have we optimized the use of androgen receptor pathway ... · have we optimized the use of androgen...

Have we optimized the use of

Androgen Receptor pathway targeted drugs

in Castrate-Resistant Prostate Cancer ?

Karim Fizazi, MD, PhD

Institut Gustave Roussy

Villejuif, France

Disclosure

Participation to advisory boards/honorarium for:

Amgen, Astellas, Astrazeneca, Bayer, Clovis,

Curevac, Essa, Genentech, Janssen, MSD, Orion,

Sanofi

Androgen Receptor is still expressed

in CRPC

Prostate cancer

in intact animalAfter castration Castration-resistant

Xenograft model of MDA PCa 2b

prostate cancer cells in SCID mice

Navone N and Fizazi K, unpublished dataAndrogen Receptor

Targeting the AR pathway

Testosterone/

Other androgens

DNA

Cell division

TestisAdrenals

Autocrine

secretion

Castration

(aLHRH or Surg.)

Abiraterone

Orteronel

Galeterone

ODM-204

Abiraterone

Orteronel

Galeterone

ODM-204

Androgen Receptor inhibitors:

-Bicalutamide

-Enzalutamide

-ODM-201

-ARN 509

-Galeterone

-ODM-204

-EPI drugs

4 new active drugs in 4 years

for post-docetaxel CRPC !

MTX+PREDCBZ+PRED

Pro

po

rtio

n o

f O

ve

rall

Su

rviv

al

0102030405060708090

100

0 6 12 18 24 30Time (months)

Cabazitaxel, De Bono J, Lancet 2010 Abiraterone, Fizazi K, Lancet Oncol 2012

Radium-223, Parker J, NEJM 2013Enzalutamide, Scher HI, NEJM 2012

0 3 6 9 12 15 18 21 24 27 30 33 36 390

20

40

60

80

100

%

Radium-223Median OS 14.9 mo

PlaceboMedian OS 11.3 mo

03 6 9 18 21 2415

100

80

60

40

20

00

Surv

ival

(%

)

Duration of overall survival (months)12

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

Enzalutamide: 18.4 months(95% CI: 17.3–NYR)

Abiraterone:

CYP17 blockade inhibits androgen synthesis

b

Abiraterone post-chemotherapy:

COU-301

AA 1000 mg daily

Prednisone 5 mg BID

n = 797

Primary end point:

• Overall survival (25%

improvement; HR=0.8)

Secondary end points:

• TTPP

• rPFS

• PSA response

Efficacy end points

Placebo daily

Prednisone 5 mg BID

n = 398

RANDOMIZED

2:1

• Progressive

mCRPC patients

(N = 1195)

• Failed 1 or 2

chemotherapy

regimens

Patients

de Bono JS, et al. N Engl J Med, 2011

• Stratification by:

Performance status 0-1 vs 2

Worst pain BPI short form; 0-3 (absent) vs 4-10 (present)

Prior chemotherapy 1 vs 2

Type of progression PSA only vs radiographic (with or without PSA)

COU-301: Abiraterone prolongs survival in

post-docetaxel mCRPC patients

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

AA

(n=791)

Placebo

(n=394)

All

Grades

Grades

3/4

All

Grades

Grades

3/4

Fluid retention 31% 2% 22% 1%

Hypokalemia 17% 3% 8% 1%

Hypertension 10% 1% 8% <1%

Cardiac

disordersa 13% 3% 11% 2%

LFT

abnormalities10% 3% 8% 3%

Abiraterone-Prednisone:

Adverse events of special interest

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

de Bono et al. N Engl J Med 2011; 346: 1995-2005

Abiraterone in asymptomatic mCRPC:

the COU-302 Phase III study

• Stratification by ECOG performance status 0 vs. 1

Ryan C, et al. American Society of Clinical Oncology Congress 2012;

Abstract LBA4518.

