Exploiting Androgen Receptor Cell Cycle Effects to Enhance CDK4/6 Inhibitor Efficacy in Estrogen Receptor Positive Metastatic Breast Cancer

The androgen receptor (AR) is expressed in 75% of estrogen receptor-positive (ER+) breast cancers (BC). Selective AR modulators (SARMs), like EP0062, present a promising therapeutic strategy for ER+ BC, particularly in patients who cannot tolerate endocrine therapy (ET) or whose tumors have developed resistance. We aimed to study the antitumor activity of EP0062 in ER+ patient-derived xenograft (PDX) models. EP0062 displayed comparable antitumor efficacy as selective ER degraders (SERDs), including in PDXs with ESR1, PIK3CA, or PTEN mutations. Tumors sensitive to both SARM and SERDs were enriched in GATA3 mutations. EP0062 treatment induced AR-target genes across all models tested. A 122-gene signature of SARM sensitivity associated with good prognosis in patients with ER+ BC was developed. Mechanistically, EP0062 downmodulated S-phase cell cycle proteins in sensitive models. In EP0062-resistant, ER-driven tumors, the addition of palbociclib restored drug sensitivity thus providing a promising strategy for metastatic patients with acquired ET resistance.