Opinioni a confronto fra Urologo ed Oncologo Il carcinoma della prostata: cosa fare dopo chemio-resistenza Il punto di vista dell’Oncologo Dott.ssa M.

Presentazione sul tema: "Opinioni a confronto fra Urologo ed Oncologo Il carcinoma della prostata: cosa fare dopo chemio-resistenza Il punto di vista dell’Oncologo Dott.ssa M."— Transcript della presentazione:

1 Opinioni a confronto fra Urologo ed Oncologo Il carcinoma della prostata: cosa fare dopo chemio-resistenza Il punto di vista dell’Oncologo Dott.ssa M. RIZZO A.O.R.N. “A. Cardarelli”, Napoli

2 The evolution of the cancer niche Nature Reviews|Cancer volume 13, July 2013 no validated predictive models

3 Tumour volume Castration Palliative Therapy Local therapy* Metastatic Symptoms Androgen-Independence Non-metastatic Hormone-sensitive 2 nd -line hormonal therapies *e.g. Radiotherapy Prostate cancer disease continuum: before 2004

4 adapted by O. Caffo presentation-AIOM Prostata-Milano, 30 nov 2012

5 S PHASE SPECIFIC Antimetabolites Hydroxyurea Podophyllotoxin Campotecine M PHASE SPECIFIC (antimitotic) vincristine vinblastine paclitaxel vinorelbina docetaxel cabazitaxel NON PHASE SPECIFIC Alkylating agents Alkylating related agents Intercalating Antibiotics (mitoxantrone) Check point G1/S p53 apoptosis drug resistance G2 PHASE SPECIFIC Bleomycin Trattamento chemioterapico nel CP

6 Docetaxel in Prostate Cancer

7 adapted by O. Caffo presentation-AIOM Prostata-Milano, 30 nov 2012

8 Tumour volume Castration Local therapy* Metastatic Symptoms Androgen-Independence Non-metastatic Hormone-sensitive 2 nd -line hormonal therapies *e.g. Radiotherapy Prostate cancer disease continuum: after 2004 Docetaxel/chemotherapy

9 Principi Di Chemioterapia: Meccanismi di Resistenza

10 Agarval N. European Urology 61 (2012) Molecular targets and mechanisms of resistance in PC resistance to hormone-therapy (?) resistance to chemotherapy (?) resistance to immunotherapy (?)

11 Tumour volume Castration Local therapy* Metastatic Symptoms Androgen-Independence Non-metastatic Hormone-sensitive 2 nd -line hormonal therapies *e.g. Radiotherapy Prostate cancer disease continuum: after 2005 Docetaxel/chemotherapy Rechallenge of Docetaxel

12 Tumour volume Castration Local therapy* Metastatic Symptoms Androgen-Independence Non-metastatic Hormone-sensitive 2 nd -line hormonal therapies *e.g. Radiotherapy Prostate cancer disease continuum: after 2012 Docetaxel/chemotherapy Rechallenge of Docetaxel Cabazitaxel

13 Cabazitaxel 25 mg/m 2 IV q3w + Prednisone 10 mg/day PO for 10 courses (n = 378) Cabazitaxel 25 mg/m 2 IV q3w + Prednisone 10 mg/day PO for 10 courses (n = 378) Mitoxantrone 12 mg/m 2 IV q3w + Prednisone 10 mg/day PO for 10 courses (n = 377) Mitoxantrone 12 mg/m 2 IV q3w + Prednisone 10 mg/day PO for 10 courses (n = 377) Patients with metastatic CRPC progressing on docetaxel (N = 755) Stratified by ECOG PS (0,1 vs 2) and measurable vs nonmeasurable disease Primary endpoint: OS Secondary endpoints: PFS, response rate, safety de Bono JS, et al. Lancet. 2010;376:1147-1154. TROPIC: phase III registration trial of second-line Cabazitaxel

14 Chemotherapy with Docetaxel Not more than once adapted by O. Caffo presentation-AIOM Prostata-Milano, 30 nov 2012

15 Blocco del fuso mitotico Bassa affinità P-gp Pre-clinica attività in tumori refrattari a docetaxel In vitro: blocco del trasporto intracellulare del recettore androgenico Cabazitaxel Microtubule stabilization Darshan M.S. et al Can Res 2011;15; 71(18): 6019-29 Cabazitaxel vs Docetaxel

16 Docetaxe l 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 ✔ Active in chemotherapy-resistant or insensitive patients RECHALLENGE (?)TROPIC (?) Cabazitaxel: key differences with docetaxel

17 Patients who progressed while receiving docetaxel 100 90 80 70 60 50 40 30 20 10 0 0 612182430 Time (Months) Proportion of Overall Survival Number at Risk MTX + PRED CBZ + PRED 230 239 172 194 98 130 33 44 2929 1010 MTX + PRED CBZ + PRED Symbols = Censors ASCO 2011 MTXCBZ 10.913.8 ASCO GU 2011

