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Endocrinology ofEndocrinology ofProstate CancerProstate Cancer
Hormonal Pathways of the Hormonal Pathways of the Male Endocrine SystemMale Endocrine System
TestosteroneTestosterone
OriginOrigin DistributionDistribution
Source:Source: Adapted from Coffey DS. In: Walsh PC, et al, eds.Adapted from Coffey DS. In: Walsh PC, et al, eds.Campbell’s Urology.Campbell’s Urology. 6th ed. 1992:221-266. 6th ed. 1992:221-266.
5% from adrenals5% from adrenals
95%from testes
2% not bound2% not bound
54%bound with
albumin44% bound with
sex-hormone-binding globulin
Circulating AndrogensCirculating Androgens
Daily ProductionDaily Production Relative PotencyRelative Potency
Sources: Adapted from Partin AW, Rodriguez R. In: Walsh PC, et al, eds. Sources: Adapted from Partin AW, Rodriguez R. In: Walsh PC, et al, eds. Campbell’s Campbell’s UrologyUrology. 8th ed. 2002:1237-1296; Labrie F, et al.. 8th ed. 2002:1237-1296; Labrie F, et al. Cancer. Cancer.1993; 71(Suppl 3):1059-1067.1993; 71(Suppl 3):1059-1067.
DHTDHT(1.1%)(1.1%)
TT(20.7%)(20.7%)
ANDAND(5.4%)(5.4%)
DHEADHEA(72.7%)(72.7%)
2.02.0
1.21.2
0.00.0
0.20.2
0.40.4
0.60.6
1.61.6
RatioRatio
DHTDHT ANDAND DHEADHEATT
Testosterone Pathway Testosterone Pathway in Prostatic Cellsin Prostatic Cells
(Free)
HormonalHormonalTherapy OptionsTherapy Options
Hormonal TherapyHormonal Therapy
• Bilateral orchiectomyBilateral orchiectomy• LHRH analogsLHRH analogs• AntiandrogensAntiandrogens• Combined Androgen Blockade (CAB)Combined Androgen Blockade (CAB)• Androgen antagonist Androgen antagonist
Bilateral OrchiectomyBilateral Orchiectomy
• In 1941, Huggins and Hodges made original discovery of In 1941, Huggins and Hodges made original discovery of hormonal effect on prostate cancerhormonal effect on prostate cancer
• Same studies also showed that bilateral orchiectomy Same studies also showed that bilateral orchiectomy improved pain or neurological symptoms in 71% of patients improved pain or neurological symptoms in 71% of patients with metastatic diseasewith metastatic disease
• Advantages:Advantages:– Immediate castration without testosterone surgeImmediate castration without testosterone surge– Outpatient procedure, general anesthesia not requiredOutpatient procedure, general anesthesia not required– No compliance issuesNo compliance issues
• Disadvantages:Disadvantages:– IrreversibleIrreversible
Huggins C, Hodges CV. Cancer Res. 1941;1:293-7.Huggins C, et al. Arch Surgery. 1941;43:209.Schroder FH. Campbell’s Urology, 8th ed. Philadelphia, Pa. WB Saunders;2002:3190-91.
Hormonal Therapy in Hormonal Therapy in Metastatic DiseaseMetastatic Disease
• HT has been most widely used in HT has been most widely used in metastatic disease metastatic disease
• When to initiate HT is often debatedWhen to initiate HT is often debated• MRC (UK) StudyMRC (UK) Study
– 938 patients with locally advanced and 938 patients with locally advanced and asymptomatic, metastatic prostate cancer asymptomatic, metastatic prostate cancer
– Early HT (89% orchiectomy; within 6 weeks of Early HT (89% orchiectomy; within 6 weeks of entry) vs Deferred HT (71.5% orchiectomy) entry) vs Deferred HT (71.5% orchiectomy)
• Survival, local and distant progression, Survival, local and distant progression, major complications evaluatedmajor complications evaluated
MRC Prostate Cancer Working Group Party Investigators Group Br J Urol. 1997;79:235-246.
MRC Trial: ResultsMRC Trial: Results
• 934 evaluable patients results934 evaluable patients results
MRC Prostate Cancer Working Group Party Investigators Group Br J Urol. 1997;79:235-246.
Deferred ARMDeferred ARM
(# of patients)(# of patients)
Immediate ARM Immediate ARM (# of patients)(# of patients)
P valuesP values
DeathDeath 361361 328328 P=0.02P=0.02
Two-tailedTwo-tailed
Cause Specific Cause Specific DeathDeath
257257 203203 P=0.001P=0.001
Two-tailedTwo-tailed
TURTUR 141141 6565 PP<0.001<0.001
Two-tailedTwo-tailed
469 in the immediate HT group and 465 in the deferred HT
Mechanism of Action Mechanism of Action of LHRH Analogsof LHRH Analogs
HYPOTHALAMUSHYPOTHALAMUS
PITUITARYPITUITARY
PROSTATEPROSTATETestosteroneTestosterone
DHTDHT
ADRENALADRENAL
CortisolCortisolTestosteroneTestosteroneCRHCRH
ACTHACTHLHLH
TestosteroneTestosterone AdrenalAdrenalandrogensandrogens
Induction/StimulationInduction/Stimulation Feedback/RegulationFeedback/Regulation
Adapted from Foote JE, Crawford ED. Adapted from Foote JE, Crawford ED. Semin Urol.Semin Urol.1988;6(4):291-302.1988;6(4):291-302.
LHRH-As
LHRH
TESTES
Time to Induction of Castration Time to Induction of Castration with with
Long-Term LHRH Analog TherapyLong-Term LHRH Analog Therapy
Mean Serum Testosterone LevelsMean Serum Testosterone Levels
Adapted from Debruyne FMJ, et al.Adapted from Debruyne FMJ, et al. J Urol J Urol.1988;140:775-777..1988;140:775-777.
