Simple SummaryThe treatment landscape for advanced breast cancer (BC) has been expanding due to the development of biological drugs with demonstrated efficacy across all breast cancer subtypes. The role of poly adenosine diphosphate–ribose polymerase (PARP) inhibitors in advanced BC is well established for the treatment of germlineBRCA1/2mutated (gBRCA1/2m) HER2-negative BC, regardless of hormone receptor (HR) expression. Nevertheless, there is very little data on the efficacy of other drugs in the event of disease progression in patients with gBRCA1/2m BC. This review provides an update on the efficacy of biological drugs, approved in the US and Europe, for the treatment of advanced BC in this patient population.AbstractWe explored the outcomes of germlineBRCA1/2pathogenic/likely pathogenic variants (PVs/LPVs) in the endocrine-sensitive disease treated with first-line standard of care cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Three studies retrospectively showed a reduction in the overall survival (OS) and progression-free survival (PFS) in gBRCA1/2m patients compared to both the germinalBRCA1/2wild type (gBRCA1/2wt) and the untested population. Regarding the efficacy of PI3Kα inhibitors, there are no subgroups or biomarker analyses in which germinal BRCA status was explored. However, the biological interactions between the PIK3CA/AKT/mTOR pathway andBRCA1/2at a molecular level could help us to understand the activity of these drugs when used to treat BC inBRCA1/2PVs/LPVs carriers. The efficacy of trastuzumab deruxtecan (T-DXd), an antibody–drug conjugate (ADC) targeting HER2 for HER2-low and HER2-positive (HER2+) BC, has been increasingly described. Unfortunately, data on T-DXd in HER2+ or HER2-low metastatic BC harboring germinalBRCA1/2PVs/LPVs is lacking. Including germinalBRCA1/2status in the subgroup analysis of the registration trials of this ADC would be of great interest, especially in the phase III trial DESTINY-breast04. This trial enrolled patients with HER2-negative (HER2−) and both HR+ and HR− metastatic disease, which can now be categorized as HER2-low. The HER2-low subgroup includes tumors that were previously classified as triple negative, so it is highly likely that some women were germlineBRCA1/2PVs/LPVs carriers and this data was not reported. GermlineBRCA1/2status will be available for a higher number of individuals with BC in the near future, and data on the prognostic and predictive role of these PVs/LPVs is needed in order to choose the best treatment options.