, aiming to differentiate with a dual CERAN/SERD profile and a tolerability package suitable for chronic combination. The signal in the post-CDK4/6 cohort is operationally important: randomized studies of CDK4/6 continuation or switch after progression have generally delivered modest PFS deltas, so a double-digit median in a single-arm dataset will attract attention even if cross-trial comparisons are fraught. The apparent enrichment in ESR1-mutant disease aligns with the broader field’s push to neutralize ligand-independent ER signaling. Still, activity in wild-type tumors is equally relevant for a frontline label that cannot rely on ESR1 mutation prevalence. The absence of pharmacokinetic interaction with ribociclib simplifies combination risk management, a nontrivial consideration as regulators scrutinize additive toxicity in multi-agent regimens.
For sites, the combo looks manageable within familiar ribociclib workflows, including hematologic monitoring and QTc management, without additional burdens from palazestrant. If the biomarker-agnostic activity holds, enrollment may not hinge on ESR1 mutation status, potentially broadening reach while still encouraging ctDNA surveillance to inform resistance dynamics. Sponsors and CROs should read this as further momentum toward CDK4/6-based backbones paired with next-gen endocrine agents, intensifying competition with oral SERDs and ER degraders targeting both frontline and post-CDK4/6 niches. Regulators will expect randomized evidence, especially for any claim of benefit after prior CDK4/6 exposure, where practice patterns remain unsettled. Payers will benchmark against established ribociclib combinations, making the magnitude and durability of benefit in clearly defined subgroups critical.
What comes next will hinge on OPERA-02’s design and execution: comparator selection, stratification by prior adjuvant exposure and ESR1 status, and clarity on statistical powering for PFS and key secondary endpoints such as time to chemotherapy and overall survival. The bar in untreated metastatic disease is high, and any advantage over aromatase inhibitor or fulvestrant backbones will need to be unambiguous to shift prescribing. In the post-CDK4/6 setting, OPERA-01 will need to delineate how palazestrant stacks up against approved options and whether reintroduction of a CDK4/6 inhibitor is essential. Watch for maturation of safety with more prolonged exposure, consistency across metastatic sites, including liver and bone-dominant disease, and early signals from global enrollment that speak to operational scalability. The field will also watch how Olema navigates partnerships around ribociclib and hedges across other combinations, given a crowded endocrine innovation pipeline converging on similar clinical territory.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
