A progressione da docetaxel, quali razionali e quali evidenze per i trattamenti successivi?

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1 IRCCS Azienda Ospedaliera Universitaria San Martino IST Istituto Nazionale per la Ricerca sul Cancro A progressione da docetaxel, quali razionali e quali evidenze per i trattamenti successivi? Giuseppe Fornarini U.O. Oncologia medica 1

2 OT ABI taxotere

3 ADT-> TXT COU 301 AA+P vs P OS 15.8 vs 11.2 AFFIRM ENZA vs placebo OS 18.4 vs 13.6 TROPIC Caba vs mitoxantrone OS 15.1 vs 12.7 AFFIRM ENZA vs placebo OS 18.4 vs 13.6 ADT-> ABI-> TXT TROPIC Caba vs mitoxantrone OS 15.1 vs 12.7

4 ADT-> TXT COU 301 AA+P vs P OS 15.8 vs 11.2 AFFIRM ENZA vs placebo OS 18.4 vs 13.6 TROPIC Caba vs mitoxantrone OS 15.1 vs 12.7 AFFIRM ENZA vs placebo OS 18.4 vs 13.6 ADT-> ABI-> TXT TROPIC Caba vs mitoxantrone OS 15.1 vs 12.7

5 : come scegliere? AA ENZA CABA ENZA CABA ABI ENZA CABA ABI CABA CABA ENZA ABI ABI ENZA

6 innumerevoli combinazioni di sequenze e a complicare la scelta subentrano ulteriori variabili: sintomatico Malattia viscerale asintomatico PS LDH/Hb/ALP

7 : come scegliere? Nessuno studio Head to Head No confronti: differente popolazione inserita negli studi Anticipo nei trattamenti Diversa gestione dei pazienti Aumento del PSA o riduzione non corrisponde sempre a risposta

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16 CAST: 63 pts CAB-> ABI OS was 19.1 month - PFS 8.1 month 69 pts ABI-> CAB OS was 17.0 months - PFS 6.5 month Although partial responses to cabazitaxel occurred in both groups, Abi Cab treated patients had a significantly decreased antitumor response from cabazitaxel than Cab Abi treated patients (median PFS 5.0 versus 2.6 months, p < 0.001). Wissing MD et all. Int J Cancer 2014 Sep 20. doi: /ijc [Epub ahead of print]

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21 Azad A. ESMO 214

22 Azad A. ESMO 214

23 SAGB.CAB c 25/11/2014 Retrospective cohort of 275 consecutive patients treated with cabazitaxel Treatment sequences received: DOC CAB only (n=158) DOC ABI or ENZ CAB (n=68) DOC CAB ABI or ENZ (n=43) Prognostic factors of overall survival analysed by multivariate stepwise logistic regression Oudard S et al, ESMO 2014 (poster 789P)

24 SAGB.CAB c 25/11/2014 Retrospective cohort of 275 consecutive patients treated with cabazitaxel Prognostic factors of survival Variable HR (CI 95%) P Metastatic site Bone only Ref <0.001 Visceral 2.19 ( ) Bone + lymph node 1.43 ( ) Lymph node only 0.34 ( ) Duration of response to 1 st ADT > 12 months Ref months 1.66 ( ) Number of active therapies DOC CAB only Ref <0.001 DOC CAB ART 0.33 ( ) DOC ART CAB 0.56 ( ) Oudard S et al, ESMO 2014 (poster 789P) 24

25 SAGB.CAB c 25/11/2014 Clinical characteristics of patients by treatment sequence DOC CAB (n=158) DOC CAB ART (n=43) DOC ART CAB (n=74) Median age (yr) Gleason 8-10 (%) Duration of response to 1 st ADT 12 mths (%) ECOG 2 or more (%) Pain (%) Hb, median (g/dl) ALP, median (UI/mL) PSA, median (ng/ml) Patients treated with DOC CAB ABI or ENZ more likely to have poor PS and pain at initiation of first life-extending therapy post-doc Oudard S et al, ESMO 2014 (poster 789P) 25

26 SAGB.CAB c 25/11/2014 Overall survival from initiation of next life-extending therapy post-docetaxel 100% 90% 80% 70% 60% DOC ABI or ENZ CAB (n=68) DOC CAB ABI or ENZ (n=43) DOC CAB only (n=158) 50% 40% 30% 20% 10% 0% Months Trend for better OS (p=0.06) in patients treated with DOC CABA ABI or ENZA Oudard S et al, ESMO 2014 (poster 789P)

27 come identificare la miglior sequenza fattori predittivi-prognostici

28 120% 100% Who are the non-responders to enzalutamide 100% 80% 67% 60% 50% 40% 20% 0% 25% High AR nuclear + CYP17 expression 17% 0% ARv7 presence 40% 33% 9% ERG presence Retrospective analysis in 153 mcrpc patients treated with cabazitaxel plus prednisone 2 nd ADT included anti-androgens, DES, estramustine, ketoconazole, abiraterone, enzalutamide Efstathiou E et al. Eur Urol 2014 (epub ahead of print)

