Trastuzumab deruxtecan (T-DXd) is a HER2-targeted antibody-drug conjugate recently approved for HER2-low expressing solid tumours following demonstration of clinical efficacy in breast, gastric, and lung cancers. HER2 expression has been documented in 30-60% of metastatic castration-resistant prostate cancers (mCRPC), yet the therapeutic potential of HER2-targeted ADCs in this indication remains unexplored. We evaluated the anti-tumour efficacy of T-DXd across prostate cancer models with varying HER2 expression levels.

HER2 expression was characterized by immunohistochemistry in prostate cancer cell lines (DU145, PC-3, 22Rv1). Subcutaneous xenograft studies were conducted in male NSG mice using HER2-moderate (DU145), HER2-low (PC-3), and HER2-negative (22Rv1) models. Mice bearing established tumours (150-200 mm³) were randomized to vehicle control, docetaxel (10 mg/kg IV, Q7D×3), or T-DXd (6 mg/kg IV, Q14D×3) treatment groups (n=8-10/group). Tumour volumes were measured twice weekly. HER2 expression, proliferation (Ki-67), and apoptosis (cleaved caspase-3) were assessed by IHC in harvested tumours.

T-DXd demonstrated robust anti-tumour activity across HER2-expressing models. In DU145 xenografts (HER2 IHC 2+), T-DXd achieved 82% tumour growth inhibition (TGI) with 50% complete regressions, significantly outperforming docetaxel (46% TGI, 0% regressions; p<0.001). In PC-3 xenografts (HER2 IHC 1+), T-DXd demonstrated 68% TGI with 20% regressions versus docetaxel (38% TGI; p<0.01). Notably, T-DXd showed minimal activity in HER2-negative 22Rv1 xenografts (22% TGI), confirming target-dependent efficacy. IHC analysis revealed marked reduction in Ki-67 and increased cleaved caspase-3 staining in T-DXd-treated tumours from HER2-expressing models. T-DXd was well-tolerated with no significant body weight loss across all cohorts.

Trastuzumab deruxtecan demonstrates potent anti-tumour efficacy in HER2-expressing prostate cancer models, including HER2-low tumours, with superior activity compared to standard chemotherapy. These findings provide preclinical rationale for clinical evaluation of T-DXd in HER2-expressing mCRPC and establish validated xenograft models for next-generation HER2-targeted ADC development. Given the recent tumour-agnostic approval of T-DXd for HER2-low cancers, these data support expansion of HER2-targeted therapy beyond traditional indications.