Results and Exploratory Biomarker Analyses of a Phase II Study CHANGEABLE: Combination of PD-1 Inhibitor and Niraparib in GErm-Line-mutAted Metastatic Breast Cancer.

This phase II trial evaluated the efficacy and safety of combining niraparib with the PD-1 inhibitor HX008 in patients with metastatic breast cancer who had germline DNA damage response (DDR) mutations. The study included 37 patients, divided into a primary cohort of HER2-negative individuals with germline BRCA1/2 or PALB2 mutations (n = 29) and an exploratory cohort of patients who were either HER2-negative with other DDR mutations, had brain metastases, or were HER2-positive (n = 8). The main cohort achieved an objective response rate (ORR) of 76% and a disease control rate (DCR) of 97%, with a median progression-free survival (PFS) of 7.3 months. The exploratory cohort had an ORR of 25% and a DCR of 75%, while patients with brain metastases showed a 40% ORR. Among treatment-related adverse events of Grade 3 or higher, the most frequently observed were anemia (35.1%), thrombocytopenia (10.8%), and neutropenia (8.1%). No treatment-related deaths were reported. Somatic XPO1 mutations correlated with better response. Somatic TP53 mutations significantly correlated with shorter PFS, while ASXL1 mutations correlated with longer PFS. This chemotherapy-free regimen demonstrates promising efficacy and a tolerable safety profile in patients with metastatic breast cancer and germline DDR mutations, providing a novel therapeutic option for this patient population, even those with brain metastases.