Level with ZOLADEXLevel with ZOLADEX®® (goserelin acetate implant) (goserelin acetate implant) 3.6 mg depot 3.6 mg depot
Castrate levelCastrate level
166166 164164 156156 144144 6565 6262 127127 5050 46 No. of patients46 No. of patients
00
11
22
33
44
00 44 88 122 166 200 244 322 366 Time (weeks)Time (weeks)
Mean serumMean serumtestosteronetestosterone
(ng/mL)(ng/mL)
Single-Therapy Androgen Suppression in Men with Advanced Single-Therapy Androgen Suppression in Men with Advanced Prostate Cancer: A Systematic Review and Meta-Analysis Prostate Cancer: A Systematic Review and Meta-Analysis
• 24 RCT involving 6600 patients, (1966 - 1998)24 RCT involving 6600 patients, (1966 - 1998)
• Results Results
– LHRHa are equivalent to orchiectomy (10 trials, n=1908, HR- LHRHa are equivalent to orchiectomy (10 trials, n=1908, HR- 1.262, 95% CI, 0.915-1.386). 1.262, 95% CI, 0.915-1.386).
– There was no difference in OS among the LHRH analoguesThere was no difference in OS among the LHRH analogues• Leuprolide (hazard ratio, 1.0994 [CI, 0.207 to 5.835]) Leuprolide (hazard ratio, 1.0994 [CI, 0.207 to 5.835])
• Buserelin (hazard ratio, 1.1315 [CI, 0.533 to 2.404]) Buserelin (hazard ratio, 1.1315 [CI, 0.533 to 2.404])
• Goserelin (hazard ratio, 1.1172 [CI, 0.898 to 1.390]). Goserelin (hazard ratio, 1.1172 [CI, 0.898 to 1.390]).
– Nonsteroidal antiandrogens are associated with lower OS( 8 Nonsteroidal antiandrogens are associated with lower OS( 8 trials, 2717 patients, HR 1.2158 [CI, 0.988 to 1.496]). trials, 2717 patients, HR 1.2158 [CI, 0.988 to 1.496]).
– Treatment withdrawals are less frequent with LHRHa (0% to 4%) Treatment withdrawals are less frequent with LHRHa (0% to 4%) than with nonsteroidal antiandrogens (4% to 10%). than with nonsteroidal antiandrogens (4% to 10%).
Seidenfield et al Annals of Intern Med 2000, 132; 7: 566-577
Pivotal Trial Overall Survival Pivotal Trial Overall Survival
Adapted from: Kaisary AV, et al. Br J Urol. 1991;67:502-508.
Est
ima
ted
Su
rviv
al P
roba
bilit
y
0 24 48 72 96 120 144168192 216
Length of Survival (Weeks)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Est
ima
ted
Su
rviv
al P
roba
bilit
y
0 24 48 72 96 120 144168192 216
Length of Survival (Weeks)
Eligible “Depot Period” PatientsAll Eligible Patients
ZOLADEX
Bilateral Orchiectomy
ZOLADEX
Bilateral Orchiectomyp = 0.23 p = 0.33
n = 176 ZOLADEX®® (goserelin acetate implant)n = 182 bilateral orchiectomy
n = 148 ZOLADEXn = 144 bilateral orchiectomy
Pivotal TrialPivotal Trial Pharmacological Adverse Events Pharmacological Adverse Events
Adapted from: Kaisary AV, et al. Br J Urol. 1991;67:502-508.
0 20 40 60 80 100
Breast Tenderness
Gynecomastia
Hot Flashes
Decrease inErections
Decrease in Libido
Percent of Event Rate
73% (37/51)
79% (34/43)
84% (43/51)
85% (41/48)
63% (96/152)
58% (94/163)
4.8% (8/168)
4% (7/173)
0.6% (1/167)
1.2% (2/173)
ZOLADEX®®
(goserelin acetate implant)
Bilateral Orchiectomy
ARM IGoserelin 3.6 mg/
Flutamide 250 mg + RT (n = 226)
RTOG 86-10 RTOG 86-10 Radiotherapy + Neoadjuvant/Concomitant Radiotherapy + Neoadjuvant/Concomitant
ZOLADEXZOLADEX®® (goserelin acetate implant) (goserelin acetate implant) Study Design Study Design
Randomized
Locally Advanced T2 – 4, N+/-, M0
(N = 471)
ARM IIRT Alone (n = 230)
Pilepich MV, et al. Int J Radiat Oncol Biol Phys 2001; 50:1243-1252. Reprinted with permission.
Median follow-up at 4.5 years and
6.7 years
RTOG 86-10RTOG 86-10Local FailureLocal Failure
Pilepich MV, et al. Int J Radiat Oncol Biol Phys. 2001;50:1243-1252.
100
75
50
25
0
0 1 2 3 4 5 6 7 8 9
Per
cent
Years from Date of Randomization
At risk116104
6352
RT + Hormones 72/226RT Alone 98/230
Failed/Total p = 0.016
Locally Advanced(T1-2, N+; T3)
(N=945)
Randomized
Radiotherapy + goserelin
3.6 mg (n=477)
Radiotherapy Alone(n=468)
RTOG 85-31 Trial Radiotherapy Radiotherapy + Adjuvant+ Adjuvant
ZOLADEXZOLADEX®® (goserelin acetate implant) (goserelin acetate implant)
Study Design
Pilepich MV et al. J Clin Oncol. 1997; 15: 1013-1021.Lawton CA, et al. Int J Radiat Oncol Biol Phys. 2001;49:937-946.
