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

1. Hormonal Manipulations in
Early Prostate Cancer
Dr T. Raja
Consultant Medical Oncology,
Apollo Speciality Hospital,
Chennai

2. Prostate Cancer Continuum
Localised
prostate Locally Metastatic Hormone
High-grade PIN cancer advanced disease insensitive
TxN0M0 T3-4 D1.5 D2 D2.5 D3
Time (years)
PIN, prostatic intraepithelial Neoplasia

3. Treatment for Prostate Cancer
Localised
prostate Locally Metastatic Hormone
High-grade PIN cancer advanced disease insensitive
TxN0M0 T3-4 D1.5 D2 D2.5 D3
Time (years)
Treatment options: Radical Hormonal therapy
prostatectomy
Chemotherapy
Radiotherapy
‘Watchful waiting’
Radiotherapy
Hormonal therapy
‘Watchful waiting’
PIN, prostatic intraepithelial neoplasia

4. Testosterone suppression
with ‘Zoladex’ (goserelin)
Mean 18 ‘Zoladex’ (goserelin) 3.6 mg (n=42)
testosterone
16 ‘Zoladex’ (goserelin) 10.8 mg (n=38)
concentration
(nmol/L) 14
12
10
8
6
4 Upper castrate limit
2
0
0 4 8 12 16 20 24 26 28 32 36 40 44
Time (weeks)
Dijkman et al 1995

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

14. LAPC: Adjuvant to RT (EORTC 22863)

15. EORTC 22863 Study
Study
 Open label, randomized (1:1) phase III trial
 26 centres Primary endpoint:
Patients • Disease Free Survival
 < 80 years of age
Secondary endpoint:
 PS: 0-2
• Overall Survival
 Newly diagnosed • Distant MFS
 Stage: • Cause Specific Mortality
– T1-2, WHO grade 3
• Locoregional Control
– T3-4 of any grade
Histological confirmed primary adeno-carcinoma

16. EORTC 22863 Study
Enrollment begin with 1987 to 1995

18. PFS: Sites of Disease Progression

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)

20. 58.1%
39.8%

21. Overall Survival at 10 years
(HR 0·56, 95% CI 0·41–0·75; p=0·0001)

22. Prostate Cancer Mortality: 10 yrs
follow-up
30.4%
10.3%

23. Locoregional failure rate at 10
years
(HR 0·21, 95% CI 0·12–0·40; p<0·0001)
23.5% 6.0%

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.

30. GnRH Antagonists – Mechanism of Action

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.

33. Current and Future Hormonal Therapy Drugs
UROLOGY 78: S494–S498, 2011

34. NCCN Guidelines Version 3.2012
ADT based on Recurrence risk
 Low risk: T1-T2a, Gleasons <=6,
PSA <10 No treatment
 Intermediate risk: T2b-T2c, Gleason >=7,
PSA 10-20 ADT 4-6m0s
 High risk: T3a, Gleasons 10, PSA >20
ADT 4-6mos
 Locally advancee: T3b-T4 ADT 2-3yrs

35. Thank You for your attention