Transcript Emerging Therapies for Prostate Cancer

Benefits and Risks of GnRH/LHRH
Agonists and Antagonists in
Advanced Prostate Cancer Patients
John Trachtenberg, MD
Director, Prostate Cancer
Princess Margaret Hospital
Professor, Department of Surgery
University of Toronto
Toronto, Ontario, Canada
Leuprolide vs Diethylstilbestrol for
Metastatic Prostate Cancer

Increased incidence of flare

Decreased rate of initial response

Better adverse event profile

No difference in objective response

No difference in 1-year survival
Leuprolide Study Group. N Engl J Med. 1984;311(20):1281.
Alternatives to Surgical
Castration in the Treatment
of Advanced Prostate Cancer

LHRH agonists

Combined androgen blockade (CAB)

LHRH (GnRH) antagonists
Comparison of Goserelin with
Orchiectomy in Metastatic Prostate Cancer



Study compared goserelin with orchiectomy in 358
patients with metastatic prostatic carcinoma
(292 evaluable)
Randomized 1:1 to treatment with goserelin acetate
implant 3.6 mg or bilateral orchiectomy
Endpoints
– Subjective responses
– Objective responses
– Overall survival
– Effects of testosterone withdrawal
– Adverse effects
Kaisary AV, et al. Br J Urol. 1991;67:502.
Comparison of Goserelin with
Orchiectomy in Metastatic
Prostate Cancer: Study Results
Goserelin Acetate Orchiectomy
(n = 148)
(n = 144)
Response* (%)
Complete and partial
No change
Disease progression
71
18
11
72
22
6
Mean time to response (wk)
9.0
10.2
Median duration of response
in responding pts (wk)
53.7
50.1
Median time to treatment
failure in all pts (wk)
26.9
40.3
*All between-group P values were nonsignificant.
Kaisary AV, et al. Br J Urol. 1991;67:502.
Comparison of Goserelin with
Orchiectomy in Metastatic Prostate
Cancer: Study Results (cont’d)
Goserelin
Acetate
Orchiectomy
All Patients*
No. of patients
No. of deaths
Median survival (wk)
176
102
110
182
116
99
“Depot period” patients*
No. of patients
No. of deaths
Median survival (wk)
148
84
115
144
89
104
*No significant between-group differences. Kaisary AV, et al. Br J Urol. 1991;67:502.
Physiologic Effects of
Testosterone Withdrawal
73% (37/51)
79% (34/43)
Decrease in libido
Decrease in
erections
84% (43/51)
85% (41/48)
63% (96/152)
58% (94/163)
Hot flashes
Breast swelling
4.8% (8/168)
4% (7/173)
Goserelin acetate implant
0.6% (1/167)
1.2% (2/173)
Breast tenderness
0
20
Orchiectomy
40
60
Percentage
Kaisary AV, et al. Br J Urol. 1991;67:502.
80
100
Clinical Efficacy of 3-Month
Depot of Goserelin Acetate

Two randomized, multicenter trials compared
pharmacodynamics and tolerability of the 10.8 mg
and 3.6 mg goserelin acetate depots

Patients with histologically confirmed prostate
cancer, either locally advanced (T3, T4) or
metastatic disease (M1) and life expectancy
>6 months (N = 160)

Primary endpoint: mean serum testosterone level
(between weeks 4 and 12, and at the end of weeks
4, 8, and 12)
del Moral FP, et al. Urology. 1996;48:894.
Mean Testosterone (nmol/L)
Clinical Efficacy of 3-Month Depot
of Goserelin Acetate Mean Serum
Testosterone Levels over 48 Weeks
20.0
Goserelin acetate
17.5
10.8 mg depot
15.0
3.6 mg depot
12.5
10.0
7.5
5.0
Castrate level
2.5
0.0
0 1 2 3 4 6 8 10 12 14 16 18 20 22 24 36 48
Nominal Study Week
del Moral FP, et al. Urology. 1996;48:894.
Combined Androgen Blockade
LHRH Agonist Plus Anti-androgen


Eliminate flare
– 5%–33% incidence in patients with
metastatic disease
Improve survival by decreasing effect of
adrenal androgens
– A controlled trial of leuprolide with and
without flutamide in prostatic carcinoma
 Improved PFS (16.5 vs 13.9 mo)
 Improved survival (35.6 vs 28.3 mo)
Crawford et al, N Engl J Med. 1989;321:418.
Combined Androgen Blockade
LHRH Agonist Plus Anti-androgen
(cont’d)

Eliminate flare
– Modest QOL cost (diarrhea, anemia)

Improve survival by decreasing effect of adrenal
androgens (bilateral orchiectomy with or without
flutamide for metastatic prostate cancer)

Shows no clinically important survival advantage
Eisenberger et al, N Engl J Med. 1998;339:1036.
GnRH Antagonists in
Advanced Prostate Cancer
Abarelix Studies