Median follow-up at 4.5 years and 5.6 years
RTOG 85-31RTOG 85-31Local Local Failure Failure
Reprinted from the International Journal of Radiation Oncology Biology and Physics, Vol. 49, CA Lawton, K Winter, K Murray, et al. Updated results of the Phase III radiation therapy for unfavorable prognosis carcinoma of the prostate, pp 937-946, with permission from Elsevier Science.
100
75
50
25
0
0 1 2 3 4 5 6 7 8 9
Per
cent
Years from Date of Randomization
RT + Adjuvant ZOLADEX®® 92/477(goserelin acetate implant)
RT + ZOLADEX at Relapse 155/468
Failed/Total
p < 0.0001
RTOG 85-31RTOG 85-31Distant MetastasesDistant Metastases
Reprinted from the International Journal of Radiation Oncology Biology and Physics, Vol. 49, CA Lawton, K Winter, K Murray, et al. Updated results of the Phase III radiation therapy for unfavorable prognosis carcinoma of the prostate, pp 937-946, with permission from Elsevier Science.
100
75
50
25
0
0 1 2 3 4 5 6 7 8 9
Per
cent
Years from Date of Randomization
RT + Adjuvant ZOLADEX®® 103/477 (goserelin acetate implant)
RT + ZOLADEX at Relapse 154/468
Failed/Total
p < 0.0001
RTOG 85-31RTOG 85-31Disease-Free SurvivalDisease-Free Survival
Lawton et al. Int J Radiat Oncol Biol Phys. 2001; 49: 937-946. Reprinted with permission.
Median follow-up of 5.6 years
100
75
50
25
0
0 1 2 3 4 5 6 7 8 9
Per
cent
Years from Date of Randomization
RT + Adjuvant goserelin 244/477
RT Alone 306/468
Failed/Total
p < 0.0001
T1-4, N0, M0(n=415)
Randomized
Radiotherapy + adjuvant goserelin
3.6 mg (n=207)
Radiotherapy Alone(n=208)
Hormonal Therapyat Progression
EORTC 22863 EORTC 22863 Radiotherapy + Adjuvant Radiotherapy + Adjuvant ZOLADEXZOLADEX®® (goserelin acetate implant) (goserelin acetate implant)
vs Radiotherapy Alonevs Radiotherapy AloneStudy Design
EORTC = European Organization for Research and Treatment of CancerRadiation: 50 Gy over 5 weeks + 20 Gy over 2 weeksZOLADEX 3.6 mg sc every 4 weeks starting day 1 of radiation and continuing for 3 yearsCyproterone acetate: 150 mg po qd for 1 month starting 1 week prior to ZOLADEXBolla M, et al. NEJM. 1997;295-300.
Median follow-up at 45 months and
66 months
EORTC 22863EORTC 22863 Biochemical Disease Free Survival 66-Month Biochemical Disease Free Survival 66-Month
Follow-upFollow-up
Bolla M, et al. Lancet. 2002;360:103-108.
Combined Treatment
Radiotherapy AloneLog-rank test p < .0001Hazard ratio 0.42(95% Cl: 0.28-0.64)
Time Since Randomization (Years)
O N Number of Patients at Risk
36 66 64 59 50 29 17 9 4 3
56 170 169 157 138 116 76 50 26 13
0 1 2 3 4 5 6 7 8
Bio
chem
ical
ly D
efin
edD
isea
se-F
ree
Sur
viva
l (%
)100908070605040302010
0
EORTC 22863 EORTC 22863 Overall Survival (OS)Overall Survival (OS)
• At 66-month follow-upAt 66-month follow-up– OS was 78% in the RT + ZOLADEX group OS was 78% in the RT + ZOLADEX group
and 62% for RT alone (p = 0.0002)and 62% for RT alone (p = 0.0002)
Bolla M, et al. Lancet. 2002;360:103-108.
EORTC 22863EORTC 22863Overall Survival 66-Month Follow-upOverall Survival 66-Month Follow-up
Bolla M, et al. Lancet. 2002;360:103-108.
Combined Treatment
Radiotherapy Alone
Time Since Randomization (Years)0 1 2 3 4 5 6 7 8
Log-rank test p < .0001Hazard ratio 0.51(95% Cl: 0.36-0.73)
Ove
rall
Sur
viva
l (%
)100908070605040302010
0
O N Number of Patients at Risk
81 208 199 177 146 106 70 46 30 16
50 207 197 183 166 142 93 71 43 24
AntiandrogensAntiandrogens
Antiandrogen Dosing RegimenAntiandrogen Dosing Regimen
• Combination therapy with an LHRH-ACombination therapy with an LHRH-A– Flutamide Flutamide
• 2 capsules (125 mg each) 3 times daily2 capsules (125 mg each) 3 times daily
• Half-life (T½) = 4-7 hours Half-life (T½) = 4-7 hours
– CASODEXCASODEX®® (bicalutamide) Tablets (bicalutamide) Tablets• 1 tablet (50 mg) once daily1 tablet (50 mg) once daily
• T½ = 5.8 daysT½ = 5.8 days
– Combination therapy with bilateral Combination therapy with bilateral orchiectomyorchiectomyNilutamideNilutamide
• 2 tablets (150 mg each) once a day (300 mg) for 30 days 2 tablets (150 mg each) once a day (300 mg) for 30 days followed by 1 tablet (150 mg each) once a day (150 mg)followed by 1 tablet (150 mg each) once a day (150 mg)
• T½ = 56 hoursT½ = 56 hours
• Montherapy 150mg casodexMontherapy 150mg casodex
Combined Androgen BlockadeCombined Androgen BlockadeCABCAB
Reprinted from Urology, Vol. 50, P Schellhammer, R Sharifi, N Block, et al. A controlled trial of bicalutamideversus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy inpatients with advanced phase prostate cancer, pp 330-336, 1997, with permission from Elsevier Science.