Patients

• Progressive chemo-

naïve mCRPC

• Asymptomatic or

mildly symptomatic

Ra

nd

om

isa

tio

n1

: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-302: Abiraterone in docetaxel-naïve

CRPC patients

Radiographic progression-free survival (rPFS)

Abiraterone acetateControl

Abiraterone acetatePlacebo

AA + PPL + P

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

Ryan C, et al. N Engl J Med 2013 Ryan C et al., Lancet Oncol 2015

Overall survival

(Final analysis)

100

80

60

40

20

00

Ove

rall

Surv

ival

(%

)

9 21 30 48 6039Time to Death (Months)

24123 36 45 54

HR (95% CI): 0.81 (0.70-0.93)

p Value: 0.0033

Prednisone, 30.3 mos

Abiraterone, 34.7 mos

6 15 18 27 33 42 51 57

26-30 September 2014, Madrid, Spain esmo.org

Cou-302: Safety Profile

Abiraterone(n = 542)

%

Prednisone(n = 540)

%

All Grades Grade 3/4 All Grades Grade 3/4

Fluid retention/edema 31 1 24 2

Hypokalemia 19 3 13 2

Hypertension 24 5 14 3

Cardiac disorders 23 8 18 4

Atrial fibrillation 6 2 5 1

ALT increased 13 6 5 1

AST increased 12 3 5 1

ALT, alanine aminotransferase; AST, aspartate aminotransferase.

AFFIRM: Enzalutamide in mCRPC

patients post-chemotherapy

Scher HI et al. N Engl J Med 2012; 367(13): 1187–1197.

mCRPC

1–2 prior

chemotherapy

regimens*

(n = 1,199)

R

2:1

Enzalutamide 160 mg qd (n =

800)

Placebo per qd (n = 399)

*≥ 1 docetaxel (glucocorticoids

were allowed but not required)

AFFIRM is a phase III randomised, double-blind,

placebo-controlled trial

mCRPC, metastatic castrate-resistant prostate cancer;

qd, once per day;

R, randomisation

Recruitment in 156 centres from 15 countries across 5 continents between September 2009 and November 2010

AFFIRM: Overall survival

3 6 9 18 21 2415

100

80

60

40

20

00

Su

rviv

al

(%)

Duration of overall survival (months)12

775 701 627 72 7 0211800 400Enzalutamide, n =

376 317 263 33 3 081399 167Placebo, n =

Placebo: 13.6 months

(95% CI: 11.3–15.8)

Enzalutamide: 18.4 months

(95% CI: 17.3–NYR)

HR = 0.63 (95%CI: 0.53–0.75); p<0.001

37% reduction in risk of death

4.8 month

difference in

median

overall

survival

CI, confidence interval;

HR, hazard ratio;

NYR, not yet reached

No at

risk:


AFFIRM: Summary of adverse events

LFT, liver function test

*abnormalities on LFT included hyperbilirubinaemia and increased levels of aspartate aminotransferase or alanine aminotransferase

The adverse event reporting period for the Enzalutamide group was more than twice that for the placebo group

Adverse events, n (%)

Total events (all grades) Grade ≥ 3 events

Enzalutamide

(n = 800)

Placebo

(n = 399)

Enzalutamide

(n = 800)

Placebo

(n = 399)

≥1 Adverse event 785 (98) 390 (98) 362 (45) 212 (53)

Any serious adverse event 268 (34) 154 (39) 227 (28) 134 (34)

Discontinuation due to adverse event 61 (8) 39 (10) 37 (5) 28 (7)

Adverse event leading to death 23 (3) 14 (4) 23 (3) 14 (4)

Adverse events of interest, n (%)

Fatigue 269 (34) 116 (29) 50 (6) 29 (7)

Cardiac disorder (any) 49 (6) 30 (8) 7 (1) 8 (2)

Myocardial infarction 2 (<1) 2 (<1) 2 (<1) 2 (<1)

LFT abnormality* 8 (1) 6 (2) 3 (<1) 3 (<1)

Seizure 5 (<1) 0 5 (<1) 0


Prevail: Enzalutamide in docetaxel-naïve

mCRPC patients

832

Placebo 801 305 79

128

20

34

5

5

0

1

0

0

0

Radiographic Progression-Free Survival (Months)0 3 6 9 12 15 18 21

Enzalutamide

Placebo

Ra

dio

gra

ph

ic P

ro

gres

sion

-Fre

e S

urviv

al

(%)

60

50

40

30

20

10

0

90

80

70

100 Hazard Ratio: 0.186

(95% CI: 0.15,0.23)

