Emma Zattarin, Antonio Marra, Antonella Palazzo, Gaia Griguolo, Claudio Vernieri, Julian Etessami, Letizia Pontolillo, Giusy Landa, Arianna Daneri, Matteo De Monte, Riccardo Cuoghi Costantini, Elena Tenedini, Ornella Ponzoni, Maria Grazia Razeti, Caterina Sposetti, Elena Barbieri, Martina Manni, Federica Caggia, Laura Cortesi, Giuseppe Curigliano, Emilio Bria, Massimo Dominici, Valentina Guarneri, Matteo Lambertini, Angela Toss
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.