The remarkable success of hormone therapy of prostate cancer

1
The remarkable success of hormone therapy of
prostate cancer
Riyadh
April 17th, 2007
2
Charles B. Huggins, Nobel Prize 1966
The beginning of androgen blockade (1941)
Castration in advanced prostate cancer
3
The Gazette, oct 15, 2005
4
Good news
5
Prostate cancer deaths in the USA

• 1992 40,400 13,350
• 2007 27,050 33

American Cancer Society
6
Androgen blockade

• major progress duringthe last 25 years
• major positive effect on survival

7
Hormonal treatments for prostate and breast
cancer have probably saved more lives than any
single cancer drug
R. Peto, ECCO Meeting, sept 2003
8
Hormone therapy on the rise
The number of men with early prostate cancers who
undergo hormone deprivation has increased
dramatically.
Percentage of men 80 and older with low-risk
disease who received hormone therapy within six
months of diagnosis
1991 4
1999 31
Source Cancer, 2005
USA TODAY, Sept 19, 2006
9
In Japan, 50of patients receive hormonal
therapy as primary treatment at the localized
stage
10
Bad news
11
Much remains to be done to take maximal benefit
of androgen blockade
12
Doctors underestimate the risk of death from
prostate cancer, and put too much emphasis on
other causes of death
13
Very surprising finding
Many patients with metastatic prostate cancer
never received hormone therapy in the USA
!!!From 9110 men who died from prostate cancer
between 1991 and 2000, 38 of black and 25 of
white men did not receive androgen blockade
before dying
LU-YAO et al., J. Urol., 176, 526-531, 2006SEER
Medicare data bases
14
Such data illustrate the serious challenge facing
the application of results of clinical research
into clinical practice in some medical
conditions, especially prostate cancer
15
Common errors related to androgen blockade
1- Monotherapy (GnRH agonist alone, orchiectomy
alone or antiandrogen alone) instead of combined
androgen blockade 2- Too short duration of
treatment 3- Treatment started too
late 4- Intermittent treatment
16
Monotherapy(Castration or antiandrogen alone)
17
In 1979-80, we made the most exciting discovery
that chronic administration of GnRH agonists in
men induces medical castration (Labrie et al.,
J. Androl., 1, 209-228, 1980)
18
First Prostate Cancer Patient Treated with an
GnRH Agonist
19
First prostate cancer patient treatedwith an
GnRH agonist (Labrie et al, 1980)
12
9
Testosterone (ng/ml)
6
3
0
0
2
4
6
8
10
12
14
16
Days of treatment
20
Surgery
21
In a metaanalysis of several studies (5000 men),
hormonal treatment given immediately versus
waiting until disease progressed, the risk of
dying from prostate cancer within 10 years
dropped by one third
R. Peto, ECCO Meeting, sept 2003
22
Endocrine treatment (immediate/deferred)Prostate
cancer mortalityM- (no distant metastases
recorded)
100
Orch / GnRHa DES / EE
86.8
Annual prostate cancer death rates Immediate Def
erred Years 2.71 4.36 0-4 (SE 0.16) (SE
0.22) Years 3.40 5.10 5-9 (SE 0.25) (SE
0.35) Years 1.70 2.83 10 (SE 0.27) (SE 0.42)
6.9
80
Deferred
74.0
79.9 -7.0 (SE 1.2)
11.7
60
Estimated percentage still not dead from
Prostate cancer
62.3 11.7 (SE 1.8)
40
M0/? Logrank 2p gt 0.1NS
20
M0/? Actuarial estimate and SE - allocated
IMMEDIATE - allocated DEFERRED
0
0
5
10
years
23
Seven randomized trials show that early treatment
prolongs life. No negative study exists
24
Effect of androgen blockade on prostate cancer
death
STUDY BENEFITS AT 5 YEARS EORTC, Bolla et al.
(1997) 77 (P0.01) RTOG 85-31 37 for
Gleason score 8-10 Pilepich et al.
(1997) (P0.03) Messing et al. (1999) 81
(P0.001) Granfors et al. (1998) 39
(P0.06) Hanks et al. (2000) 59 for Gleason
score 8-10 (P0.007) DAmico et al.
(2004) 41 decrease in overall death (Plt0.04)
25
Lovely results Quite remarquable It will
take us a nice step forward Richard Peto,
Oxford, Sept 2002
26
Early prostate cancer (EPC) trial

• Largest study in prostate cancer Placebo
  versus 150 mg bicalutamide
• Serious flawsA- Monotherapy suboptimal
  regimenB- Too short duration of treatment EPC -
  23 (3292) 2 years of treatment (inefficient)
  - 24 (3603) 5 years (suboptimal)
  - 25 (1218) 5 years
  Total 8113 PTS

