endocrinology of prostate cancer. hormonal pathways of the male endocrine system

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


TURTUR 141141 6565 PP<0.001<0.001


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


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


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


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)


EORTC 22863EORTC 22863Overall Survival 66-Month Follow-upOverall Survival 66-Month Follow-up


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


Pro

por

tion

Aliv

e (%

)


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


5-Year Survival6500 Men in 20 Trials of Nilutamide/Flutamide

Pro

por

tion

Aliv

e (%

)


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

[email protected]

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.)



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


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


-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


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)


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


- 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


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


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


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) ?

endocrinology of prostate cancer. hormonal pathways of the male endocrine system

Documents

mrc prostate cancer

metastatic disease ht

orchiectomy survival

hormonal therapy options

evaluable patients

metastatic disease advantages

binding globulin slide

patients immediate arm