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Benefits and Risks of GnRH/LHRH Benefits and Risks of GnRH/LHRH Agonists and Antagonists inAgonists and Antagonists in
Advanced Prostate Cancer PatientsAdvanced Prostate Cancer Patients
John Trachtenberg, MDJohn Trachtenberg, MDDirector, Prostate Cancer Director, Prostate Cancer
Princess Margaret HospitalPrincess Margaret Hospital
Professor, Department of SurgeryProfessor, Department of Surgery
University of Toronto University of Toronto
Toronto, Ontario, CanadaToronto, Ontario, Canada
Leuprolide vs Diethylstilbestrol for Leuprolide vs Diethylstilbestrol for Metastatic Prostate CancerMetastatic Prostate Cancer
Increased incidence of flareIncreased incidence of flare Decreased rate of initial responseDecreased rate of initial response Better adverse event profileBetter adverse event profile No difference in objective responseNo difference in objective response No difference in 1-year survival No difference in 1-year survival
Leuprolide Study Group. N Engl J Med. 1984;311(20):1281.
Alternatives to Surgical Alternatives to Surgical Castration in the Treatment Castration in the Treatment
of Advanced Prostate Cancerof Advanced Prostate Cancer
LHRH agonistsLHRH agonists Combined androgen blockade (CAB)Combined androgen blockade (CAB) LHRH (GnRH) antagonistsLHRH (GnRH) antagonists
Comparison of Goserelin with Comparison of Goserelin with Orchiectomy in Metastatic Prostate Cancer Orchiectomy in Metastatic Prostate Cancer
Study compared goserelin with orchiectomy in 358 Study compared goserelin with orchiectomy in 358 patients with metastatic prostatic carcinomapatients with metastatic prostatic carcinoma(292 evaluable)(292 evaluable)
Randomized 1:1 to treatment with goserelin acetate Randomized 1:1 to treatment with goserelin acetate implant 3.6 mg or bilateral orchiectomyimplant 3.6 mg or bilateral orchiectomy
EndpointsEndpoints– Subjective responsesSubjective responses– Objective responsesObjective responses– Overall survivalOverall survival– Effects of testosterone withdrawalEffects of testosterone withdrawal– Adverse effectsAdverse effects
Kaisary AV, et al. Br J Urol. 1991;67:502.
Response* (%)Response* (%)Complete and partialComplete and partial 7171 7272No changeNo change 1818 2222Disease progressionDisease progression 1111 66
Mean time to response (wk)Mean time to response (wk) 9.09.0 10.210.2
Median duration of response Median duration of response 53.753.7 50.150.1in responding pts (wk) in responding pts (wk)
Median time to treatmentMedian time to treatment 26.926.9 40.340.3failure in all pts (wk)failure in all pts (wk)
**All between-group P values were nonsignificant.Kaisary AV, et al. Br J Urol. 1991;67:502.
Comparison of Goserelin with Comparison of Goserelin with Orchiectomy in Metastatic Orchiectomy in Metastatic
Prostate Cancer: Study ResultsProstate Cancer: Study ResultsGoserelin AcetateGoserelin Acetate OrchiectomyOrchiectomy
(n = 148)(n = 148) (n = 144)(n = 144)
All PatientsAll Patients**No. of patientsNo. of patients 176176 182182No. of deathsNo. of deaths 102102 116116Median survival (wk)Median survival (wk) 110110 9999
““Depot period” patientsDepot period” patients**No. of patientsNo. of patients 148148 144144No. of deathsNo. of deaths 8484 8989
Median survival (wk)Median survival (wk) 115115 104104*No significant between-group differences. Kaisary AV, et al. Br J Urol. 1991;67:502.
GoserelinGoserelinAcetateAcetate OrchiectomyOrchiectomy
Comparison of Goserelin with Comparison of Goserelin with Orchiectomy in Metastatic Prostate Orchiectomy in Metastatic Prostate
Cancer: Study Results Cancer: Study Results (cont’d)(cont’d)
0 20 40 60 80 100
Breast tenderness
Breast swelling
Hot flashes
Decrease inerections
Decrease in libido
Kaisary AV, et al. Br J Urol. 1991;67:502.