P < 0.0001

Beer T, N Engl J Med 2014; 371: 424-33

Prevail: safety of Enzalutamide

pre-docetaxel

All Grades (%) Grade ≥3 events (%)

Enzalutamide

(n=871)

Placebo

(n=844)

Enzalutamide

(n=871)

Placebo

(n=844)

Fatigue 35.6 25.8 1.8 1.9

Back pain 27.0 22.2 2.5 3.0

Constipation 22.2 17.2 0.5 0.4

Arthralgia 20.3 16.0 1.4 1.1

Cardiac AEs 10.1 7.8 2.8 2.1

Hypertension 13.4 4.1 6.8 2.3

ALT increased 0.9 0.6 0.2 0.1

Seizure 0.0† 0.1 0.0† 0.0

Comparison between 302 & PREVAILOverall Study Design

COU-AA-302 PREVAIL

Number of pts 1,088 1,717

Conditions

• Progressive chemo-naïvemCRPC

• Asymptomatic/mildly symptom• No visceral mets

• Progressive chemo-naïvemCRPC

• Asymptomatic/mildly symptom• Visceral mets allowed

Treatment• AA+ Prednisone• Prednisone

• ENZA (Steroid is allowed)• Placebo (Steroid is allowed)

Primary endpoints• rPFS• OS

• rPFS• OS

Secondary endpoints

• Time to opiate use Time to initiation of chemotherapy

• Time to ECOG-PS deterioration• TTPP

• Time to initiation of chemotherapy

• Time to 1st SRE

Designmulticenter, randomized, double-

blind, placebo-controlledmulticenter, randomized, double-

blind, placebo-controlled

Locations151 sites in 12 countries

（USA、EU、Australia、Canada）

207 sites in 22 countries（USA、EU、Australia、Canada

Asia 〔including Japan〕）

Stratification • ECOG PS 0 vs. 1

Short response to ADT predicts poor response to Enzalutamide (post-docetaxel)

PFS

TTCRPC

P<0.001

Loriot Y et al., Eur J Cancer 2015

PSA decrease ≥ 50%

8% 58%

Treatment decision making in CRPC:

several obvious situations

• History of seizure

• Visceral metastases

• Patient too old/sick

• Contra-indication to

steroids (severe

diabetes, etc)

• Enzalutamide

• Radium-223

• Taxanes

• Abiraterone

Drug-drug interactions with enzalutamide

• Enzalutamide = powerful CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer:– Avoid Cabazitaxel, – Be careful with many drugs (zolpidem, fentanyl,

clopidrogel, lovastatin, triazolam, amiodarone, etc)

• CYP2C8 induces Enzalutamide metabolism intoits active metabolite and its elimination:– Avoid CYP2C8 inhibitors (gemfibrozil) and inducers

(rifampicine)

• Avoid any drug that increases the risk of seizure(anti-depressors, neuroleptics, tramadol)

Drug-drug interactions with abiraterone

• Abiraterone = CYP 2C8 inducer (ex: pioglitazone, anti-diabetes: AUC increased x 1.5)

• Abiraterone= CYP 2D6 inhibitor (ex: dextromethorphan: AUC is increased x 3, thioridazine=Melleril)

• Abiraterone is a substrate of CYP 3A4: theoretically, be careful with strong CYP3A4 inducers (rifampicine). No effect of ketoconazole

How to best treat mCRPC?

• Earlier treatment?

• Sequential treatments?

• Combinations?

• Personalized treatments?


• Ealier treatment

• Sequential treatments

• Combinations

• Personalized treatments

Who Dies of Prostate Cancer?

Metastases

Upfrontlocalized cancer

De novometastases

Death

56% of deaths

44% of deaths

Patrikidou A. Prostate Cancer Prostatic Dis. 2014;17:348-352.

LATITUDE: study design

mHNPC, metastatic hormone naive prostate cancer; q.d., once daily; rPFS, radiographic progression-free survival.

Randomized, double-blind, active-controlled, multicentre, phase 3 study

Efficacy endpoints

Primary:

• OS

• rPFS

Secondary:

• Time to next skeletal-related event


Abiraterone 1000 mg QD+ Prednisone 5 mg QD

+ ADT

Placebo 1000 mg QD + Placebo 5 mg QD

+ ADT

Ra

nd

om

iza

tio

n 1

:1

Primary endpoints

▪ OS

▪ rPFS

ADT + abiraterone 1,000 mg q.d.