CASODEXCASODEX®® (bicalutamide) (bicalutamide)50 mg CAB Trial50 mg CAB TrialOverall SurvivalOverall Survival
0 365 730 1095 1460 1825
Pro
port
ion
Sur
vivi
ng
Day
CASODEX + LHRH-A (n = 404)
Flutamide + LHRH-A (n = 409)
p = 0.151.0
0.9
0.5
0.3
0.0
0.8
0.7
0.6
0.4
0.2
0.1
Median Follow-up 160 weeks
Overall Survival for Four CAB GroupsOverall Survival for Four CAB Groups
Reprinted from Urology, Vol. 52, MF Sarosdy, PF Schellhammer, R Sharifi, et al. Comparison of goserelin and leuprolide in combined androgen blockade therapy, pp 82-88, 1998, with permission from Elsevier Science.
n = 136
n = 268
n = 272
n = 137
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Pro
por
tion
Sur
vivi
ng
365 730 1095 1460 18250Time to Death (Days)
leuprolide + CASODEX® (bicalutamide)ZOLADEX® (goserelin acetate implant) + CASODEXZOLADEX + flutamideleuprolide + flutamide
p = 0.26p = 0.99p = 0.047
p = 0.008
Overview of CAB TrialsOverview of CAB TrialsMeta-AnalysesMeta-Analyses
*Prostate Cancer Trialists’ Collaborative Group. Lancet. 1995;346:265-269.†Crawford ED, Eisenberger MA, McLeod DG, et al. NEJM. 1989;321:419-424.
Prostate Cancer Trialists’ Collaborative Group. Lancet. 2000;355:1491-1498.
PCTCG Meta-analysis PCTCG Meta-analysis Treatments TestedTreatments Tested
• 27 trials involving 8275 patients27 trials involving 8275 patients– Flutamide, 4803Flutamide, 4803
– Nilutamide, 1688Nilutamide, 1688
– Cyproterone acetate, 1784Cyproterone acetate, 1784
– 88% with metastatic disease, 12% with locally88% with metastatic disease, 12% with locally
– advanced diseaseadvanced disease
• Usual dosages: nilutamide 300 mg/daily, flutamide Usual dosages: nilutamide 300 mg/daily, flutamide 750 mg/daily, cyproterone acetate 150 to 200 mg/daily750 mg/daily, cyproterone acetate 150 to 200 mg/daily
• Updated information on 13 previously analyzed trials* and 5 new Updated information on 13 previously analyzed trials* and 5 new trials, including SWOG-8894 (leuprolide trials, including SWOG-8894 (leuprolide flutamide) flutamide)††
Meta-analysesMeta-analysesCAB vs CastrationCAB vs Castration
PCTCG = Prostate Cancer Trialists’ Collaborative Group; CPA = cyproterone acetate; NSAA = nonsteroidal antiandrogen; PH = proportional hazards, LR = log hazard ratio. Due to the continual analysis of survival at different time intervals, some of the analyses above contain the same patients.
1. PCTCG. Lancet. 2000;355:1491-1498; 2. Caubet JF, et al. Urology. 1997;49:71-78; 3. Klotz LH, et al. Can J Urol. 1996;3:246-250; 4. Debruyne FM, et al. Eur Urol. 1996;30(suppl 2):264; 5. Bennett CL, et al. Prostate Cancer Prostate Dis. 1999;2:4-8.
PCTCG1: overall n = 8215 P > 0.1PCTCG1: nilutamide n = 1751 P > 0.1PCTCG1: flutamide n = 4803 P = 0.02PCTCG1: flutamide + nilutamide n = 6354 P = 0.004PCTCG1: CPA n = 1661 P = 0.04Caubet2: NSAA PCTCG n = 3732 P = 0.005Caubet2: NSAA (PH) n = 1978 P < 0.001Caubet2: NSAA (LR) n = 2357 P < 0.001Klotz3: NSAA n = 3015 P > 0.041Debruyne4: nilutamide n = 1191 P > 0.038Bennett5: flutamide n = 1128 P = 0.05
Overview of Published CAB Meta-analyses8% to 22% lower risk of death over a given time period than castration
Hazard Ratio and 95% Confidence Limits
0.5 1.51.0CAB Better CAB Worse
Meta-Analyses27 Randomized Trials of CAB vs AS Alone
Prostate Cancer Trialists’ Collaborative Group. Lancet. 2000;355:1491-1498.
Pro
por
tion
Aliv
e (%
)
Time Since Randomization (Years)
100
0
80
60
40
20
0 5 10
Androgen Suppression OnlyAndrogen Suppression + Antiandrogen
Treatment Betterby 0.7% (SE 1.1)Logrank p > 0.1
AbsoluteDifference1.8% (SE 1.3)
23.6%
25.4%
6.2%5.5%
10-Year Survival>8000 Prostate Cancer Patients in 27 Trials of Antiandrogens
(Nilutamide, Flutamide, or Cyproterone Acetate)
Meta-Analyses20 Randomized Trials of CAB vs AS Alone
Prostate Cancer Trialists’ Collaborative Group. Lancet. 2000;355:1491-1498.
