Prima e seconda linea di
trattamento
Chemioterapia, abiraterone,
enzalutamide: evidenze, indicazioni,
cros-resistenza. Quali sequenze?
G. Cartenì
Direttore U.O.S.C. di Oncologia
Medica A.O.R.N.
A. Cardarelli Napoli
mCRPC
mCRPC
mHDPC
HDPC - HSPC
Docetaxel
ADT
±
AWS
Asymptomatic:
- W&S or AA/Enz.
DCT sensitive mCRPC
Sipuleucel-T
Enzalutamide
Wait & See ?
Abiraterone
Abiraterone
Docetaxel
Enzalutamide
Docetaxel
DCT
Rechallenge
Bone Symptoms:
- DCT or Alphar.
Visceral Mets:
DCT
Alpharadin
Zoledronic Acid ?
Denosumab ?
DCT Refractory
mCRPC
Abiraterone
Cabazitaxel
Enzalutamide
Alpharadin
Mitox. + Pdn
Which possible changes in Decision
Making in the Pre-CT Setting ?
TAX-327
High Grade Tumours
Allowed
Allowed
Visceral Metastases
Allowed
Not Allowed
Symptomatic Cases
Allowed
Not Allowed
Asymptomatic Cases *
Allowed
Allowed
COU-302 / PREVAIL
Docetaxel resistant CRPC: il problema delle
sequenze.
Qual è la giusta posizione dei nuovi agenti ormonali e della CHT?
Docetaxel
Nuovi agenti
ormonali
CHT
CHT
Nuovi agenti
ormonali
Nuovi agenti
ormonali
Nuovi agenti
ormonali
x 3 strategie
Se aggiungiamo
RAD-223 il
quadro si
complica!
Abiraterone
Cabaziataxel
Enzalutamide
Cabaziataxel
Cabaziataxel
Abiraterone
Cabaziataxel
Enzalutamide
Abiraterone
Enzalutamide
Enzalutamide
Abiraterone
x 6 combinazioni
Possiamo escludere la CHT dal trattamento del
CRPC Docetaxel resistant?
Suggested and Potential
biologic and clinical parameters
in second line for mCRPC
GLEASON SCORE ( 7 vs >7)
Short prior HT before CT ( 24 vs > 24 months)
PD during DOCETAXEL (primary and acquired)
PD after DOCETAXEL ( 3, 6 months)
Liver metastases
Visceral metastases
CT-CT-HT vs CT-HT-CT sequences
PS
Testosterone levels
Toxicity to prior treatment
Comorbidity : liver, hematologic, Hypertension and cardiac disorders
Future Oncol June 2013
Characteristic
Cox Proportional
Hazards Regression for
PFS
Hazard Ratio (95% CI)
p-value
Months of Prior Hormonal Therapy
0.96 (0.92, 0.99)
0.019
Time to PD Following Docetaxel
0.98 (0.89, 1.09)
0.75
Prior Cycles of Docetaxel
0.99 (0.93, 1.06)
0.80
Age
0.97 (0.93, 1.01)
0.11
Baseline PSA (/100)
0.93 (0.77, 1.11)
0.42
PSA Doubling Time
0.95 (0.84, 1.08)
0.46
Gleason Score
0.86 (0.64, 1.16)
0.33
Gleason Score, ≥8 versus ≤7
0.50 (0.26, 0.95)
0.033
Visceral Disease
2.74 (1.33, 5.65)
0.006
ECOG, 1 versus 0
1.28 (0.83, 1.98)
0.27
Prior Abiraterone
1.58 (0.55, 4.48)
0.39
Visceral Disease
4.16 (1.86, 9.30)
<0.001
Gleason Score, ≥8 versus ≤7
0.36 (0.18, 0.72)
0.004
Univariable
Multivariable
Di Lorenzo et al. Future Oncol 2013
Predictors of poor
response to ABI
●
408 mCRPC pts enrolled in 19 centres
●
Gleason at diagnosis:



8-10: 51.2%
7: 36.1%
<7: 12.7%
●
Median duration of ABI therapy: 6.1 months
●
Predictors of poor response to ABI:


Univariate: age, Gleason, number of mets, baseline
PSA, duration of HT, number of lines of chemo,
duration of chemo
Multivariate analysis: Gleason 8-10
predict
POOR response to ABI
Azria et al. ASCO GU 2012 (poster 149)
Suggested and Potential
biologic and clinical parameters
in second line for mCRPC
GLEASON SCORE (>7)
cabazitaxel
Short prior HT before CT ( 24 vs > 24 months)
PD during DOCETAXEL (primary and acquired)
PD after DOCETAXEL ( 3, 6 months)
Liver metastases
Visceral metastases
CT-CT-HT vs CT-HT-CT sequences
PS
Testosterone levels
Toxicity to prior treatment
Comorbidity : liver, hematologic, Hypertension and cardiac disorders
Gleason Score e
cabazitaxel OS
Abstract # 137 : Efficacy of cabazitaxel and itsTropic
relationship with
predictors
of poor posthoc
response to second
and
EAP
hormonal therapies (2d HT) in metastatic castration-resistant prostate cancer (mCRPC). ( J2 )
Stephane Oudard - Department of Medical Oncology, Georges Pompidou
European Hospital
analysis
Conclusioni:
OS e PFS in patients treated with Cabazitaxel not related to:
●