27
With todays knowledge, monotherapy is not an
acceptable androgen blockade
28
Two equally important sources of androgens are
present in men.
29
Intact - normal
LHRH

Testosterone
Pituitary Gland
LH
ACTH


Testosterone
DHEA
DHT Prostate
Testis
Adrenal
30
Sources of androgens in adult men (65-year old)
40 50
Adrenals
50 60
Testicles
31
A SERUM TESTOSTERONE
B PROSTATE CANCER DIHYDROTESTOSTERONE
6
4
4
DHT (ng/g tissue)
Testosterone (ng/ml)
2
2
50
0
0
32
ng/g tissue
30 patients
6
4
2
25
0
LHRH agonist flutamide
Pretreatment
Nishiyama et al Clin. Cancer Res 10, 7121-7126,
2004
33
Androgens

• Testis Adrenals
• Testosterone Androstenedione 6.5
  mg/day (4-dione) 3 mg/day
• Dihydrotestosterone Dehydroepiandrosterone (DHT)
  (DHEA)
• 0.1 mg/day 24 mg/day

Horton, 1978
34
Circulation
Circulation
Intracellular compartment
35
STEROIDOGENIC AND STEROID-METABOLIZING ENZYMES IN
PERIPHERAL INTRACRINE HUMAN TISSUES
DHEA-S
DHEA-S
Sult
Slfatase
17b-HSD 1, 5, 13
5-DIOL
DHEA
DHEA
DHEA
17b- 2, 4
3b-HSD
3b-HSD
ADRENAL
17b-HSD 5, 13
4-DIONE
TESTO
17b-HSD 2, 9, 1 0, 11
5a-red 1, 2
5a -red 1, 2
17b-HSD 5, 13
DHT
A-DIONE
17b-HSD 2
3a-HSD
3a-HSD
17b-HSD 5, 13
Aromatase
Aromatase
3a-DIOL
ADT
17b-HSD 2, 9, 10, 11
3a-DIOL-G
ADT-G
17b-HSD 1, 7, 12
E2
E1
17b-HSD 2, 4, 8
Sult
Ugt
Sult
Ugt
Slfatase
Slfatase
E1-S
E1-G
E2-S
E2-G
PERIPHERAL TISSUES (INTRACRINOLOGY
36
Ventral Prostate Weight
30
20
10
0
Intact
Control
DHEA (10mg)
4-Dione (1.5mg)
TESTO (0.75mg)
DHT (0.1mg)
Orchiectomized
37
What is combined androgen blockade?GnRH agonist
or antagonist or orchiectomyflutamide
(Eulexin), bicalutamide (Casodex) or nilutamide
(Anandron) - not with cyproterone acetate
(Androcur)
38
(No Transcript)
39
Choice of antiandrogen

A- Non steroidal
YES
O
O
O
H


H
O
S
N

N
N
NH
F
O
O2N
CH3
HO
O
O2N
NC
CF3
CF3
CF3

Flutamide
Nilutamide
Bicalutamide
B- Steroidal
NO
O
O
OAc
OAc
O
O
Cl
Cl
Cyproterone Acetate
Chlormadinone acetate
40
The benefit of combined androgen blockade with
bicalutamide castration vs castration alone
has been estimated at a 20 reduction of the
risk of death (overall survival) in metastatic
disease (Klotz et al, BJU Int, 93, 1177-1182,
2004)
41
There is a 98.5 probability that bicalutamide in
combination with castration is better than
castration alone
Klotz et al., BJU Int. 93, 1177-1182, 2004
42
Combined androgen blockadecompared to castration
alonehas the following advantages

• 1- More complete and partial responses
• 2- Improved control of metastatic pain
• 3- Longer disease-free survival
• 4- Longer survival

43
An international panel of experts calls for
physicians to re-consider the benefits of CAB as
a treatment option, proven effective in extending
survival and delaying disease progression in men
with advanced prostate cancer
Survey of 330 oncologists and urologists, june
2006
44
We need to ensure that patients with advanced
prostate cancer have access to this treatment
(CAB) which offers the greatest hope for
extending survival
Dr Heather Payne, London, UK, 2006
45
Hormone therapy has now moved to early stages of
prostate cancer
46
Localized disease - Choices of treatment

• Radical prostatectomy alone Or hormone
  therapy
• Radiation therapy alone Or hormone therapy
• Hormone therapy alone
• Will be followed by hormone therapy in up to
  50 of cases

47
40
30
Cumulative incidence of deathfrom prostate
cancer ()
20
Watchful waiting
10
Radical Prostatectomy
0
0
2
4
6
8
10
Years of follow-up

