Transcript Limits of Tumorectomy in clinical localized renal cell cancer

Treatment strategies for
metastatic prostate cancer
Oliver Hakenberg
Department of Urology, Rostock University
prostate cancer is hormone-dependent
testosterone
testes
orchidectomy
antiandrogens
hypothalamus
pineal gland
LHRH
analogues
Prostata
prolactine
LHRH
antiandrogens
adrenal glands
cortisole
LHRH = luteinising hormone releasing hormone
LH = luteinising hormone
ACTH = adrenocorticotropal hormone
adrenal
androgens
Pathologic fractures after orchidektomy
% cumulative incidence
of osteoporotic fractures
n=235
50
40
orchidectomy
30
20
no orchidectomy
10
0
0
1
Daniell et al, J Urol 1997
2
3
4
5
6
7
8
9 years
Immediate androgen ablation
• permanent
– advanced metastatic disease M+
– locally advanced, if androgen ablation is the
only treatment option
• adjuvant/temporary
– radical prostatectomy with positive nodes
(pN+)
– adjuvant with radiotherapy in intermediate and
high risk disease
Early or delayed
androgen ablation?
Overall survival
RPE pN+
early vs observation/delayed
randomized
n= 98
Cancer-specific survival
Messing et al, Lancet Oncology 2006
androgen ablation
• ↓ gonadal testosterone
• 10-30% serum androgens from other sources
• Adrenal cortex: DHEA + androstendione →
transformed to testosterone in periphery
(including prostate)
• progression after xx months → hormone resistant
hormone resistance?
• de novo intratumoral androgen synthesis in
progressive CRPC
• → maintenance of intracellular andogen levels
• → androgen receptor (AR) stimulation despite
low serume testosterone
• „castration-resistant prostate cancer“ = CRPC
Locke et al, Cancer Res 2008
3 new developments
• autologous vaccine sipuleucel-T (IMPACT)
– mCRPC docetaxel-naive (85%)
– improved OS vs placebo
• cabazitaxel (TROPIC)
– mCRPC doxetaxel-refractory
– improved OS vs mitoxantrone
• arbiraterone
– hormonal principle in CPRC
Kantoff et al, N Engl J Med 2010
De Bono et al, Lancet 2010
Arbiraterone
inhibition of testosterone biosynthesis
• arbiraterone acetate inhibits
– C17,20 lyase
– 17 hydroxylase
– Inhibition selective & irreversible
•
•
•
•
adrenals, testes, prostate cancer cells
arbiraterone acetate: prodrug
good oral bioavailability
Development of resistance
Sonpavde et al, Eur Urol 2011
Attard et al, Cancer Res 2009
Study data: arbiraterone in CRPC
• phase I
– chemotherapy-naive CRPC patients
• phase-II NCT 00474383
– progression after docetaxel
• phase-III NCT 00638690
– progression after docetaxel
• phase III NCT 00887198
– asymptomatic, low metastatic load in
chemotherapy-naive patients
phase I
• n=21
• chemo-naive, CRPC
– 12/21 with PSA↓>50% and > 3 months
– of which in 6/12 PSA↓ > 90%
– PR (RESIST) in 5/8 patients and ↓analgesic
medication
– no grade grade 3/4 toxicity
Attard et al, J Clin Oncol 2008
phase II a
•
•
•
•
•
chemotherapy-naive CRPC patients
PSA↓> 50% in 70-80% of patients
RESIST response 37.5%
median time to PSA-rise 225 days
dexamethasone at progression with
arbiraterone: further PSA↓>50% in 33%
Attard et al, J Clin Oncol 2009
phase II b
• n= 47 docetaxele-pretreated CRPC
• PSA↓> 50% in 51% of patients
• 35 with RESIST
– PR 17%
– SD 66%
• 23% ECOG improvement
Reid et al, J Clin Oncol 2009
Reid et al, J Clin Oncol 2009
Reid et al, J Clin Oncol 2009
Phase II c
• docetaxele-pretreated CRPC
• better efficacy without ketoconazole
pretreatment
– 53% vs 33% PSA-response without/with
– 31% vs 4% PSA↓>90% without/with
ketoconazole
– median time to progression 198 vs 99 days
with/without ketoconazole
Danila et al, J Clin Oncol 2009
phase III (COU-AA-301)
• n=1195 docetaxel-refractory CRPC
• arbiraterone vs placebo 2:1 randomisation
• stratification
–
–
–
–
ECOG 0-1 vs 2
prior chemotherapy schedules 1 vs 2
pain score
type of progression: PSA vs XR
phase III (COU-AA-301)
1.interim analysis 2010
•
•
•
•
•
OS 14.8 vs 10.4 months
TTP 10.2 vs 6.6 months
rPFS 5.6 vs 3.6 months
PSA RR 29.1% vs 5.5%
toxicity
–
–
–
–
hyperhydration 2.3% vs 1.0%
hypokalaemia 3.8% vs 0.8%
hypertension 1.3% vs 0.3%
