Endocrine‐based treatments in clinically‐relevant subgroups of hormone receptor‐positive/HER2‐negative metastatic breast cancer: systematic review and meta‐analysis

A precise assessment of the efficacy of first‐/second‐line endocrine therapies (ET) ± target therapies (TT) in clinically‐relevant subgroups of hormone receptor‐positive (HR+)/HER2‐negative metastatic breast cancer (MBC) has not yet been conducted. To improve our current knowledge and support clinical decision‐making, we thus conducted a systematic literature search to identify all first‐/second‐line phase II/III randomized clinical trials (RCT) of currently approved or most promising ET ± TT. Then, we performed a meta‐analysis to assess progression‐free (PFS) and/or overall survival (OS) benefit in several clinically‐relevant prespecified subgroups. Thirty‐five RCT were included (17,595 patients). Pooled results show significant reductions in the risk of relapse or death of 26–41% and 12–27%, respectively, depending on the clinical subgroup. Combination strategies proved to be more effective than single‐agent ET (PFS hazard ratio (HR) range for combinations: 0.60–0.65 vs. HR range for single agent ET: 0.59–1.37; OS HR range for combinations: 0.74–0.87 vs. HR range for single agent ET: 0.68–0.98), with CDK4/6‐inhibitors(i) + ET being the most effective regimen. Single agent ET showed comparable efficacy with ET+TT combinations in nonvisceral (p = 0.63) and endocrine sensitive disease (p = 0.79), while mTORi‐based combinations proved to be a valid therapeutic option in endocrine‐resistant tumors, as well as PI3Ki + ET in PIK3CA‐mutant tumors. These results strengthen international treatment guidelines and can aid therapeutic decision‐making.