Platinum-based chemotherapy in metastatic castration-resistant prostate cancer: a narrative review and dual stratification framework based on HRR genotype and aggressive-variant/neuroendocrine phenotype.

Metastatic prostate cancer is highly heterogeneous, posing challenges for the precise use of platinum-based chemotherapy. This narrative review proposes a dual "genotype-phenotype" stratification framework to support structured clinical decision-making. On the genotype arm, we review the "response gradient" within homologous recombination repair (HRR) gene aberrations, with strong evidence that BRCA2 mutations (especially biallelic loss) are the most robust predictors of platinum sensitivity, whereas the benefit in other genes (e.g., ATM, CDK12) is uncertain. On the phenotype arm, we focus on aggressive-variant/neuroendocrine prostate cancer (AVPC/NEPC), showing that platinum-containing regimens can induce high initial response rates but require optimization to prolong response duration. In addition, we critically synthesize evidence on sequential and combination strategies of platinum with poly(ADP-ribose) polymerase (PARP) inhibitors and taxanes, and discuss toxicity management in older and comorbid patients. Future progress will likely require integration of functional HRD assays, dynamic liquid-biopsy monitoring, and individualized supportive care to determine how short-term platinum responses can be translated into more durable clinical benefit.