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.

Background: Next-generation sequencing has revealed TP53 alterations in localized prostate cancer (PCa), suggesting growing clinical potential for p53 immunohistochemistry (IHC). Prior research supports the use of IHC for the detection of p53 overexpression to predict the presence of TP53 alterations known to be associated with adverse outcomes. However, to reach a consensus definition of p53 overexpression in PCa, further insights are needed. This study aimed to compare two fundamental approaches of evaluating p53 expression across a variety of specimens regarding PCa progression. Methods: This study included 84 patients (75% self-identified as African American) diagnosed with PCa between 1996 and 2021 at the DC VA Medical Center. Representative sections of core biopsies, radical prostatectomies, transurethral prostate resections, and metastatic deposits were examined. p53 nuclear expression was scored according to the highest intensity observed (0, 1+, 2+, 3+) and the percentage (0%, 5%) of tumor cells expressing any level of intensity in the aggregate tumor area. All slides were reviewed by two independent pathologists. Pertinent clinical data were collected. Results: A total of 34 patients (40%) exhibited p53 nuclear expression, of which 18 (21%) showed the maximum (3+) intensity. The presence of maximum intensity, regardless of percentage, was found to be associated with Grade Group (p < 0.001), higher PSA at biopsy (p < 0.001), BCR (p < 0.001) and metastasis (p < 0.001). Importantly, maximum p53 intensity was identified only in patients who developed metastatic disease. Conclusions: Maximum (3+) p53 nuclear intensity of any percentage is highly associated with disease progression in PCa, suggesting that optimal determination of p53 overexpression should incorporate intensity.

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.