73% (37/51)73% (37/51)79% (34/43)79% (34/43)
84% (43/51)84% (43/51)85% (41/48)85% (41/48)
63% (96/152)63% (96/152)58% (94/163)58% (94/163)
4.8% (8/168)4.8% (8/168)4% (7/173)4% (7/173)
0.6% (1/167)0.6% (1/167)1.2% (2/173)1.2% (2/173)
Goserelin acetate implantGoserelin acetate implant
OrchiectomyOrchiectomy
PercentagePercentage
Physiologic Effects ofPhysiologic Effects ofTestosterone WithdrawalTestosterone Withdrawal
del Moral FP, et al. Urology. 1996;48:894.
Clinical Efficacy of 3-Month Clinical Efficacy of 3-Month Depot of Goserelin AcetateDepot of Goserelin Acetate
Two randomized, multicenter trials compared Two randomized, multicenter trials compared pharmacodynamics and tolerability of the 10.8 mgpharmacodynamics and tolerability of the 10.8 mgand 3.6 mg goserelin acetate depotsand 3.6 mg goserelin acetate depots
Patients with histologically confirmed prostate Patients with histologically confirmed prostate cancer, either locally advanced (T3, T4) or cancer, either locally advanced (T3, T4) or metastatic disease (M1) and life expectancymetastatic disease (M1) and life expectancy>6 months (N = 160)>6 months (N = 160)
Primary endpoint: mean serum testosterone level Primary endpoint: mean serum testosterone level (between weeks 4 and 12, and at the end of weeks (between weeks 4 and 12, and at the end of weeks 4, 8, and 12)4, 8, and 12)
del Moral FP, et al. Urology. 1996;48:894.
Nominal Study WeekNominal Study Week
Me
an
Te
sto
ste
ron
e (n
mo
l/L)
Me
an
Te
sto
ste
ron
e (n
mo
l/L)
10.8 mg depot10.8 mg depot
3.6 mg depot 3.6 mg depot
0 1 2 3 4 6 8 10 12 14 16 18 2022 24 36 48
0.0
2.5
5.0
7.5
10.0
12.5
15.0
17.5
20.0
Castrate levelCastrate level
Goserelin acetateGoserelin acetate
Clinical Efficacy of 3-Month Depot Clinical Efficacy of 3-Month Depot of Goserelin Acetate Mean Serum of Goserelin Acetate Mean Serum
Testosterone Levels over 48 WeeksTestosterone Levels over 48 Weeks
Combined Androgen BlockadeCombined Androgen Blockade LHRH Agonist Plus Anti-androgen LHRH Agonist Plus Anti-androgen
Eliminate flareEliminate flare
– 5%–33% incidence in patients with 5%–33% incidence in patients with metastatic diseasemetastatic disease
Improve survival by decreasing effect ofImprove survival by decreasing effect ofadrenal androgensadrenal androgens
– A controlled trial of leuprolide with and A controlled trial of leuprolide with and without flutamide in prostatic carcinomawithout flutamide in prostatic carcinoma Improved PFS (16.5 vs 13.9 mo)Improved PFS (16.5 vs 13.9 mo) Improved survival (35.6 vs 28.3 mo)Improved survival (35.6 vs 28.3 mo)
Crawford et al, Crawford et al, N Engl J MedN Engl J Med. 1989;321:418.. 1989;321:418.
Combined Androgen BlockadeCombined Androgen Blockade LHRH Agonist Plus Anti-androgen LHRH Agonist Plus Anti-androgen
(cont’d)(cont’d)
Eliminate flareEliminate flare
– Modest QOL cost (diarrhea, anemia)Modest QOL cost (diarrhea, anemia) Improve survival by decreasing effect of adrenal Improve survival by decreasing effect of adrenal
androgens (bilateral orchiectomy with or without androgens (bilateral orchiectomy with or without flutamide for metastatic prostate cancer)flutamide for metastatic prostate cancer)
Shows no clinically important survival advantageShows no clinically important survival advantage
Eisenberger et al, Eisenberger et al, N Engl J MedN Engl J Med. 1998;339:1036.. 1998;339:1036.