Gleason Score (0-7; 8-10)
Duration of HT pre-TXT (+/- 20 Months )
Multivariate analysis: SHORT OS and PFS in pts with low PS
(ECOG 2), high ALP and PAIN
●
Oudard et al, ASCO GU 2013
PSA RR, PFS
and lenght of ADT predocetaxel
Conclusioni: A previous
duration of prostate cancer sensitivity to ADT
≥16 months is the only significant predictive factor for efficacy of
subsequent endocrine manipulations in patients with CRPC. This
parameter shall be integrated into the decision-making process for these patients
Loriot Y. et al, ASCO 2012
Suggested and Potential
biologic and clinical parameters
in second line for mCRPC
GLEASON SCORE ( >7)
cabazitaxel
Short prior HT before CT ( 24 months)
cabazitaxel
PD during DOCETAXEL (primary and acquired)
PD after DOCETAXEL ( 3, 6 months)
Liver metastases
Visceral metastases
CT-CT-HT vs CT-HT-CT sequences
PS
Testosterone levels
Toxicity to prior treatment
Comorbidity : liver, hematologic, Hypertension and cardiac disorders
Patients who progressed
while receiving docetaxel
Proportion of Overall Survival
100
90
80
70
MTX
CBZ
10.9
13.8
60
50
40
ASCO GU 2011
30
Symbols = Censors
20
MTX + PRED
CBZ + PRED
10
0
Number at Risk
0
6
12
18
24
30
MTX + PRED
CBZ + PRED
230
239
172
194
98
130
33
44
2
9
1
0
Time (Months)
Patients who
progressed after
completion with
docetaxel
Proportion of Overall Survival
100
90
80
70
60
50
MTX
CBZ
15.6
18
40
30
Symbols = Censors
20
MTX + PRED
CBZ + PRED
10
ASCO GU 2011
0
Number at Risk
MTX + PRED
CBZ + PRED
0
6
12
18
24
30
147
139
128
127
90
101
34
46
9
19
0
4
Time (Months)
37: acquired refractory and 7: primary refractory
Mukherji D. et al,
ASCO 2012
Abiraterone PSA RR
Conclusions: patients refractory
to docetaxel have very limited
response to Abiraterone.
0 responses among primary
refractory
Suggested and Potential
biologic and clinical parameters
in second line for mCRPC
GLEASON SCORE ( 7 vs >7)
cabazitaxel
Short prior HT before CT ( 24 vs > 24 months)
cabazitaxel
PD during DOCETAXEL (primary )
cabazitaxel
PD after DOCETAXEL ( 3, 6 months)
both options
Liver metastases
Visceral metastases
CT-CT-HT vs CT-HT-CT sequences
PS
Testosterone levels
Toxicity to prior treatment
Comorbidity : liver, hematologic, Hypertension and cardiac disorders
Exploratory analysis of the visceral
disease (VD) patient subset in COUAA-301, a phase III study of
abiraterone acetate (AA) in mCRPC
●
COU-AA-301: 1.195 pazienti enrolled
in the study. 352 (29%) showed
visceral metastases while 843 (71%)
no visceral met. (V-)

Click to edit the
outline text format

●
●
OS in visceral negative: 17,1 vs 12,3
months with risk reduction of death
31% (p<0,001)
OS in V+ ::12,9 vs 8,3 months with
risk reduction of death of 21%
(p=0,10)
ASCO GU 2013
Oscar B. Goodmanet al
Second Outline
Level

