Traitement médical du Cancer de la Prostate:

du désert à

la profusion

Prof. Karim Fizazi, MD, PhDInstitut Gustave Roussy

Villejuif, France

Disclosure

•

Participation in advisory

boards

or as a speaker for:Amgen, Astellas-Medivation, Astrazeneca, Bayer, BMS, Celgene, Dendreon, Exelixis, Ipsen, Janssen-Cougar, Keocyt, Millennium-

Takeda, Novartis, Sanofi-Aventis

Advanced prostate cancer: Natural history

(in the 2000s)

Local Treatment

PSA relapse (ADT)

Metastatic

Castrate-Resistant

Prostate Cancer

Castrate-resistant, M0

Metastatic

Hormone-Sensitive prostate cancer

Docetaxel

Zoledronate

ADT

A decade

of research in prostate cancer

2004-2009: No significant result

2010-2012:- Sipuleucel-T- Cabazitaxel- Denosumab- Abiraterone- Alpharadin- MDV 3100

Endocrine therapies

Testosterone

DNA

Cell division

TestisAdrenals

Autocrinesecretion

Castration(aLHRHor surgery)

Abiraterone

Abiraterone

Androgen Receptorinhibitors:-Bicalutamide-Enzalutamide(MDV 3100)

CYP17 blockade inhibits androgen synthesis

b

Abiraterone

acetate Phase III post-chemo

study design

Abiraterone

1000mg dailyPrednisone 5mg BID

n=797

Primary end point:

•

OS (HR 0.8)

Secondary end points:

•

TTPP

•

rPFS

•

PSA response

Efficacy end points (ITT)

Placebo dailyPrednisone 5mg BID

n=398

R

A

N

D

O

M

I

Z

E

D

2:1

•

1195 patients with progressive mCRPC

•

Failed 1 or 2 chemotherapy regimens, 1 of which contained docetaxel

Patients COU 301

COU-301: Abiraterone

prolongs survival in post-docetaxel

mCRPC

patients

Fizazi K, et al. Lancet Oncol. 2012;13:983–992.

Clinical benefit of abiraterone

October

2008 January

2010

Images courtesy of Dr Fizazi.

Abiraterone

in asymptomatic mCRPC: the COU-AA-302 Phase III study

•

Stratification by ECOG performance status 0 vs. 1Ryan C, et al. American Society of Clinical Oncology Congress

2012; Abstract LBA4518.

Patients•Progressive chemo-naïve mCRPC

•Asymptomatic or mildly symptomatic

Ran

do

mis

ati

on

1:1 Abiraterone acetate

+ prednisone (n = 546)

Placebo + prednisone (n = 542)

Co-primary endpoints•Radiographic progression-free survival

•Overall survival

Secondary•Time to opiate use (cancer-related pain)

•Time to initiation of chemotherapy

•Time to ECOG-PS deterioration

•Time to PSA progression

COU-AA-302: interim results•

Statistically significant radiographically-

evidenced progression-free survival (rPFS)

Ryan C, et al. ASCO 2012; Abstract LBA 4518.

Abiraterone

acetateControl

Data cut off: 20/12/2010

Abiraterone

acetatePlacebo

AA + PPL + P

HR 0.43 (95% CI: 0.35–0.52; P < 0.0001)

COU-AA-302: interim results

•

Overall survival

Data cut off: 20/12/2011

Abiraterone

acetateControl

HR 0.75 (95% CI: 0.61–0.93); P = 0.0097

Abiraterone

acetatePlacebo

Ryan C, et al. ASCO 2012; Abstract LBA 4518.

AFFIRM: A Phase 3 Trial of MDV3100 vs. Placebo in Post-Chemotherapy

Treated CRPC

Clinicaltrials.gov

identifier: NCT00974311

R

A

N

D

O

M

I

Z

E

D

2:1

R

A

N

D

O

M

I

Z

E

D

2:1

Primary Endpoint:

Overall Survival

MDV3100160 mg daily

n = 800

MDV3100160 mg daily

n = 800

Placebon = 399Placebon = 399

Patient Population:

1199 patients with progressive CRPC

Failed docetaxel chemotherapy

MDV3100 Prolonged Survival by a Median of 4.8 Months in the Phase 3 AFFIRM Trial

HR = 0.631 (0.529, 0.752) P < 0.000137% Reduction in Risk of Death

MDV3100: 18.4 months (95% CI: 17.3, NYR)

Placebo: 13.6 months (95% CI: 11.3, 15.8)

Surv

ival

(%)

