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 Prima e seconda linea di trattamento
Chemioterapia, abiraterone, enzalutamide: evidenze, indicazioni, cros-resistenza. Quali sequenze?
G. CartenìDirettore U.O.S.C. di Oncologia Medica A.O.R.N.A. Cardarelli Napoli
Prima e seconda linea di trattamento
mHDPC mCRPC
HDPC - HSPC DCT sensitive mCRPC DCT Refractory mCRPC
mCRPC
Cabazitaxel
Enzalutamide
Zoledronic Acid ?
Alpharadin
± AWS
ADT
Mitox. + Pdn
Abiraterone
Wait & See ?
Docetaxel
Abiraterone
Sipuleucel-T
Abiraterone
Docetaxel
DCT Rechallenge
Denosumab ?
Alpharadin
Asymptomatic: - W&S or AA/Enz.
Bone Symptoms: - DCT or Alphar.
Visceral Mets: DCT
Enzalutamide
EnzalutamideDocetaxel
High Grade Tumours
Allowed Allowed
AllowedNot Allowed
AllowedNot Allowed
Allowed Allowed
Visceral Metastases
Symptomatic Cases
Asymptomatic Cases *
TAX-327 COU-302 / PREVAIL
Which possible changes in Decision
Making in the Pre-CT Setting ?
Docetaxel resistant CRPC: il problema delle sequenze.
Nuovi agenti ormonali
CHT
Do
cetaxel
Nuovi agenti ormonali
CHT
Nuovi agenti ormonali
Nuovi agenti ormonali
Abiraterone
Enzalutamide
Cabaziataxel
Cabaziataxel
Cabaziataxel
Cabaziataxel
Abiraterone
Enzalutamide
Abiraterone
EnzalutamideAbiraterone
Enzalutamide
x 3 strategie x 6 combinazioni
Se aggiungiamo RAD-223 il quadro si complica!
Possiamo escludere la CHT dal trattamento del CRPC Docetaxel resistant?
Qual è la giusta posizione dei nuovi agenti ormonali e della CHT?
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
Suggested and Potential biologic and clinical parameters
Future Oncol June 2013
Cox Proportional Hazards Regression for
PFSCharacteristic Hazard Ratio (95% CI) p-value
Univariable
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
Multivariable
Visceral Disease 4.16 (1.86, 9.30) <0.001
Gleason Score, ≥8 versus ≤7 0.36 (0.18, 0.72) 0.004
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 8-10predict POOR response to ABI
Azria et al. ASCO GU 2012 (poster 149)
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
Suggested and Potential biologic and clinical parameters
Gleason Score e cabazitaxel OS
Tropic and EAP posthoc 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
Abstract # 137 : Efficacy of cabazitaxel and its relationship with predictors of poor response to second hormonal therapies (2d HT) in metastatic castration-resistant prostate cancer (mCRPC). ( J2 ) Stephane Oudard - Department of Medical Oncology, Georges Pompidou European Hospital
PSA RR, PFSand lenght of ADT pre-
docetaxel
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
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
Suggested and Potential biologic and clinical parameters
Patients who progressed while receiving docetaxel
100
90
80
70
60
50
40
30
20
10
0
0 6 12 18 24 30 Time (Months)
Pro
por
tion
of O
vera
ll S
urvi
val
Number at Risk
MTX + PREDCBZ + PRED
230239
172194
98130
3344
29
10
MTX + PRED CBZ + PRED
Symbols = Censors
MTX CBZ
10.9 13.8
ASCO GU 2011
Patients who progressed after completion with
docetaxel100
90
80
70
60
50
40
30
20
10
0
0 6 12 18 24 30 Time (Months)
Pro
por
tion
of O
vera
ll S
urvi
val
Number at RiskMTX + PREDCBZ + PRED
147139
128127
90101
3446
919
04
MTX + PRED CBZ + PRED
Symbols = Censors
MTX CBZ
15.6 18
ASCO GU 2011
Mukherji D. et al, ASCO 2012
37: acquired refractory and 7: primary refractory
Abiraterone PSA RR
Conclusions: patients refractory to docetaxel have very limited response to Abiraterone.0 responses among primary refractory
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
Suggested and Potential biologic and clinical parameters
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Eighth Outline Level
● Ninth Outline LevelFare clic per modificare stili del testo dello schema
Secondo livello Terzo livello
Quarto livello» Quinto livello
Exploratory analysis of the visceral disease (VD) patient subset in COU-
AA-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-)
● 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)
Oscar B. Goodmanet al
ASCO GU 2013
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
Suggested and Potential biologic and clinical parameters
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
Angelergues et al. ASCO 2013
49% dei pazienti trattati con docetaxel riceve due ulteriori linee.
40% Dei pazienti riceve due ulteriori linee dopo TXT
Angelergues et al, Abst 5063, ASCO 2013
● 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.
•125 pts treated with cabazitaxel and retrospectively analyzed.
•Median OS from the first docetaxel was 65 mo in patients treated with abiraterone/enzalutamide after Cabazitaxel vs 39 mo in patients receiving these agents before Cabazitaxel.
Pazienti trattati n maniera sequenziale con abiraterone e cabazitaxel in 22 centri ospedalieri in Olanda.
90 pts treated
with TXT
Caba Abi
Abi Caba
48 pts
42 pts
Wissing et al. ESMO 2013, abs 2904
Overall survival Total PFS Total PSA-PFS
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
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
Caba Abi
Abi Caba
77 pts
36 pts
Sonpavde et al. ESMO 2013, abs 2905
La sequenza Caba Abi vs. Abi Caba: esperienze cliniche.
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).
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
Suggested and Potential biologic and clinical parameters
PS 2: HT
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
Suggested and Potential biologic and clinical parameters
Un algoritmo è possibile?
Gallardo et al. Crit Rev Oncol/Hemat 2013, in press