GnRH Antagonists inGnRH Antagonists in Advanced Prostate Cancer Advanced Prostate Cancer
Abarelix StudiesAbarelix Studies
2 phase III studies of abarelix2 phase III studies of abarelix
– 149-98-02149-98-0211: compared abarelix: compared abarelixwith leuprolidewith leuprolide
– 149-98-03149-98-0322: compared abarelix with leuprolide : compared abarelix with leuprolide plus bicalutamideplus bicalutamide
Study objectivesStudy objectives
– Compare rates of avoidance of testosterone Compare rates of avoidance of testosterone surgesurge
– Compare rates of reduction of testosterone to Compare rates of reduction of testosterone to castrate levelcastrate level
1. McLeod D, et al. Urology. 2001;58:756. 2. Trachtenberg J, et al. J Urol. 2002;167:1670.
24%24% < .001< .00157%57% < .001< .00172% < .00175%75% < .001< .00125%25% < .001< .00154%54% < .001< .00168% < .00172%72% < .001< .001
AbarelixAbarelixComparatorComparator PP-value-value11
149-98-02149-98-0211
(vs L)(vs L)
149-98-03149-98-0322
(vs L + B)(vs L + B)
CastrateCastrate‡‡
82%82% 0%0% < .001< .00186%86% 0%0% < .001< .001
149-98-02 (vs L)149-98-02 (vs L)11 149-98-03 (vs L + B)149-98-03 (vs L + B)22
AbarelixAbarelixComparatorComparator PP-value-value††Surge*Surge*
*Calculation of T surge: 2 of 3 testosterone level measurements between days 2 and 8 exceeded PT baseline level by ≥10%.†Fisher’s exact test‡Definition of castration: Testosterone ≤50 ng/dL
Day 2Day 2Day 4Day 4Day 8 Day 15 Day 15 Day 2 Day 2 Day 4 Day 4 Day 8Day 15 Day 15
0%0%0%0%0%
10%10%0%0%0%0%0%
21%21%
Abarelix Studies: Surge and Castrate LevelsAbarelix Studies: Surge and Castrate Levels
1. McLeod D, et al. Urology. 2001;58:756. 2.Trachtenberg J, et al. J Urol. 2002;167:1670.
0
100
200
300
400
500
600
0
100
200
300
400
500
600
1 8 15 29
T L
evel
(n
g/d
L)
T L
evel
(n
g/d
L)
Study DayStudy Day15
T L
evel
(n
g/d
L)
Study DayStudy Day1 8 29
Leuprolide + Bicalutamide AbarelixAbarelix
*P < .001 when compared with abarelix.
**
*
*
Trachtenberg J, et al. J Urol. 2002;167:1670. With permission from Lippincott, Williams, & Wilkins. www.lww.com
Abarelix Studies:Abarelix Studies:Median Testosterone LevelsMedian Testosterone Levels
Study 149-98-03 Through Day 29 Study 149-98-03 Through Day 29
Study 149-98-02
1 67 737 79 8531251913 49 55 614337
-100
-20
0
Med
ian
Per
cen
tag
eM
edia
n P
erce
nta
ge
Ch
ang
e in
PS
AC
han
ge
in P
SA
n - LD1741748888 8787
179179 1761768585
n - AD
Time (Days)Time (Days)
-80
-40
-60
Abarelix Abarelix
LeuprolideLeuprolide
Abarelix Studies: Median Percentage Abarelix Studies: Median Percentage Change from Baseline PSAChange from Baseline PSA
*
*
Note: Bars represent interquartile range. *P .001.
Reprinted from McLeod D, et al. Urol. 2001;58:756. With permission from Elsevier Science.
Abarelix Studies:Abarelix Studies:Clinical Relevance of Clinical Relevance of
Testosterone Fluctuations Testosterone Fluctuations
2%–3% of abarelix patients per month had 2%–3% of abarelix patients per month had testosterone fluctuations after 6 months compared testosterone fluctuations after 6 months compared with no leuprolide patients.with no leuprolide patients.
