Sacituzumab govitecan (TROP2–SN-38 TOP1 ADC) + berzosertib (ATR inhibitor) lifts disease control to 86% in platinum-refractory EPSCC

Berzosertib is an IV ATR (replication-stress response) inhibitor combined here with either conventional TOP1 inhibition (topotecan) or tumor-targeted TOP1 payload delivery via the TROP2-directed ADC sacituzumab govitecan (SG; SN-38 payload) across 3 pooled prospective Phase II studies (NCT03896503/NCT02487095/NCT04826341) in platinum-refractory extrapulmonary small cell carcinoma (EPSCC; 41 enrolled, 34 evaluable: topotecan+berzosertib n=20; SG+berzosertib n=14) without intent for head-to-head comparison. RECIST ORR was 10% (95% CI 2.8–30.1) with topotecan+berzosertib vs 21.4% (95% CI 7.6–47.6) with SG+berzosertib, with DCR 45% vs 86%, respectively; durable benefit was seen in subsets (SG cohort PFS ≥6.8 months and OS up to 19.7 months; topotecan cohort OS >18 months in some patients) across multiple primaries (e.g., bladder, prostate, larynx)—notably above the typical ~3–11% ORR reported for single-agent topotecan in chemorefractory relapsed small cell settings. Grade 3–4 hematologic AEs were more frequent with topotecan+berzosertib, while GI toxicity/alopecia were more common with SG+berzosertib; in the SG cohort, UGT1A1 intermediate/poor metabolizers had far higher grade 3–4 toxicity rates (90% vs 10%), and early ctDNA declines tracked response (baseline ctDNA correlated with tumor burden, r=0.83; P=0.006) alongside responder enrichment for E2F-driven and neuroendocrine lineage programs (NES 1.64–1.67; P<0.001).