Docetaxel - Ecole des Sciences du Cancer

The Evolution of Castrate-Resistant
Prostate Cancer and the Role of Bone
Targeted Agents
Karim Fizazi, MD, PhD
Institut Gustave Roussy
Villejuif, France
Disclosure
• Participation to advisory boards for:
Amgen, Astellas, Bayer, BMS, Dendreon, Ipsen,
Janssen, Takeda, Novartis, Sanofi-Aventis
Advanced prostate cancer:
Natural history (in the 2000s)
Local Treatment
PSA relapse (ADT)
Castrate-resistant, M0
Docetaxel
Zoledronate
ADT
Metastatic Hormone-Sensitive
prostate cancer
Metastatic Castrate-Resistant Prostate Cancer
(CRPC)
Osteolytic and osteoblastic bone metastases:
presence of osteoclasts irrespective of radiology
Osteolysis
Osteoblastosis
PC
Osteolysis1
Black arrows = osteoclasts
Osteoblastosis2
1. Roodman GD. N Engl J Med 2004;350:1655–1664
2. Amgen, data on file
Skeletal-Related Events (SRE) in men with bone
metastases from prostate cancer
Pain requiring
Radiation to
Bone
Pathologic
Fracture
Spinal Cord
Compression
Surgery to
Bone
33%
25%
8%
4%
Saad, et al. J Urol 2003;169(Suppl).
Zoledronate: Time to Skeletal-Related Event
in mCRPC
Percent without event
100
Interval over 5 Months
80
60
40
Median, days
® 4 mg
488
Zoledronate
ZOMETA
488
Placebo
321
321
Placebo
20
0
0
Zol 4 mg
Placebo
214
298
P value
.009
0.009
120
240
360
Days§
480
600
720
149
128
97
78
70
44
47
32
35
20
3
3
RR = 0.64 (95% CI = 0.485-0.845)
Saad et al. JNCI 2004; 96:879
Proportion (%) of Patients With
Each SRE
33
Percent of patients
35
30
26
25
25
20
17
15
8
10
4
5
6
7
2
4
0
Radiation to
bone
Fractures
Spinal cord Antineoplastic
compression
therapy
Zoled acid 4 mg (N = 214)
Saad et al. JNCI 2004; 96:879
Surgery to
bone
Placebo (N = 208)
0
1
Hypercalcemia
Trapeze Phase III trial in mCRPC:
SSE-Free Interval
Nick James, ASCO 2013
TAX 327
Study Design
Mitoxantrone 12 mg/m2 q 21 days
Prednisone 5 mg po bid
Patient Stratification
Pain level
PPI > 2 or AS > 10
vs.
PPI < 2 or AS < 10
KPS
R
Docetaxel 75 mg/m2 q 21 days
Prednisone 5 mg po bid
Dexamethasone 8 mg 12, 3 and 1 hour prior to D
N=1006
Docetaxel 30 mg/m2 /wk 5 of 6 wks
Prednisone 5 mg po bid
Dexamethasone 8 mg 1 hour prior to D
< 70 vs. > 80
Intended Treatment Duration in all 3 arms = 30 weeks
Tannock IF, et al: NEJM 351:1502-12, 2004
TAX 327 – Overall Survival
Tannock IF, et al: NEJM 351:1502-12, 2004
SWOG 9916
D/E*
Docetaxel 60 mg/m2 IV J2/ 3 semaines
estramustine 280 mg po x3/j, J1-5
R
Prémédication: Dexamethasone 20 mg PO x3/j à débuter la veille au soir
M/P
mitoxantrone 12 mg/m2 IV toutes les
3 semaines
prednisone 5 mg po x2/j en continue
* Protocole amendé: Coumadine 2 mg PO chaque jour + Aspirine 325 mg PO
Petrylak DP, et al: NEJM 351:1513-20, 2004
SWOG 9916: Taux de réponse
Réponse Objective
% de patients
p = 0.15
17%
11%
Taxotere/ mitoxantrone
estramustine /prednisone
n=103
n=93
% de patients avec une baisse du PSA 50%
Réponse PSA
p < 0.0001
PSA
50%
27%
Taxotere/ mitoxantrone
estramustine /prednisone
n=303
n=303
SWOG 9916
PFS
OS
Petrylak DP, et al: NEJM 351:1513-20, 2004
Randomized phase II trial:
Prednisone ± Docetaxel
n=111
Fossa, Eur Urol 2007, 52: 1691-8
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 + Dasatinib
Negative Phase III trials
Since 2004: Docetaxel= standard
treatment for castration-resistant
prostate cancer
2015: Docetaxel to be used also in
hormone-sensitive metastatic
prostate cancer ?