• No. at Risk
• Radical 347 343 332 284 210 118Prostatectomy
• Watchful waiting 348 341 326 279 198 104

Bill-Axelson et al., NEJM 352, 1977-84, 2005
48
Can combined androgen blockade provide long-term
control or possible cure of localized prostate
cancer?
Fernand Labrie, Bernard Candas, José-Luis Gomez,
and Léonello Cusan
Urology 60, 115-119, 2002
49
Effect of duration of continuous CAB on the of
patients with PSA remaining under control for a
minimum of 5 years following cessation of CAB
100
11/12
long term control or cure
7/8
80
60

3/8
40
1/3
20
0/11
0
10
12
0
2
4
6
8
Years of continuous CAB
Labrie et al, Urology 60115-119, 2002
50
Time to progression

• 1.00

GnRH agonist
0.75
Plt0.01
Bicalutamide 80 mg (n102)
0.50
GnRH agonist alone (n102)
0.25
0
200
180
160
140
120
100
80
60
40
20
0
Weeks
Akaza et al., Asco Proc., 2005
51
Kaplan-Meier Plot of Time to PSA normalization
(lt0.2ng/mL )
1.00
CAB
0.75
0.50
PSA normalization rate ()
LH-RH agonist
0.25
0.0
0
20
40
60
80
100
120
140
160
180
WEEKS
Time to PSA normalization (Weeks) - Stage C
Median estimated using the Kaplan-Meier method
52
Some cases of localized prostate cancer can be
cured by hormonal therapy alone Almost all
cases of localized prostate cancer can be cured
by combined androgen blockade
Ueno et al., Int. J. Urol, 2006
Labrie et al., 2002, Urology 60 115-119.
53
Is combined androgen blockade cytostatic or
cytotoxic?
54
PROSTATE CANCER
LOCALIZED
ADVANCED
55
Combined androgen blockade is cytotoxic. Long
term and continuous combined androgen blockade
can cure localized prostate cancer
56
Does resistance to combined androgen blockade
occur in localized disease?
57
Resistance to combined androgen blockade does not
occuror is very rarein localized disease.
58
Do androgen - insensitive cancer cells exist at
start of prostate cancer?
59
No - as long as cancer is localized, it is
highly androgen - sensitive
60
Major objective prevent cancer from migrating
to the bones
61
Never use intermittent hormone therapy always
use continuous hormone therapy
62
Hormonal therapy is very efficient in localized
disease but treatment must be continued for many
years(6 or more)
63
The best treatment for localized prostate cancer
might well be long-term combined androgen
blockade alone
64
Combined androgen blockade is much more efficient
than monotherapy
65
PROGRESSIONS AT 5.4 YEARS (monotherapy)
40
212/611 34.7
CASODEX (150mg)
PLACEBO
30
123/607 20.3

20
567/4061 14
343/4052 8.5
10
0/26
0
T2 Labrie et al, 2002 CAB
81 W.WAITING
T1-T4 (Mo)
Wirth et al, 2004
Iversen et al, 2004
MONOTHERAPY CASODEX (150 mg)
66
Prostate cancer mortality Immediate versus
deferred androgen blockade
Ratio of death rates
A- Monotherapy Orchiectomy / LHRH agonist vs
Placebo
10
M
34
M -
20
B- Combined androgen blockade Orchiectomy
/ LHRH agonist pure antiandrogen (Flutamide,
Nilutamide, or Bicalutamide) vs Castration
M
90 cure
M -
Immediate
better
M Distant metastases
0
0.5
1.0
67
More than 90 of localized cancers can be cured
by combined androgen blockade(Labrie et al., J
Urol, 60 115-119, 2002)
68
The lifesaving benefit of hormone treatment in
prostate cancer has been vastly underrated
R. Peto, ECCO Meeting, sept. 2003
69
Cancer-fighting drugs improved survival rates,
especially for cancer of the prostate, where drug
innovations have been the greatest.
NCI data from 2.1 million patients F.R.
Lichtenberg, 2004
70
The only recommended hormone therapy is combined
androgen blockade
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(No Transcript)
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Androgen blockade in prostate cancer
Monotherapy or Combination GnRH agonist
aloneGnRH antagonist alone Orchiectomy
DES Proscar aloneProscar castrationCyproteron
e acetate alone Cyproterone acetate with
castrationFlutamide aloneNilutamide
alone Bicalutamide aloneMegaceMedroxyprogesteron
e acetate
CombinedAndrogen blockade GnRH agonist, GnRH
antagonist orOrchiectomy Flutamide
or Nilutamide orBicalutamide (150 mg or more
daily)
73
Frequent errors related to androgen blockade

