The HER2 paradox in ovarian clear cell carcinoma: Expression and intrinsic resistance to trastuzumab deruxtecan (T-DXd).

5563 Background: Trastuzumab deruxtecan (T-DXd) shows potent activity in HER2-expressing ovarian cancer (OC). However, efficacy across histologic subtypes remains under-characterized. Specifically, data on T-DXd response in ovarian clear cell carcinoma (OCCC), a distinct chemo-resistant entity, are lacking. This study aimed to evaluate T-DXd efficacy in recurrent OC across different histologic subtypes. Methods: We retrospectively analyzed 59 patients with recurrent OC who received T-DXd treatment between 2020 and 2025 at Yonsei Cancer Center. HER2 status (IHC), objective response rate (ORR), progression-free survival (PFS), duration of response, and safety were assessed by histology. Results: Patients included HGSC (n=38), Mucinous (n=9), OCCC (n=10), and Endometrioid (n=2). Median age was 55; median prior lines of therapy was 3. Notably, 100% of OCCC, mucinous, and endometrioid tumors were HER2 2+/3+, vs. 89.5% in HGSC. Despite high HER2 expression, outcomes diverged. ORR was 55.3% (26/47) for HGSC/Mucinous vs. 0% (0/12) for OCCC/Endometrioid ( P <0.001). Specifically, HGSC achieved 57.9% ORR (2 CRs) vs. 0% in OCCC. PFS was significantly shorter in the OCCC/Endometrioid group (median 1.2 vs 6.9 months; HR 18.3; P <0.0001). OCCC patients showed rapid progression. Regarding safety, among 54 evaluable patients, 36 (66.7%) experienced Grade 3-4 adverse events, and 5 cases (9.3%) of ILD occurred; however, no new safety signals or treatment-related deaths were reported. Conclusions: T-DXd showed robust efficacy in recurrent HGSC and mucinous OC but no response in OCCC and endometrioid OC. Thus, HER2 expression alone does not guarantee T-DXd response in OCCC, possibly due to its chemo-refractory nature. Mechanisms of T-DXd resistance in OCCC warrant investigation. Tumor response. Histology HGSC (n=38) Mucinous (n=9) Endometrioid (n=2) Clear cell (n=10) Objective response 1 (n, %) 22 (58%) 4 (44%) 0 (0%) 0 (0%) CR 2 (5%) 0 (0%) 0 (0%) 0 (0%) PR 20 (53%) 4 (44%) 0 (0%) 0 (0%) SD 14 (37%) 4 (44%) 0 (0%) 0 (0%) PD 2 (5%) 1 (11%) 2 (100%) 10 (100%) 1 P =0.0006.