Selective progesterone receptor modulators in early stage breast cancer: a randomized, placebo-controlled Phase II window of opportunity trial using telapristone acetate.

Background: Selective progesterone receptor modulators (SPRMs) show preclinical activity against hormone-sensitive breast cancer, but have not been tested in patients with early, treatment-naive tumors. Methods: In a double-blind pre-surgical window trial of oral telapristone acetate (TPA) 12 mg daily vs. placebo, 70 early stage breast cancer patients were randomized 1:1 (stratified by menopause) and treated for 2-10 weeks. The primary endpoint was change in Ki67 between diagnostic biopsy and surgical specimens. Gene expression pre- and post-therapy was assessed using RNA-sequencing and gene set enrichment analysis (GSEA) was performed to determine pathways enriched in response to TPA and placebo treatments. Results: Among 61 evaluable women, (29 placebo and 32 TPA) 91% of tumors were ER/PR positive. The mean Ki67 declined by 5.5% in all TPA-treated women (p= 0.003), and by 4.2% in all placebo-treated women (p=0.04). After menopausal stratification, the Ki67 decline remained significant in 22 TPA-treated premenopausal women (p=0.03). Differential gene expression analysis showed no significant modulation overall. However, in a subset of tumors that demonstrated ≥30% relative reduction in Ki67 in the TPA group, genes related to cell cycle progression, and those in the HER2 amplicon were significantly downregulated. In contrast, no significantly enriched pathways were identified in the placebo group. Conclusions: TPA-treated patients whose Ki67 decreased by ≥30% demonstrated a selective anti-proliferative signal, with a potentially important effect on HER2 amplicon genes. Evaluation of SPRMs in a neoadjuvant trial is merited, with attention to predictors of response to SPRM therapy, and inclusion of pre and postmenopausal women.