Next generation of drugs in breast cancer

In hormone receptor (HR)-positive/HER2-negative metastatic breast cancer, first-line therapy consisting of endocrine treatment and a CDK4/6-inhibitor is the standard-of-care. Despite prolonged disease control, patients will eventually progress and require further lines of treatment. Elacestrant is the only oral selective estrogen receptor degrader currently approved, with several other drugs of this class under clinical development alone or in combination with targeted agents. Other approaches of HR-targeting include novel selective estrogen-receptor modulators such as lasofoxifene. While drugs targeting the PI3K/AKT/mTOR pathway combined with endocrine therapy have been proven active, their broad clinical use has been hampered by relevant toxicity. This may change with inavolisib, a selective PIK3CA inhibitor with improved safety profile. In HER2-positive metastatic disease, identifying the optimal treatment approach for patients progressing on prior trastuzumab deruxtecan is currently the most relevant clinical challenge. Novel approaches under clinical investigation include biparatopic antibodies such as zanidatamab or next-generation tyrosine kinase inhibitors such as ZN-1041 or zongertinib. Next-generation PARP1-specific PARP inhibitors may have a broader therapeutic margin and improved clinical activity. Finally, a plethora of novel antibody–drugs conjugates is under clinical development, including the TROP2-directed sacituzumab tirumotecan and HER3-targeting patritumab deruxtecan. This short review summarizes results of promising drugs for the treatment of metastatic breast cancer with a focus on compounds in later clinical development.