Real-world effectiveness of PARP inhibitors after CDK4/6 inhibitor therapy in BRCA-mutated HR-positive/HER2-negative advanced breast cancer.

Poly(ADP-ribose) polymerase inhibitors (PARPi) are established as standard-of-care therapy for patients with hormone receptor-positive/HER2-negative advanced breast cancer (HR+/HER2- aBC) who harbor germline BRCA1/2 likely pathogenic or pathogenic variants (LP/PV). However, the real-world efficacy of PARPi following tumor progression on first-line (1 L) cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) remains inadequately explored. In this cohort of 81 patients with HR+/HER2- aBC harboring germline BRCA LP/PV, 64 (79%) received 1 L treatment with CDK4/6i plus ET. Considering the subsequent therapy administered after tumor progression on 1 L CDK4/6i, patients treated with PARPi showed a significantly longer median real-world PFS (11.8 months) compared to those receiving ET, monochemotherapy, or polychemotherapy. This benefit was confirmed in a multivariable analysis, supporting PARPi as the preferred option in eligible patients. Our findings suggest that PARPi should be prioritized in the post-CDK4/6i treatment sequence for BRCA LP/PV carriers with HR+/HER2 aBC and highlight the critical role of germline BRCA testing.