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5ARI’s in Prevention and Management of Prostate Cancer – Current Status and Perspectives Fritz H. Schröder, MD, PhD Professor of Urology Department of Urology University Medical Center Rotterdam, The Netherlands


Definitions • Primary prevention: population based prevention • Secondary prevention: prevention in defined risk groups (screening) • Tertiary prevention: prevention of progression of minimal disease


To be covered • Why consider prevention of prostate cancer (PC)? • 5-alpha reductase inhibition (5ARI) • 5ARI’s and PC – clinically useful? • Conclusions


Prostate Cancer incidence and mortality - crude rates / 100,000 men (Globocan 2000, 1998 data) 150 100

Incidence Mortality

50 0 Northern Northern East Asia South America Europe East Asia


Reasons for geographic differences in incidence and mortality • Race - unlikely - increase in migrants • Genetic - little evidence • Lifestyle - diet - most likely • Hormones - possible


To be covered • Why consider prevention of prostate cancer (PC)? • 5-alpha reductase inhibition (5ARI) • 5ARI’s and PC – clinically useful? • Conclusions


Endocrine effects - Finasteride (F) Dutasteride (D) - ARIA studies • F inhibits 5αR type II, D inhibits type I and type II • Dosages: F 5 mg/day, D 0.5 mg/day • Reduction of plasma DHT after 2 weeks: F 76%, D 90% • Tissue concentrations DHT (BPH), • 24 weeks: F 70%, D>97% reduction (ARIA 2001)


Dutasteride phase II BPH studies (n-=2158 placebo, 2167 Dutasteride ). Incidence of prostate cancer after 27 months (54 in placebo, 27 in Dutasteride groups) Andriole et al 2004


PCPT - Goal and Methods (Thompson 2003) • Does use of Finasteride (F) reduce the risk of biopsy detectable prostate cancer over a 7 year period? • A randomised, placebo-controlled trial of 18.882 men age 55 or older • Entry criteria: normal DRE, PSA <= 3.0 ng/mL • Follow-up: yearly or with indication, biosy with abnormal DRE or PSA >= 4.0 ng/mL or after 7 years • Endpoint: prevalence of PC over a 7 year period


PCPT - results • 18.882 men were randomised • Included in analysis: Placebo 4.692, F 4.368 • PC detected by biopsy: Placebo 1.147 (24.5%), F 803 (18.4%). Reduction in F group 24.8% • Gleason scores >= 7: Placebo: 22.2% of 1.068 PC, 5.1% of all F: 37.0% of 757 PC, 6.4% of all (p<0.001)


Results ( Andriole et al 2009)

• REDUCE shows a 23% reduction of positive biopsies in the Dutasteride arm (P=0.0001) • 93.6% of cancers found at protocol biopsy • No significant increase of Gleason 7 10 cancers with Dutasteride • Significant increase of Gleason 8 – 10 PC after 4 years, disadvantage?


FDA turns down Dutasteride in December 2010 • Arguments FDA: 1. Biopsies at 2 and 4 years are not done “for cause”, not in line with clinical practice. 2. An increase of Gleason 8-10 PC is seen in for cause and end of study biopsies 3. Decreased detection of Gleason ≤6 cancers is not worthwhile, 80% are insignificant


Trends in changes in PSA levels over time for groups defined by their final prostate cancer status. (Marberger el al 2012) â&#x20AC;˘

URCE/DUT/0024/12


Proportions of PC missed in D versus P arms because of no rise in PSA (Marberger et al 2012) • Totals: D arm 210/1149 (18.3%) P arm 104/356 (29.2%) • Missed per Gleason score in D arm: Gleason 6 156/1149 (13.6)

Gleason 7

47/1149 (4.1%)

Gleason ≥8

7/1149 (0.6%)

Clinically significant PC 68/1149 (5.9%) in the P arm: 30/356 (8.4%) URCE/DUT/0024/12


55–59

60–64

100 80 60 40 20 0

0 20 40 60 80 100 0 20 40 60 80 100

Gleason score 5

100 80 60 40 20 0

0 20 40 60 80 100

Gleason score 6

100 80 60 40 20 0

0 20 40 60 80 100

Gleason score 7

100 80 60 40 20 Years 0 0

5

10 15 20 0

5

10 15 20 0

5

10 15 20 0

Gleason score 8–10

0 20 40 60 80 100 5

10 15 20

Age at diagnosis, y

Deceased, %

Alive, %

70–74

Gleason score 2– 4

100 80 60 40 20 0

following diagnosis

65–69

20-year outcomes following conservative management of PCa Survival Non-prostate cancer mortality Prostate cancer mortality Albertsen et al. JAMA 2005; 293: 2095–101


What has REDUCE shown us? • The extent of the PSA decrease in the first 6 months does not predict the diagnosis of prostate cancer • Patients receiving dutasteride should have a new PSA baseline established after 6 months of treatment with dutasteride • Any confirmed increase from lowest PSA level while on dutasteride may signal the presence of prostate cancer • Treatment with dutasteride does not interfere with the use of PSA in the diagnosis of prostate cancer after a new baseline has been established URCE/DUT/0024/12