100

80

60

40

20

90

50

30

0

10

70

Scher H, N Engl

J Med 2012

Taxanes for CRPC

•

Well-established

drug in Oncology

•

Main toxicity:–

Peripheral

neurotoxicity

–

Nail

Toxicity

•

Crosses the blood-brain barrier

in vivo

(humans?)•

Active in some

docetaxel-resistant models

•

Main toxicity:–

Hemato

(G-CSF)

–

Diarrhea

Docetaxel Cabazitaxel

Cabazitaxel in Second-line CRPC TROPIC Phase III Study

R

A

N

D

O

M

I

Z

E

Mitoxantrone

12mg/m2 q3w

Prednisone 10mg qd

mHRPCProgressionafter TXT

Cabazitaxel

25mg/m2 q3w

Prednisone

10mg qd

360 pts

360 pts

R

A

N

D

O

M

I

Z

E

Stratification factor :ECOG PS (0,1 vs

2)Mesurable/non_mesurable

Primary Endpoint:Overall survival

Secondary Endpoint:PSA response, PSA progression, PFS, RR, Pain progression, Safety, PK of cabazitaxel

Enrolment closed: 745/720 ptsHypothesis: 25% Reduction in the risk of deathor median OS=10.67 months for cabazitaxel

vs

8 months511 events, duration 36 months

Cabazitaxel

vs

Mitoxantrone: Overall Survival

MP CBZP

Median OS (months) 12.7 15.1

Hazard ratio 0.72

95% CI 0.61–0.84

P-value <.0001

Median FU: 13.7 mo

MTX+PREDCBZ+PREDPr

opor

tion

of O

vera

llSu

rviv

al

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 30

377378

300321

188231

6790

1128

14

Number

at

RiskMTX + PREDCBZ + PRED

28% risk of death reduction

Time (months)

De Bono et al., Lancet 2010;376:1147-54

Is prostate cancer a chemosensitive neoplasm?

•

High response

rate

(>50%) in first-line•

Benefit

in OS in first-line (Docetaxel)

•

Second-line

chemotherapy

with demonstrated

activity

(Cabazitaxel)

•

Chemotherapy improves

PFS/OS when used

in the localized

setting

to prevent

relapse

YES

YES

YES: OS !

First answer

in 2014?

Sipuleucel-T: Autologous

APCs

cultured with

antigen

fusion protein

(PAP)

Sipuleucel-T autologous

vaccine: Overall Survival

0 6 12 18 24 30 36 42 48 54 60 660

25

50

75

100

Perc

ent S

urvi

val

Survival (Months)

p

= 0.032 (Cox model)HR = 0.78

[95% CI: 0.61, 0.98]

Sipuleucel-T (n = 341) vs

Placebo (n=171)Median OS: 25.8 vs

21.7 months

Kantoff PW, NEJM 2010, 363: 411-22Small EJ, J Clin Oncol 2009; 24: 3089-94

The “vicious cycle” of bone metastases

BoneRANK

RANKL

Bone Resorption

Osteoclast

Prostate cancer cells

Ca2+

Growth Factors (TGF-IGFs, FGFs,

PDGFs, BMPs)

Cytokines and Growth Factors (ET-1, IL-6, IL-8, TNF-

, PTHrP, etc)

Adapted from Roodman

GD. N Engl J Med. 2004;350:1655-64.

RA

NK

L

Direct effectson tumor?

Osteoblastlineage

Targeting

RANK-L: Proof of concept

OPG

RANKL

CTR CTROSB+ 2b

OSB+ 2a

OSB + LNCaP

OSB+ PC3

Fizazi et al., Clin Cancer Res 2003;9:2587–2597Fizazi et al., J Clin Oncol 2009; 27: 1564-71

RANK-L overexpressedby osteoblasts

in bone metastases

Positive randomized Phase II: Denosumabdecreases uNTx (biomarker for osteolysis)

Phase III trial of Denosumab in bone metastases from castrate-

resistant prostate cancer (103)

Denosumab

120 mg SC andPlacebo IV* every 4 weeks

Zoledronic

acid 4 mg IV* andPlacebo SC every 4 weeks

Castration-resistant prostate cancer and bone metastases

Key Inclusion

Current or prior intravenous bisphosphonate

administration

Key Exclusion

+ Supplemental Calcium and Vitamin D

SRE

n= 1901 patients

Denosumab: Time to First SRE

Zoledronic

Acid 951 733 544 407 299 207 140 93 64 47

Denosumab 950 758 582 472 361 259 168 115 70 39

Subjects at risk:

