Case report of response of HER2-expressing prostate cancer to trastuzumab deruxtecan

Despite advances in treatment, the management of metastatic castration-resistant prostate cancer (mCRPC) remains challenging, with treatment-emergent neuroendocrine prostate cancer (t-NEPC) being a particularly aggressive subtype. HER2 is overexpressed in a subset of prostate cancer, although no data exist about HER2 expression in t-NEPC. A patient of Georgetown University (Washington DC) was diagnosed in March 2019 with high-volume metastatic prostate cancer (grade group 5, Gleason score 4 + 5 = 9). He received androgen-deprivation therapy and docetaxel. However, his PSA level trended up, and imaging showed progression despite achieving castrate testosterone levels. During the next 4 years, he was treated consecutively with 6 additional lines of therapy. All treatments elicited a transient response followed by rapid progression. He subsequently developed brain metastases and had craniotomy with tumor resection followed by radiotherapy. Histopathology was consistent with transformation to t-NEPC. IHC for HER2 showed strong (IHC3+) expression in both the primary prostate tumor and the brain metastases. In February 2024, he started off-label treatment with trastuzumab deruxtecan (T-DXd). After 4 cycles, a 57% overall reduction in tumor volume across sites was seen, including in the brain. As of August 2024 he has been on T-DXd for 6 months, and clinically he is doing well. The authors conclude that this case highlights that T-DXd seems to have antitumor activity in HER2-expressing mCRPC, including aggressive subtypes like t-NEPC.