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

Oukseub Lee, Megan E. Sullivan, Yanfei Xu, Chiara Rogers, Miguel Muzzio, Irene Helenowski, Ali Shidfar, Zexian Zeng, Hari Singhal, Borko Jovanovic, Nora Hansen, Kevin P. Bethke, Peter H. Gann, William Gradishar, J. Julie Kim, Susan E. Clare, Seema A. Khan*

*Corresponding author for this work

Research output: Contribution to journalArticle

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Purpose: Selective progesterone receptor modulators (SPRMs) show preclinical activity against hormone-sensitive breast cancer, but have not been tested in patients with early, treatment-naïve tumors. Patients and Methods: In a double-blind presurgical window trial of oral telapristone acetate (TPA) 12 mg daily versus placebo, 70 patients with early-stage breast cancer were randomized 1:1 (stratified by menopause) and treated for 2 to 10 weeks. The primary endpoint was change in Ki67 between diagnostic biopsy and surgical specimens. Gene expression pre- and posttherapy was assessed using RNA-sequencing and gene set enrichment analysis was performed to determine pathways enriched in response to TPA and placebo treatments. Results: Among 61 evaluable women (29 placebo and 32 telapristone acetate), 91% of tumors were ER/PR positive. The mean Ki67 declined by 5.5% in all women treated with telapristone acetate (P = 0.003), and by 4.2% in all women treated with placebo (P = 0.04). After menopausal stratification, the Ki67 decline remained significant in 22 telapristone acetate–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 telapristone acetate 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: Patients treated with telapristone acetate whose Ki67 decreased by ≥30% demonstrated a selective antiproliferative 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.

Original languageEnglish (US)
Pages (from-to)25-34
Number of pages10
JournalClinical Cancer Research
Issue number1
StatePublished - Jan 1 2020


ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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