Mr Testos, 65 ans, consulte pour des douleurs lombaires modérées. Son PSA est élevé à 60 ng/mL, des biopsies révèlent un ADK Gleason 7, la scintigraphie montre 5 lésions secondaires.
Quel traitement proposez vous?
1‐ Castration + bicalutamide 3 semaines
2‐ Castration + bicalutamide continu
3‐ Castration + 6 cycles de docetaxel
4‐ Castration + 6 injections d’acide zoledronique
5‐ Castration + docetaxel + acide zoledronique
Zoledronic acid in hormone-sensitive CaP: Survival
(Stampede)
SOC
SOC+ZA
405 deaths
197 deaths
HR (95%CI) 0.93 (0.79, 1.11)
P‐value 0.44
Non‐PH p‐value 0.83
Median OS (95% CI)
SOC
67m (60, 91m)
SOC+ZA
80m (70, NR)
Restricted mean OS time
SOC
58.5m SOC+Doc
59.5m
Diff (95%CI) 1.0m (‐1.4, 3.4m) James N, ASCO 2015
Three available phase III trials:
GETUG 15, Chaarted and Stampede
METASTATIC
HORMONE-NAÏVE
PROSTATE
CANCER
MAIN
STRATIFICATION
FACTORS:
Extent of disease
ECOG PS
Prior Adjuvant ADT
GETUG 15
Chaarted
n=385
n= 790
ARM A:
ADT + docetaxel
75mg/m2/21 d x 6/9
cycles
ARM B:
ADT (androgen
deprivation
therapy alone)
Accrual: 2004-2008
Accrual: 2006-2012
Docetaxel in HSPC: Clinical PFS is improved
• GETUG 15:
– Median: 15 vs 23 months
– HR: 0.75 [0.59‐0.94] p=0.015
• Chaarted:
– Median: 19.8 vs 32.7 months
– HR=0.49 (0.37‐0.45) (<0.0001)
Gravis G, Lancet Oncol 2013; 14: 149‐58
Sweeney C, ESMO 2014
Docetaxel in HSPC: Overall Survival
GETUG 15 (1/2 poor‐risk pts)
ADT + D: 61 months
ADT: 47 months
HR: 0.9 [0.7–1.2]; P = .44
CHAARTED (2/3 poor‐risk pts)
ADT + D: 58 months
ADT alone: 44 months
HR = 0.61 (0.47–0.80) P = .0003
Gravis G. Lancet Oncol. 2013;14:149‐158; Gravis G. Eur Urol 2015; Sweeney C. NEJM 2015
CHAARTED: OS by Disease Extent (volume)
Sweeney C, et al. N Engl J Med. 2015;373:737‐746.
STAMPEDE: Docetaxel – Survival, M1 Patients
SOC
SOC + Doc
343 deaths
134 deaths
HR (95% CI) 0.73 (0.59, 0.89)
P value 0.002
Median OS (95% CI)
SOC
43 mo (24, 88 mo)
SOC + Doc
65 mo (27, NR)
Non‐PH P value 0.23
Restricted mean OS time
SOC
49.3 mo SOC + Doc
56.1 mo
Diff (95% CI) 6.8 mo (2.8, 11.0 mo) James N. ASCO 2015. Abstract 5001.
M1 docetaxel: Survival
Results based on 2993 men / 1254 deaths
Trial name
CHAARTED
GETUG15
STAMPEDE (SOC +/‐ Doc)
STAMPEDE (SOC+ZA +/‐ Doc)
Overall
Favours SOC + docetaxel
HR=0.77 (0.68, 0.87) p<0.0001
.5
1
2
Favours SOC
Heterogeneity:2=4.80, df=3, p=0.187, I2 = 37.5%
10% absolute improvement in survival
(from 40% to 50%) at 4 years
Vale C, ECC 2015
What is the price to pay for this clinical benefit?
• Patient’s price:
– Classical docetaxel toxicity
– Toxicity‐related deaths (1%)
• Society:
– Docetaxel=generic
– Large magnitude of clinical/survival benefit
Likely very cost‐effective
Chemotherapy for Metastatic Hormone‐Sensitive Prostate Cancer?
YES, New standard of care!
Next questions: 1. Should we use taxanes even earlier in patients with localized CaP ?
