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-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

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

5. Numbers needed to invite and diagnose are still high
ERSPC Göteborg 2008
(n = ) (n = 19904)
f/u (yrs)
NNI
NND
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 %* 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)
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%) %
(39.1%) %
> 3 (12.5%) %
(only trial to incorporate 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. 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“

14. 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)
= %
39,000 – 55,000 men will be needed to show superiority in specificity
and non-inferiority of sensitivity for Arm B (delayed screening)

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

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

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

18. Enrolment from February 2014 – October 2016 (33 ms)
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. PSA risk groups – Arm A (n = 11215)
First results
after 2nd year of enrolment (02/ /2016) – n = 22516
PSA risk groups – Arm A (n = 11215)
low risk 88.85%
intermediate %
high risk %
unpublished data, 27/10/2016

22. Confirmation of PSA > 3 ng/ml
N = 173 > 3 ng/ml
N = nd 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
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

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