Human epidermal growth factor receptor 2 (HER2) is a molecular target of interest in prostate cancer due to its association with poor prognosis and its potential role in androgen receptor signaling. However, earlier clinical trials investigating HER2-targeted therapies, including antibodies and small molecules, have shown limited efficacy. More recent studies using the HER2 antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) suggest potential therapeutic benefit in prostate cancer. However, its effective utilization requires a HER2 IHC scoring system that accurately represents HER2 expression patterns unique to prostate cancer, which is currently not established. We have developed a modified HER2 IHC scoring system that, unlike the breast and gastrointestinal tumor HER2 IHC grading scales, considers the distinct spatiotemporal expression of HER2 in prostate tumors. In this commentary, we discussed two patients with metastatic prostate cancer who were classified as HER2 IHC 3+ using our prostate cancer-specific scoring system and who demonstrated meaningful clinical responses and responded to treatment with T-DXd. We further review the historical evolution of HER2 testing in prostate cancer, as well as factors that may have contributed to the failure of previous clinical trials targeting HER2 in prostate tumors. Our aim is to highlight the need for developing a standardized HER2 IHC grading model in prostate cancer, which could improve the predictive value of HER2 IHC expression, enabling a more accurate identification of patients likely to benefit from HER2-targeted ADCs.