This document discusses hormonal manipulation in early prostate cancer. It begins with an overview of the prostate cancer treatment continuum and various treatment options including radical prostatectomy, radiotherapy, hormonal therapy, and watchful waiting. It then focuses on the luteinizing hormone-releasing hormone (LHRH) agonist Zoladex (goserelin), reviewing its efficacy as neoadjuvant therapy prior to radical prostatectomy, and as adjuvant therapy following both radical prostatectomy and radiotherapy. Long-term clinical trial data is presented demonstrating improved survival outcomes when Zoladex is used as an adjuvant therapy. Other LHRH agonists such as leuprolide are also discussed. The mechanisms of action and clinical benefits
5. Rationale for combination therapy
Androgens
ACTH ‘Casodex’
(bicalutamide)
Adrenal gland
LHRH Hypothalamus
DHT
X
Other
‘Zoladex’ target
(goserelin) tissues
Pituitary gland Androgen
DHT receptor
Testis
Prostate cell
LH
Circulating testosterone
-ve feedback control
6. Topics for Discussion
LAPC:
Neo-adjuvant to RP
Adjuvant to RP
Adjuvant to RT (Long Term Data & Duration)
LHRH analogue: Approved indications in Prostate
Cancer
7. ‘Zoladex’ (goserelin) Neo-adjuvant to Radical
Prostatectomy
Clinical down-staging and downsizing Fourcade et al 1993
Clinical down-staging and significantly Montironi et al 1999
fewer positive margins Bono et al 2001
PROSIT
Significantly fewer positive margins and Meyer et al 1999
reduction in risk of PSA failure
No difference in PSA progression Witjes et al 1998
PSA, prostate-specific antigen
8. Topics for Discussion
LAPC:
Neo-adjuvant to RP
Adjuvant to RP
Adjuvant to RT (Long Term Data & Duration)
LHRH analogue: Approved indications in
Prostate Cancer
9. ‘Zoladex’ (goserelin) adjuvant to radical prostatectomy the
LHRH agonist that is… proven to have
Significant improvement in Messing et al 1999, 2003
overall and disease-free ECOG 7887
survival
Prayer-Galetti et al 2000
Significant improvement in
disease-free survival
ECOG, Eastern Co-operative Oncology Group
10. ECOG 7887 trial: study design
Radical prostatectomy
+ lymph node dissection
(n=98)
Randomised
Immediate hormonal therapy
Observation until
(70% ‘Zoladex’ [goserelin],
progression
30% bilateral orchiectomy)
(n=51)
(n=47)
Messing et al 1999, 2003
11. ECOG 7887 trial: long-term survival
p=0.001
Patients100
87.2
(%) p=0.025
80 72.4
Median follow-
60 56.9
up 10 years
49
40
All patients
20 were high risk
at baseline (T1-
0 2, N+)
Overall survival Cause-specific survival
Radical prostatectomy + ‘Zoladex’ (goserelin) /
orchiectomy (n=47)
Radical prostatectomy only (n=51)
Messing et al 2003
12. Topics for Discussion
LAPC:
Neo-adjuvant to RP
Adjuvant to RP
Adjuvant to RT (Long Term Data &
Duration)
LHRH analogue: Approved indications in Prostate Cancer
13. LAPC: Adjuvant to RT
RTOG 85-31 significantly reduced risk of;
– local failure
– distant metastasis
significantly prolonged;
– disease-free survival
– overall survival
The long-term results:
RTOG 92-02 • 24 months of ADT after total
androgen suppression and RT is
superior to total androgen
suppression and RT alone
19. Distant-Metastasis-Free Survival
(at 10 years)
Combined Rx Group RT Group
51% 30·2%
(95% CI 42·3–59·1) (95% CI 23·1–37·6)
HR 0·50, 95% CI (0·38–0·65); (p<0·0001)
24. Zoladex 10.8mg – Approved Indications
in Prostate Cancer
In the treatment of metastatic prostate cancer where Zoladex has
demonstrated comparable survival benefits to surgical castrations
In the treatment of locally advanced prostate cancer, as an
alternative to surgical castration where Zoladex has demonstrated
