Real-world clinical outcomes of Trastuzumab Deruxtecan in HER2-expressing ovarian and endometrial Cancer

Objective Trastuzumab deruxtecan (T-DXd), a HER2-directed antibody-drug conjugate, received FDA approval on April 5, 2024 for HER2-expressing solid tumors based on the phase II DESTINY-PanTumor02 trial ( n = 40 per tumor type). Despite rapid clinical adoption, real-world evidence in gynecologic cancers remains limited. This study aims to address this gap. Methods This single-center retrospective cohort study included patients with ovarian cancer (OC) or endometrial cancer (EC) who received T-DXd between September 2022 and January 2026. Primary outcomes were real-world progression free survival (rwPFS) and real-world response rate (rwRR). Secondary outcomes included real-world disease control rate (rwDCR), safety, and time on treatment (TOT). Exploratory analysis aimed to evaluate predictors of progression or death on T-DXd using multivariate cox regression. Results As of February 2026, 40 patients (20 OC, 20 EC) received T-DXd, with a median follow-up of 23 months. All 40 were analyzed for PFS; 37 were response evaluable. HER2 IHC expression was 12.5% 1+, 62.5% 2+, and 20% 3+. Median rwPFS was 6.2 months (95% CI, 3.3–8.6), with a rwRR of 45.9% and rwDCR of 67.6%. rwRR increased significantly with HER2 expression (1+ 16.7%, 2+ 39.1%, 3+ 86%, p = 0.03). In multivariate analysis, PARP inhibitor exposure was associated with significantly shorter PFS (HR 4.36, p = 0.04). Four patients (10%) developed pneumonitis: three (7.5%) grade 1/2, and one (2.5%) grade 3. Conclusions T-DXd demonstrated promising real-world clinical outcomes in OC and EC that mirror DESTINY-PanTumor02. Responses were observed across HER2 IHC expression levels (1+ to 3+), with highest rwRR among HER2 3+. Prior PARP inhibitor exposure was associated with significantly shorter PFS, warranting further exploration.