5-Year Survival6500 Men in 20 Trials of Nilutamide/Flutamide
Pro
por
tion
Aliv
e (%
)
Time Since Randomization (Years)
100
0
80
60
40
20
0 2 5
Androgen Suppression OnlyAndrogen Suppression Antiandrogen
Treatment Betterby 2.9% (SE 1.3)Logrank p = 0.005
27.6%
24.7%
1 3 4
CAB ConclusionsCAB Conclusions
• CAB may improve absolute 5-year CAB may improve absolute 5-year survival by about 2% to 3%survival by about 2% to 3%
• Choice of antiandrogenChoice of antiandrogen– Nonsteroidal antiandrogens improve Nonsteroidal antiandrogens improve
outcomes while steroidal antiandrogens outcomes while steroidal antiandrogens (CPA, not approved in the US) do not(CPA, not approved in the US) do not
• Various CAB regimens similarly well Various CAB regimens similarly well toleratedtolerated
Antiandrogen monotherapyAntiandrogen monotherapy
Efficacy and tolerability of bicalutamide in early Efficacy and tolerability of bicalutamide in early localy advanced, non-metastatic prostate localy advanced, non-metastatic prostate
cancer.SPGC 6cancer.SPGC 6
Median F.U 7.1 year
HR 0.47p<0.001
progresjon
%patiant
0
10
20
30
40
50
60
70
80Bicalutamid
Placebo
Iversen P et al. Efficacy and tolerability of bicalutamide in early non-metastatic prostate cancer: Latest findings from The Scandinavian Prostatic Cancer Group study no 6 (Spcg-6) of The Early Prostate Cancer Programme. Eur Urol Suppl
2006;5(2):251, Abs 914
Figur utarbeidet av AstraZeneca ASLokalavansert
Overall survival– locally advanced PCOverall survival– locally advanced PCSPCG-6SPCG-6
Prop
orti
on s
urv
ivin
g
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Time to death (years)0 1 2 3 4 5 6 7 8 9 10
HR=0.65 (0.50, 0.85) p=0.001 Bicalutamid events = 105 (41.2%)
placebo events = 131 (52.4%)
PlaceboBicalutamid
1.0
0.8
0.6
0.4
0.2
0.00 1 2 3 4 5 6
Time to death (year)
Ove
rall
su
rviv
al
7 8 9 10
Median F. U: 7.1 yearMedian F. U: 7.1 year
Iversen P et al. Efficacy and tolerability of bicalutamide in early non-metastatic prostate cancer: Latest findings from The Scandinavian Prostatic Cancer Group study no 6 (Spcg-6) of The Early Prostate Cancer Programme. Eur Urol Suppl 2006;5(2):251,
Abs 914
Figur utarbeidet av AstraZeneca AS
Early versus Late ADTEarly versus Late ADT
• 4 trials (n=2,167)4 trials (n=2,167)
– All trials were conducted prior to use of PSA testing & were All trials were conducted prior to use of PSA testing & were heterogenousheterogenous
– All studies found PFS was consistently better in the early All studies found PFS was consistently better in the early intervention group at all time points. intervention group at all time points.
Wilt T, et al Cochrane Reviews 2001, Issue 4.
Overall Survival (%)
1 yr 2 yr 5 yr 10 yr
Early ADT 88 73 44 18
Deferred ADT
86 71 37 12
OR1.16
95% CI: 0.90 to 1.49
1.08 95% CI: 0.89 to
1.33
1.19 95% CI: 0.95 to
1.50
1.50 95% CI: 1.04 to
2.16
Timing of ADTTiming of ADTConclusionsConclusions
• Early ADT offers a statistically significant benefit in PFS & OSEarly ADT offers a statistically significant benefit in PFS & OS
• Early ADT reduces disease progression and complications due to Early ADT reduces disease progression and complications due to progression. progression.
• There was no statistically significant difference in prostate cancer specific There was no statistically significant difference in prostate cancer specific survival survival
• Early ADT leads to higher costs Early ADT leads to higher costs
• Treatment is most cost effective when started after the onset of symptomsTreatment is most cost effective when started after the onset of symptoms
• Complications due to disease progression are more frequent in the deferred Complications due to disease progression are more frequent in the deferred treatment group. treatment group.
• Adverse events due to treatment are more frequent in the early treatment Adverse events due to treatment are more frequent in the early treatment group.group.
Is intermittent ADT better than continuous ADT?Is intermittent ADT better than continuous ADT?
• RationaleRationale– Prolonged ADT may cause androgen independenceProlonged ADT may cause androgen independence
– Side effects are lesser with intermittent ADTSide effects are lesser with intermittent ADT
• No prospective randomized trials No prospective randomized trials
• No guidelines for starting & stopping therapyNo guidelines for starting & stopping therapy
• No data available on testosterone levels, QOL, BMD & sexual functionNo data available on testosterone levels, QOL, BMD & sexual function
• Two phase III studies are underwayTwo phase III studies are underway
• Hormonal changes Hormonal changes associated with aging associated with aging correlate with bone losscorrelate with bone loss
– Lower testosterone levelsLower testosterone levels– Leads to less aromatization Leads to less aromatization
(conversion) of testosterone (conversion) of testosterone to estradiolto estradiol
– Estradiol protects / Estradiol protects / strengthens bonestrengthens bone
• Therefore lower levels = less Therefore lower levels = less protectionprotection
E2
Osteoporosis Risk Factors for menOsteoporosis Risk Factors for men
Hormonal TherapyHormonal Therapy• BMD loss with hormonal therapyBMD loss with hormonal therapy
– Decrease T by >95%Decrease T by >95%
– Decrease EDecrease E22 by >80% by >80%
– With orchiectomy the BMD loss is 2.4% at 1 year With orchiectomy the BMD loss is 2.4% at 1 year and 10% at 2 yearsand 10% at 2 years
– With GnRH Agonist, the BMD loss is 3.4% at 1 With GnRH Agonist, the BMD loss is 3.4% at 1 year and 6.5% at 2 yearsyear and 6.5% at 2 years
1 yr 2 yr
Orchiectomy 2.4% 10%
GnRH Agonist 3.4% 6.5%
Hormonal TherapyHormonal Therapy
• This decrease in BMD is associated with an increase in This decrease in BMD is associated with an increase in fracturesfractures
• Men without prostate cancer over the age of 65 who are not on Men without prostate cancer over the age of 65 who are not on hormonal therapy have a fracture rate of 0.5% per yearhormonal therapy have a fracture rate of 0.5% per year