cardiopulmonary 4.1% vs 2.3%
De Bono et al, ESMO 2010
arbiraterone
• n=1195 docetaxel resistant
• 2:1 randomisation
– arbiraterone 1000 mg + 5 mg prednisone
vs
– placebo + 5 mg prednisone
• overall survival
– arbiraterone
– placebo
14.8 months
10.9 months
de Bono et al, N Engl J Med 2011
treatment options
for metastatic prostate cancer
• hormonal
– androgen ablation
• orchidectomy
• LHRH-antagonists or –agonists
• androgen blockers
– androgen conversion blocker
• arbiraterone
• chemotherapy
– docetaxel
– cabazitaxel
•
•
•
•
bisphosphonates
pain treatment
nuclear medical tretament: samarium, strontium
best supportive care
Prognosis of metastatic prostate cancer
•
•
•
•
initial response to androgen ablation > 80%
progression in 50-60% of patients within 2 years
after that median survival 23-37 months
5 year survival rate with M+oss 20%
androgen antagonists
• steroidal
– cyproterone acetate
• non-steroidal
– bicalutamide
– flutamide
– nilutamide
Early Prostate Cancer Program
reduction of the risk of PSA progression
by 59 %
Kaplan-Meier curve of time to PSA progression
1.0
proportion without event
0.9
0.8
0.7
0.6
0.5
0.4
0.3
bicalutamide 150 mg + standard care
Placebo + standard care
0.2
0.1
0.0
0
6
12
18
24
30
36
time (months)
HR 0.41; 95% CI 0.38, 0.45; p<<0.0001
42
48
54
60
natural course of prostate cancer
after radical prostatectomy and PSA recurrence
(n= 311)
distant
metastases
PSA recurrence
0
Pound et al., JAMA 1999
5
death of
prostate cancer
10
15
years
Hormone-independent prostate cancer
hormone independent
hormone naive
hormone
withdrawal
hormone
dependent
hormone
sensitive
hormone
independent
definition of castration-resistant prostate hormonerefractory prostate cancer (HRPC)
• serume testosteron at castration level
• secondary hormonal treatment without effect
• ketoconazole
• estrogens
• rising PSA at 3 consecutive measurements at intervals of 1
week at leastt
•
with continued LHRH – blockade and after witrhdrawal of androgen blocker
•
lowest PSA limit: 0.4 ng/ml
Chemotherapy for prostate
cancer?
Reviews
response rates
P.Walsh 1995:
1985:
(17 Studien)
%
„This
is going
to be an extremely short 6,5
discussion.
Not only does
it fail to cure the cancer, it doesn’tM.
even
prolong
Eisenberger,
J Clinsurvival
Oncol 1985 to any
significant degree, and its side effects only add to the
unpleasantness of having prostate cancer.“
1992: (26 Studien)
8,7 %
Yagoda & Petrylak, Cancer 1993
chemotherapy for prostate cancer –
mitoxantrone for HRPC?
• phase III: mitoxantrone (12mg/m²) + prednisone (10mg/d)
prednisone (10mg/d)
vs.
– 161 patients. (80 M+P; 81 P)
• phase III: mitoxantrone (14mg/m²) + hydrocortisone (40mg/d) vs.
hydrocortisone (40mg/d)
– 242 patients
results
– improvement in pain
– improvement in quality of life
– duration of response 5-7 months
– no influence on survival
Tannock et al. 1996
Kantoff et al. 1999
docetaxel
• TAX 327
• SWOG 9916
• both studies showed overall survival
advantage for docetaxel
Petrylak, N Engl J Med 2004
Tannock, N Engl J Med 2004
docetaxel chemotherapy
overall survival SWOG 9916
no.
at
Risk
100%
D + E 338
M + P 336
80%
median
survival
(months)
no (n)
died
217
235
18
16
HR: 0.80 (95% CI 0.67, 0.97), p = 0.01
med. F/U: 1 J
60%
40%
20%
0
12
Petrylak et al, N Engl J Med 2004
24
36
48
months
SWOG 99-16
Petrylak J NCI 2006
Survival in subgroups
docetaxel 3 weekly vs mitoxantrone
hazard ratio in favour of
docetaxel
mitoxantrone
Intent to Treat
age < 65
age ≥ 65
age ≥ 75
pain
no
pain
yes
KPS ≥ 80
KPS ≤ 70
0.2
Tannock et al, N Engl J Med 2004
0.4
0.6
0.8
1
1.2
1.4
Cochrane Review
chemotherapy of HRPC
• n=6929 patients; 47 studies
• investigated substances:
–
–
–
–
–
–
–
EMP
docetaxel
5-FU
cyclophosphamide
doxorubicine
mitoxantrone
vinorelbine
Shelley M, Harrison C et al. Cochrane Database Syst Rev 2006
Cochrane Review
• PSA response (>50%):
–
–
–
–
–
–
–
EMP
docetaxel
5-FU
cyclophosphamide
doxorubicine
mitoxantrone
vinorelbine
Shelley M, Harrison C et al. Cochrane Database Syst Rev 2006
48%
52%
20%
n.d.
