francesco massari u.o.c. di oncologia medica du azienda ospedaliera universitaria integrata...
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Francesco Massari
U.O.C. di Oncologia Medica dUAzienda Ospedaliera Universitaria Integrata
Università di Verona
Androgen suppression strategies for prostate cancer
History of hormone therapy in prostate cancer
1941
1970
Huggins has shown that surgical castration is effective in the treatment of
CaP and therapy with estrogen (DES; dietilstilbestrolo)
inhibits the growth of CaP
Medical castration was studied Treatment with estrogen (DES) demonstrated comparable efficacy to castration in the treatment of CaP, but with important cardiovascular side effects
Shally demonstrated that treatment with GnRH agonists inhibits tumor growth of CaP
19771982
Andrew SchallyNobel 1977
Charles HugginsNobel 1966
1985-9
Today, GnRH agonists are still the predominant form of androgen deprivation therapy (ADT)
Leuprorelin and goserelin, GnRH agonists, are introduced as a treatment of CaP
HORMONE THERAPY
• ORCHIECTOMY• ESTROGEN THERAPY• AGONIST GnRH
• ANTIANDROGEN• GnRH ANTAGONIST
GnRH agonist
Brawer MK, Rev Urol, 2001
GnRH Agonist: biphasic mechanism of action
↑LH, ↑FSH, ↑T
↓LH, ↓T, ↑FSH
Step 1
Step 2
GnRH agonist vs orchidectomy
Patients prefer injections to surgery Testosterone suppression is reversible
22%(n=32)
78% (n=115)
0
20
40
60
80
100
Goserelin Orchidectomy
Patie
nts’
pre
fere
nce
Cassileth BR, et al. Qual Life Res 1992; 1: 323–330Kaku H, et al. The Prostate 2006; 66: 439–444
GnRH agonist efficacy is similar to orchidectomy
Suppression of testosterone after withdrawal of treatment with agonists
Test
oste
rone
leve
ls (n
g/m
L)
BF = before therapy with LHRHaT 2.9–10.7 mg/mL
3M vs. basal (BL): P=0.0034
Kaku H, et al. The Prostate 2006; 66: 439–444
ANTIANDROGENS
ANTIANDROGENS CLASSIFICATION
• Antiandrogens are classified on the basis of their chemical structure, in:
- Steroid Antiandrogens (acetate ciproterone)
- Non steroid Antiandrogens (Bicalutamide, Flutamide, Nilutamide)
Hypotalamus
Pituitary gland
TesticleAdrenal gland
T
Androgen target cell
DHT
Nucleus
5--reduttasi
Synthesys of proteins, enzymes, etc...
Testosterone (T)
LH
LHRH
Adrenal Androgeng
Steroid Antiandrogens: mechanism of action
Steroid antiandrogens
BLOCKADE
1. Compete with testosterone and DHT in binding to receptors in the nucleus of prostate cells by promoting apoptosis and inhibiting the growth of CaP.
2. Block gonadotropin secretion
Androgen target cell
Hypotalamus
Pituitary gland
TesticleAdrenal gland
T
DHT
Nucleus
5--reduttasi
Synthesys of proteins, enzymes, etc...
Testosterone (T)
LH
LHRH
BLOCKADE
Adrenal Androgeng
Antiandrogens
1. Compete with testosterone and DHT in binding to receptors in the nucleus of prostate cells by promoting apoptosis and inhibiting the growth of CaP.
2. Do not block gonadotropin secretion and therefore testosterone levels do not drop, but remain normal and may even slightly increase.
Non-Steroid Antiandrogens: mechanism of action
Permanent association of LHRH and antiandrogen
MAB(Maximal Androgen Blockade)
New hormonal therapy in prostatic carcinoma: combined treatment with an LHRH agonist and an antiandrogen. Clin Invest Med. 1982;5(4):267-75.