+ prednisone 5 mg q.d.

ADT + placebos q.d.

Patients

▪ de novo mHNPC

Meets at least 2 of 3 high-risk criteria

▪ Gleason score ≥ 8

▪ Presence of ≥ 3 lesions on bone scan

▪ Presence of measurable visceral lesion

Fizazi K, N Engl J Med 2017; 377: 352-60

LATITUDE: Abiraterone in mCSPC38% risk reduction of death

53% risk reduction of progression/death

Overall survival rate at 3 years:ADT + AA + P: 66%ADT + placebos: 49%

Median follow-up: 30.4 months


EMA approval

Stampede Abiraterone

James ND, N Engl J Med 2017

LATITUDE: Prespecified Secondary and Exploratory End Points

ADT+AA+P(n = 597)

ADT+placebos

(n = 602)

Hazard Ratio (95% CI)

P Value*

Secondary end points

Time to pain progression —mo

NR 16.60.70 (0.58–

0.83)< 0.001

Time to PSA progression —mo

33.2 7.40.30 (0.26–

0.35)< 0.001

Time to next symptomatic skeletal event — mo

NR NR0.70 (0.54–

0.92)0.009

Time to chemotherapy —mo

NR 38.90.44 (0.35–

0.56)< 0.001

Time to subsequent prostate cancer therapy —mo

NR 21.60.42 (0.35–

0.50)< 0.001

Exploratory end point

Patients with a PSA response (decline ≥ 50% from baseline) — %

91 671.36 (1.28–

1.45)* < 0.001


Addition of Abiraterone to ADT significantly

improved fatigue: PROs from LATITUDE

*1 cycle = 28 days. PRO, patient reported outcomes.

Chi K, et al. Data presented at ESMO 2017 (abstract 7830).

0.4

0.2

0.0

-0.2

-0.4

Cycle*

ADT + PlacebosADT + AAP

Mea

n c

han

ge

from

base

lin

e

in w

ors

t fa

tig

ue

score

(B

FI)

7 9530 15 17 2119 23 25 27 29 31 332 4 6 8 11 1310 121

Worse

Better

0

465

407

372

259

305

171

216

106 46

44

14

2

1

6 12 18 24 30 36 42

HR 0.65 (95% CI, 0.53-0.81)

P = 0.0001

ADT + AAP, NR

ADT + Placebos, NR

Months

118

Pati

ents

wit

hou

t w

ors

t

fati

gu

e p

rog

ress

ion

(%

)

100

80

60

20

0

40

597

602

Patients at risk

ADT + AAP

ADT + Placebos

35% Risk Reduction

for Worst Fatigue ProgressionMean Change From Baseline

Differed from Cycle 5 Onward

An indirect comparison to determine the relative

efficacy of Abiraterone vs Docetaxel in mHSPC

CrI, credible interval; P, Bayesian probabilities.

Feyerabend S, et al. Data presented at ESMO 2017 (abstr 803P).

HR (95% CrI): 0.85 (0.63, 1.14)

P (HR < 1) = 86.7%

Analyses suggest that ADT + AAP has greater reduction in

risk of progression and death vs ADT + Doc

HR (95% CrI): 0.71 (0.49, 1.02)

P (HR < 1) = 96.8%

Posterior Density: rPFS - Main AnalysisPosterior Density: OS - Main Analysis

Abiraterone or docetaxel?

Direct comparison from STAMPEDE

Strong evidence

favouring AAP

Sydes M, et al. Data presented at ESMO 2017. (abstract LBA31).

Toxicity profiles quite different and well known

Weak evidence favouring AAP

No good evidence of a difference

Favours

SOC+AAP

Favours

SOC+DocP

Hazard ratio

Metastatic

progression-free survival

Progression-free survival

Failure-free

survival

Symptomatic skeletal events

Cause-specific

survival

Overall survival

Head-to-head data in 566 pts (Nov-2011 to Mar-2013)

Proportionately different time spent in each

disease state

SOC +Abiraterone 1000 mgPrednisone 5 mg BID

Co-primary endpoints: OS and PFS (HR: 0.75)

SOC +

Local radiotherapy

RANDOMIZED

• Patients with newly diagnosed (castration-naïve) metastatic CaP

• 1156 pts planned

PEACE-1: European Phase III Trial in de novo Metastatic Prostate Cancer (revised design)

Study sponsor: Unicancer

SOC

SOC +

Local radiotherapy +Abiraterone-Pred

ClinicalTrials.gov. Identifier: NCT01957436.