High‐Risk Prostate Cancer: GETUG 12 Trial
Stratification
•Gleason 8
•PSA >20
•T3
•pN+/pN–
R
A
N
D
O
M
I
Z
E
ADT (3 years) + RTX
Docetaxel + Estramustine
(4 cycles)
ADT (3 years) + RTX
Primary endpoint: Progression‐free survival
n = 413 pts (Accrual: 2002–2006)
Fizazi K, et al. Lancet Oncol. 2015;16:787‐794.
Docetaxel in Localized CaP: Relapse‐Free Survival (GETUG 12)
HR = 0.71 [0.54–0.94]
P = 0.017 62% [52–69]
50% [44–57]
Fizazi K, et al. Lancet Oncol. 2015;16:787‐794.
Chemotherapy for Metastatic Hormone‐Sensitive Prostate Cancer?
YES, New standard of care!
Next questions: 1. Should we use taxanes even earlier in patients with localized CaP ?
2. Should we use other drugs (abi, enza), perhaps on top of docetaxel?
PEACE‐1: European Phase III Trial in de novo Metastatic Prostate Cancer (revised design)
Androgen deprivation therapy (ADT)
+/‐ docetaxel
ADT +
• Patients with newly diagnosed (hormone‐naive) metastatic CaP
• 916 patients planned
R
A
N
D
O
M
I
Z
E
D
Abiraterone 1000 mg
Prednisone 5 mg BID
+/‐ docetaxel
ADT +
Local radiotherapy
+/‐ docetaxel
ADT +
Local radiotherapy +
Abiraterone‐Pred
+/‐ docetaxel
Study sponsor: Unicancer
ClinicalTrials.gov. Identifier: NCT01957436.
Co‐primary endpoints: OS and PFS (HR: 0.75)
Castration-Resistant Prostate Cancer (CRPC):
A decade of research 2010-2014:
2004-2009:
No significant result
- Sipuleucel-T
- Cabazitaxel
- Denosumab
- Abiraterone
- Alpharadin
- Enzalutamide
Sipuleucel-T: Mechanism of Action
Induces an immune response against prostatic acid phosphatase (PAP)
HARVEST
APCs FROM PATIENT
PAP antigen
APC
Recombinant PAP antigen combines with resting APC
APC takes up the antigen
Antigen is processed and presented on the APC surface
Active T‐cell
T‐cells proliferate and attack cancer cells
Fully activated, the APC is now sipuleucel‐T
INFUSE
BACK INTO PATIENT
Sipuleucel‐T activates T‐cells in the body
Adapted from De Francesco L. Nat Biotechnology 2010;28:531-2 and www.dendreon.com
PAP: prostatic acid phosphatase; APC: antigen-presentation cell
Sipuleucel-T autologous vaccine:
Overall Survival
Sipuleucel-T (n = 341) vs Placebo
(n=171)
Median OS: 25.8 vs 21.7 months
p = 0.032 (Cox model)
HR = 0.78 [95% CI: 0.61, 0.98]
Percent Survival
100
75
50
25
0
0
6
12
18
24
30
36
42
48
54
60
66
Survival (Months)
Small EJ, J Clin Oncol 2009; 24: 3089-94
Kantoff PW, NEJM 2010, 363: 411-22
Taxanes for CRPC
Docetaxel
• Well-established drug in
Oncology
• Main toxicity:
– Peripheral neurotoxicity
– Nail Toxicity
Cabazitaxel
• Crosses the blood-brain
barrier in vivo (humans?)
• Active in some docetaxelresistant models
• Main toxicity:
– Hemato (G-CSF)
– Diarrhea
Cabazitaxel vs Mitoxantrone: Overall Survival
100
Median OS (months)
Proportion of Overall Survival
90
Hazard ratio
80
70
60
MP
CBZP
12.7
15.1
0.72
95% CI
0.61–0.84
P-value
<.0001
50
28% risk of death reduction
40
30
MTX+PRED
20
CBZ+PRED
10
0
Number at Risk
0
MTX + PRED 377
CBZ + PRED 378
6
12
18
24
30
300
321
188
231
67
90
11
28
1
4
Time (months)
Median FU: 13.7 mo
De Bono et al. Lancet 2010
PEACE-2: European Phase III Trial of
Cabazitaxel and Pelvic irradiation in patients
with high-risk localized prostate cancer
Androgen deprivation
therapy (ADT) x 3 y
+ RXT (prostate)
Pts with high-risk
localized CaP:
at least 2 of the
following criteria:
• Gleason≥8
• ≥ T3
• PSA>20 ng/mL
R
A
N
D
O
M
I
Z
E
D
N= 1050 pts planned
ADT
+ RXT (Pelvis)
Primary end point:
•cPFS (HR: 070)
Secondary endpoints:
ADT
+ Cabazitaxel x 4 cycles
+ RXT (prostate)
ADT
+ Cabazitaxel x 4 cycles
+ RXT (Pelvis)
•
•
•
•
•
•
•
•
PSA response at 3 months
bPFS
Metastases-free survival
CaP-specific survival
OS
Acute/Lg term tolerance
QoL
Biomarkers (biopsy)
Study sponsor: Unicancer
Planned accrual duration: 4 years
Courtesy of K Fizazi
The “vicious cycle” of bone metastases
Prostate
cancer cells
, PTHrP, etc)
RANKL
Cytokines and Growth
Factors (ET-1, IL-6, IL-8, TNF-
Direct effects
on tumor?