F. Labrie, maximal (complete) androgen blockade
• Schmitt B. et al., Maximal androgen blockade for advanced prostate cancer (Cochrane database – 2009)
• Samson D. et al., Systematic review and metanalysis of monotherapy compared with combined androgen blockade for patients with advanced prostatic cancer (Cancer – 2002)
MAB EVIDENCES - METANALYSES
• 21 trials comparing survival (n= 6871 patients)
• 2 years survival (20 trials)NO SIGNIFICANT IMPROVEMENT
• 2 years survival (10 trials) MODEST SIGNIFICANT DIFFERENCE IN FAVOR OF MAB
MAB METANALYSES SAMSON
MAB produces a modest overall and cancer-specific survival at five years but is associated with increased adverse events and reduced quality of life
MAB METANALYSES SCHMITT 2009
Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials
Prostate Cancer Trialists’ Collaborative Group
Lancet 2000; 355: 1491-98
36 studies36 studies
31 studies31 studies
27 studies27 studies
relevant
eligible for analysis
Evaluable (8275 patients)
Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials
With NON-STEROIDAL antiandrogens, there was a significant 8% reduction in the risk of death (p= 0.005)
With STEROIDAL antiandrogens there was a significant 13% increase in the risk of death (p= 0.04)
PCTCG meta-analysis (n= 8275)
5-year survival favoured MAB (25.4% vs. 23.6%)
Lancet 2000; 355: 1491-98
Lancet 2000; 355: 1491-98
MAB with NON-steroidal antiandrogen
MAB with NON-steroidal antiandrogen
Use intermittent administration of LHRH agonists
IAD(Intermittent Androgene Deprivation)
Intermittent androgen deprivation (IAD):
Phase II studiesStudy Year N Cycles Off (month)
Akakura 1993 7 LHRH 4 2 -11
Goldemberg 1995 47 CAB 2 10
Higano 1996 22 CAB 3 6
Tuun 1996 20 CAB 2 9
Oliver 1997 20 CAB 2 9 – 42
Theyer 1997 23 CAB 1 7
Horwich 1998 16 LHRH 2 8
Bruchowsky 1998 110 CAB 1 9
Crook 1999 4 CAB 5 8.8
Strum 2000 19 CAB 3 15.5
Grossfeld 2001 27 CAB 5 9
De La Taille 2003 74 CAB 1 - 8 10
• 626 randomised for continuous vs intermittent
50% patients off therapy for > 52 weeks 20% patients off therapy for > 36 weeks• No difference in overall survival• Intermittent ADT was associated with fewer
side effects and better sexual activity
Phase III IAD: SEUG trial
Da Silva et al., European Urology 55 (2009)
Da Silva et al., European Urology 55 (2009)
Phase III IAD: SEUG trial
In conclusion, IAD is at present widely offered to patients with prostate cancer in various clinical settings, and its status should no longer be regarded as investigational
Patient survival (ITT)
Su
rviv
al D
istr
ibu
tio
n F
un
cti
on
0.00
0.25
0.50
0.75
1.00
time to death (days)
0 500 1000 1500 2000 2500 3000
STRATA: treatment=inter Censored treatment=intertreatment=konti Censored treatment=konti
Intermittent
P = 0.7
Continous
Overall Survival
No difference in progression-free survival No difference in overall survival No difference in adverse events 88% of patients off therapy on intermittent arm
for more than 50% of time
There are now 4 RCT’s with a total of >1000 patients randomized that support non-inferiority of intermittent ADT for PFS and overall survival
Summary
Maha Hussain, Catherine M. Tangen, Celestia S. Higano, E. David Crawford, Glenn Liu, George Wilding, Stephen Prescott, Atif Akdas, Eric Jay Small, Nancy Ann Dawson, Bryan J Donnelly, Peter Venner,
Ulka N. Vaishampayan, Paul F. Schellhammer, David I. Quinn, Derek Raghavan, Nicholas J. Vogelzang, Ian Murchie Thompson
J Clin Oncol 30, 2012 (suppl; abstr 4)
Intermittent (IAD) versus continuous androgen deprivation (CAD) in hormone sensitive
metastatic prostate cancer (HSM1PC) patients (pts): Results of S9346 (INT-0162), an
international phase III trial.
The trial accrued 3,040 patients with newly diagnosed hormone-sensitive metastatic prostate cancer between 1995 and 2008.
