Combining Serum Prostate Health Index With Urinary PCA3 and TMPRSS2:ERG RNA Testing Improves Detection of Clinically Significant Prostate Cancer

Purpose: We sought to determine whether combining prostate health index (Phi) with urinary prostate cancer antigen 3 (PCA3) and TMPRSS2:ERG (T2:ERG) could improve selection of men for prostate biopsy. These biomarkers have been validated in prostate cancer (PCa) detection separately, but their combination has not previously been developed. Materials and Methods: Prebiopsy blood and post–digital rectal examination urine specimens were assayed to predict subsequent biopsy outcomes from training and validation cohorts (1073 participants across 11 academic centers). Clinical algorithms for combining Phi and PCA3-T2:ERG to predict Grade Group ≥ 2 (GG ≥ 2) PCa were formulated using the training cohort (N = 512). Prediction rules and hypotheses were locked before validation using biopsy-naïve men from the NCI Early Detection Research Network urinary PCA3 trial (N = 561). Rules were compared in weighted sum of specificity and sensitivity with weights specified a priori, and P values were obtained through bootstrap in the validation study. Results: Primary validation analysis showed that Phi combined with urinary PCA3 outperformed Phi alone ( P = .002). Furthermore, serum Phi combined with urinary PCA3-T2:ERG outperformed urinary PCA3-T2:ERG in each of the 3 algorithms reflecting different potential clinical workflows: (1) serum Phi and urine PCA3-T2:ERG tested simultaneously, either exceeding its own threshold ( P = .04); (2) urine PCA3-T2:ERG first and those in the grey zone resolved by subsequent serum Phi ( P = .03); and (3) serum Phi first and those in the grey zone resolved by subsequent urine PCA3-T2:ERG ( P = .002). Conclusions: Combining serum Phi with urinary PCA3 RNA alone or together with urinary T2:ERG RNA, simultaneously or sequentially, improves selection of men for initial prostate biopsy and represents an avenue to improve early detection of aggressive PCa.