A recent case study indicates that trastuzumab deruxtecan (T-DXd) could offer a new treatment avenue for men with treatment-emergent neuroendocrine prostate cancer (t-NEPC) expressing human epidermal growth factor receptor 2 (HER2). Researchers from the Washington DC Veterans Affairs Medical Center and The George Washington University School of Medicine reported the findings in the Annals of Internal Medicine, highlighting the potential of HER2-targeted therapy in this aggressive prostate cancer subtype.
Case Details
The study focused on a 60-year-old man diagnosed with high-volume metastatic prostate cancer in March 2019. After multiple unsuccessful treatments, the patient showed a notable response to T-DXd. According to Senior Author Maneesh Jain, MD, HER2 expression varies in prostate cancer, with higher expression correlating with advanced grade and stage. However, data on HER2 expression in t-NEPC has been lacking.
The patient initially received androgen-deprivation therapy and docetaxel, but his prostate-specific antigen (PSA) levels continued to rise, and imaging revealed disease progression. Over the next four years, he underwent six additional lines of therapy, each providing only temporary relief before rapid progression recurred. Eventually, he developed symptomatic brain metastases, necessitating a craniotomy followed by radiotherapy. Histopathology confirmed the transformation to t-NEPC, a particularly challenging form of metastatic castration-resistant prostate cancer (mCRPC).
Molecular testing revealed a low tumor mutational burden, but immunohistochemistry (IHC) for HER2 showed strong expression in both the primary prostate tumor and the brain metastasis. The researchers used a modified prostate cancer-specific scoring system developed by Jain and colleagues to assess HER2 expression.
Treatment and Outcome
In February 2024, the patient began off-label treatment with T-DXd. After four cycles, a 57% reduction in tumor volume was observed across all sites, including the brain. Computed tomography also showed stable bone metastases. Furthermore, his blood counts and lactate dehydrogenase levels normalized, and his overall performance status improved significantly.
As of October 2024, the patient's visceral and brain metastases remained stable, and his clinical condition was good, despite an initial recommendation for palliative hospice care months earlier. Although scans in July 2024 showed slight progression in two bone metastases, the overall response to T-DXd was considered significant.
Implications and Future Directions
Dr. Jain emphasized that HER2 testing via IHC should be considered for all patients with mCRPC to identify those who may benefit from T-DXd, especially in light of the FDA’s tumor-agnostic approval for HER2-positive solid tumors. He also noted that IHC is the most effective method for detecting HER2 expression in this context, as HER2 mutations and amplifications are rare in prostate cancer and are not typically identified through next-generation sequencing.
However, Jain cautioned that the current patient, who showed strong HER2 expression on the modified prostate cancer-specific scoring system, would have been scored as low based on current guidelines relying on breast cancer data. This discrepancy could lead to the denial of beneficial treatment with T-DXd.
The Washington D.C. Veterans Affairs Medical Center is set to be the primary site for the upcoming multicenter CaRPET (Castrate Resistant Prostate Cancer Enhertu Therapy) trial. This phase II clinical trial will evaluate the response to anti-HER2 ADCs in mCRPC. The trial aims to assess the response to T-DXd at various levels of HER2 immunoexpression using the researchers' scoring system to establish the expression threshold needed for treatment response in prostate cancer. The trial will involve eight sites across the U.S., including seven Veterans Affairs sites and George Washington University.
