Clinical Response to Novel Combination of Trastuzumab Deruxtecan and Abiraterone in HER2-Expressing Metastatic Castration-Resistant Prostate Cancer.

Abstract

Human Epidermal Growth Factor Receptor 2 (HER2) is expressed in approximately 60-70% of patients with metastatic castration-resistant prostate cancer (mCRPC) and may contribute to androgen resistance. This case report describes a patient with HER2-expressing mCRPC who progressed on multiple lines of therapy and subsequently had a significant response to combination treatment with the HER2-targeting antibody-drug-conjugate (ADC) trastuzumab deruxtecan (T-DXd) and re-challenge of abiraterone, despite having progressed on this prior. Unlike other HER2-expressing malignancies, HER2 overexpression in prostate cancer (PCa) occurs in the absence of HER2 mutations and amplifications and, as such, is not detected by next-generation sequencing. Therefore, identifying patients with mCRPC who could benefit from T-DXd necessitates HER2 testing by immunohistochemistry (IHC), a practice not routinely performed. As a result, T-DXd remains underutilized in patients with mCRPC, despite a tumor-agnostic approval for patients with advanced HER2-expressing (IHC 3+) solid tumors. This case highlights the potential of combining T-DXd with androgen receptor pathway inhibitors to overcome treatment resistance and underscores the importance of routine HER2 IHC testing in patients with advanced PCa.