PI3K Inhibition in Combination with Tamoxifen in Patients with Metastatic HR+/HER2− Breast Cancer: Clinical and Circulating Tumor DNA Results

作者：Rosie A.B. Voorthuis, Mafalda Oliveira, Annelot G.J. van Rossum, Leonora W. de Boo, Ingrid A.M. Mandjes, Cristina Saura, S Manrique Muñoz, D. Lopez Garcia, Mariëtte Schrier, Karolina Sikorska, Marta López‐Yurda, Margaret Schot, Tatjana T Westphal, Catharina M. Korse, Shubha Anand, R. Bernards, William M. Gallaher, Karin Beelen, C. Caldas, Cortes Javier, Sabine Linn, Richard D. Baird · 发表于：Clinical Cancer Research · 年份：2026 · DOI：10.1158/1078-0432.ccr-25-2833 · 被引用次数：1 · 研究领域：Advanced Breast Cancer Therapies、PI3K/AKT/mTOR signaling in cancer、PARP inhibition in cancer therapy

PURPOSE: To determine the safety and efficacy of taselisib, a selective PI3K inhibitor, in combination with tamoxifen. PATIENTS AND METHODS: POSEIDON is a phase II, randomized, placebo-controlled trial conducted from June 2016 to March 2020. Eligible patients were refractory upon prior endocrine therapy. Prior treatment with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and everolimus was allowed. Patients were randomized (1:1) to receive either taselisib (4 mg) + tamoxifen (20 mg) or placebo + tamoxifen. The primary endpoint of the trial was investigator-assessed progression-free survival (PFS) in the intention-to-treat (ITT) population (two-sided α 0.2, 90% power). Exploratory biomarker analysis with regards to prognosis and treatment resistance was conducted in circulating tumor (ct)DNA. RESULTS: POSEIDON met its primary endpoint, in which patients treated with taselisib + tamoxifen had improved PFS compared with patients treated with placebo + tamoxifen in the ITT population (median PFS 4.8 months vs. 3.2 months; stratified hazard ratio 0.69; 80% confidence interval, 0.49-0.98, P = 0.17). However, toxicity of taselisib was significant, with diarrhea (40% any grade) as the most common adverse event. Exploratory analyses indicated that high tumor fraction (TF) determined in ctDNA at baseline is associated with worse PFS and overall survival (P < 0.0001). CONCLUSIONS: Our findings suggest efficacy of PI3K inhibition + tamoxifen beyond second-line treatment and after prior ...