Hormonal Manipulations in Early Prostate Cancer

Dr T. Raja Consultant Medical Oncology, Apollo Speciality Hospital,Chennai

Prostate Cancer Continuum

Time (years)

High-grade PINMetastatic

diseaseHormone

insensitive

D1.5 D2 D2.5 D3TxN0M0 T3-4

Locallyadvanced

Localisedprostatecancer

PIN, prostatic intraepithelial Neoplasia

Treatment for Prostate Cancer

High-grade PINMetastatic

diseaseHormone

insensitive

Radical prostatectomy Radiotherapy

‘Watchful waiting’ Radiotherapy Hormonal therapy‘Watchful waiting’

Hormonal therapy

D1.5 D2 D2.5 D3TxN0M0 T3-4

Locallyadvanced

Localisedprostatecancer

Treatment options:

Chemotherapy

Time (years)

PIN, prostatic intraepithelial neoplasia

Testosterone suppression with ‘Zoladex’ (goserelin)

Upper castrate limit

0 4 8 12 16 20 24 26 28 32 36 40 440

2

4

6

8

10

12

14

16

18

Time (weeks)

‘Zoladex’ (goserelin) 3.6 mg (n=42)‘Zoladex’ (goserelin) 10.8 mg (n=38)

Meantestosteroneconcentration(nmol/L)

Dijkman et al 1995

Rationale for combination therapy

LHRH Hypothalamus

Pituitary gland

LH

ACTH

Adrenal gland

Testis

Circulating testosterone

Androgens

Othertargettissues

DHT

Prostate cell

Androgenreceptor

-ve feedback control

DHT

‘Zoladex’(goserelin)

‘Casodex’(bicalutamide)

X

Topics for DiscussionLAPC:

Neo-adjuvant to RP

Adjuvant to RP

Adjuvant to RT (Long Term Data & Duration)

LHRH analogue: Approved indications in Prostate Cancer

‘Zoladex’ (goserelin) Neo-adjuvant to Radical Prostatectomy

Fourcade et al 1993

Montironi et al 1999Bono et al 2001PROSIT

Meyer et al 1999

Witjes et al 1998

Clinical down-staging and downsizing

Clinical down-staging and significantly fewer positive margins

Significantly fewer positive margins and reduction in risk of PSA failure

No difference in PSA progression

PSA, prostate-specific antigen

Topics for DiscussionLAPC:

Neo-adjuvant to RP

Adjuvant to RP Adjuvant to RT (Long Term Data & Duration)

LHRH analogue: Approved indications in Prostate Cancer

‘Zoladex’ (goserelin) adjuvant to radical prostatectomy the LHRH agonist that is… proven to have

Messing et al 1999, 2003ECOG 7887

Prayer-Galetti et al 2000

Significant improvement in overall and disease-free survival

Significant improvement in disease-free survival

ECOG, Eastern Co-operative Oncology Group

ECOG 7887 trial: study design

Radical prostatectomy+ lymph node dissection

(n=98)

Randomised

Immediate hormonal therapy(70% ‘Zoladex’ [goserelin],30% bilateral orchiectomy)

(n=47)

Messing et al 1999, 2003

Observation until progression

(n=51)

Messing et al 2003

ECOG 7887 trial: long-term survival

Median follow-up 10 years

All patients were high risk at baseline (T1-2, N+)

Patients(%)

Overall survival Cause-specific survival0

20

40

60

80

100 Overall survival; 'Zoladex' (gosere-

lin) (n=33) / or-chiectomy (n=13);

72.4

Cause-specific survival; 'Zoladex' (goserelin) (n=33) /

orchiectomy (n=13); 87.2

Overall survival; Radical prostatec-tomy alone (n=51);

49

Cause-specific survival; Radical prostatectomy

alone (n=51); 56.9

p=0.025

p=0.001

Radical prostatectomy + ‘Zoladex’ (goserelin) / orchiectomy (n=47)Radical prostatectomy only (n=51)

Topics for DiscussionLAPC:

Neo-adjuvant to RP

Adjuvant to RP

Adjuvant to RT (Long Term Data & Duration)

LHRH analogue: Approved indications in Prostate Cancer

LAPC: Adjuvant to RT

RTOG 85-31

RTOG 92-02

significantly reduced risk of;

– local failure

– distant metastasis

significantly prolonged;

– disease-free survival

– overall survival

The long-term results:• 24 months of ADT after total

androgen suppression and RT is superior to total androgen suppression and RT alone

LAPC: Adjuvant to RT (EORTC 22863)

EORTC 22863 StudyStudy Open label, randomized (1:1) phase III trial

26 centres

Patients

< 80 years of age

PS: 0-2

Newly diagnosed

Stage:

– T1-2, WHO grade 3

– T3-4 of any grade

Histological confirmed primary adeno-carcinoma

Primary endpoint:

• Disease Free Survival

Secondary endpoint:

• Overall Survival

• Distant MFS

• Cause Specific Mortality

• Locoregional Control

EORTC 22863 Study

Enrollment begin with 1987 to 1995

PFS: Sites of Disease Progression

Distant-Metastasis-Free Survival (at 10 years)

Combined Rx Group

51%

(95% CI 42·3–59·1)

RT Group

30·2%

(95% CI 23·1–37·6)

HR 0·50, 95% CI (0·38–0·65); (p<0·0001)

39.8%

58.1%

Overall Survival at 10 years

(HR 0·56, 95% CI 0·41–0·75; p=0·0001)

Prostate Cancer Mortality: 10 yrs follow-up

10.3%

30.4%

Locoregional failure rate at 10 years

(HR 0·21, 95% CI 0·12–0·40; p<0·0001)

6.0%23.5%

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

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

Leuprolide neoadjuvant / adjuvant to RT: post-RT PSA levels

Laverdière et al 1997

Series10

1

2

12 24

PSA level ng/mL

1.56

1.20

0.60 0.65

0.2

0.5

RT alone (n=41)Leuprolide / flutamide before RT (n=43) Leuprolide / flutamide before and after RT (n=36)

Time post-radiotherapy (months)

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

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.

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.

GnRH Antagonists – Mechanism of Action

GnRH Receptor AntagonistsDagerelix

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

Other new agents

A selective and irreversible inhibitor of CYP17, abiraterone,

MDV3100, a novel small molecule that acts as an oral nonsteroidal antiandrogen agent.

Current and Future Hormonal Therapy Drugs

UROLOGY 78: S494–S498, 2011

NCCN Guidelines Version 3.2012ADT 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

Thank You for your attention