• 1- Monotherapy instead of combined androgen
  blockade
• 2- Too short duration of treatment
• 3- Treatment started too late
• 4- Intermittent treatment

74
(No Transcript)
75
Men dont need to die from prostate cancer
anymoreif properly diagnosed and treated
76
STUDIES ON ANDROGEN BLOCKADE
NR Non randomized R Randomized
B- Localized disease
R VACURG (Orchiectomy, Estrogens) (1967)
R Bolla et al (LHRH agonists) (1997)
NR Labrie et al (CAB) (1997)
NR GnRH agonist (Labrie et al, 1980)
A- Advanced disease
NR Combined androgen blockade (Labrie et al, 1982)
NR ORCHIECTOMY ESTROGENS (Huggins) (1941)
R VACURG (Estrogens, orchiectomy) (1967)
R CAB (Crawford et al, 1988)
N.S.
1940
1980
1990
2000
2005
1950
1960
1970
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COLLABORATORS (COMBINED ANDROGEN BLOCKADE)
ASSELIN, JACQUES AUCLAIR, CLAUDE BEAULIEU,
MICHÈLE BÉGIN, D. BÉLANGER, ALAIN BERGERON,
NICOLE BORGEAT, PIERRE BORSANYI,
JEAN-PIERRE BOSSÉ, CLAUDE BROCHU, MICHÈLE BRUN,
DANIEL CARMICHAEL, R. CARON, SIMON CANDAS,
BERNARD CHEN, C. CLICHE, JACQUES CÔTÉ,
JEAN COUET, JACQUES COUTURE, MARCEL COY,
DAVID COY, ESTHER J. CRAWFORD, DAVID CUSAN,
LEONELLO DELISLE, ROBERT DESY, LOUISE DIAMOND,
PIERRE DROUIN, JACQUES DUBÉ, DONALD DUBÉ,
JEAN-Y. DUPONT, ANDRÉ
EMOND, JEAN FAURE, NACIA FAZEKAS, ATTILA
T.A. FERLAND, LOUISE FOURNIER, ANDRÉA FRADET,
YVES FRENETTE, G. GAGNÉ, CLAUDE GAGNON,
JACQUES GAREAU, JACQUES GIASSON,
MARCELLE GIGUÈRE, MICHEL GIRARD,
JEAN-GUY GODBOUT, MARTIN GOMEZ, JOSÉ GOURDEAU,
YVES GUAY, JOCELYNE HARNOIS, C. HOULE,
JEAN-G HUSSON, JEAN-MARC KELLY, PAUL A. KLEDZIK,
GARY, S. KOUTSILIERIS, MICHEL LABERGE,
JEAN-GUY LABRIE, CLAUDE LABRIE, FERNAND LACHANCE,
ROGER LACOSTE, DANIEL LACOURSIÈRE, YVES LAGACÉ,
LISETTE
LAPOINTE, STEVEN LAROCHE, BRUNO LAVERDIÈRE,
JACQUES LEBLANC, GILLES LEFEBVRE,
FLEUR-ANGE LEMAY, ANDRÉ LEMAY, MARTIN LI,
SHENGMIN LUPIEN, PAUL J. LUO, S LUTHY,
ISABELLE LUU-THE, VAN MALENFANT, M. MANHES,
GILLES MARCHETTI, BIANCA MARTEL,
CÉLINE MASSICOTTE, J. MONFETTE, GERARD MOORJANI,
SITAL PAQUET, JEAN-PIERRE PELLETIER,
GEORGES PINAULT, SYLVIE PLANTE, MICHEL POULIN,
RICHARD POYET, PATRICK PROULX, LOUISE RAYNAUD,
JEAN-PIERRE REEVES, JERRY J. RESKO, J. ROBERT,
GILLES
ROUSSEAU, L. RUEL, FRANÇOIS SAMSON, YVAN SANDOW,
JERGEN SAVARY, MURIELLE SCHALLY, AUDREW VICTOR
SÉGUIN, CARL SIMARD, JACQUES SINGH, MOHAN SOURLA,
ANTIGONE ST-ARNAUD, RENÉ SUBURU, RAUL TETU,
BERNARD THIBAULT, MARIE-MARTHE TOLIS,
GEORGE TRUDEL, CLAUDE TURINA, E. TREMBLAY,
M. TREMBLAY, ROLAND R. TREMBLAY, YVES TRUDEL,
CLAUDE VAILLANCOURT, L. VALLIÈRES, ANDRÉ VAN DER
KWAST, T. H. VEILLEUX, RAYMONDE VON DER OHE,
M. ZHAO, H.F.
78
PhotoJacques Boissin/Canadian Press
79
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