Standard of Care (SOC)= Androgen deprivation therapy (ADT) +/- docetaxel (Stratification)

ENZAMET

Enzalutamide 160mg/daily +

LHRHA (or orchidectomy) until progression

EligibilityMetastatic prostate cancerStarting 1st line ADTAdequate organ function

Screening Randomisation 1:1

Non-steroidal anti-androgen +

LHRHA (or orchidectomy) until progression

StratificationComorbiditiesVolume of diseaseStudy siteBone anti-resorptive therapyUse of early docetaxel

Who Dies of Prostate Cancer?

Metastases

Upfrontlocalized cancer

De novometastases

Death

44% of deaths

Patrikidou A. Prostate Cancer Prostatic Dis. 2014;17:348-352.

Phase III trials in M0 CRPC

Zibotentan (n=1421)

Miller K, Prostate Cancer Prostatic Dis 2013; 16: 187-92Nelson JB, Cancer 2008; 113:2 478-87Smith MR, Lancet 2012; 379: 39-46

Atrasentan (n=941)

Denosumab (n=1432)

PROSPER Trial Design: Enzalutamide in

M0 CRPC

Hussain M et al. ASCO 2014. Poster TPS5094

AR targeting works !

ODM-201 has a unique profile

Compound AR

affinity

Ki (nM)

Antagonism

WT AR

IC50 (nM)

Proliferation

VCaP

IC50 (nM)

enzalutamide 78 155 400

ARN-509 53 168 300

ODM-201 9 65 500

ORM-15341

(main metabolite)8 25 600 No CYP inhibition or

induction with therapeutic

doses

Fizazi K et al., ECC2013 poster E17-2119

enzalutamide 19%*

ARN-509 29%*

ODM-201 +

main metabolite 3% **

*Refs. Clegg et al, Cancer Research 2012; Forster at al,

Prostate 2011

** Rat autoradiography (QWBA confirms brain/plasma ratio

of 14C-ODM-201 related radioactivity was 0.04-0.06,

indicating negligible penetration to the brain

ODM-201 and ARN-509 (AR inhibitors): PSA response

ODM-201

No chemotherapy Chemotherapy

Fizazi K, Lancet Oncol 2014; 15: 975-85

Smith MR et al. ASCO GU 2013, Abstract # LBA 7

ARN-509


• Earlier treatment


• Combinations


Should We Keep Using “Old” Hormonal Manipulations Before

Using Next-generation AR-Targeting Drugs?

TERRAIN Study Design

Primary endpoint

Progression-free survival (PFS)

• Radiographic progression (central review)

• Skeletal-related event

• Change in new antineoplastic therapy

• Death

ENZA160 mg/day

n = 184

BIC50 mg/day

n = 191

RANDOMIZED

1:1

Patient population

• 375 men with progressive mCRPC

• Asymptomatic/mildly symptomatic

• Chemotherapy naive

• No requirement for steroids

Secondary endpoints

• PSA response


TERRAIN trial: NCT01288911

Statistical design

• The final analysis was planned at ≥220 progression events with 85% power to detect a target hazard ratio of 0.67 (assuming a median PFS of 9 months vs 6 months1)

• The data cutoff date was 19 October 2014, with 240 events for the primary efficacy endpoint

Shore ND, Lancet Oncol 2016; 17: 153-63

100

90

80

70

60

50

40

30

20

10

00 3 6 9 12 15 18 21 24 27 30 33

Progression-Free Survival in TERRAINP

atie

nts

wit

ho

ut

PFS

eve

nt

(%)

184

191

159

133

131

85

107

61

86

44

71

30

52

13

33

7

21

4

13

2

8

2

5

1

ENZA BIC

Time (months)ENZAPatients at riskBIC Patients at risk

Median (95% CI):15.7 months (11.5, 19.4)