comparable survival benefits to an anti-androgen
As adjuvant treatment to radiotherapy in patients with high-risk
localised or locally advanced prostate cancer where Zoladex has
demonstrated improved disease-free survival and overall survival
As neo-adjuvant treatment prior to radiotherapy in patients with
high-risk localised or locally advanced prostate cancer where
Zoladex has demonstrated improved disease-free survival
As adjuvant treatment to radical prostatectomy in patients with
locally advanced prostate cancer at high risk of disease
progression where Zoladex has demonstrated improved disease-
free survival
Ref : Zoladex 10.8mg – Summary of Product Characteristics
25. Leuprolide in Prostate Cancer
Clinical Data
In a randomised, open-label, multi-centre
comparative trial, leuprorelin in
combination with flutamide has been
shown to significantly improve DFS and OS
when used as an adjuvant therapy to RT in
88 patients with high-risk localised (T1-T2
and PSA of at least 10 ng/mL or a Gleason
score of at least 7), or locally advanced (T3-
T4) prostate cancer
Ref : Prostap 3 Leuprorelin Acetate Depot Injection 11.25mg - Summary of Product Characteristics
26. Leuprolide neoadjuvant / adjuvant to RT:
post-RT PSA levels
RT alone (n=41)
PSA level 2 Leuprolide / flutamide before RT (n=43)
ng/mL Leuprolide / flutamide before and after RT (n=36)
1.56
1.20
1
0.60 0.65
0.5
0.2
0
12 24
Time post-radiotherapy (months)
Laverdière et al 1997
27. Leuprorelin Acetate Depot Injection 11.25mg –
Approved Indications in Prostate Cancer
Metastatic prostate cancer
Locally advanced prostate cancer, as an alternative to
surgical castration.
As an adjuvant treatment to radiotherapy in patients with
high-risk localised or locally advanced prostate cancer.
As an adjuvant treatment to radical prostatectomy in
patients with locally advanced prostate cancer at high risk
of disease progression
Ref : Prostap 3 Leuprorelin Acetate Depot Injection 11.25mg - Summary of Product Characteristics
28. Urology. 2011 Nov;78(5 Suppl):S494-8.
Dreicer R, Bajorin DF, McLeod DG, Petrylak DP, Moul
JW
The luteinizing hormone-releasing
hormone agonists resulted in a
periodic return of noncastrate
testosterone levels once the receptor
desensitization attenuated and the
effect of androgen agonism resumed.
29. Therefore, the introduction of an androgen receptor
antagonist (gonadotropin-releasing hormone antagonist)
appeared, conceptually at least, to be a preferable
alternative.
The first such agent, degarelix, has proved to provide rapid
testosterone suppression without the initial testosterone
surge associated with luteinizing hormone-releasing
hormone agonists.
31. GnRH Receptor Antagonists
Dagerelix
Degarelix(FIRMAGON) is a gonadotrophin releasing hormone
(GnRH) antagonist indicated for treatment of adult male patients
with advanced hormone-dependent prostate cancer
Starting Dose : 240 mg administered as two subcutaneous
injections of 120 mg each
Maintenance Dose ( Monthly) : 80 mg administered as one
subcutaneous injection
96% of patients had T supression (T˂ 0.5ng/ml) within 3 days of
starting dose and 100% after 1 month
Long term treatment & maintenance dose upto 1 year has shown
that 97% of patients had sustained T supression (T˂0.5ng/ml)
Advantage : Since degarelix does not induce a testosterone surge it
is not necessary to add an anti-androgen as surge protection at
initiation of therapy
Ref : Firmagon – Summary of Prescribing Information
32. Other new agents
A selective and irreversible inhibitor of
CYP17, abiraterone,
MDV3100, a novel small molecule that acts
as an oral nonsteroidal antiandrogen agent.