PURPOSE: To test any-cause discontinuation and ISUP GG upgrading rates during Active Surveillance (AS) in patients that underwent previous negative biopsies (PNBs) before prostate cancer (PCa) diagnosis vs. biopsy naive patients. METHODS: Retrospective analysis of 961 AS patients (2008-2020). Three definitions of PNBs were used: (1) PNBs status (biopsy naïve vs. PNBs); (2) number of PNBs (0 vs. 1 vs. ≥ 2); (3) histology at last PNB (no vs. negative vs. HGPIN/ASAP). Kaplan-Meier plots and multivariable Cox models tested any-cause and ISUP GG upgrading discontinuation rates. RESULTS: Overall, 760 (79.1%) vs. 201 (20.9%) patients were biopsy naïve vs. PNBs. Specifically, 760 (79.1%) vs. 138 (14.4%) vs. 63 (6.5%) patients had 0 vs. 1 vs. ≥ 2 PNBs. Last, 760 (79.1%) vs. 134 (13.9%) vs. 67 (7%) patients had no vs. negative PNB vs. HGPIN/ASAP. PNBs were not associated with any-cause discontinuation rates. Conversely, PNBs were associated with lower rates of ISUP GG upgrading: (1) PNBs vs. biopsy naïve (HR:0.6, p = 0.04); (2) 1 vs. 0 PNBs (HR:0.6, p = 0.1) and 2 vs. 0 PNBs, (HR:0.5, p = 0.1); (3) negative PNB vs. biopsy naïve (HR:0.7, p = 0.3) and HGPIN/ASAP vs. biopsy naïve (HR:0.4, p = 0.04). However, last PNB ≤ 18 months (HR:0.4, p = 0.02), but not last PNB > 18 months (HR:0.8, p = 0.5) were associated with lower rates of ISUP GG upgrading. CONCLUSION: PNBs status is associated with lower rates of ISUP GG upgrading during AS for PCa. The number of PNBs and time from last PNB to PCa diagnosis (≤ 18 months) appear also to be critical for patient selection.

Cancer Prognostics and Health Outcomes Unit Division of Urology University of Montréal Health Center Montréal QC Canada

Department of Oncology and Haemato Oncology Università Degli Studi Di Milano 20122 Milan Italy

Department of Pathology IEO European Institute of Oncology IRCCS Via Ripamonti 435 Milan Italy

Department of Radiotherapy IEO European Institute of Oncology IRCCS Via Ripamonti 435 Milan Italy

Department of Urology 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Urology Ehime University Graduate School of Medicine Ehime Japan

Department of Urology IEO European Institute of Oncology IRCCS Via Giuseppe Ripamonti 435 Milan Italy

Department of Urology Medical University of Vienna Vienna Austria

Department of Urology The Jikei University School of Medicine Tokyo Japan

Department of Urology University Medical Center Hamburg Eppendorf Hamburg Germany

Department of Urology University of Texas Southwestern Medical Center Dallas TX USA

Department of Urology Weill Cornell Medical College New York NY USA

Division of Radiology IEO European Institute of Oncology IRCCS Via Ripamonti 435 Milan Italy

European Association of Urology Research Foundation Arnhem Netherlands

Institute for Urology and Reproductive Health Sechenov University Moscow Russia

Karl Landsteiner Institute of Urology and Andrology Vienna Austria

Precision Imaging and Research Unit Department of Medical Imaging and Radiation Sciences IEO European Institute of Oncology IRCCS 20141 Milan Italy

Research Division of Urology Department of Special Surgery The University of Jordan Amman Jordan

Università degli Studi di Milano Milan Italy

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