Prognostic value of Ki67 and PSA-immunostaining in <i>de novo</i> metastatic hormone-sensitive prostate cancer

INTRODUCTION: Prostate cancer comprises biologically distinct subtypes. Ki67 reflects tumour proliferation, while prostate-specific antigen immunostaining (PSA-IHC) indicates differentiation, with low PSA-IHC suggesting dedifferentiation. The prognostic role of these markers in de novo metastatic hormone-sensitive prostate cancer (mHSPC) remains unclear. AIM: To evaluate the prognostic value of Ki67 and PSA-IHC, individually and combined, in de novo mHSPC, and explore their relevance across treatment modalities. METHODS: We retrospectively analysed patients diagnosed with de novo mHSPC (2015-2020) who ultimately died from prostate cancer. Clinical data included age, ISUP grade, baseline and 7-month PSA, metastatic sites, and first-line treatment. Ki67 (MIB-1) and PSA-IHC were quantified as the percentage of positive nuclei and cytoplasmic staining, respectively. The 75th percentile defined high vs low expression. Endpoints were biochemical (bPFS), radiological (rPFS), castration-resistant progression-free survival (CRPC-FS), and overall survival (OS). Exploratory analyses were performed by treatment type: androgen receptor pathway inhibitors (ARPIs) or taxanes. RESULTS: Sixty-seven patients were included (median age 77 years). Most had high-grade tumours (ISUP ≥3, 83.6%). High Ki67 (>P75) correlated with shorter OS (10 vs 21 months, p=0.013). PSA-IHC >P75 predicted longer bPFS (13 vs 9 months, p=0.027). Combined stratification identified distinct prognostic groups (p=0.034): PSA-IHC low/Ki67 high defined a high-risk phenotype with poor outcomes, particularly among taxane-treated patients (p=0.006). CONCLUSIONS: Combined Ki67 and PSA-IHC assessment refines risk stratification in de novo mHSPC, identifying a high-risk PSA-IHC low/Ki67 high subgroup with markedly worse prognosis. These findings warrant prospective validation.