1. 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

2. mCRPC mHDPC mCRPC DCT Refractory mCRPC HDPC - HSPC DCT sensitive mCRPC
Sipuleucel-T
Abiraterone
Docetaxel
Enzalutamide
Cabazitaxel
Wait & See ?
Abiraterone
ADT
± AWS
Enzalutamide
Abiraterone
Docetaxel
Enzalutamide
Asymptomatic:
- W&S or AA/Enz.
Bone Symptoms:
- DCT or Alphar.
Visceral Mets:
DCT
Alpharadin
DCT Rechallenge
Docetaxel
Mitox. + Pdn
Alpharadin
Zoledronic Acid ?
Denosumab ?

3. Which possible changes in Decision Making in the Pre-CT Setting ?
TAX COU-302 / PREVAIL
High Grade Tumours
Allowed Allowed
Visceral Metastases
Allowed Not Allowed
Symptomatic Cases
Allowed Not Allowed
Asymptomatic Cases *
Allowed Allowed

4. Qual è la giusta posizione dei nuovi agenti ormonali e della CHT?
Docetaxel resistant CRPC: il problema delle sequenze.
Qual è la giusta posizione dei nuovi agenti ormonali e della CHT?
Docetaxel
Nuovi agenti ormonali
CHT
Abiraterone
Cabaziataxel
Enzalutamide
Cabaziataxel
Cabaziataxel
Abiraterone
CHT
Nuovi agenti ormonali
Cabaziataxel
Enzalutamide
Nuovi agenti ormonali
Nuovi agenti ormonali
Abiraterone
Enzalutamide
Enzalutamide
Abiraterone
x 3 strategie
x 6 combinazioni
Possiamo escludere la CHT dal trattamento del CRPC Docetaxel resistant?
Se aggiungiamo RAD-223 il quadro si complica!

5. in second line for mCRPC
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

6. 6
Future Oncol June 2013

7. Cox Proportional Hazards Regression for PFS
Characteristic
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
4.16 (1.86, 9.30)
<0.001
0.36 (0.18, 0.72)
0.004
Di Lorenzo et al. Future Oncol 2013

8. 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 predict POOR response to ABI
Azria et al. ASCO GU 2012 (poster 149)

9. in second line for mCRPC
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

10. 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

11. PSA RR, PFS and 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

12. in second line for mCRPC
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

13. Patients who progressed while receiving docetaxel
100 90 80 70 60 50 40 30 20 10
MTX
CBZ
10.9
13.8
Proportion of Overall Survival
ASCO GU 2011
Symbols = Censors
MTX + PRED
CBZ + PRED
Number at Risk 6 12 18 24 30
Time (Months)
MTX + PRED
CBZ + PRED
230
239
172
194 98
130 33 44 2 9 1

14. Patients who progressed after completion with docetaxel
100 90 80 70 60 50 40 30 20 10
Proportion of Overall Survival
MTX
CBZ
15.6 18
Symbols = Censors
MTX + PRED
CBZ + PRED
ASCO GU 2011 6 12 18 24 30
Time (Months)
Number at Risk
MTX + PRED
CBZ + PRED
147
139
128
127 90
101 34 46 9 19 4

15. 37: acquired refractory and 7: primary refractory
Mukherji D. et al, ASCO 2012

16. Abiraterone PSA RR 0 responses among primary refractory
Conclusions: patients refractory to docetaxel have very limited response to Abiraterone.
0 responses among primary refractory

17. in second line for mCRPC
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

18. 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: 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)
ASCO GU 2013
Oscar B. Goodmanet al

19. in second line for mCRPC
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

20. 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

21. Angelergues et al, Abst 5063, ASCO 2013
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.
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.

22. La sequenza Caba Abi vs. Abi  Caba: esperienze cliniche.
(mos)
Abi  Caba
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.
Caba
Abi
48 pts
90 pts treated with TXT
Abi
Caba
42 pts
Overall survival
Total PFS
Total PSA-PFS
Wissing et al. ESMO 2013, abs 2904

23. 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.
Caba
Abi
77 pts
113 pts inclusi
Abi
Caba
36 pts
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

24. in second line for mCRPC
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

25. 2525
PS 2: HT

26. in second line for mCRPC
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  abiraterone/enzalutamide
Testosterone levels
Toxicity to prior treatment
Comorbidity : liver, hematologic, Hypertension and cardiac disorders

27. in second line for mCRPC
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  abiraterone/enzalutamide
High Serum Testosterone levels  abiraterone/enzalutamide
Toxicity to prior treatment
Comorbidity : liver, hematologic, Hypertension and cardiac disorders

28. 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  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

29. Un algoritmo è possibile?
Gallardo et al. Crit Rev Oncol/Hemat 2013, in press