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$\textit{Background:}$ Early detection and treatment of asymptomatic men with advanced and high-risk prostate cancer (PCa) may improve survival rates. $\textit{Objective:}$ To determine outcomes for men diagnosed with advanced PCa following prostate-specific antigen (PSA) testing who were excluded from the ProtecT randomised trial. $\textit{Design, setting, and participants:}$ Mortality was compared for 492 men followed up for a median of 7.4 yr to a contemporaneous cohort of men from the UK Anglia Cancer Network (ACN) and with a matched subset from the ACN. $\textit{Outcome measurements and statistical analysis:}$ PCa-specific and all-cause mortality were compared using Kaplan-Meier analysis and Cox’s proportional hazards regression. $\textit{Results and limitations:}$ Of the 492 men excluded from the ProtecT cohort, 37 (8%) had metastases (N1, M0 = 5, M1 = 32) and 305 had locally advanced disease (62%). The median PSA was 17 $\mu$g/l. Treatments included radical prostatectomy (RP; $n$ = 54; 11%), radiotherapy (RT; $n$ = 245; 50%), androgen deprivation therapy (ADT; $n$ = 122; 25%), other treatments ($n$ = 11; 2%), and unknown ($n$ = 60; 12%). There were 49 PCa-specific deaths (10%), of whom 14 men had received radical treatment (5%); and 129 all-cause deaths (26%). In matched ProtecT and ACN cohorts, 37 (9%) and 64 (16%), respectively, died of PCa, while 89 (22%) and 103 (26%) died of all causes. ProtecT men had a 45% lower risk of death from PCa compared to matched cases (hazard ratio 0.55, 95% confidence interval 0.38–0.83; $p$ = 0.0037), but mortality was similar in those treated radically. The non-randomised design is a limitation. $\textit{Conclusions:}$ Men with PSA-detected advanced PCa excluded from ProtecT and treated radically had low rates of PCa death at 7.4-yr follow-up. Among men who underwent nonradical treatment, the ProtecT group had a lower rate of PCa death. Early detection through PSA testing, leadtime bias, and group heterogeneity are possible factors in this finding. $\textit{Patient summary:}$ Prostate cancer that has spread outside the prostate gland without causing symptoms can be detected via prostate-specific antigen testing and treated, leading to low rates of death from this disease.

BACKGROUND: Identification of men harbouring insignificant prostate cancer (PC) is important in selecting patients for active surveillance. Tools have been developed in PSA-screened populations to identify such men based on clinical and biopsy parameters. METHODS: Prospectively collected case series of 848 patients was treated with radical prostatectomy between July 2007 and October 2011 at an English tertiary care centre. Tumour volume was assessed by pathological examination. For each tool, receiver operator characteristics were calculated for predicting insignificant disease by three different criteria and the area under each curve compared. Comparison of accuracy in screened and unscreened populations was performed. RESULTS: Of 848 patients, 415 had Gleason 3+3 disease on biopsy. Of these, 32.0% had extra-prostatic extension and 50.2% were upgraded. One had positive lymph nodes. Two hundred and six (24% of cohort) were D'Amico low risk. Of these, 143 had more than two biopsy cores involved. None of the tools evaluated has adequate discriminative power in predicting insignificant tumour burden. Accuracy is low in PSA-screened and -unscreened populations. CONCLUSIONS: In our unscreened population, tools designed to identify insignificant PC are inaccurate. Detection of a wider size range of prostate tumours in the unscreened may contribute to relative inaccuracy.