Study Centers: Prof. P. Albers, PD Dr. C. Arsov (Düsseldorf)

1. Risk-adapted prostate cancer (PCa) early detection study based on a “baseline” PSA value in young men – a prospective multicenter randomized trial (PROBASE)

2. Steering Committee Study Centers: Prof. P. Albers, PD Dr. C. Arsov (Düsseldorf) Prof. N. Becker (DKFZ, Heidelberg) Prof. J. Gschwend, PD Dr. K. Herkommer (TU München) Prof. M. Hohenfellner, PD Dr. B. Hadaschik (Heidelberg) Prof. M. Kuczyk, PD Dr. F. Imkamp (Hannover) Study Coordinator: Prof. R. Siener (Bonn) Reference Radiologist: Prof. G. Antoch (Düsseldorf) Reference Pathologist: Prof. G. Kristiansen (Bonn) International Advisory Board: Prof. F. Schröder (Rotterdam, NL) Prof. H. Lilja (MSKCC, New York, USA) Prof. A. Vickers (MSKCC, New York, USA) Prof. F. Hamdy (Oxford, UK) Prof. A. Semjonow (Münster, D) Sponsor:

3. Reduction of „overdiagnosis“ • age-adjustmentofscreening • clinicalriskcalculators (e.g. Rotterdam) • (PSA, DRE, TRUS-Volume, Phi) • molecularriskcalculators (STHLM3) • (SNPs, MSMB, MIC1, hK2) • 4. MRI-basedbiopsies

4. Rationale for age-adjusted PSA screening „The baseline PSA“

5. Numbers needed to invite and diagnose are still high ERSPC 2009 2011 2013 Göteborg 2008 (n = 162243) (n = 19904) f/u (yrs) 9 11 13 14 NNI 1410 979 781 293 NND 48 35 27 12 Schröder F et al. NEJM 2009 Schröder F et al. Lancet Oncology 2014 Hugosson J et al. Lancet Oncology 2010

6. Comparison of Screening Programs mortality reduction method PAP smear (cervical carcinoma) 64% coniotomy colonoscopy (distal CRC) 50% endoscopy PSA 27%* RP / RT / AS stool test (CRC) 23% endoscopy mammography (breast cancer) 20% (part.) mastect. *Schröder F et al. Lancet Oncology 2014 after clearance for non-compliance

7. Reduction in PCA mortality is age-specific: Göteborg age group PCA-deaths PCA-deaths Δ (yrs) screening (n) control (n) (n) 50-54 5 8 3 55-59 12 35 23 60-64 27 35 8 N = 19904 2-yearly screening, 2008 last screening round = youngest patient = 64 yrs Median f/u after diagnosis of PCA: screening group 6.7 yrs, control 4.3 yrs Hugosson J et al. Lancet Ondology 2010

8. Vickers A et al. (MSKCC) BMC 2014

9. Unnecessary Diagnosis of PCA Definition: PCA is diagnosed by screening but the patient would not have died from prostate cancer 25 yrs later Δ 17% 26% 25% Vickers A et al. (MSKCC) BMC 2014

10. Göteborg: age-dependent incidence of PCA PCA risk at 70 yrs dependent on baseline PSA 1st round of PSA testing risk of developing PCA during f/u < 1 (48.4%) 2.6% 1-2.99 (39.1%) 17.6% > 3 (12.5%) 45.5% (only trial to incorporate 50-55 yrs old men) Godtman RA et al. J Urol 2015

11. „baseline“ PSA und prognosis PSA at 45 yrs risk for metastasis after 25 yrs PSA < 1.1 ng/ml 1.38% PSA > 1.6 ng/ml up to 9.82% 10x higher risk > 1.6 ng/ml Vickers A et al. (MSKCC) BMJ 2013

12. Trial Design

13. Arm A = immediate risk-adapted screening Arm B = delayed risk-adapted screening I° endpoint = rate of metastasis after 15 yrs Trial Design = composite primary endpoint „delayed screening does not detect fewer metastasis but avoids overdetection“

14. incidence of metastases in 45 yrs old men 15 yrs later: 0.21% (Vickers et al., 2012) effect of screening = 30% reduction (Schröder et al., 2012) = 0.13-0.15% 39,000 – 55,000 men will be needed to show superiority in specificity and non-inferiority of sensitivity for Arm B (delayed screening) Trial Design

15. Translational Research Projects Düsseldorf: biomarkers e. g. PITX2 Hannover: SNPs, gene expression Heidelberg: (circulating) miRNA Munich: molecular genetics, family history

16. invited February 10, 2014 PROBASE „first-proband-in“ analysed: February 17, 2014

17. Enrolment from February 2014 – October 2016 (33 ms) 22526 men

18. Enrolment from February 2014 – October 2016 (33 ms) 22526 men 682 men / ms projected future accrual time: = 2020

19. Enrolment from February 2014 – October 2016 (33 ms)

20. First results • after 1st year of enrolment (02/2014-01/2015) • 6,178 probands randomized / 47,234 invited, acceptance rate 13.1% Arsov C et al, EAU 2015

21. First results • after 2nd year of enrolment (02/2014-01/2016) – n = 22516 PSA risk groups – Arm A (n = 11215) low risk 88.85% intermediate 9.60% high risk 1.54% unpublished data, 27/10/2016

22. Confirmation of PSA > 3 ng/ml N = 173 > 3 ng/ml N = 167 2nd PSA available N = 93 confirmed = 55.7% unpublished data, 27/10/2016

23. Digital Rectal Examination (until September 2016) Arm B (no immediate PSA, DRE is offered) N = 3761 exams (out of 10902) N = 42 suspicious (1.1%) N = 23/42 with biopsy (54.8%) N = 1 x Gleason 6 „positive predictive value“ of a positive DRE = 4.3% unpublished data, 09/2016

24. Detected Prostate Cancers (until October 2016) Arm A (N = 11215) N = 93 with confirmed PSA > 3 ng/ml N = 47 with biopsy N = 15 PCA detected „incidence“: 0.13% „clinically relevant“: 11/15 (73%) unpublished data, 27/10/2016

25. Summary of First Results • enrolment in time • observedriskgroups like expected (PSA > 3 = 1.54%) • elevated PSA > 3 ng/ml isconfirmed in only 56% • biopsyof high riskpatientsrefusedisnearly 20% • DRE cannotdetectearlyprostatecancer (N = 3761) • 15 prostatecancersdetected = expected rate of 0.13% • > 50% clinicallysignificant unpublished data, 27/10/2016

26. We should continue risk-adapted screening and please.... not back to the roots !