Growth Factors
(TGF-IGFs, FGFs, PDGFs,
BMPs)
Osteoclast
Bone
Resorption
Osteoblast
lineage
RANKL
RANK
Adapted from Roodman GD. N Engl J Med. 2004;350:1655-64.
Bone
Ca2+
Targeting RANK-L: Proof of concept
RANK-L overexpressed
by osteoblasts
in bone metastases
CTR
OSB
+ 2b
OSB
+ 2a
OSB +
LNCaP
Positive randomized Phase II: Denosumab
decreases uNTx (biomarker for osteolysis)
OSB
CTR
+ PC3
OPG
RANKL
Fizazi et al., Clin Cancer Res 2003;9:2587–2597
Fizazi et al., J Clin Oncol 2009; 27: 1564-71
Proportion of Subjects Without SRE
Denosumab: Time to First SRE in patients
with established bone metastases
HR 0.82 (95% CI: 0.71, 0.95)
P = 0.0002 (Non-inferiority)
P = 0.008 (Superiority)
1.00
18% Risk Reduction
0.75
0.50
KM Estimate of
Median Months
0.25
Denosumab
Zoledronic acid
20.7
17.1
0
0
3
6
9
12
15
18
21
24
27
Study Month
Subjects at risk:
Zoledronic Acid
951
733
544
407
299
207
140
93
64
47
Denosumab
950
758
582
472
361
259
168
115
70
39
Fizazi et al. Lancet 2011; 377: 811-822
Denosumab: time to first symptomatic event (SSE) Fizazi K et al., EAU 2014
Preventing the onset of the worst enemy:
Spinal cord compression
9
8
8%
2.7%
4%
7
%
6
5
4
3
2
1
0
Placebo
Zoledronic
acid
ZA pivotal trial
Saad, et al. J Natl Cancer Inst 2004;96:879–82;
Fizazi et al. Lancet 2011; 377: 811-822
Zoledronic
acid
Dmab
103 trial
Osteonecrosis of the jaw
• Data from 3 randomized trials (n=5723)
• ONJ in 89 (1.6%) pts
– 37 (1.3%) zoledronic acid
– 52 (1.8%) denosumab (p = 0.13)
• Tooth extraction in 62% of pts with ONJ
– Disruption of denosumab recommended
– Antibiotics recommended
• ONJ conservative treatment in >95%
• ONJ resolution in 36%
Saad F, Ann Oncol 2012; 23: 1341-7
Bone-targeted agents:
Are they worth using?
•
•
•
•
Morbidity reduced
Prevention vs treatment
Overall good tolerance
Cheaper than most new
cancer drugs
• No demonstrated role in
survival
• ONJ (1-2%), hypocalcemia
Does Zoledronic Acid prevent the onset of bone
metastases? The ZEUS trial
1433 patients
Prostate cancer, M0
+/- local treatment, +/- ADT
High-risk PCa with at least one of
the following criteria:
• Gleason Score 8-10
• pN+
• PSA 20 at diagnosis
R
Zoledronic acid 4 mg Q3
months
No zoledronic acid*
Median follow-up: 4.8 years
Treatment duration 4 years
Overall survival
Primary endpoint: Bone metastases
Zoledronate
Control
13.7%
13%
p=0.72
Wirth M, EAU 2013
No benefit of zoledronic acid in pts with castrate‐sensitive metastatic CaP
n= 645 pts with HSPC and bone mets
Immediate Zoledronic Acid
R
Zoledronic Acid when CRPC
Median time to SRE:
32 mo vs 30 mo (HR=0.97)
Smith MR, J Clin Oncol 2014; 32: 1143‐50
Should Denosumab be used to prevent
the onset of bone metastases in CRPC?