50% (CAVE: only 1 study!)
33%
n.d.
results
• only DOC
=>
months)
• pain ↓
• quality of life ↑
overall survival ↑ (<2.5
DOC > Mit + Pred
DOC > Mit + Pred
authors‘ conclusion:
„At the present time this* probably represents the best
chemotherapeutic regime available for men with HRPC“
*- docetaxel q3w
Shelley M, Harrison C et al. Cochrane Database Syst Rev 2006
secondary hormone manipulation or chemotherapy?
secondary
hormone
manipulation
chemotherapy
CALGB9583
SWOG 9916
TAX-327
AAW +
Ketokonazol
EMP docetaxel
vs MP
DP q3w
vs DP q1w vs MP
n
260
770
1006
overall survival in
better arm
16.7 months
17.5 months
18.9 months
overall survival in
worse arm
15.3 months
15.6 months
16.5 months
Bellmunt, Eur Urol Suppl 2009
open questions
•
•
•
•
•
•
when to start with chemotherapy?
should asymptomatic M+ patients be treated?
how long to continue treatment?
secondary treatment?
intermittent chemotherapy?
re-exposition?
Early vs late chemotherapy?
• for
– benefit established for other entities (breast cancer,
colorectal cancer)
– lower tumour mass
– treatment prolongs survival
• against
– toxicity vs unreliable response
– early induction of chemotherapy-refractory state
– outcome is not influenced since no difference in
survival between symptomatic vs asymptomatic
patients (TAX327)
forms of HRPC
indications for starting with chemotherapy
• only rising PSA
• asymptomatic, low metastatic load
 no indication
PSA doubling time?
 individual decision
inclusion in study?
• asymptomatic, large metastatic load
 yes
• symptomatic metastases
 yes
Estimating the prognosis in CPRC
PSA doubling time
• günstig
– TAX 327:
PSA-DT > 55 Tage
– Oudard et al: PSA-DT > 45 Tage
Armstrong et al, Clin Cancer Res 2007
Oudard et al, Ann Oncol 2007
nomographic estimation
Armstrong, A. J. et al. Clin Cancer Res 2007;13:6396-6403
rising PSA under chemotherapy…
• often initiial PSA flare-up
• no negative influence on survival, unless there
are signs of clinical progression
=> minimum of 8 weeks treatment before
deciding to discontinue !
Olbert Anticancer Drugs 2006
PSA-Flare with chemotherapy
in patients with subsequent PSA response or stable disease
PSA values
normalized to a
starting point of
100 ng/ml
Thuret etrestrictions
al, Ann Oncol
2008
Copyright
may apply.
Chemotherapy until…
• best number of cycles unknown
• TAX 327: mean of 8 cycles
• but: chronic toxicity increases with no of
cycles
• intermittend chemotherapy?
When to discontinue chemotherapy…?
• definite worsening of physical state
• PSA doubling time < 3 Monate
• slow PSA increase:
- discontinue if clinically progressive
Miller et al. Akt Urol 2006
First line chemotherapy
docetaxel Mono (75mg/m² KO d1, q21d)
Second line chemotherapy
options:
– docetaxel (M  D)
– docetaxel weekly
– mitoxantrone (D  M)
– satraplatin (SPARC)
– cabazitaxel
PR: 44-85%
PR: 72%
PR: 6-15%
Cabazitaxel second line
overall survival
open label, randomized, n= 755
CPRC patients with progression on docetaxel
cabazitaxel 25 mg/m2 q3w + prednisone 10 mg p.o. daily
vs
mitoxantrone 12 mg/m2 q3w i.v.+ prednisone 10 mg p.o. daily
mean survival overall
CABA
15.1 months
MITO
12.7 months
de Bono et al, Lancet 2010
Cabazitaxel second line
progression-free survival
de Bono et al, Lancet 2010
ketoconazole
•
•
•
•
200 or 400 mg tid p.o. ketoconazole
+ hydrocortisone replacement doses 30-0-10 mg p.o.
n= 114
response depends on disease burden
Keizman et al, Prostate 2010
Beltran et al, Eur Urol 2011
Hypothetical calculation
Future prognosis of metastatic prostate cancer?
•
•
•
•
•
•
initial response to androgen ablation > 80%
progression in 50-60% of patients within 2 years
after that median survival 23-37 months
+ 4 months with docetaxel
+ 4 months with cabazitaxel
+ 4 months with arbiraterone
„This will buy you three months“
Rostock