Evolving treatment algorithm for hormone receptor-positive, HER2-negative metastatic breast cancer: new drugs and future therapeutic strategies

Summary The treatment algorithm for hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (MBC) is rapidly evolving, as shown by the approval of three new agents in 2025: inavolisib, imlunestrant and datopotamab-deruxtecan. Endocrine therapy (ET) is the cornerstone of systemic treatment, while chemotherapy is generally reserved for later lines of treatment, particularly since the combination of ET and CDK4/6 inhibitors has shown remarkable efficacy in the first-line setting, outperforming both single agent and polychemotherapy. Improved understanding of the mechanisms underlying endocrine resistance, including aberrant activation of the PI3K/AKT/mTOR pathway and acquired ESR1 gene mutations, has led to the development and integration of targeted agents into the treatment landscape of HR-positive, HER2-negative MBC. The PIK3CA inhibitor inavolisib, in combination with palbociclib and fulvestrant, has been established as a new treatment standard for patients with endocrine-resistant, PIK3CA-mutated HR-positive, HER2-negative MBC. Likewise, the oral selective estrogen receptor degrader (SERD) imlunestrant has broadened treatment options for patients with ESR1-mutated disease, after progression on ET, regardless of prior CDK4/6 inhibitor exposure. Antibody–drug conjugates (ADCs) have also reshaped the therapeutic landscape, progressively replacing conventional chemotherapy and shifting its use to later lines of treatment. Together with trastuzumab-deruxtecan and sacituzumab-govitecan, datopotamab-deruxtecan has become the third ADC approved for the treatment of patients with HR-positive, HER2-negative MBC. Collectively, these advances reflect a dynamic and rapidly expanding treatment landscape. However, optimal sequencing strategy remains undefined. This short review aims to provide an overview of the three recently approved agents and offers a glimpse into future therapeutic strategies for HR-positive, HER2-negative MBC.