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31 SAGB.CAB c 25/11/2014 Constitutively active splice variant AR-FL ARv7 Antonarakis et al. NEJM 2014 (epub ahead of print on 4 Sept); Guo Z et al. Int J Biol Sci 2011; 7: AR-FL: Full-Length Androgen Receptor; NTD: N-Terminal Domain; DBD: DNA-Binding Domain; LBD: Ligand- Binding Domain; U: Unique N- or C-terminal sequence

32 SAGB.CAB c 25/11/2014 ARv7 and resistance to ABI or ENZ Clinical or radiological PFS Enzalutamide Abiraterone AR-V7 Negative HR 8.5 (95% CI ) p< AR-V7 Negative HR 16.5 (95% CI ) p< AR-V7 Positive AR-V7 Positive US patients prospectively enrolled to receive enzalutamide (n=31) or abiraterone (n=31) Antonarakis et al. NEJM 2014 (epub ahead of print on 4 Sept) Antonarakis, ESMO 2014 (abstract 7980)

33 SAGB.CAB c 25/11/2014 Overall survival ARv7 and resistance to ABI or ENZ Updated overall survival (all combined) AR-V7 negative Median OS >16.0 mo (CI 95%: 16.0-NR) AR-V7 Positive Median OS 9.9 mo (CI 95%: ) HR 5.5 (CI 95%, ) P< Time (months) 62 US patients prospectively enrolled to receive enzalutamide (n=31) or abiraterone (n=31) Antonarakis et al. NEJM 2014 (epub ahead of print on 4 Sept); Antonaralis, ESMO 2014 (abstract 7980)

34 Prevalence di AR V7 in CRPC (n 62) Pre Enza, Pre ABI: 11.6% Post Enza only: 25.0% Post Abi only: 51.2% Post Enza and Post Abi: 66.7% AR-V7, the most important AR transcriptional variant, is expressed at detectable in CTCs in a significant proportion of mcrpc patients Detection of AR- V7 may be associated with primary and acquired resistance to Enzalutamide and abiraterone Antonarakis E.S. NEJM 2014

35 SAGB.CAB c 25/11/2014 Docetaxel refractory patients Retrospective review of 186 mcrpc patients 33 (17.7%) docetaxel refractory* Subsequent therapies: cabazitaxel Cabazitaxel AR-targeted agents (ABI or ENZ) Multivariate analysis: significant OS benefit with cabazitaxel versus new AR-targeted agents Abiraterone Retrospective study of 44 patients with mcrpc Treated with docetaxel ABI 7/44 patients docetaxel refractory No PSA, radiological or clinical response to ABI *Docetaxel refractoriness defined as disease progression occurring within 3 mths from docetaxel initiation and after adequate exposure to docetaxel (ie cumulative dose of 225 mg/m2). Di Lorenzo et al. Eur Urol 2014, 65: De Bono Mukherji D. ASCO 2012

36 NLR and activity of docetaxel HR (CI 95%) Age ( median) 1.24 ( ) ALP ( median) 1.65 ( ) Duration of initial ADT (< median) 1.41 ( ) dnlr ( median) 1.29 ( ) Hemoglobin (<median) Pain at baseline (PPI 2) VENICE (1224 patients) dnlr 2 & duration of 1 st ADT are prognostic for OS (MVA analysis) 1.45 ( ) 1.56 ( ) P <0.001 <0.001 <0.001 <0.001 <0.001 OS benefit particularily marked for high dnlr vs mitoxantrone DOC (n=156) dnlr <2 M (n=181) DOC (n=176) dnlr 2 Confirmed PSA decrease 50% with docetaxel: dnlr <2: 70% dnlr 2: 55% M (n=155) Median OS Difference 2.2 mths 4.3 mths HR [95% CI] *Posthoc analyses Van Soest R et al. ESMO 2014 (poster P786) dnlr: derived neutrophil lymphocyte ratio; ALP: Alkalin Phosphatase; M: mitoxantrone TAX327 (1006 patients) 0.80 [ ] 0.72 [ ]

37 conclusioni Assenza di studi comparativi La ridotta risposta alla ADT in prima linea ( non la durata della terapia ormonale) e un alto NLR sembra rappresentare un fattore prognostico e predittivo di bassa risposta agli AR-TA la sequenza ABI-ENZA e viceversa non sembra essere attiva.

38 conclusioni La ricerca della variante AR-V7 nelle CTC sembra essere promettente ma richiede un validazione prospettica La sopravvivenza è correlata al numero di linee di trattamento attive ricevute La chemioterapia impatta decisamente sulla sopravvivenza globale il corretto posizionamento va valutato sul singolo malato.

39 Grazie per l'attenzione!!!!