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Chemioterapia, abiraterone, enzalutamide: evidenze, indicazioni, cros-resistenza. Quali sequenze? G. Cartenì Direttore U.O.S.C. di Oncologia Medica A.O.R.N.

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Presentation on theme: "Chemioterapia, abiraterone, enzalutamide: evidenze, indicazioni, cros-resistenza. Quali sequenze? G. Cartenì Direttore U.O.S.C. di Oncologia Medica A.O.R.N."— Presentation transcript:

1 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

2 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 Docetaxel

3 High Grade Tumours Allowed Allowed Allowed Not 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 ?

4 Docetaxel resistant CRPC: il problema delle sequenze. Nuovi agenti ormonali CHT Docetaxel Nuovi agenti ormonali CHT Nuovi agenti ormonali Abiraterone Enzalutamide Cabaziataxel Abiraterone Enzalutamide Abiraterone EnzalutamideAbiraterone Enzalutamide x 3 strategiex 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?

5 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

6 Future Oncol June 2013

7 Cox Proportional Hazards Regression for PFS CharacteristicHazard Ratio (95% CI)p-value Univariable Months of Prior Hormonal Therapy0.96 (0.92, 0.99)0.019 Time to PD Following Docetaxel0.98 (0.89, 1.09)0.75 Prior Cycles of Docetaxel0.99 (0.93, 1.06)0.80 Age0.97 (0.93, 1.01)0.11 Baseline PSA (/100)0.93 (0.77, 1.11)0.42 PSA Doubling Time0.95 (0.84, 1.08)0.46 Gleason Score0.86 (0.64, 1.16)0.33 Gleason Score, ≥8 versus ≤70.50 (0.26, 0.95)0.033 Visceral Disease2.74 (1.33, 5.65)0.006 ECOG, 1 versus (0.83, 1.98)0.27 Prior Abiraterone1.58 (0.55, 4.48)0.39 Multivariable Visceral Disease 4.16 (1.86, 9.30) <0.001 Gleason Score, ≥8 versus ≤ (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 8-10 predict POOR response to ABI Azria et al. ASCO GU 2012 (poster 149 )

9 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

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 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

13 Patients who progressed while receiving docetaxel Time (Months) Proportion of Overall Survival Number at Risk MTX + PRED CBZ + PRED MTX + PRED CBZ + PRED Symbols = Censors MTXCBZ ASCO GU 2011

14 Patients who progressed after completion with docetaxel Time (Months) Proportion of Overall Survival Number at Risk MTX + PRED CBZ + PRED MTX + PRED CBZ + PRED Symbols = Censors MTXCBZ ASCO GU 2011

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

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

17 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

18 Click to edit the outline text format Second Outline Level  Third Outline Level Fourth Outline Level  Fifth Outline Level  Sixth Outline Level  Seventh Outline Level  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: 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

19 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

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 % dei pazienti trattati con enzalutamide riceve abiraterone in terza linea. Loriot et al. Ann. Oncol Angelergues et al. ASCO % dei pazienti trattati con docetaxel riceve due ulteriori linee. 40% Dei pazienti riceve due ulteriori linee dopo TXT

21 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.

22 Pazienti trattati n maniera sequenziale con abiraterone e cabazitaxel in 22 centri ospedalieri in Olanda. 90 pts treated with TXT CabaAbi Caba 48 pts 42 pts Wissing et al. ESMO 2013, abs 2904 Overall survivalTotal PFSTotal PSA-PFS La sequenza Caba  Abi vs. Abi  Caba: esperienze cliniche. Caba  Abi (mos) Abi  Caba (mos) Treatment duration Median F-Up Median OS Total-PFS PSA-PFS9.66.4

23 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 CabaAbi 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).

24 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

25 PS 2: HT

26 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

27 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

28 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

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


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