TEODORO SAVA Oncologia do AOUI Verona

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1 TEODORO SAVA Oncologia do AOUI Verona

2 Emerging treatment continuum for mcrpc First-line therapies Second-line therapies Enzalutamide No metastases /castrate sensitive Metastases Death Adapted from Antonarakis & Eisenberger N Engl J Med 2011; 364:2055-8

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4 Ruolo del trattamento chemioterapico nel mcrpc Ricordare esistenza del docetaxel Quando fare e cosa ci aspettiamo Ricordare esistenza del cabazitaxel Quando fare e cosa ci aspettiamo Integrare chemioterapia ed ormonoterapia Quando o meglio cosa prima?

5 Ruolo del trattamento chemioterapico nel mcrpc Ricordare esistenza del docetaxel Quando fare e cosa ci aspettiamo Ricordare esistenza del cabazitaxel Quando fare e cosa ci aspettiamo Integrare chemioterapia ed ormonoterapia Quando o meglio cosa prima?

6 Quando iniziare chemioterapia

7 SWOG 9916 Overall Survival Probability of surviving Docetaxel + estramustine Mitoxantrone + prednisone HR: 0.80 (95% CI 0.67, 0.97), p = Months Docetaxel + estramustine Mitoxantrone + prednisone HR=0.80 (95% CI: ); p=0.02 No. at risk No. of deaths Median OS (months) Petrylak DP, et al. New Engl J Med 2004; 351:

8 TAX 327 dati di OS aggiornati Probability of surviving survival Docetaxel q3w Docetaxel qw Mitoxantrone Median Hazard (months) ratio p-value Docetaxel q3w: Docetaxel qw: Mitoxantrone Years 30 months 43 months Berthold DR, et al. J Clin Oncol 2008;26:

9 TAX 327: 2004 vs 2007 Docetaxel q3w (n = 335) Docetaxel weekly (n = 334) Mitoxantrone (n = 337) Original data 2003 n (%) dead 166 (50%) 190 (57%) 201 (60%) Median survival* Hazard ratio* 18.9 ( ) 17.4 ( ) 0.76 ( ) 0.91 ( ) 16.5 ( ) p value Updated data 2007 n (%) dead 285 (85.1%) 285 (85.4%) 297 (88.1%) Median survival* Hazard ratio* p value 19.2 ( ) 17.8 ( ) 0.79 ( ) 0.87 ( ) ( ) Tannock I, et al. NEJM 2004: 351: Berthold DR, et al. J Clin Oncol 2008;26:242 45

10 Ruolo del trattamento chemioterapico nel mcrpc Ricordare esistenza del docetaxel Quando fare e cosa ci aspettiamo Ricordare esistenza del cabazitaxel Quando fare e cosa ci aspettiamo Integrare chemioterapia ed ormonoterapia Quando o meglio cosa prima?

11 Cabazitaxel: blocco del fuso, bassa affinità P-gp e blocco trasporto AR Cabazitaxel Blocco del fuso mitotico Bassa affinità P-gp Attività in tumori refrattari a docetaxel In vitro: blocco del trasporto intracellulare del recettore androgenico Microtubule stabilization Darshan M.S. et al Can Res 2011;15; 71(18):

12 Cabazitaxel: key differences with docetaxel Docetaxel Cabazitaxel Stabilization of microtubules Activity in taxane-sensitive cell lines Activity in taxane-sensitive in vivo tumor models Orally bioavailable in murine models Crosses blood-brain-barrier in vivo Active in chemotherapy-resistant or insensitive cell lines Active in chemotherapy-resistant or insensitive in vivo tumor models

13 Phase III TROPIC study mcrpc patients who progressed during or after treatment with a docetaxel-containing regimen N = 755 STRATIFICATION ECOG PS: 0, 1 vs 2 Measurable vs non-measurable disease R A N D O M I Z E Cabazitaxel 25 mg/m² q 3 wk + oral prednisone 10 mg daily for 10 cycles (n = 378) Posttreatment follow-up Mitoxantrone 12 mg/m² q 3 wk + oral prednisone 10 mg daily for 10 cycles (n = 377) PRIMARY END POINT: OS SECONDARY END POINTS: PFS, response rate, and safety de Bono JS, Lancet 2010

