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Navone N and Fizazi K, unpublished dataAndrogen Receptor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:
Scher HI et al. N Engl J Med 2012; 367(13): 1187–1197.
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
Scher HI et al. N Engl J Med 2012; 367(13): 1187–1197.
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?
How to best treat mCRPC?
• 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
• Time to PSA progression
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
Fizazi K, N Engl J Med 2017; 377: 352-60
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
Fizazi K, N Engl J Med 2017; 377: 352-60
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
How to best treat mCRPC?
• Earlier treatment
• Sequential treatments
• Combinations
• Personalized treatments
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
• Time to PSA progression
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
Shore ND, Lancet Oncol 2016; 17: 153-63
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%
Shore ND, Lancet Oncol 2016; 17: 153-63
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
Best PSA variation (%) during the treatment (n= 29)
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
Best PSA variation (%) during the treatment (n= 15)
Lavaud P, Eur Urol 2017
How to best treat mCRPC?
• Earlier treatment
• Sequential treatments
• Combinations
• Personalized treatments
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)
How to best treat mCRPC?
• Earlier treatment
• Sequential treatments
• 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