Clinical Efficacy and Whole Exome Sequencing of Liquid Biopsies in a Phase IB/II study of Bazedoxifene and Palbociclib in Hormone Receptor-Positive Breast Cancer

Abstract Purpose: Sensitivity to endocrine therapy (ET) is critical for the clinical benefit from the combination of palbociclib plus ET in hormone receptor-positive/HER2-negative (HR+/HER2-) advanced breast cancer. Bazedoxifene is a third-generation selective ER modulator and selective ER degrader with activity in preclinical models of endocrine-resistant breast cancer, including models harboring ESR1 mutations. Clinical trials in healthy women showed that bazedoxifene is well tolerated. Patients and Methods: We conducted a phase Ib/II study of bazedoxifene plus palbociclib in patients with HR+/HER2- advanced breast cancer who progressed on prior ET (N=36) (NCT02448771). Results: The study met its primary endpoint, with a clinical benefit rate of 33.3%, and the safety profile was consistent with what has previously been seen with palbociclib monotherapy. The median progression free survival (PFS) was 3.6 months (CI95% 2.0-7.2). An activating PIK3CA mutation at baseline was associated with a shorter PFS (HR = 4.4, CI95% 1.5-13, P = 0.0026) but activating ESR1 mutations did not impact the PFS. Longitudinal plasma circulating tumor DNA whole exome sequencing (WES) (N=68 plasma samples) provided an overview of the tumor heterogeneity, the sub-clonal genetic evolution and identified actionable mutations acquired during treatment. Conclusions: The combination of palbocilib and bazedoxifene has clinical efficacy and an acceptable safety profile in a heavily pre-treated patient population with advanced HR+/HER2- breast cancer. These results merit continued investigation of bazedoxifene in breast cancer.