Median (95% CI):5.8 months (4.8, 8.1)

Hazard ratio (95% CI): 0.44 (0.34, 0.57); P <0.0001


PSA Response by Week 13 with ENZA or BICA

100

80

60

40

20

0

-20

-40

-60

-100

-80Pe

rce

nta

ge C

han

ge in

PSA

fro

m B

ase

line

ENZA BIC

PSA response: 21%

Observations

PSA response: 82%


BICA ENZA

STRIVE trial: Enzalutamide vs Bicalutamide in early CRPC

Penson DP, J Clin Oncol 2016; 34: 2098-2106

n=396 pts

(M0=139; M1=257

Composite PFS: HR= 0.24 (95% CI, 0.18 to 0.32; P < .001)

Median PFS:

19.4 months Enza vs 5.7 months Bica

Terrain: Quality of life

Time to QoL deterioration (FACT-P)

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

Time (months)

100

90

80

70

60

50

40

30

20

10

036 39

Patients at risk :

Enzalutamide

Bicalutamide

184

191

121

88

91

50

71

30

55

20

45

15

33

10

19

6

12

4

6

1

3

1

2

1

1

0

0

0

Enzalutamide :Median = 13.8 mo

(IC95% : 11.1 – 22.1)

Bicalutamide :Median = 8.5 mo

(IC95% : 5.8 – 11.3)

Pa

tie

nts

with

ou

t d

eg

rad

ation

(%

)

HR=0.64 (IC95% : 0.46–0.88) ; p=0.0067

Shore N. et al, Lancet Oncol 2016; 17: 153-163

CRPC progressing on abiraterone or enzalutamide:

How to treat?

Cross-resistance between

abiraterone and enzalutamide

Author Year

published

N pts Duration of

2nd

treatment

PSA

≥ 50%

Median

PFS

ENZ ABI

Loriot et al. 2013 38 3 mo 8% 2.7 mo

Noonan et al. 2013 30 13 wks 3% 3.6 mo

ABI ENZ

Schrader et al. 2013 35 4.9 mo 29% -

Badrising et al. 2014 61 3 mo 21% -

Bianchini et al. 2014 39 2.9 mo 23% -

Schmid et al. 2014 35 2.8 mo 10% -

Brasso et al. 2014 137 3.2 mo 18% -

Zhang T et al. Expert Opin Pharmacotherap 2014;16:1-9

Docetaxel post-Abiraterone

(COU-302)

200

100

50

-50

-100

Réd

uc

tio

n m

ax

ima

le d

u P

SA

(%

)

-0

150

Flaig T, ASCO GU 2016

PSA response rate=47%

TTP: 7.6 months

De Bono J, Eur Urol 2016

Cabazitaxel post-Abiraterone

(and post-docetaxel)

• n=79 pts

• PSA response>30%: 62%

• PSA response>50%: 35%

• PFS: 4.4 mo

• OS: 11 mo

• In vitro: Caba active against

both enza-S and enza-R cells

Al Nakouzi N, Eur Urol 2015; 68: 228-35

PSA response

A proposed decision tree for metastatic CRPC(2017)

mCRPC- Cancer progression- Testo<0.50 ng/mL

Majority of patients(If drug availaible)

Abirateroneor

Enzalutamide

Progression:

Docetaxel

(Switch to Enza?)(Radium-223?)

Progression:

CabazitaxelRadium-223

Patients who experience progression

after a short ADT period

Docetaxel

Progression: consider:

CabazitaxelAbiraterone

EnzalutamideRadium-223

mCRPC patient initially treated with ADT + Docetaxel

???

Denosumab (or ZA), Vit D/Calcium, Supp. care

Fizazi K, Eur J Cancer 2016; 66: 125-130

PSA response for CRPC pts treated with docetaxel according to primary treatment

for M1

Decre

ase In

cre

ase

100

90

80

70

60

50

40

30

20

10

0

10

20

30

40

50

60

70

80

90

100

Best PSA variation (%) during the treatment (n= 80)

