Determinants of long-term response to patritumab deruxtecan (HER3-DXd) in breast cancer patient-derived xenografts

Purpose: Novel antibody-drug conjugates (ADCs) have shown potent antitumor activity across multiple cancer types. Here, we aimed to identify potential determinants of response to patritumab deruxtecan (HER3-DXd), a HER3-directed ADC linked to a potent topoisomerase I inhibitor (TOP1i) payload, in breast cancer (BC) patient-derived xenograft (PDX) models. Experimental Design: The antitumor activity of HER3-DXd was assessed in 31 BC PDXs and classified according to tumor growth inhibition and duration of response. We analyzed the sensitivity to HER3-DXd according to the molecular characteristics of the PDX models, the sensitivity to the TOP1i irinotecan, and prior patient treatments. The biological effects following treatment with HER3- DXd were assessed and associated to treatment response. Results: Fourteen out of 31 (45%) PDXs exhibited a profound and sustained response to HER3-DXd. Basal-like PAM50 intrinsic subtype was associated with long-term response, across HER3/ERBB3 expression levels. We also observed a positive association between HER3-DXd and irinotecan sensitivity in the PDXs, as well as short-lasting antitumor response in models derived from patients with prior repeated exposure to chemotherapy. HER3-DXd showed sustained activity in BRCA1/BRCA2-mutated PARPi-resistant PDX models. Long-term responders exhibited persistent DNA damage and lacked early transcriptional activation of the G2/M cell cycle checkpoint to allow for DNA repair and R-loop resolution, in parallel resulting in immune pathways activation. Conclusions: HER3-DXd exhibited potent antitumor activity in breast cancer PDX models, including those with BRCA1/BRCA2 alterations and PARPi resistance. Notably, characteristics linked to long-term response were primarily associated with the TOP1i payload activity. Overall design: This study includes RNA-seq profiling of 10 BC PDX models, both untreated and treated with HER3-DXd (3 mg/kg) at 24 hours (24h) and 7 days (7d). Baseline RNA-seq profiling was also performed for all 31 BC PDX models in the cohort.