1.8% (4/221) of patients did not have the intended 1.8% (4/221) of patients did not have the intended therapeutic benefit of abarelix, as correlated with therapeutic benefit of abarelix, as correlated with testosterone values >50 ng/dL.testosterone values >50 ng/dL.
In US studies, testosterone fluctuations after In US studies, testosterone fluctuations after 6 months of treatment were of little clinical 6 months of treatment were of little clinical relevance.relevance.
ABACAS 1 ABACAS 1
Comparison of the efficacy andComparison of the efficacy andsafety of abarelix vs goserelinsafety of abarelix vs goserelinplus bicalutamideplus bicalutamide
177 patients with advanced or 177 patients with advanced or metastatic prostate cancermetastatic prostate cancer
1-year, randomized, open-label, 1-year, randomized, open-label, multicenter, phase III trialmulticenter, phase III trial
ABACAS 1ABACAS 1Patient DemographicsPatient Demographics
Goserelin+
Abarelix Bicalutamide Total (n = 87) (n = 90) (N = 177)
PCa stage N1–M0 (D1) 17 (20%) 19 (21%) 36 (20.3%)Nx–M1 (D2) 39 (44.8%) 39 (43.3%) 78 (44.1%)Rising PSA 30 (34.5%) 31 (34.4%) 61 (34.5%)
Gleason score7–10 47 (54%) 50 (56%) 97 (55%)
ABACAS 1 Study ResultsABACAS 1 Study Results Goserelin
Total +Endpoint Abarelix Bicalutamide
Median time to medical castration 7 days 21 days
Castration rates (day 3) 36% 0%
Testosterone surge 0% 96%
Testosterone fluctuations above castrate levels 22% 8%
Disease progression rates 9% 9%
Immediate-Onset Systemic Immediate-Onset Systemic Allergic ReactionsAllergic Reactions
Of 1400 patients treated with abarelix, Of 1400 patients treated with abarelix, systemic reactions requiring discontinuation systemic reactions requiring discontinuation occurred in 6 patients. occurred in 6 patients.
Reactions occurred within 10 minutes of Reactions occurred within 10 minutes of receiving abarelix. receiving abarelix.
All patients recovered. All patients recovered. Rates of allergic reactions requiring medical Rates of allergic reactions requiring medical
intervention are similar in comparative clinical intervention are similar in comparative clinical studies.studies.
Summary Summary
Objective of androgen ablation in prostate Objective of androgen ablation in prostate cancer treatment is to deprive prostate cancer cancer treatment is to deprive prostate cancer cells of testosterone.cells of testosterone.
Surgical castration (orchiectomy) was the Surgical castration (orchiectomy) was the initial treatment of choice for prostateinitial treatment of choice for prostatecancer management. cancer management.
Development of the LHRH agonists offered an Development of the LHRH agonists offered an effective alternative to surgical castration.effective alternative to surgical castration.
Clinical trials demonstrated comparable Clinical trials demonstrated comparable efficacy between an LHRH agonist andefficacy between an LHRH agonist andbilateral orchiectomy.bilateral orchiectomy.
Summary Summary (cont’d)(cont’d) The discovery and development of the GnRH The discovery and development of the GnRH
antagonists have advanced treatment ofantagonists have advanced treatment ofprostate cancer.prostate cancer.
The GnRH antagonist abarelix has demonstrated The GnRH antagonist abarelix has demonstrated favorable efficacy and tolerability in phase IIIfavorable efficacy and tolerability in phase IIIclinical trials.clinical trials.
GnRH antagonistsGnRH antagonists– Cause an immediate and rapid suppression of Cause an immediate and rapid suppression of
testosterone levelstestosterone levels– Are not associated with testosterone surge and Are not associated with testosterone surge and
clinical flareclinical flare– Can be used in patients for whom LHRH agonists Can be used in patients for whom LHRH agonists
are contraindicatedare contraindicated– Are well tolerated and have an acceptable Are well tolerated and have an acceptable
safety profilesafety profile