Noninferiority Design The trial was designed to assess whether overall survival (OS) with IAD was noninferior to CAD
The design of the trial specified that survival with IAD would be noninferior to CAD if the 95% confidence interval for the hazard ratio (HR; IAD versus CAD) excluded 1.2
ADT: risk and benefits
M. Hussain, J Clin Oncol 30, 2012 (suppl; abstr 4)
M. Hussain, J Clin Oncol 30, 2012 (suppl; abstr 4)
Overall Survival
The mean OS was 5.8 years for patients receiving CAD and 5.1 for patients receiving IAD, representing a 9% increase in relative risk of death for IAD (HR 1.09, 95% CI [0.95 - 1.24]).
Because the upper limit of the CI did not exclude 1.2, the noninferiority criterion was not met.
M. Hussain, J Clin Oncol 30, 2012 (suppl; abstr 4)
• Loss of libido and sexual interest, erectile dysfunction, impotence
• Fatigue• Hot flushes• Decline in intellectual capacity,
depression• Decrease in muscular strenght• Increase in (abdominal) fat
apposition• Decline in physical activity and
general vitality• Osteoporosis • Cardiovascular diseases
Side-effects of hormonal therapy
• ADT is associated with an increased risk of multiple side effects (may reduce QoL and/or OS)
• Osteoporosis, obesity, sarcopenia, lipid alterations, insuline resistence, increased risk of diabetes and cardiovascular morbidity
• Lifestyle interventions, especially in setting with the highest risk-benefit ratio,to alleviate comorbidites
ADT: risk and benefits
Isbarn H, Eur. Urol 2008
ADT and cardiovascular events
D'Amico, A. V. et al. J Clin Oncol; 25:2420-2425 2007
ADT and cardiovascular death
Tsai, H. K. et al. J. Natl. Cancer Inst. 2007 99:1516-1524
GnRH Antagonist: a new pharmacological class for the treatment of advanced prostate cancer hormone-sensitive
↓LH, ↓FSH, ↓T
GnRH Antagonist : mechanism of action
GnRH receptor blockade
Brawer MK, Rev Urol, 2001
Mechanism of GnRH receptor blocking direct
Immediate Action with rapid suppression of testosterone
No initial stimulation of pituitary GnRH receptor and therefore no initial transient increase in testosterone
Degarelix: mechanism of action
Degarelix
Princivalle M et al. J Pharmacol Exp Ther 2007; 320: 1113-1118
Binding of degarelix with the GnRH receptors is stronger and more durable than that of GnRH agonists
GnRH receptors
Dosage of CS21
Degarelix240 mg (2 x 3 ml s.c.)
Day 0Attack Dose
Day 28-364Maintenance Dose
Leuprolide7,5 mg (i.m.)
Degarelix160 mg (1 x 4 ml s.c.)
Degarelix80 mg (1 x 4 ml s.c.)
Leuprolide7,5 mg (i.m.)*
Monthly dosing: a total for each patient were administered 12 doses.
Inspections:Day 0, 1, 3, 7, 14, 28 56, +28…364
Other visits after day 3 and day 7 subsequently at 9th administration
*Administration of antiandrogens at the discretion of the investigator
N = 610 patients(ITT)
Boccon-Gibod L et al. Presentazione poster. 23esimo Congresso EAU, Milano, Italia, 2008
CS21: End-points
Primary End-point:• Probability of testosterone ≤ 0.5 ng / ml at all monthly
measurements from day 28 to day 364
Secondary end-points:• Percentage of patients with initial transient increase in
testosterone• Percentage of patients with testosterone ≤ 0.5 ng/ml on day 3
(miniflare) • Percentage change in PSA from baseline at day 28 and time to
PSA failure • Frequency and severity of adverse events
Boccon-Gibod L et al. Presentazione poster. 23esimo Congresso EAU, Milano, Italia, 2008
Degarelix is not inferior in inducing suppression of testosterone <0.5 ng / ml for 1 year