The « 147 » trial
Pts with PSA DT ≤ 6 months
Overall population
HR = 0.85 (95% CI, 0.730.98)
P = 0.028
Proportion of patients
0.8
0.6
0.4
0.2
Placebo (n = 716)
Median:
25.2 months
Events:
370
Denosumab (n = 716)
29.5 months
335
HR = 0.77 (95% CI, 0.640.93)
P = 0.0064
1.0
Proportion of patients with
bone metastasis-free survival
1.0
0.8
Risk reduction
23%
0.6
0.4
Median
months
0.2
Placebo
18.7
Denosumab
25.9
Delay
(months)
7.2
0.0
0.0
0
3
6
9 12 15 18 21 24 27 30 33 36 39 42
Study month
Smith MR, et al. Lancet 2012;379:39–46
Smith MR, et al. J Clin Oncol 2013
0
6
12
18
24
Study month
30
36
Endocrine therapies
Adrenals
Testis
Castration
(aLHRH or Surg.)
Abiraterone
Testosterone
Androgen Receptor inhibitors:
-Bicalutamide
-Enzalutamide
-ODM-201
-ARN 509
Autocrine
secretion
Abiraterone
DNA
Cell division
b
Abiraterone:
CYP17 blockade inhibits androgen synthesis
55
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-Prednisone:
Adverse events of special interest
AA
(n=791)
All
Grades
Grades
3/4
Placebo
(n=394)
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
abnormalities
10%
3%
8%
3%
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
Patients
•Progressive chemonaïve mCRPC
•Asymptomatic or
mildly symptomatic
Randomisation 1:1
Co-primary endpoints
Abiraterone acetate +
prednisone
(n = 546)
•Radiographic progressionfree survival
•Overall survival
Secondary
•Time to opiate use (cancerrelated pain)
Placebo + prednisone
(n = 542)
•Time to initiation of
chemotherapy
•Time to ECOG-PS
deterioration
•Time to PSA progression
• Stratification by ECOG performance status 0 vs. 1
Ryan C, et al. American Society of Clinical Oncology Congress 2012;
Abstract LBA4518.
Abiraterone in docetaxel-naïve
CRPC: COU-302
• Radiographic progression-free survival (rPFS)
HR 0.43 (95% CI: 0.35–0.52; P < 0.0001)
Abiraterone acetate
Control
AA + P
PL + P
Abiraterone acetate
Placebo
Data cut off: 20/12/2010
Ryan C, et al. N Engl J Med 2013
COU 302: Final OS Analysis:
Abiraterone in chemotherapy‐naïve CRPC
100
Overall Survival (%)
HR (95% CI): 0.81 (0.70‐0.93)
p Value: 0.0033
80
Abiraterone, 34.7 mos 60
40
Prednisone, 30.3 mos 20
0
51
54
57
60
546 438 525 504 483 453 422 394 359 330 296 273 235 218 202 189 118 59
542 534 509 493 466 438 401 363 322 292 261 227 201 176 148 132 84 42
15
10
0
1
0
0
0
3
6
9
12
15
18
21
24
27
30
33
36
39
42
45
48
Time to Death (Months)
Abiraterone
Prednisone
•
•
Median follow‐up of 49.2 mos
44% of patients in the prednisone arm received abiraterone as subsequent therapy 26‐30 September 2014, Madrid, Spain
esmo.org
Ryan C, et al, Lancet Oncol 2015
Significant Improvement in Time to Opiate Use for Cancer‐Related Pain in the Final Analysis
Patients Without Opiate Use (%)
100
HR (95% CI): 0.72 (0.61‐0.85)
p Value: 0.0001
80
Abiraterone, 33.4 mos 60
40
Prednisone, 23.4 mos 20
0
0
3
6
9
12
15
18
21
24
27
30
33
36
39
42
45
48
51
54
57
60
9
6
0
1
0
0
Time to Opiate Use (Months)
Abiraterone
Prednisone
546 519 495 454 407 364 328 297 263 244 219 192 169 162 143 128 74 35
542 500 442 406 365 317 273 237 208 186 168 141 121 108 97 85 56 25
•
At the time of IA3, the median time to opiate use had not been reached for abiraterone
•
All secondary end points showed significant improvement with abiraterone
26‐30 September 2014, Madrid, Spain
esmo.org
PEACE‐1: European Phase III Trial in de novo Metastatic Prostate Cancer (revised design)
Androgen deprivation therapy (ADT)
+/‐ docetaxel
ADT +
• Patients with newly diagnosed (hormone‐naive) metastatic CaP
• 916 patients planned
R
A
N
D
O
M
I
Z
E
D
Abiraterone 1000 mg
Prednisone 5 mg BID
+/‐ docetaxel
ADT +
Local radiotherapy
+/‐ docetaxel
ADT +
Local radiotherapy +
Abiraterone‐Pred
+/‐ docetaxel
Study sponsor: Unicancer
ClinicalTrials.gov. Identifier: NCT01957436.