14 Summary of patient characteristics MP (n = 377) CBZP (n = 378) Age (years) Median [range] 67 [47 89] 68 [46 92] 65 (%) ECOG PS (%) 0, PSA (ng/ml) Median [range] [ ] [2 7842] Disease site (%) Bone Lymph node Visceral

15 Cabazitaxel significantly OS vs mitoxantrone Proportion of OS (%) No. at risk: Cabazitaxel Mito % MTX Pts received anti tubuline drug after Progression Disease Median OS 15.1 Vs 12.7 months 30% relative reduction in risk of death de Bono JS, Lancet 2010 Cabazitaxel Mitoxantrone Months Median OS (months) % patients alive at: 12 months 18 months 24 months Hazard ratio for OS Cabazitaxel Mitoxantrone % CI P value <

16 Overall survival Subgroup analysis Factor Subgroup Number HR (95% CI) Favours CBZP Favours MP ITT population ECOG Status ECOG Status Measurable disease Measurable disease No. of prior chemo No. of prior chemo Age Age Rising PSA at baseline Rising PSA at baseline All patients 0,1 2 No Yes 1 >2 <65 >65 No Yes ( ) 0.71 ( ) 0.78 ( ) 0.72 ( ) 0.71 ( ) 0.71 ( ) 0.73 ( ) 0.81 ( ) 0.66 ( ) 0.85 ( ) 0.68 ( ) Total docetaxel dose* Total docetaxel dose Total docetaxel dose Total docetaxel dose Total docetaxel dose Progression Progression Progression <225 mg/m 2 >225 to 450 mg/m 2 >450 to 675 mg/m 2 >675 to 900 mg/m 2 >900 mg/m 2 During last docetaxel treatment <3 months since last docetaxel dose 3 and 6 months since last docetaxel dose ( ) 0.61 ( ) 0.81 ( ) 0.77 ( ) 0.57 ( ) 0.71 ( ) 0.70 ( ) 0.76 ( ) *The protocol was amended after the first 59 patients were enrolled in order to mandate that eligible patients had to have received >225 mg/m² of docetaxel.

17 Secondary end points: PFS Proportion of PFS (%) Cabazitaxel Mitoxantrone Median PFS (months) Cabazitaxel Mitoxantrone Hazard ratio % CI P value < PFS composite end point: PSA progression, pain progression, tumour progression, symptom deterioration, or death. No. at risk: Months PFS defined as the first of any: Tumor progression or PSA progression or Pain progression de Bono JS, Lancet 2010

18 Secondary endpoints Cabazitaxel significantly improved PSA response Cabazitaxel Mitoxantrone No. evaluable patients PSA response rate, % % CI P value Cabazitaxel PSA, prostate-specific antigen de Bono JS, et al. Lancet 2010;376(9747):

19 Secondary endpoints Cabazitaxel significantly improved tumour response Cabazitaxel Mitoxantrone No. evaluable patients Tumour response rate, % % CI P value Cabazitaxel PSA, prostate-specific antigen de Bono JS, et al. Lancet 2010;376(9747):

20 Secondary end points: Time to PSA Progression Cabazitaxel Mitoxantrone Median TT PSA (months) Hazard ratio % CI P value Secondary end points: Time to Tumor Progression Cabazitaxel Mitoxantrone Median TTP (months) Hazard ratio % CI P value <0.0010

21 Secondary end points No worsening of performance despite longer treatment with cabazitaxel ECOG change from baseline (%) Change in ECOG performance status from baseline during treatment period % 2.2% Improved (n = 12) 79.3% 78.0% Stable (n = 567) 19.6% 19.8% Worse (n = 142) Cabazitaxel Mitoxantrone Performance status remained stable in most patients and was similar between groups de Bono JS, et al. Lancet 2010;376(9747):

22 Secondary end points - Pain scores suggested less severe pain with cabazitaxel Average AUC of PPI by treatment Average AUC of analgesic score by treatment Assessment of pain scores suggested less severe pain in the cabazitaxel group during treatment compared with mitoxantrone Analgesic use was comparable between the groups AUC, area under the curve; PPI, present pain index

