Blood-based Genomic Alteration Signature for Predicting Progression-free Survival in De Novo Metastatic Hormone-Sensitive Prostate Cancer: A Real-World Study

Metastatic hormone-sensitive prostate cancer (mHSPC) often progresses to castration-resistant prostate cancer despite current therapies, necessitating the use of reliable biomarkers. This study aimed to develop a novel model for predicting progression-free survival (PFS) using circulating tumor DNA (ctDNA) sequencing. We analyzed 127 patients with mHSPC and compared ctDNA mutations with those in matched primary tumor tissues. A four-gene signature (TRPC: TP53, RB1, PTEN, and CDK12) was identified, forming the basis of the blood-based TRPC (b.TRPC) model. The b.TRPC model demonstrated high specificity and sensitivity in predicting PFS, outperforming ctDNA markers. Internal and external validation confirmed that b.TRPC is an independent prognostic factor with superior predictive performance for 0.5-, 1-, and 2-year PFS. The model also showed significant clinical relevance, with bTRPC-positive patients exhibiting shorter survival times under ADT and doublet therapy, although this disparity diminished with triplet therapy. These findings highlight the potential of ctDNA-based gene mutation analysis to guide personalized treatment strategies for mHSPC, offering a non-invasive alternative to tissue-based analyses and improving prognostic accuracy.