To be covered • Why consider prevention of prostate cancer (PC)? • 5-alpha reductase inhibition (5ARI) • 5ARI’s and PC - clinically useful? • Conclusions


REDEEM: Inclusion and endpoint • 502 men with clinical stage T1c‒T2a prostate cancer, 155 on placebo, 147 on Dutasteride • Age ≥48 and ≤82 years • ≥10 core biopsy for entry (local biopsy) • <4 cores positive, <50% of any one core positive, Gleason score 6≤ • Serum PSA ≤11 ng/mL • Main end point: time to progression


REDEEM Study Design Multicenter, randomized, placebo-controlled trial

1.5 year biopsy

3 year biopsy

Placebo Avodart (dutasteride) 0.5mg/day

4 month f/u

Screening

Randomization


Time to Prostate Cancer Progression (ITT)

Relative Risk Reduction

44.3% (13.1%, 64.3%)

38.9% (12.4%, 57.4%) REDEEM: DS Figure 7.1


Finasteride in tertiary prevention (Andriole et al 1995) • • • •

Randomised, placebo-controlled study 110 men with rising PSA after RP Baseline levels of 0.6 - 10.0 ng/mL Treatment: 10 mg Finasteride/day or placebo • Double blind for 12 months • Endpoint: change in PSA kinetics


PSA progression after radical prostatectomy - Finasteride vs placebo (Andriole et al 1995)


ARTS Study Design (Schrรถder et al 2013) Multicenter, randomized, double-blind, placebo-controlled trial (n=276)

-3 0 weeks Baseline Negative bone scan

PSA nadir

Treatment period 2 years Follow-up

Screening

Randomization

End of treatment

Placebo Avodart (dutasteride) 0.5mg/day

3

6

9

12

15

Months

18

21

24 +4 months


Inclusion and end points ARTS study • 294 men with rising PSA after potentially curative management • PSA DT: 3 institutional PSA tests at least 4 weeks apart • PSA DT larger than 3 months, smaller than 2 years • End points: Time to PSA doubling and clinical progression


Response and progression • Response: PSA decrease or increase to ≤ 15% from baseline in 24 months • Progression – PSADT ≤ 3 months – PSA rise to > 20 or > 10 ng/ml after RT or RP – clinical PD (also to M+)


Baseline characteristics


Study population, course of trial • 294 randomized subjects (ITT) – 147 in Placebo, 147 in Dutasteride

– 64 centers, 9 countries – 233 (79%) radical prostatectomy, 61 (21%) primary radiotherapy • 52 salvage radiotherapy (following RP)

• 187 subjects (64%) completed 24-month treatment – 52% Pbo vs 76% Dut

• Main reasons for premature withdrawal: – Disease progression: 22% Pbo vs 11% Dut – Investigator decision: 12% Pbo vs 3% Dut

– Subject decision: 7% Pbo vs 3% Dut


Primary endpoint: time to PSA doubling


Primary endpoint: time to PSA doubling (Kaplan Meier Plot)


Secondary Endpoint: Time to Disease Progression • Days since treatment to the earliest of the following events: – PSADT <= 3 months – PSA value is at least 50% more than baseline PSA, and (>10ng/ml for RP or >20ng/ml for PRT subjects) – Surgical intervention or non-surgical intervention for prostate cancer – Bone scan detects metastases – Prostate biopsy is positive • Risk reduction: 59% (CI: 33%-75%) • Incidence: 49/144 (34%) Pbo vs 25/146 (17%) Dutasteride


Kaplan-Meier Plot of Time to Disease Progression


Reasons for disease progression


Secondary Endpoint: Time to PSA Rise • Days since treatment start when ALL PSA results on and after this day is more than 15% of baseline PSA

• Risk reduction: 72% (CI: 62%-79%) Log-rank: p<0.001 • Incidence: 88% Pbo vs 49% Dut


Conclusions • PSA doubling is delayed significantly by dutasteride treatment compared to placebo, irrespective of the previous radical therapy. • Disease progression and PSA rise are significantly delayed by dutasteride treatment compared to placebo. • No safety issues identified – Adverse events comparable in two treatments – Low sexual AE (expected in this population with prior radical therapy) – Cardiovascular AEs of special interest are comparable in two treatments


Summary Prevention • The REDUCE study shows a 23% reduction of PC under Dutasteride but an unexplained rise of Gleason 8-10 PC which can be identified • REDEEM and ARTS studies do not show an increase of Gleason 8-10 PC and reveal an effect of Dutasteride on PC progression • The data support use of 5ARI’s to prevent progression of PC in tertiary prevention • Studies with longer follow-up are desirable • 5ARIs may still be useful in secondary prevention


5ARI's prevention and management of prostate cancer: current status and perspetives