0

1.00

Prop

ortio

n of

Sub

ject

s W

ithou

t SR

E

0 3 6 9 12 15 18 21 24 27

0.25

0.50

0.75

KM Estimate of

Median MonthsDenosumabZoledronic

acid

20.717.1

HR 0.82 (95% CI: 0.71, 0.95) P = 0.0002 (Non-inferiority)

P = 0.008 (Superiority)

Study Month

18% Risk Reduction

Fizazi et al. Lancet 2011; 377: 811-822

0

1

2

3

4

5

6

7

8

9

%

Spinal cord compression

Preventing the onset of the worst enemy:

Placebo Zoledronicacid

Dmab

103 trialZA pivotal

trial

8% 4% 2.7%

Zoledronicacid

Denosumab

(120 mg Q4W) is not approved in the EU for use in patients with

advanced cancer to delay SREs. Denosumab

is investigational in that setting Saad, et al. J Natl Cancer Inst 2004;96:879–82; Fizazi et al. Lancet 2011; 377: 811-822

Radiopharmaceuticals: α

versus β-emitters

α-emitter:Radium-223

α-particles:2 neutrons + 2 protonsRelative mass: 7000

β-emitters:Strontium-89Samarium-153

β-particles:1 electronRelative mass: 1

Cell killing

and marrow

penetration: Two

advantages

of α-emitters

Large molecule+

High Linear

Energy

Transfer

More DNA double-strand

breaksIn (cancer) cells

Low

marrow

penetration

(≤100 μm )

Limited hematological

toxicity

TREATMENT

6 injections at 4-week intervals

Radium-223 (50 kBq/kg) + Best standard of care

Radium-223 (50 kBq/kg) + Best standard of care

Placebo (saline) + Best standard of care

Placebo (saline) + Best standard of care

RA

N D

O M I

ZE

D

2:1

N = 922

PATIENTS

•

Confirmed symptomatic CRPC

•

≥

2 bone metastases

•

No known visceral metastases

•

Post-

docetaxel

or unfit for docetaxel

•

Confirmed symptomatic CRPC

•

≥

2 bone metastases

•

No known visceral metastases

•

Post-

docetaxel

or unfit for docetaxel

ALSYMPCA (ALpharadin

in SYMptomatic Prostate CAncer) Phase III Study Design

Clinicaltrials.gov

identifier: NCT00699751.

•

Total ALP: < 220 U/L vs

≥

220 U/L

•

Bisphosphonate

use: Yes vs

No

•

Prior docetaxel: Yes vs

No

•

Total ALP: < 220 U/L vs

≥

220 U/L•

Bisphosphonate

use: Yes vs

No•

Prior docetaxel: Yes vs

No

STRATIFICATION

Planned follow-up is 3 years

Radium-223 Phase III trial (ALSYMPCA): Overall Survival

Radium-223, n = 614Median OS: 14.9 months

Placebo, n = 307Median OS: 11.3 months

HR = 0.69595% CI, 0.581, 0.832

P = 0.00007

Month 0 3 6 9 12 15 18 21 24 27 30 33 36 39

Radium-223 614 578 504 369 274 178 105 60 41 18 7 1 0 0

Placebo 307 288 228 157 103 67 39 24 14 7 4 2 1 0

0

10

20

30

40

50

60

70

80

90

100

%

n=921

Parker C, ASCO 2012

Systemic

treatment

for CRPC in 2012-2013

Local Treatment

PSA relapse (ADT)

Metastatic

Castrate-Resistant

Prostate Cancer

Castrate-resistant, M0

Metastatic

Hormone-Sensitive prostate cancer

Docetaxel

Zoledronate

Cabazitaxel

Denosumab

AbirateroneAbiraterone EnzalutamideRadium 223

Continuous

ADT

ADT

The cornucopia

of new drugs for CRPC

•

Endocrine agents–

Abiraterone

–

Enzalutamide•

Immunotherapy–

Sipuleucel-T

•

Chemotherapy–

Cabazitaxel

•

Bone-targeting

agents–

Denosumab

–

Alpharadin

The cornucopia

of new drugsfor CRPC in the future

•

Endocrine agents–

ODM 201

(ESMO 12)

–

ARN 509

(ASCO 12)–

Orteronel

•

Immunotherapy–

Ipilimumab

(2013?)

–

Prostvac–

Tasquinimod

•

Bone-targeting

agents–

Cabozantinib

(ASCO 12)

–

Dasatinib (2013?)•

HSP-targeting

drugs

–

OGX 011, OGX 427