PARP inhibitor resistant BRCA-mutated advanced breast cancer: current landscape and emerging treatments.

Purpose of review: Patients with advanced breast cancer (aBC) treated with PARP inhibitors (PARPi) can eventually experience disease progression for emerging treatment resistance. This review aims to depict the treatment the molecular landscape, and the innovative therapies for patients with PARPi-resistant BRCA-mutated aBC.

Recent findings: No specific therapy is specifically available in the setting post-PARPi-failure, with antibody-drug conjugates or nonplatinum-based chemotherapy (PBC) representing the best treatment options in this setting. Mechanisms of on-target PARPi resistance can be classified in reversions (60%) and nonreversion (40%); reverse mutations restore PARP functions. According to the first evidence of clinical validity, these alterations are associated with lower efficacy of PARPi and PBC. However, their clinical utility needs to be assessed.

Summary: PARPi-resistant aBC represents a clinical unmet need due to the lack of specific targeted therapies and validated prognostic and predictive biomarkers. Constant efforts are required to better define the mechanisms of PARPi resistance and, consequently, develop biomarker-based treatment approach to prevent or overcame resistance.