23 Integrated - Most frequent adverse events* MP (n = 371) CBZP (n = 371) All grades (%) Grade 3 (%) All grades (%) Grade 3 (%) Any adverse event Febrile neutropenia Diarrhoea Fatigue Back pain Nausea Vomiting Haematuria Arrhythmia 2 <1 5 1 Abdominal pain *Sorted by 2% incidence for grade 3 events in the cabazitaxel arm Grade 3 peripheral neuropathy was uncommon with 3 (0.8%) patients in each arm Grade 2 increased lacrimation occurred in 1 (0.3%) patients in cabazitaxel arm Onycholysis was rare with 2 (0.5%) patients in each arm

24 Haematological results MP (n = 371) CBZP (n = 371) All grades (%) Grade 3 (%) All grades (%) Grade 3 (%) Haematology Anaemia Leukopenia Neutropenia* Thrombocytopenia *Prophylactic use of G-CSF was permitted except for cycle 1 of treatment at the discretion of the investigator 58% grade 3 neutropenia in MP arm of the TROPIC study compares to 22% reported for the TAX327 (first-line) study

25 ASCO GU 2013 Cabazitaxel Italian EAP

26 ASCO GU 2013 Cabazitaxel Italian EAP

27 ASCO GU 2013 Cabazitaxel Italian EAP

28 Ruolo del trattamento chemioterapico nel mcrpc Ricordare esistenza del docetaxel Quando fare e cosa ci aspettiamo Ricordare esistenza del cabazitaxel Quando fare e cosa ci aspettiamo Integrare chemioterapia ed ormonoterapia Quando o meglio cosa prima?

29 A new age in the management of mcrpc patients works in progress Ha senso la sequenza di tutti i nuovi farmaci (cross resistenza?)? Possiamo prevedere chi si beneficerà di cosa? Considerazione personale

30 Docetaxel Enzalutamide Abiraterone

31 Docetaxel Abiraterone Enzalutamide Eur Urol (2013), in press European Journal of Cancer (2013), in press.

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33 Sequenza dei trattamenti post docetaxel: Caba vs Abi/Enza I pazienti che hanno ricevuto nuove terapie ormonali dopo cabazitaxel hanno evidenziato una migliore OS rispetto a quelli che hanno ricevuto gli stessi trattamenti prima di cabazitaxel. Angelergues et al. Abstract 5063 / ASCO 2013

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35 Quale terapia scegliere: Abi vs Doc o Caba vs Abi o Enza? Comorbidità, età Malattia viscerale o meno Cinetica della malattia (sintomatica, PSA?) Gleason (?) Efficacia e sopportazione Docetaxel Durata ormonoterapia

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37 Abiraterone e durata 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

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39 <br /><br />E3805<br />CHAARTED: ChemoHormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

40 Primary endpoint: Overall survival Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

41 Clinical interpretation Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

42 Sequenza dei trattamenti post docetaxel: terapie nuove vs tradizionali Impatto della sequenza delle nuove terapie sulla sopravvivenza globale media dei pazienti con mcrpc. Stime di sopravvivenza a seconda del trattamento disponibile Studio retrospettivo. Gruppo 1: corrispondente al periodo in cui erano disponibili solo i farmaci convenzionali (docetaxel, mitoxantrone). Gruppo 2: corrispondente al periodo in cui nuovi farmaci come cabazitaxel, enzalutamide, abiraterone sono stati approvati per l utilizzo dopo docetaxel. La sopravvivenza globale media è stata di 10,6 mesi (95% IC: 7,8 15,7) nel gruppo 1 rispetto ai 32,5 mesi (95% IC: 25 42,4) nel gruppo 2 (p<0,0001). A 12 mesi, la sopravvivenza globale è stata del 46,4% (95% IC: 34 57,9) nel gruppo 1 vs 86,6% (95% IC: 75,9 92,8) nel gruppo 2. La sopravvivenza è migliorata negli anni probabilmente grazie alla diagnosi precoce, a schemi di dosaggio di docetaxel più intensivi e all'uso di nuovi farmaci. Chaumard-Billotey N, et al. Poster: P417; ECCO-ESMO-ESTRO Amsterdam, The Netherlands.

43 Ruolo del trattamento chemioterapico nel mcrpc Considerazioni personali: ETEROGENEITA della patologia e dei pazienti P.S. Comorbidità Efficacia e durata dell OT e se possibile non trascuriamo/ritardiamo la chemioterapia.

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