Long-term outcomes of cribriform-positive and cribriform-negative prostate cancer treated with radical prostatectomy in the ProtecT trial

Objectives: To retrospectively analyse the results of the Prostate Testing for Cancer and Treatment (ProtecT; ClinicalTrials.gov identifier: NCT02044172) trial to establish the association between cribriform-positive and -negative prostate cancer (PCa) and the 15-year risk of metastasis or death from PCa in patients who underwent radical prostatectomy (RP). Patients and Methods: Between 1999 and 2009, the ProtecT phase 3 clinical trial enrolled 1643 men with clinically localised PCa who were randomised to receive active monitoring, RP, or radiotherapy. In this secondary analysis of the trial, a centralised histopathological review was conducted on available RP pathology slides to classify patients as cribriform-positive if they had invasive cribriform carcinoma and/or intraductal carcinoma. The primary outcome was a composite of progression to metastatic disease or death from PCa. Exposures included age, prostate-specific antigen density, RP Grade Group (GG), pathological T stage (pT), and cribriform status. Multivariable Cox proportional hazards regression models assessed 15-year risk. Cumulative incidence curves were compared using the Gray test. Results: Of 480 men with RP specimens reviewed, 143 (30%) had cribriform-positive disease and 337 (70%) had cribriform-negative disease. All 21 metastatic or lethal events occurred exclusively in the cribriform-positive group (15-year cumulative incidence 14%). Within the cribriform-positive cohort, risk was concentrated in patients with pT3b stage and/or GG ≥3 (15-year cumulative incidence 27%). In multivariable analysis of cribriform-positive patients, pT3b stage (hazard ratio [HR] 8.19, 95% confidence interval [CI] 2.39–28.10; P < 0.001) and GG 3 disease (HR 5.12, 95% CI 1.59–16.40; P = 0.006) were independent predictors of adverse outcomes. Conversely, cribriform-positive patients with GG 2 and ≤pT3a had a 15-year event rate of only 3%. Conclusion: In the ProtecT trial, the 15-year risk of metastasis or death after RP was a binary outcome defined by cribriform status. The concentration of risk in men with cribriform-positive, high-grade and/or pT3b tumours identifies a target population for adjuvant therapy trials, while supporting management de-escalation for most RP patients.