Therapeutic Challenges in Metastatic Castration-Resistant Prostate Cancer: A Case Study and Review of Prostate-Specific Membrane Antigen-Targeted Therapy Failures in Highly Prostate-Specific Membrane Antigen-Avid Disease

Prostate cancer (PCa) is a leading cause of cancer-related deaths globally, with metastatic castration-resistant prostate cancer (mCRPC) posing significant treatment challenges. This case report discusses a 65-year-old male with mCRPC who initially responded to hormonal therapy but later showed disease progression despite additional chemotherapy. He subsequently received ¹⁷⁷Lu-PSMA and ²²⁵Ac-PSMA therapies, both of which failed to halt disease progression despite having an intense PSMA avid metastatic disease. This case highlights the complexity of treatment responses in mCRPC, particularly when intense PSMA avidity does not correlate with therapeutic effectiveness. It suggests that underlying genomic alterations may contribute to resistance, highlighting the potential role of circulating tumor DNA (ctDNA) in identifying biomarkers that predict treatment outcomes. Further research is necessary to explore these genomics, along with other potential resistance mechanisms, to enhance personalized treatment strategies for patients with mCRPC.