Decrease In

crease

100

90

80

70

60

50

40

30

20

10

0

10

20

30

40

50

60

70

80

90

100


Docetaxel for CRPC

if upfront ADT alone

Docetaxel for CRPC

if upfront ADT+Doce

Lavaud P, Eur Urol 2017

PSA response for CRPC pts treated with abiraterone/enzalutamide when treated

upfront with ADT+Docetaxel for M1D

ecr

eas

e

In

crea

se

100

90

80

70

60

50

40

30

20

10

0

10

20

30

40

50

60

70

80

90

100


Lavaud P, Eur Urol 2017




• Combinations


Combining drug X to docetaxel:

a failing strategy so far…

• Doc + Oblimersen

• Doc + DN-101

• Doc + Bevacizumab

• Doc + VEGF-Trap

• Doc + Lenalidomide

• Doc + Atrasentan

• Doc + Zibotentan

• Doc + GVAX

• Doc + Dasatinib

• Doc + Custirsen

Negative Phase III trials

PS

A C

ha

ng

e (

%)

-100-90

-75

-50

-30

0

25

50

75

10030% Redunction: 87%(52/60) 50% Redunction: 77%(46/60) 90% Redunction: 47%(28/60)

Abiraterone + Enzalutamide Phase I-II trial

≥PSA 50 decline in 78% of patients (47 out of 60)≥PSA 90 decline in 50% of patients (30 out of 60)PSA≤ 0.1 ng/ml in 13% of patients (8 out of 60)

Exploratory: association of lack of PSA decline with resistance (p=0.008)

PSA

ch

ange

(%

)

Efstathiou E, ASCO 2014

Current combination strategies

(ongoing Phase III)

• Abiraterone + Enzalutamide (US)

• Abiraterone + ARN-509 (ACIS)

• Abiraterone + Radium-223 (ERA)

• Enzalutamide + Radium-223 (PEACE-3)




• Combinations

• Personalized treatment

Success stories of Personalized Medicine

Breast cancer:

Trastuzumab in HER2 + tumors(Slamon,

N Engl J Med 2001, 344: 783-92)

Colo-rectal cancer:

Cetuximab in K-ras wt tumors(Karapetis CS,

N Engl J Med 2008; 359: 1757-65)

Mutated K-rasWild type K-ras

Non-small cell lung cancer:

Crizotinib in Alk+ tumors(Shaw AT,

ESMO 2012, Abstr 2862)

Crizotinib

Chemotherapy

PFS

AR splice variants

N-Terminal Domain

DNA binding

domain

Nuclear localization

domain

Ligand Binding domain

Splice variant -> AR constitutively active

(no need for androgens)

AR splice variants (V7)

CTCs: AR-V7 is a promising

predictor of treatment response

Antonarakis ES et al. N Engl J Med 2014;371:1028-38; Antonarakis ES et al. JAMA Oncol 2015; 1:582-91

PSA

ch

ange

, %

100

50

–50

–100

*

†

* * *

†

††

100

50

0

–50

–100

†*

†*

†* †

† ††

†† † †

††

††

† † †

† †

100

50

0

–50

–100

Abiraterone Enzalutamide Taxanes

PSA response rate:AR-V7 positive: 0% (95% CI: 0-26%)AR-V7 negative: 52.6% (95% CI: 29-76%)P=0.004

PSA response rate:AR-V7 positive: 0% (95% CI: 0-46%)AR-V7 negative: 68.0% (95% CI: 46-85%)P=0.004

PSA response rate:AR-V7 positive: 41% (95% CI: 18-67%)AR-V7 negative: 65% (95% CI: 41-85%)P=0.19

Docetaxel, n=30Cabazitaxel, n=7

AR-V7 positive AR-V7 negative

AR gains and mutations are associated with

primary resistance to next generation AR axis

targeted agents (Abiraterone)

Romanel A, Science Trans Med 2015

Association between AR aberrations

(cfDNA) and PFS on Enzalutamide

Wyatt AW, JAMA Oncol 2016

Zhao et al., JAMA Oncol 2017

Conclusion

• Sequential treatment still routinely used for CRPC, combination remains experimental

• The field is changing in 2017:

– M1 CSPC: Abiraterone

– M0 CRPC: Enzalutamide

• Cross-resistance between Abi and Enza (20% responders) but Taxanes still active after abi/enza

• Biomarkers clearly emerging

have we optimized the use of androgen receptor pathway ... · have we optimized the use of androgen...

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