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<p>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 to selective ER degraders (SERDs), including in PDXs with <i>ESR1</i>, <i>PIK3CA</i>, or <i>PTEN</i> mutations. Tumors sensitive to SARMs were enriched in <i>GATA3</i> mutations. EP0062 treatment induced AR-target genes across all models tested. A transcriptional signature associated with SARM sensitivity was identified, primarily driven by proliferation-related processes, consistent with a significant decrease in S-phase cell cycle proteins upon treatment in EP0062-sensitive models. In some EP0062-resistant tumors, the combination with palbociclib enhanced the antitumor effect of EP0062, suggesting a potential strategy for metastatic patients with acquired ET resistance.</p>

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Exploiting androgen receptor agonism as a treatment strategy in estrogen receptor-positive metastatic breast cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月17日

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  • Laia Monserrat,
  • Judith García-García,
  • Cristina Molina,
  • Andreu Òdena,
  • Taras Yuziv Duda,
  • Irene Agustí-Barea,
  • Gilles Flamen,
  • Cristina Viaplana,
  • Aerica Nagornyuk,
  • Ruth Maldonado-Padrol,
  • Claudia Yáñez-Bartolomé,
  • Flaminia Pedretti,
  • Marta Guzmán,
  • Olga Rodríguez,
  • Fara Brasó-Maristany,
  • Eduardo García-Galea,
  • Rodrigo Dienstmann,
  • Motoki Takaku,
  • Aleix Prat,
  • Sarat Chandarlapaty,
  • Julia Ponomarenko,
  • Cristina Saura,
  • Mafalda Oliveira,
  • Lara Nonell,
  • Meritxell Bellet,
  • Guillermo P. Vicent,
  • Violeta Serra

摘要

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 to selective ER degraders (SERDs), including in PDXs with ESR1, PIK3CA, or PTEN mutations. Tumors sensitive to SARMs were enriched in GATA3 mutations. EP0062 treatment induced AR-target genes across all models tested. A transcriptional signature associated with SARM sensitivity was identified, primarily driven by proliferation-related processes, consistent with a significant decrease in S-phase cell cycle proteins upon treatment in EP0062-sensitive models. In some EP0062-resistant tumors, the combination with palbociclib enhanced the antitumor effect of EP0062, suggesting a potential strategy for metastatic patients with acquired ET resistance.