• With hormone therapy there was a 5% incidence of osteoporotic With hormone therapy there was a 5% incidence of osteoporotic fractures seen in a median of 22 monthsfractures seen in a median of 22 months
• In one series, within 7 years 28% of prostate cancer patients In one series, within 7 years 28% of prostate cancer patients treated with orchiectomy had a fracture vs. 1% of patients who treated with orchiectomy had a fracture vs. 1% of patients who did not undergo orchiectomydid not undergo orchiectomy
Overall ConclusionsOverall Conclusions
• Numerous options available for treatment of prostate Numerous options available for treatment of prostate cancer at different stages of diseasecancer at different stages of disease
• No consensus on therapy of curative intentNo consensus on therapy of curative intent• Treatment options should be discussed with patientsTreatment options should be discussed with patients• Risk and benefits of treatment need to be carefully Risk and benefits of treatment need to be carefully
consideredconsidered• Hormonal therapy for locally advanced and metastatic Hormonal therapy for locally advanced and metastatic
prostate cancer is effective but not curativeprostate cancer is effective but not curative• Further clinical studies in localized, locally advanced Further clinical studies in localized, locally advanced
and metastatic prostate cancer need to be considered and metastatic prostate cancer need to be considered
CASTRATED RESISTANCE PC.CASTRATED RESISTANCE PC.CRPCCRPC
Hormone refractory prostate carcinomaHormone refractory prostate carcinoma
• Definition:Definition:
Disease progression despite castrate serum levels of testosteroneDisease progression despite castrate serum levels of testosterone
• Progression’ is defined by:Progression’ is defined by:
– Increase in size of measurable lesionsIncrease in size of measurable lesions
– Appearance of new measurable lesions Appearance of new measurable lesions
– Increase in PSA >50% on at least 2 consecutive measurementsIncrease in PSA >50% on at least 2 consecutive measurements
– Increase in pain associated with new bony lesionsIncrease in pain associated with new bony lesions
• Duration of responseDuration of response
– Limited or no metastases-5 yearsLimited or no metastases-5 years
– Metastatic disease-2 yearsMetastatic disease-2 years
• Median survival approximately 1 yearMedian survival approximately 1 year
CRPC :Progresjon av PSA, CRPC :Progresjon av PSA, SymptomerSymptomer
Harris W P et al. (2009) Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletionNat Clin Pract Urol doi:10.1038/ncpuro1296
Androgen deprivation therapy
(ADT) Androgen action
Mechanisms of castration resistance in prostate cancer
Harris W P et al. (2009) Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletionNat Clin Pract Urol doi:10.1038/ncpuro1296
Treatment of CRCPTreatment of CRCP
Casteration? Testestron? <20 ngCasteration? Testestron? <20 ng
1-Total androgen blokade(TAB1-Total androgen blokade(TAB))
-LHRH +Antiandrogen-LHRH +Antiandrogen response ca.25% i ca 6-8 man response ca.25% i ca 6-8 man
2- Withdrawal2- Withdrawal
..
3-Antiandrogen "switching (3-Antiandrogen "switching (bicalutamide bicalutamide flutamide )flutamide )
Biochemist response up to 40% ca 6 manBiochemist response up to 40% ca 6 man
4-Stroid (Prednisolon)4-Stroid (Prednisolon)
5-Østrogen 5-Østrogen ((Response rate ca 86%) Response rate ca 86%) cardivasculare side effectcardivasculare side effect
6-Ketoconazole6-Ketoconazole (hemmer steroid synthesis) (hemmer steroid synthesis) 20-30 % response20-30 % response
7-Abiratern 7-Abiratern
Definition of Castrate Testosterone: Definition of Castrate Testosterone: A Treatment Decision Algorithm from A Treatment Decision Algorithm from NCCN 2003NCCN 2003 Guidelines Guidelines
Hormoneablation
(advanced PCa)
Orchiectomy
LHRHagonist
Testosterone
< 20ng/dL
> 20 ng/d
LConsider
orchiectomy
If patient refuses orchiectomy, add antiandrogen or
change LHRH dose or product
ContinueLHRH
therapy
NCCN, National Comprehensive Cancer Network; PCa, prostate cancer.Adapted from Oefelein MG et al. J Urol. 2000;164:726-729.
NCCN 2008 Guidelines for patients changed the testosterone trigger from 20 ng/dL to 50 ng/dL due to lack of level
1 evidence
Ketoconazole (KC)Ketoconazole (KC)
• Ketoconazole (KC) is an antifungal drug that is a Ketoconazole (KC) is an antifungal drug that is a nonspecific inhibitor of P450 enzymesnonspecific inhibitor of P450 enzymes
• Inhibition of (CYP17), which is a key enzyme that Inhibition of (CYP17), which is a key enzyme that mediates androgen synthesis. KC in combination mediates androgen synthesis. KC in combination with hydrocortisone (HC) has been widely used to with hydrocortisone (HC) has been widely used to treat patients with CRPC as a secondary hormonal treat patients with CRPC as a secondary hormonal agent in patients whose disease is progressing agent in patients whose disease is progressing following ADT and AAWD.following ADT and AAWD.
• KC is associated with significant toxicities without a KC is associated with significant toxicities without a definitive demonstration of improvement in overall definitive demonstration of improvement in overall survival.survival. (e.g., fatigue, nausea, liver enzyme (e.g., fatigue, nausea, liver enzyme elevations and neurotoxicity)elevations and neurotoxicity)
Abiraterone Acetate: A Promising Drug for the Abiraterone Acetate: A Promising Drug for the Treatment of Castration-resistant Prostate CancerTreatment of Castration-resistant Prostate Cancer
Neeraj Agarwal; Thomas E Hutson; Nicholas J Vogelzang; Guru SonpavdeNeeraj Agarwal; Thomas E Hutson; Nicholas J Vogelzang; Guru SonpavdeAuthors and Disclosures Authors and Disclosures
Posted: 06/18/2010; Future Oncology. 2010;6(5):665-679. © 2010 Future Medicine Ltd.Posted: 06/18/2010; Future Oncology. 2010;6(5):665-679. © 2010 Future Medicine Ltd.
