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

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:

Reduction of „overdiagnosis“ age-adjustment of screening clinical risk calculators (e.g. Rotterdam) (PSA, DRE, TRUS-Volume, Phi) molecular risk calculators (STHLM3) (SNPs, MSMB, MIC1, hK2) 4. MRI-based biopsies

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

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

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

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

Vickers A et al. (MSKCC) BMC 2014

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

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

„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

Trial Design

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

Trial Design 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)

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

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

Enrolment from February 2014 – October 2016 (33 ms)

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

Enrolment from February 2014 – October 2016 (33 ms)

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

PSA risk groups – Arm A (n = 11215) 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

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

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

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

Summary of First Results enrolment in time observed risk groups like expected (PSA > 3 = 1.54%) elevated PSA > 3 ng/ml is confirmed in only 56% biopsy of high risk patients refused is nearly 20% DRE cannot detect early prostate cancer (N = 3761) 15 prostate cancers detected = expected rate of 0.13% > 50% clinically significant unpublished data, 27/10/2016

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