2 phase III studies of abarelix
– 149-98-021: compared abarelix
with leuprolide
– 149-98-032: compared abarelix with
leuprolide plus bicalutamide
Study objectives
– Compare rates of avoidance of
testosterone surge
– Compare rates of reduction of
testosterone to castrate level
1. McLeod D, et al. Urology. 2001;58:756. 2. Trachtenberg J, et al. J Urol. 2002;167:1670.
Abarelix Studies: Surge and Castrate Levels
Surge*
149-98-02 (vs L)1
149-98-03 (vs L + B)2
Castrate‡
149-98-021
(vs L)
149-98-032
(vs L + B)
Day 2
Day 4
Day 8
Day 15
Day 2
Day 4
Day 8
Day 15
Comparator
Abarelix
P-value†
82%
86%
0%
0%
< .001
< .001
Comparator
Abarelix
P-value1
0%
0%
0%
10%
0%
0%
0%
21%
24%
57%
72%
75%
25%
54%
68%
72%
< .001
< .001
< .001
< .001
< .001
< .001
< .001
< .001
*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
1. McLeod D, et al. Urology. 2001;58:756. 2.Trachtenberg J, et al. J Urol. 2002;167:1670.
Abarelix Studies:
Median Testosterone Levels
Study 149-98-03 Through Day 29
Leuprolide + Bicalutamide
Abarelix
600
600
500
*
T Level (ng/dL)
T Level (ng/dL)
*
*
400
300
200
*
100
8
15
400
300
200
100
0
1
500
29
0
1
Study Day
*P < .001 when compared with abarelix.
Trachtenberg J, et al. J Urol. 2002;167:1670.
With permission from Lippincott, Williams, & Wilkins. www.lww.com
8
15
Study Day
29
Abarelix Studies: Median Percentage
Change from Baseline PSA
Study 149-98-02
Median Percentage
Change in PSA
0
*
Leuprolide
-20
Abarelix
-40
*
-60
-80
-100
n - LD
n - AD
88
174
1
87
179
7
85
176
13 19 25 31 37 43 49 55 61 67 73 79 85
Time (Days)
Note: Bars represent interquartile range. *P  .001.
Reprinted from McLeod D, et al. Urol. 2001;58:756. With permission from Elsevier Science.
Abarelix Studies:
Clinical Relevance of
Testosterone Fluctuations

2%–3% of abarelix patients per month had
testosterone fluctuations after 6 months compared
with no leuprolide patients.

1.8% (4/221) of patients did not have the intended
therapeutic benefit of abarelix, as correlated with
testosterone values >50 ng/dL.

In US studies, testosterone fluctuations after
6 months of treatment were of little clinical
relevance.
ABACAS 1



Comparison of the efficacy and
safety of abarelix vs goserelin
plus bicalutamide
177 patients with advanced or
metastatic prostate cancer
1-year, randomized, open-label,
multicenter, phase III trial
ABACAS 1
Patient Demographics
PCa stage
N1–M0 (D1)
Nx–M1 (D2)
Rising PSA
Abarelix
(n = 87)
Goserelin
+
Bicalutamide
(n = 90)
Total
(N = 177)
17 (20%)
39 (44.8%)
30 (34.5%)
19 (21%)
39 (43.3%)
31 (34.4%)
36 (20.3%)
78 (44.1%)
61 (34.5%)
50 (56%)
97 (55%)
Gleason score
7–10
47 (54%)
ABACAS 1 Study Results
Endpoint
Median time to
medical castration
Castration rates
(day 3)
Testosterone surge
Testosterone
fluctuations above
castrate levels
Disease
progression rates
Total
Abarelix
Goserelin
+
Bicalutamide
7 days
21 days
36%
0%
0%
96%
22%
8%
9%
9%
Immediate-Onset Systemic
Allergic Reactions

Of 1400 patients treated with abarelix,
systemic reactions requiring discontinuation
occurred in 6 patients.

Reactions occurred within 10 minutes of
receiving abarelix.

All patients recovered.

Rates of allergic reactions requiring medical
intervention are similar in comparative
clinical studies.
Summary

Objective of androgen ablation in prostate
cancer treatment is to deprive prostate cancer
cells of testosterone.

Surgical castration (orchiectomy) was the
initial treatment of choice for prostate
cancer management.

Development of the LHRH agonists offered an
effective alternative to surgical castration.

Clinical trials demonstrated comparable
efficacy between an LHRH agonist and
bilateral orchiectomy.
Summary (cont’d)



The discovery and development of the GnRH
antagonists have advanced treatment of
prostate cancer.
The GnRH antagonist abarelix has demonstrated
favorable efficacy and tolerability in phase III
clinical trials.
GnRH antagonists
– Cause an immediate and rapid suppression of
testosterone levels
– Are not associated with testosterone surge and
clinical flare
– Can be used in patients for whom LHRH agonists
are contraindicated
– Are well tolerated and have an acceptable
safety profile