• An orally administered small molecule that irreversibly inhibits a rate-limiting An orally administered small molecule that irreversibly inhibits a rate-limiting enzyme in androgen biosysnthesis, CYP17, and blocks the synthesis of enzyme in androgen biosysnthesis, CYP17, and blocks the synthesis of androgens in the testes, adrenal glands and prostate without causing adrenal androgens in the testes, adrenal glands and prostate without causing adrenal insufficiency.insufficiency.
• Randomised phase III trial .Randomised phase III trial .• OSOS
• Abiraterone + prednisone: 14.8 monthsAbiraterone + prednisone: 14.8 months• Placebo + prednisone: 10.8 monthsPlacebo + prednisone: 10.8 months
• The PSA responseThe PSA response– Abiraterone + prednisone: 38.0%Abiraterone + prednisone: 38.0%– Placebo + prednisone: 10.1%Placebo + prednisone: 10.1%
• AdverseAdverse– Adverse events with abiraterone treatment were obviously higher than for placebo, but Adverse events with abiraterone treatment were obviously higher than for placebo, but
in general it appeared well tolerated and an important common side effect was fluid in general it appeared well tolerated and an important common side effect was fluid retention (30.5% of patients, with 2.4% of them being severe ie grade 3/4 in severity)retention (30.5% of patients, with 2.4% of them being severe ie grade 3/4 in severity)
Firmagon® - A novel GnRH receptor blocker for hormonal treatment of prostate
cancer
Gero Kramer
Clinic for Urology
Medical University of Vienna
GnRH agonists: disadvantages GnRH agonists: disadvantages
•Testosterone surge Testosterone surge delay in castrationdelay in castration11 flare symptomsflare symptoms22
•Testosterone microsurges Testosterone microsurges
•Testosterone breakthroughsTestosterone breakthroughs
•Testosterone control not comparable Testosterone control not comparable with orchiectomywith orchiectomy
1 Thompson IM. Rev Urol 2001; 3 (Suppl 3): S10-S14;2 Heidenreich A et al. EAU Guidelines on prostate cancer 2007 www.uroweb.org;
Objectives for Firmagon Objectives for Firmagon development development
To mimic the effects of surgical castrationNo testosterone surge
Fast and sustained suppression of testosterone and PSA
Similar or better safety profile compared withGnRH agonists
x
x
Firmagon a GnRH blockerFirmagon a GnRH blockerDirect mode of actionDirect mode of action
•Immediate onset with Immediate onset with fast testosterone and fast testosterone and PSA suppressionPSA suppression
•No testosterone surgeNo testosterone surge
Princivalle M, J Pharmacol Exp Ther 2007; 320: 1113-1118
Firmagon
MoleculeMolecule• A fully synthetic, linear decapeptide amideA fully synthetic, linear decapeptide amide
• A natural gelling depot A natural gelling depot
• Requires no additional constituentsRequires no additional constituents
• Low histamine releaseLow histamine release
White, 1st European Multidisciplinary Meeting on Urological Cancers,Barcelona, Spain, 2007.
PHASE III TRIALPHASE III TRIAL
A multi-centre randomized trial
comparing the efficacy and safety of FIRMAGON®
(degarelix) with leuprolide 7.5 mg in patients with
prostate cancer requiring androgen deprivation
therapy (CS21)
Dosing schedule CS21Dosing schedule CS21
Dosing monthly with a total of 12 days
N=610 patients
(ITT)
Firmagon240 mg (2x3 mL s.c)
Day 0Starter dose
Day 28-364Maintenance dose
Leuprolide7.5 mg (i.m.)
Firmagon160 mg (1x4 mL s.c)
Firmagon80 mg (1x4 mL s.c)
Leuprolide7.5 mg (i.m.)*
*Anti-androgen was allowed Klotz L et al. BJU Int 2008;102:1531-8
CS21- study endpoints
Primary endpoint:
Probability of testosterone ≤0.5 ng/mL at all monthly measurements
Secondary endpoints included:
Patients with testosterone surge and microsurges
Change in PSA from baseline to day 28 and time to PSA failure
Safety
Klotz L et al. BJU Int 2008;102:1531-8
Number of pats.
Age (median), yrs.