Third Outline
Level
 Fourth
Outline Level
 Fifth
Outline
Level
Suggested and Potential
biologic and clinical parameters
in second line for mCRPC
GLEASON SCORE ( 7 vs >7)
cabazitaxel
Short prior HT before CT ( 24 vs > 24 months)
cabazitaxel
PD during DOCETAXEL (primary )
cabazitaxel
PD after DOCETAXEL ( 3, 6 months)
both options
Liver metastases
cabazitaxel
Visceral metastases
cabazitaxel
CT-CT-HT vs CT-HT-CT sequences
PS
Testosterone levels
Toxicity to prior treatment
Comorbidity : liver, hematologic, Hypertension and cardiac disorders
Docetaxel resistant CRPC: il
problema delle sequenze.
31% dei pazienti trattati con abiraterone riceve cabazitaxel in terza linea.
Sella a et al. ASCO-GU 2013 Abs 186
36% dei pazienti trattati con enzalutamide riceve abiraterone in terza linea.
Loriot et al. Ann. Oncol. 2013
49% dei pazienti trattati con docetaxel riceve due ulteriori linee.
Angelergues et al. ASCO 2013
40%
Dei pazienti riceve
due ulteriori linee
dopo TXT
Angelergues et al, Abst
5063, ASCO 2013
•
125 pts treated with cabazitaxel and retrospectively analyzed.
treated
with abiraterone/enzalutamide after Cabazitaxel vs 39 mo
in patients receiving these agents before Cabazitaxel.
•
●
●
●
Median OS from the first docetaxel was 65 mo in patients
Conclusions: patients treated with 2 prior Docetaxel lines, PSA response >30%
with Cabazitaxel and treated with new hormonal agents after Cabazitaxel
experienced prolonges OS.
Conversely intake of new hormonal agents before Cabazitaxel rather after was
associated with a reduced OS from the first Docetaxel.
Prospective randomized trials are needed.
La sequenza Caba Abi vs. Abi Caba: esperienze
cliniche.
Caba Abi
(mos)
Abi Caba
(mos)
Treatment duration
10.0
7.8
Median F-Up
21.2
21.0
Median OS
17.8
14.3
Total-PFS
7.7
5.5
PSA-PFS
9.6
6.4
Pazienti trattati n maniera sequenziale con abiraterone e cabazitaxel in 22
centri ospedalieri in Olanda.
90 pts
treated
with TXT
Overall survival
48 pts
Caba
Abi
42 pts
Abi
Caba
Total PFS
Wissing et al. ESMO 2013, abs 2904
Total PSA-PFS
La sequenza Caba Abi vs. Abi Caba:
esperienze cliniche.
Outcomes with different sequences of cabazitaxel and abiraterone acetate following
docetaxel in metastatic castration-resistant prostate cancer (mCRPC).
Pazienti trattati n maniera sequenziale con abiraterone e cabazitaxel in 22
centri ospedalieri in Olanda.
113 pts
inclusi
77 pts
Caba
Abi
36 pts
Abi
Caba
Median OS, TTF1, and TTF2 were analyzed by Kaplan-Meier method from start
of second-line therapy post-D to death for OS, to end of second-line (TTF1),
and to end of combined second- and third-line therapies (TTF2).
Sonpavde et al. ESMO 2013, abs 2905
Suggested and Potential
biologic and clinical parameters
in second line for mCRPC
GLEASON SCORE ( 7 vs >7)
cabazitaxel
Short prior HT before CT ( 24 vs > 24 months)
cabazitaxel
PD during DOCETAXEL (primary )
cabazitaxel
PD after DOCETAXEL ( 3, 6 months)
both options
Liver metastases
cabazitaxel
Visceral metastases
cabazitaxel
CT-CT-HT vs CT-HT-CT sequences
cabazitaxel
PS 2
Testosterone levels
Toxicity to prior treatment
Comorbidity : liver, hematologic, Hypertension and cardiac disorders
PS 2: HT
Suggested and Potential
biologic and clinical parameters
in second line for mCRPC
GLEASON SCORE ( 7 vs >7)
cabazitaxel
Short prior HT before CT ( 24 vs > 24 months)
cabazitaxel
PD during DOCETAXEL (primary )
cabazitaxel
PD after DOCETAXEL ( 3, 6 months)
both options
Liver metastases
cabazitaxel
Visceral metastases
cabazitaxel
CT-CT-HT vs CT-HT-CT sequences
cabazitaxel
PS 2
abiraterone/enzalutamide
Testosterone levels
Toxicity to prior treatment
Comorbidity : liver, hematologic, Hypertension and cardiac disorders
Suggested and Potential
biologic and clinical parameters
in second line for mCRPC
GLEASON SCORE ( 7 vs >7)
cabazitaxel
Short prior HT before CT ( 24 vs > 24 months)
cabazitaxel
PD during DOCETAXEL (primary )
cabazitaxel
PD after DOCETAXEL ( 3, 6 months)
both options
Liver metastases
cabazitaxel
Visceral metastases
cabazitaxel
CT-CT-HT vs CT-HT-CT sequences
cabazitaxel
PS 2
abiraterone/enzalutamide
High Serum Testosterone levels
abiraterone/enzalutamide
Toxicity to prior treatment
Comorbidity : liver, hematologic, Hypertension and cardiac disorders
Suggested and Potential
biologic and clinical parameters
GLEASON SCORE ( 7 vs >7)
cabazitaxel
Short prior HT before CT ( 24 vs > 24 months)
cabazitaxel
PD during DOCETAXEL (primary )
cabazitaxel
PD after DOCETAXEL ( 3, 6 months)
both options
Liver metastases
cabazitaxel
Visceral metastases
cabazitaxel
CT-CT-HT vs CT-HT-CT sequences
cabazitaxel
PS 2
abiraterone/enzalutamide
High Serum Testosterone levels
abiraterone/enzalutamide
Toxicity to prior treatment
abiraterone/enzalutamide
TO BE CONSIDER:
AGE and Comorbidity : liver, hematologic, Hypertension and cardiac
disorders
Un algoritmo è possibile?
Gallardo et al. Crit Rev Oncol/Hemat 2013, in press