Francesco Massari U.O.C. di Oncologia Medica dU Azienda Ospedaliera Universitaria Integrata...

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