PI3K inhibition in combination with tamoxifen in patients with metastatic HR+/HER2- breast cancer: clinical and circulating tumor DNA results.

PURPOSE: To determine the safety and efficacy of taselisib, a selective PI3K-inhibitor, in combination with tamoxifen. PATIENTS AND METHODS: POSEIDON is a phaseII, 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 (4mg) + tamoxifen (20mg) 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 alpha 0.2, 90% power). Exploratory biomarker analysis with regards to prognosis and treatment resistance were conducted in circulating tumor (ct)DNA. RESULTS: POSEIDON met its primary endpoint, where patients treated with taselisib + tamoxifen had improved PFS compared to patients treated with placebo + tamoxifen in the ITT population (median PFS 4.8 months versus. 3.2 months; stratified hazard ratio 0.69, 80% CI 0.49-0.98, p=0.17). However, toxicity of taselisib was significant with diarrhea (40% any grade) as most common adverse event. Exploratory analyses indicated that high tumor fraction determined in ctDNA at baseline is associated with worse PFS and OS (p<0.0001). CONCLUSIONS: Our findings suggest efficacy of PI3K inhibition + tamoxifen beyond second-line treatment and after prior targeted therapies, including CDK4/6 inhibition in metastatic HR+/HER2- breast cancer although the magnitude of benefit did not outweigh the tolerability of this combination. Exploratory biomarker analysis indicates that tumor fraction determined in ctDNA differentiates patients based on prognosis and may help to optimize patient selection for targeted treatment strategies.