Co‐primary endpoints: OS and PFS (HR: 0.75)
AFFIRM: Enzalutamide in mCRPC
patients post-chemotherapy
AFFIRM is a phase III randomised, double-blind,
placebo-controlled trial
mCRPC
1–2 prior
chemotherapy
regimens*
(n = 1,199)
Enzalutamide 160 mg qd (n = 800)
R
2:1
Placebo per qd (n = 399)
*≥ 1 docetaxel (glucocorticoids
were allowed but not required)
Recruitment in 156 centres from 15 countries across 5 continents between September 2009 and November 2010
Scher HI et al. N Engl J Med 2012; 367(13): 1187–1197.
mCRPC, metastatic castrate-resistant prostate cancer;
qd, once per day;
R, randomisation
Radiographic progression-free survival
100
HR = 0.40 (95% CI: 0.35−0.47) p<0.001
90
Enzalutamide: 8.3 months
(95% CI: 8.2−9.1)
80
Survival (%)
70
60
50
40
30
20
10 Placebo: 2.9 months
(95% CI: 2.8−3.4)
0
3
6
0
9
12
15
18
21
24
Duration of overall survival (months)
No at
risk: n =
Enzalutamide,
800
583
447
287
140
58
13
1
0
Placebo, n =
399
176
86
46
20
7
3
0
0
rPFS defined by RECIST 1.1 for soft tissue and Prostate Cancer Working Group (PCGW2) for bone disease
Scher HI et al. N Engl J Med 2012; 367(13): 1187–1197.
CI, confidence interval
HR, hazard ratio
AFFIRM: Overall survival
HR = 0.63 (95%CI: 0.53–0.75); p<0.001
37% reduction in risk of death
100
Enzalutamide: 18.4 months
(95% CI: 17.3–NYR)
Survival (%)
80
60
4.8 month
difference in
median overall
survival
40
Placebo: 13.6 months
(95% CI: 11.3–15.8)
20
0
No at
risk: n =
Enzalutamide,
0
3
6
9
12
15
18
21
24
Duration of overall survival (months)
800
775
701
627
400
211
72
7
0
Placebo, n = 399
376
317
263
167
81
33
3
0
Scher HI et al. N Engl J Med 2012; 367(13): 1187–1197.
CI, confidence interval;
HR, hazard ratio;
NYR, not yet reached
AFFIRM: Summary of adverse events
Total events (all grades)
Adverse events, n (%)
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)
269 (34)
116 (29)
50 (6)
29 (7)
49 (6)
30 (8)
7 (1)
8 (2)
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
Adverse events of interest, n (%)
Fatigue
Cardiac disorder (any)
Myocardial infarction
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
Scher HI et al. N Engl J Med 2012; 367(13): 1187–1197.