Success criteria Degarelix240160 mg
Degarelix24080 mg
Leuprolide7,5 mg
Responders to therapy 199 202 194
% responseFDA:
IC ≥90%98,3 %
(94,8-99,4 %)97,2 %
(93,5-98,8 %)96,4 %
(92,5-98,2 %)
Difference compared to leuprolide
EMEA:IC ≥-10
percentage points
1,9 %(da –1,8% a
5,7%)
0,9 %(da –3,2% a
5,0%)
Boccon-Gibod L et al. Presentazione poster. 23esimo Congresso EAU, Milano, Italia, 2008
Degarelix: immediate reduction of testosterone levels
Boccon-Gibod L et al. Presentazione poster. 23esimo Congresso EAU, Milano, Italia, 2008
Degarelix: faster suppression of testosterone
Patients (%) with testosterone levels ≤ 0.5 ng/ml during the first month of treatment*p <0,001 (vs leuprolide)
Boccon-Gibod L et al. Presentazione poster. 23esimo Congresso EAU, Milano, Italia, 2008
Degarelix: maintaining low levels of testosterone for 1 year
Boccon-Gibod L et al. Presentazione poster. 23esimo Congresso EAU, Milano, Italia, 2008
Degarelix: no miniflare of testosterone
Miniflare of testosterone*
Variazione: days 3 e 7 after 9th administration
Degarelix240160 mg
Degarelix24080 mg
Leuprolide7,5 mg
>0,25 ng/ml 0 0 8 (5%)*
* Increased testosterone> 0.25 ng / ml detected in any two measurements at 3 and 7 days after drug administration
Boccon-Gibod L et al. Presentazione poster. 23esimo Congresso EAU, Milano, Italia, 2008
Degarelix: faster reduction of PSA
*p <0,001 vs leuprolide;11% of patients in the leuprolide group receiving bicalutamide as anti-flare therapy
Boccon-Gibod L et al. Presentazione poster. 23esimo Congresso EAU, Milano, Italia, 2008
Degarelix: faster suppression of PSA; maintaining value for one year
Boccon-Gibod L et al. Presentazione poster. 23esimo Congresso EAU, Milano, Italia, 2008
PSA failure during first year of therapy
PSA failure*Degarelix
240160 mgDegarelix
24080 mgLeuprolide
7,5 mg
N. Patients with PSA failure 26/ 202 16/ 207 26/ 201
Probability of PSA failure14,2%
(9,9-20,2%)8,8%
(5,5-14,0%)14,1%
(9,8-20,1%)
*Two consecutive increases >50% (≥5,0 ng/ml)
Boccon-Gibod L et al. Presentazione poster. 23esimo Congresso EAU, Milano, Italia, 2008
Progression free survival (time to PSA failure/death – all patients)
Leuprolide 7,5 mg Degarelix 240/80 mg
100
95
90
85
80
Prob
abili
ty (%
)
Time (days)0 28 56 84 112 140 168 196 224 252 280 308 336 364
Degarelix 80 mg vs leuprolide HR= 0,664; IC 95% 0,385, 1,146; p = 0,0495 (log-rank)
Tombal M et al, poster EAU 2009
CS21: adverse eventsDegarelix
240160 mgDegarelix
24080 mgDegarelix both doses
Leuprolide7,5 mg
Adverse events 83% 79% 81% 78%
Injection site reaction 44% 35% 40% <1%***
Flushing 26% 26% 26% 21%
Increase weight 11% 9% 10% 12%
Lumbar pain 6% 6% 6% 8%
Artrhalgia 3% 5% 4% 9%*
Hypertension 7% 6% 6% 4%
Affaticamento 6% 3% 5% 6%
Urinary tract infection 1% 5% 3% 9%**
Nausea 5% 4% 5% 4%
Constipation 3% 5% 4% 5%
Hypercolesterolemia 6% 3% 5% 2%
Chills 3% 5% 4% 0%**
*p <0,05, **p <0,01 e ***p <0,001 vs degarelix a both doses
Boccon-Gibod L et al. Presentazione poster. 23esimo Congresso EAU, Milano, Italia, 2008
GnRH agonists are used successfully as androgen deprivation therapy, but have some limits:
Initial transient increase in testosterone with consequent delay of castration
Exacerbation of clinical symptoms (flare-up)
Miniflare e breakthrough
Adverse events
CONCLUSIONS
GnRH Antagonist have a mechanism for blocking
direct receptor:
Immediate reduction in PSA and testosterone
Low levels of PSA and testosterone, maintained
over time
No need of anti-flare therapy
CONCLUSIONS