A mouse PDX clinical trial reveals broad efficacy of niraparib and vc-seco-DUBA anti-HER2 ADC SYD985 in HER2/neu expressing endometrial cancer.

Advanced and recurrent high-risk endometrial cancer (EC) frequently develops resistance to platinum-based chemotherapy, leaving patients with limited therapeutic options. Recent studies have shown that HER2 expression spans a broad spectrum of endometrial cancers, extending beyond HER2-amplified tumors, while functional homologous recombination deficiency (HRD) represents an additional therapeutic vulnerability in a substantial subset of cases. We hypothesized that combining the PARP inhibitor niraparib with the HER2-directed antibody-drug conjugate SYD985 (trastuzumab duocarmazine) could simultaneously exploit both therapeutic vulnerabilities and improve antitumor activity across molecularly diverse high-risk EC. A Mouse Clinical Trial (MCT) was conducted using a panel of 15 genomically and molecularly characterized patient-derived xenograft (PDX) models representing all TCGA molecular subtypes of high-risk EC. Animals were randomized to receive vehicle, SYD985 (1 mg/kg, intravenous), niraparib (40-50 mg/kg, oral), the combination, or a control antibody-drug conjugate (SYD989). Antitumor efficacy was assessed by tumor growth, objective response rate, and overall survival. Whole-exome sequencing and RNA sequencing were integrated to identify molecular determinants of treatment response. Genomic profiling confirmed faithful representation of all TCGA molecular subtypes and identified Mutational Signature 3 in HCN tumors, supporting the presence of functional HRD independently of canonical BRCA1/2 alterations. The combination of niraparib and SYD985 achieved a 60% complete response rate and an 87% overall objective response rate, outperforming both monotherapies across the entire panel, including HER2-low (IHC 1 +) tumors (83.3% objective response rate). Baseline transcriptomic profiling identified reduced Wnt signaling activity as a molecular feature associated with response to niraparib, whereas activation of the HER2/PI3K/AKT, RAS/MAPK, and JAK-STAT pathways characterized tumors responsive to SYD985 irrespective of HER2 amplification status. Tumors responding to the combination therapy exhibited convergence of these transcriptomic features, supporting complementary mechanisms underlying the enhanced therapeutic efficacy. The combination of niraparib and SYD985 demonstrated broad antitumor activity across the molecular landscape of high-risk EC, including the clinically prevalent HER2-low population. These findings provide a strong preclinical rationale for the clinical evaluation of this chemotherapy-free targeted strategy.