Radiographic Progression-Free Survival (%)
Prevail: Enzalutamide in docetaxel-naïve
mCRPC patients
100
90
80
70
60
50
40
30
20
10
0
Hazard Ratio: 0.186
(95% CI: 0.15,0.23)
P < 0.0001
Enzalutamide
Placebo
0
3
6
9
12
15
Radiographic Progression-Free Survival (Months)
832
Placebo
801
305
79
18
21
128
34
5
1
0
20
5
0
0
0
Beer T, N Engl J Med 2014
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
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, TK inh, anti‐Vit K, etc)
• CYP2C8 induces Enzalutamide metabolism into its 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)
Bone-targeted radiopharmaceuticals:
α vs β-Emitters
β-emitters:
Strontium-89
Samarium-153
β-particles:
1 electron
Relative mass: 1
α-emitter:
Radium-223
α-particles:
2 neutrons + 2 protons
Relative mass: 7000
Radiopharmaceuticals
• Phase III Strontium-89 vs placebo after radiotherapy:
– Improvement in time to pain (n=126) (Porter 1993)
– No improvement (n=95) (Smeland 2003)
• Phase III Strontium-89 vs radiotherapy:
– Similar pain control (n=284) (Quilty 1994)
– Better OS: 7 months vs 11 months (p<0.05) (n=101)
(Oosterhof 2003)
• Phase III Samarium-153 vs placebo:
– Better pain control (n=118) (Serafini 1998); (n=152)
(Sartor 2004)
Cell killing and marrow penetration:
Two advantages of α-emitters
Large molecule
+
High Linear Energy Transfer
More DNA double-strand breaks
in (cancer) cells
Low marrow penetration (≤100 μm )
Limited hematological toxicity
Radium-223 (Alpharadin) phase III
in mCRPC
• Confirmed
symptomatic
CRPC
• ≥ 2 bone
metastases
• No known
visceral
metastases
• Postdocetaxel or
unfit for
docetaxel
R
A
N
D
O
M
I
S
E
D
2:
1
N = 922
n=921
Radium-223 (50
kBq/kg)
Hazard ratio 0.695
95% CI [0.581‐0.832]
P=0.00007
100
80
Radium-223
Median OS 14.9 mo
60
%
Placebo (saline)
40
Placebo
Median OS 11.3 mo
20
00
0
3
6
9
12
15
18
21
24
27
30
33
Parker C, N Engl J Med 2013
36
39
Systemic treatment for CRPC
in 2015
Radium 223
Abiraterone
Enzalutamide
Abiraterone
Cabazitaxel
PSA relapse (ADT) Sipuleucel-T Or Enzalutamide
Local Treatment
Castrate-resistant, M0
ADT + Docetaxel
Docetaxel Denosumab
Zoledronate
Metastatic Castrate-Resistant
Prostate Cancer
Metastatic Hormone-Sensitive
prostate cancer
Mr Andros, 68 ans, a reçu une castration chimique
pendant 2 ans pour cancer de le prostate Gleason 8
avec adénopathies lombo-aortiques et 3 métastases
osseuses. Son PSA est de nouveau en élévation à
12 ng/mL, il est asymptomatique.
• Que proposez vous?
1- Bicalutamide
2- Docetaxel
3- Abiraterone ou enzalutamide
4- DES
5- Poursuite de la castration seule
Short response to ADT predicts poor response to Enzalutamide (post‐docetaxel)
PSA decrease ≥ 50%
8%
PFS
58%
P<0.001
TTCRPC
Loriot Y et al., Eur J Cancer 2015
Several obvious situations
• History of seizure
• Enzalutamide
• Visceral metastases
• Radium-223
• Patient too old/sick
• Taxanes
• Contra-indication to
steroids (severe
diabetes, etc)
• Abiraterone
Should We Keep Using “Old”
Hormonal Manipulations Before Using Next‐generation AR‐Targeting Drugs?
TERRAIN Study Design
Patient population
Patient population
•375 men with •375 men with progressive mCRPC
progressive mCRPC
•Asymptomatic/mildly •Asymptomatic/mildly symptomatic
symptomatic
•Chemotherapy naive
•Chemotherapy naive
•No requirement for •No requirement for steroids
steroids
R
A
N
D
O
M
I
Z
E
D
1:1
ENZA
ENZA
160 mg/day
160 mg/day
n = 184
n = 184
Primary endpoint
Primary endpoint
Progression‐free survival Progression‐free survival (PFS)
(PFS)
•• Radiographic progression Radiographic progression (central review)
(central review)
•• Skeletal‐related event
Skeletal‐related event
BIC
BIC
50 mg/day
50 mg/day
n = 191
n = 191
•• Change in new Change in new antineoplastic therapy
antineoplastic therapy
•• Death
Death
TERRAIN trial: NCT01288911
Statistical design
Secondary endpoints
Secondary endpoints
•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)
•PSA response
•PSA response
•Time to PSA progression
•Time to PSA progression
•The data cutoff date was 19 October 2014, with 240 events for the primary efficacy endpoint
1. Kucuk O, et al. Urology. 2001;58:53‐58.
Heidenreich A. EAU 2015. Abstract 234.
Progression‐Free Survival in TERRAIN
Patients without PFS event (%)
100
ENZA BIC
Enzalutamide
Median (95% CI):
15.7 months (11.5, 19.4)
90
80
70
Hazard ratio (95% CI): 0.44 (0.34, 0.57); P <0.0001
60
50
40
30
Bicalutamide
Median (95% CI):
5.8 months (4.8, 8.1)
20
10
0
0
ENZA
Patients at risk
BIC Patients at risk
3
6
9
12
15
18
21
24
27
30
33
Time (months)
184
159
131
107
86
71
52
33
21
13
8
5
191
133
85
61
44
30
13
7
4
2
2
1
Heidenreich A. EAU 2015. Abstract 234.
