Lineage-specific circulating tumor DNA markers predict rapid progression in metastatic hormone-sensitive prostate cancer

Background Fast progression from metastatic hormone-sensitive prostate cancer (mHSPC) to metastatic castration-resistant prostate cancer (mCRPC) is associated with poor prognosis. We evaluated whether baseline plasma circulating tumor DNA-derived prostate-specific antigen and prostate-specific membrane antigen were associated with progression to metastatic castration-resistant prostate cancer and improved risk stratification beyond conventional serum biomarkers in mHSPC. Methods We prospectively analyzed 35 patients with mHSPC who underwent baseline ctDNA analysis using droplet digital PCR. ctDNA was extracted from plasma and quantified using droplet digital PCR targeting PSA and PSMA. The primary endpoint was progression to mCRPC. Survival analyses were performed using Kaplan–Meier methods, Cox regression, and restricted mean survival time (RMST). Results During a median follow-up of 29 months, 24 patients progressed to mCRPC. Elevated ctDNA-PSA and ctDNA-PSMA were significantly associated with shorter time to progression (both P < 0.001). In Cox analyses, ctDNA-PSA (HR 1.82, P = 0.002) and ctDNA-PSMA (HR 1.59, P = 0.009) were associated with progression risk. RMST analysis at 24 months demonstrated greater reductions in progression-free time for ctDNA-PSA (−10.8 months) and ctDNA-PSMA (−8.7 months) compared with serum PSA (−7.3 months). Conclusions Baseline ctDNA-PSA and PSMA provide complementary prognostic information for progression from mHSPC to mCRPC and may improve risk stratification in patients with mHSPC.