Results and exploratory biomarker analyses of a phase II study CHANGEABLE: combination of HX008 and niraparib in GErm-line-mutAted metastatic breast cancer

Background: The combination of poly (ADP-ribose) polymerase inhibitors and immune-checkpoint inhibitors demonstrated synergistic antitumor activity in preclinical studies. We aim to investigate the efficacy, safety, and biomarker analyses of the combination of niraparib and PD-1 inhibitor HX008 in metastatic breast cancer (MBC) patients with germline DNA damage response (DDR) gene mutations in a phase II trial (CHANGEABLE). Methods: Eligible patients had histologically confirmed MBC with at least one measurable disease and germline pathogenic/likely pathogenic mutations in DDR genes. Patients were enrolled into two cohorts: the main cohort (HER2-negative MBC patients with a germline mutation in BRCA1/2 or PALB2) and the exploration cohort (MBC patients with a germline mutation in other DDR genes or with brain metastases or HER2-postive MBC patients). Simon's Two-Stage design was used for recruiting patients in the main cohort. Patients with HER2-negative MBC received niraparib 200 mg orally once daily combined with HX008 200 mg intravenously every 3 weeks, while HER2-positive patients received additional pyrotinib 400mg orally once daily if having brain metastases, until disease progression. The primary endpoint was objective response rate (ORR). Next-generation sequencing (NGS) of tissue and circulating tumor DNA (ctDNA) were performed for exploratory biomarker analyses. Findings: As of February 2023, 37 patients were enrolled. In the main cohort with germline BRCA1/2 mutations, ORR was 79% (22/28), with three patients having CR; the DCR was 96% (27/28); the median PFS was 7.4 months (95%CI 5.4 to 12). In the patients having brain metastases, ORR was 40% (2/5) and DCR was 80% (4/5). The most common treatment-related adverse events of grade 3 or higher were anemia (13 [35.1%]), thrombocytopenia (4 [10.8%]), and neutropenia (3 [8.1%]). No treatment-related deaths were reported. Somatic mutations in XPO1 showed significant correlation with response. Somatic mutations in TP53 were significantly correlated with shorter PFS, while those in ASXL1 were significantly correlated with longer PFS. Interpretation: The combination of niraparib and HX008 demonstrated promising clinical benefits with a tolerable safety profile in MBC patients with germline DDR mutations, even in patients with brain metastases.