PSA Response by Week 13 with ENZA or BIC
Percentage Change in PSA from Baseline
100
80
60
40
20
ENZA BIC
Enzalutamide
Bicalutamide
PSA response: 21%
PSA response: 82%
0
‐20
‐40
‐60
‐80
‐100
Observations
Mr Andros a finalement reçu un traitement par abiraterone‐
prednisone. Celui‐ci a été efficace (cf slides suivantes) Mr Andros avant abiraterone
PSA during Abiraterone
Abi
Mr And. on Abiraterone
Abiraterone
March 09 Dec 09
March 10 Jun 10
Aug 10
Dec 10
Fev 11
May 11
Mr Andros. Progression after 2 years on abiraterone
Dec 09
May 11
Aug 11
Oct 11
Jan 12
Mar 12
Mr Andros est en bon état général, il a quelques douleurs osseuses nécessitant le paracetamol.
• Que lui proposez vous?
1‐ Poursuite abiraterone jusqu’à ce que les douleurs nécessitent des morphiniques
2‐ Poursuite abiraterone + adjonction d’un autre anti‐tumoral
3‐ Poursuite abiraterone + remplacement de la prednisone par la dexamethasone
4‐ Arrêt abiraterone + passage à l’enzalutamide
5‐ Arrêt abiraterone + passage au docetaxel
CRPC pre-treated by
abiraterone or enzalutamide:
How to treat?
Sequential use of Enzalutamide and Abiraterone:
probably not a good option for most patients
(at least post-docetaxel)
•
•
•
•
38 pts progressing on
enzalutamide and docetaxel
PSA decrease ≥ 50% in 8%
Median PFS: 2.7 months
Only 1 partial response (8%)
Loriot Y et al. Ann Oncol 2013
•
•
•
•
30 pts progressing on
enzalutamide and docetaxel
PSA decrease ≥ 50% in 3%
Median PFS: 3.5 months
No objective response
Noonan KL et al. Ann Oncol 2013
Enzalutamide post-Abiraterone
(and post-Docetaxel)
• n=39 pts
• n=35 pts
• n=61 pts
• PSA resp: 13% • PSA resp: 29%
• PSA resp: 21%
• PFS=2.8 months • PFS<4 months
• PFS=4 months
• 1 partial resp (3%)
Bianchini D
Schrader AJ, Eur Urol
Eur J Cancer 2014 2014; 65: 30-6
Badrising S, Cancer
2014; 120: 968-75
Taxane post-Abiraterone (COU-302)
De Bono J, ASCO GU 2015
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
PSA response
Al Nakouzi N, Eur Urol 2014
AR splice variants (V7)
Nuclear localization
domain
N-Terminal Domain
DNA binding
domain
Ligand Binding domain
Hot spot mutation
Splice variant -> AR constitutively active
(no need for androgens)
Response to Abiraterone
by AR-V7 status
Antonarakis E, NEJM 2014
Response to Enzalutamide
by AR-V7 status
Antonarakis E, NEJM 2014
CTCs: AR‐V7 seems a promising
predictor of treatment response
Abiraterone1
Enzalutamide1
AR‐V7 positive
PSA change, %
100
50
–50
** **
100
†
AR‐V7 negative
†††
***†
100
††
†
50
†
†
0
†
–50
–100
–100
PSA response rate:
AR‐V7 positive: 0% (95% CI: 0‐46%)
AR‐V7 negative: 68.0% (95% CI: 46‐85%)
P=0.004
Taxanes2
†
†† †
50
†
Docetaxel, n=30
Cabazitaxel, n=7
†
†
0
†
†††
–50
††
–100
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: 41% (95% CI: 18‐67%)
AR‐V7 negative: 65% (95% CI: 41‐85%)
P=0.19
1. Antonarakis ES et al. N Engl J Med 2014;371:1028-38; 2. Antonarakis ES et al. JAMA Oncol 2015; 1:582-91
Conclusion: Cancer de la prostate « avancé »
• Cancer de la prostate métastatique hormono‐naïf:
– Nouveau standard: castration + docetaxel (survie)
– Pas de rôle pour acide zoledronique
• CRPC non métastatique:
– Pas de standard!
• CRPC métastatique: – 6 traitements avec bénéfice survie
• Docetaxel, Cabazitaxel
• Abiraterone, Enzalutamide
• Radium‐223
• (Sipuleucel‐T)
– Choix de traitements, séquences à mieux définir
– Denosumab: réduction morbidité