Testosterone (ng/ml)
PSA (ng/ml)
Firmagon24080
207
72
4.1 (3-5.3)
20 (9-46)
Leuprolide7.5mg
201
74
3.8 (2.9-5)
17 (8-56)
Demographics and disease characteristics
Demographics and disease Demographics and disease characteristicscharacteristics
Leuprolide7.5 mg
Firmagon24080 mg
PCA stage31%33% Localized
26%31% Loc. Advanced
23%18% Metastatic
Gleason Score44%43% ≤ 6
26%27% 8-1031%30% 7
19%18% Unclassified
Klotz L et al. BJU Int 2008;102:1531-8
Firmagon is noninferior to leuprolide in Firmagon is noninferior to leuprolide in suppressing testosterone to <0.5 ng/mL for 1 yearsuppressing testosterone to <0.5 ng/mL for 1 year
Probability of testosterone ≤0.5 ng/mL from day 28-364
Difference to leuprolide
Responserate
Patients with treatment response
0.9 %
(-3.2 to 5.0 %)
96.4 % 97.2 %
194202
Leuprolide7.5 mg
Firmagon24080 mg
Klotz L et al. BJU Int 2008;102:1531-8
-100Med
ian
per
cen
tag
e ch
ang
e in
Tes
tost
ero
ne
(%
)
-75
-50
-25
0
25
50
75
100
0 1 3 7 14 21 28
Degarelix 240/160mg
Degarelix 240/80mg
Leuprolide 7.5mg
days
Firmagon – immediate testosterone reduction, no risk of clinical flare
*P<0.001 Firmagon (both doses) versus leuprolide Klotz L et al. BJU Int 2008;102:1531-8
T- 0.24 ng/ml
T-6,3ng/ml
Firmagon – very low testosteroneFirmagon – very low testosteronelevels maintained over 1 yearlevels maintained over 1 yearMedian (± quartile) testosterone level over time
Castration level
0
Med
ian
Tes
tost
ero
ne
(n
g/m
l)
1
2
3
4
5
6
7
8
9
0 28 84 140 196 252 308 364
Degarelix 240/160mg
Degarelix 240/80mg
Leuprolide 7.5mg
days
Klotz L et al. BJU Int 2008;102:1531-8
Med T – 0.082 ng/ml vs 0.078
Firmagon - no testosterone Firmagon - no testosterone microsurgesmicrosurges
8 pts (4%)**0> 0.25 ng/mL*
Leuprolide7.5 mg
Firmagon24080 mg
*Change: Day 3 and day 7 after 9th injection
** 4 pts with testosterone breakthrough (>0.5 ng/ml)
Klotz L et al. BJU Int 2008;102:1531-8
0
-40
-60
-80
-100
Med
ian
per
cen
tag
e ch
ang
e in
PS
A (
%)
Firmagon – significantly faster reduction in PSA
*P<0.001 versus leuprolide (Wilcoxon pairwise comparisons); 11% of leuprolide patients received bicalutamide as flare protection
-20
7 14 28 56 84 168 364days
Degarelix 240/160mg
Degarelix 240/80mg
Leuprolide 7.5mg
Klotz L et al. BJU Int 2008;102:1531-8
- 64%
- 18%
-85%
-68%
Two consecutive increases of more than 50%(at least >5.0 ng/mL)
Firmagon 240/80 mg
Leuprolide 7.5 mg
No. of failures 16 / 207 26 / 201
Probability of PSA failure
8.9%
(5.5-14.0%)
14.1%
(9.8-20.1%)
PSA failuresPSA failures
Klotz L et al. BJU Int 2008;102:1531-8
Number at riskFirmagon 207 206 201 197 193 189 187 185 181 175 169 165 161 156Leuprolide 201 197 194 192 190 188 182 179 174 172 167 162 156 150
Leuprolide 7.5 mg
Firmagon 240/80 mg
100
95
90
85
80
Pro
bab
ility
(%
)
Time (days)0 28 56 84 112 140 168 196 224 252 280 308 336 364
PSA progression-free survival PSA progression-free survival (time to PSA failure/death: ITT population)(time to PSA failure/death: ITT population)
ITT, intent-to-treat; HR, hazard ratio
HR=0.664; P=0.0495 (log-rank test)
Tombal B et al. EAU 2009; poster #38
CS21 adverse events CS21 adverse events
*p<0.05, **p<0.01, and ***p<0.001 versus Firmagon pooled
<1%***35%Injection site AEs
9%*5%Arthralgia
Leuprolide7.5 mg
Firmagon24080 mg
Chills
Urinary tract infection
Any AE
0%**5%
9%**5%
78%79%
Injection site reactions – Injection site reactions – predominantly with starter predominantly with starter
dosedose
Klotz et al 2008
n %
Firmagon24080 mg
2244
207
N
82
66
4%Maintenance
dose(s)
32%Starter dose
Any injection site reaction(s)
Musculoskeletal eventsMusculoskeletal events
Firmagon Leuprolide7.5 mg
Patients with localised disease
Musculoskeletal and connective tissue disorders
20 (16%) 16 (25%)
Patients with locally advanced disease
Musculoskeletal and connective tissue disorders
13 (10%) 10 (19%)
Back pain 6 (5%) 4 (8%)
Arthralgia 2 (2%) 7 (13%)
Iversen P et al. CURy 2009; poster #618148
Patients with metastatic disease
Musculoskeletal and connective tissue disorders
16 (21%) 17 (36%)
Back pain 4 (5%) 6 (13%)
Arthralgia 4 (5%) 6 (13%)
Pain in extremity 1 (1%) 4 (9%)
Musculoskeletal events
Firmagon Leuprolide7.5 mg
Iversen P et al. CURy 2009; poster #618148
FIRMAGON efficacyFIRMAGON efficacy
•FastFast testosterone suppression without testosterone suppression without
a surge or micro-surgesa surge or micro-surges
•Fast and sustained PSA suppressionFast and sustained PSA suppression
•No need for flare protectionNo need for flare protection
•Lower risk of PSA failure Lower risk of PSA failure
FIRMAGON conclusionsFIRMAGON conclusions
•Incidence of adverse events similar with Incidence of adverse events similar with leuprolideleuprolide
•Related to androgen suppressionRelated to androgen suppression
•Higher incidence of injection site reactions Higher incidence of injection site reactions and chills and chills
•Lower incidence of urinary tract infections Lower incidence of urinary tract infections and musculoskeletal eventsand musculoskeletal events
•No immediate-onset systemic allergic No immediate-onset systemic allergic reactions reactions
Neoadjuvant + adjuvant
Intermittent
Options for short term treatment for Firmagon®
Phase III studies ongoing
QUESTIONSQUESTIONS
•Is firmagon the best castration therapy Is firmagon the best castration therapy
??
•What is the absolute minimal level of What is the absolute minimal level of
testosterone to effectively prevent testosterone to effectively prevent
prostate cancer growth (20 ng/ml) ?prostate cancer growth (20 ng/ml) ?