Early emergence of neuroendocrine prostate cancer during triplet therapy for high-volume metastatic castration-sensitive prostate cancer

This case highlights the potential for early emergence of neuroendocrine differentiation in patients with metastatic castration-sensitive prostate cancer undergoing triplet therapy with androgen deprivation therapy, darolutamide, and docetaxel, even with marked prostate-specific antigen (PSA) suppression. In this patient, although some lesions initially responded to treatment, new metastases and radiological progression were observed early after triplet therapy was initiated. These atypical progression patterns raised the suspicion of neuroendocrine prostate cancer (NEPC), confirmed by percutaneous biopsy of an enlarged right external iliac lymph node. This enabled the timely modification of the treatment strategy. Furthermore, retrospective immunohistochemical reevaluation of the diagnostic prostate biopsy specimen obtained at the referring hospital using only four cores revealed focal neuroendocrine differentiation within the poorly differentiated Gleason pattern 5 areas, suggesting that de novo NEPC features may have been present at the time of diagnosis. As triplet therapy has become more widespread, the incidence of NEPC may increase. Clinicians should maintain a high level of vigilance for discordant PSA progression and consider early biopsy of metastatic lesions to ensure accurate diagnosis and appropriate therapeutic decision-making.