18 Patients who progressed after completion of docetaxel 100 90 80 70 60 50 40 30 20 10 0 0612182430 Time (Months) Proportion of Overall Survival Number at Risk MTX + PRED CBZ + PRED 147 139 128 127 90 101 34 46 9 19 0404 MTX + PRED CBZ + PRED Symbols = Censors MTXCBZ 15.618 ASCO GU 2011

19 Tumour volume Castration Docetaxel/chemotherapy Local therapy* Metastatic Symptoms Castration-resistant Non-metastatic Asymptomatic Hormone-sensitive 2 nd -line hormonal therapies Bicalutamide Flutamide Nilutamide Death Cabazitaxel *e.g. Radiotherapy Continued AR signalling Kohli & Tindall. Mayo Clin Proc 2010;85:77–86. Prostate cancer disease continuum: today Abiraterone

20 HSPC Dillard et al, Mol Cell Endocrinol 2008 La crescita tumorale dipende dal testosterone circolante prodotto da surrene e testicoli Il testosterone guida la crescita delle cellule tumorali prostatiche ADT mantiene la testosteronemia sotto la soglia di castrazione blocco della crescita tumorale  Ruolo del diidrotestosterone (DHT) nell’attivazione delle pathway tumorali della cellula prostatica [Huggins]  Centralità del recettore androgenico nella modulazione dei processi tumorali [Jensen] Terapia ormonale nel carcinoma prostatico (2)

21 CRPC Dillard et al, Mol Cell Endocrinol 2008 Il testosterone guida la crescita delle cellule tumorali prostatiche il TUMORE RIPRENDE A CRESCERE anche se la testosteronemia è sotto la soglia di castrazione (< 20-50 ng/dl) IL TUMORE si svincola dal testosterone circolante perchè AUTOPRODUCE TESTOSTERONE IPERSENSIBILIZZAZIONE DEL RECETTORE TESTOSTERONE - Aumento della sensibilità / affinità del AR vs testosterone - Aumento del numero e/o stabilizzazione del AR Castration-Resistance Prostate Cancer HSPC La crescita tumorale dipende dal testosterone circolante prodotto da surrene e testicoli ADT mantiene la testosteronemia sotto la soglia di castrazione blocco della crescita tumorale

22 First line chemotherapy Docetaxel LHRH analogues Anti-androgens Additional hormonal approaches Cabazitaxel *Not currently licenced in Italy mCRPC=metastatic castration-resistant prostate cancer; LHRH=luteinising hormone-releasing hormone. Abiraterone Enzalutamide* Pre-chemotherapyPost-chemotherapy Radium-223* Abiraterone* Advanced prostate cancer: future management

23 3 molecole con risultati positivi e apparentemente simili ma non confrontabili Castration-Resistance Prostate Cancer TROPIC COU-AA-301 trial AFFIRM trial 1. De Bono JS at al.Lancet 2010; 376: 1147–54 2. Fizazi K et al. Lancet Oncol 2012; 13: 983–92. 3. Scher HI et al. N Engl J Med 2012;367(13):1187-97

24 Disegno degli studi: le differenze (1) designed to detect a 20% improvement in survival Abiraterone designed to detect a 25% improvement in survival Cabazitaxel Interim analysis Mitoxantrone arm Placebo arm

25 designed to detect a 25% improvement in survival Mitoxantrone arm designed to detect a 24% improvement in survival Interim analysis Placebo arm Disegno degli studi: le differenze (2) Cabazitaxel Enzalutamide

26 designed to detect a 24% improvement in survival Enzalutamide Interim analysis Placebo arm designed to detect a 20% improvement in survival Abiraterone Interim analysis Placebo arm Disegno degli studi: le differenze (3)

27 Paesi coinvolti negli studi registrativi TROPIC (cabazitaxel) COU-AA-301 (Abiraterone) AFFIRM (Enzalutamide) Paesi Partecipanti USA, EU, Canada, Australia USA, EU, Canada,, Australia South America, Africa, India, Asia, Russia South America, Africa Età (>75Y %) PSA basal PainPts 2LPts 3LPts > 3L Cabazitaxel68 (18%)14445%69%25%6% Abiraterone69 (28%)12944%70%30%0% Enzalutamide69 (25%)107 Asintom. 72%25%3% Caratteristiche basali dei pazienti: PSA, pain e precedenti linee di CT

28 Differenti metodologie Progression based on Timing IMAGING Criteria Efficacy on PAIN compared Cabazitaxel Imaging or PSA or Pain 8 weeks ( 2 mo) PCWG 1vs mitoxantrone Abiraterone PSA and Imaging and Pain 4 mo or 7 mo or 10 mo differentvs placebo Enzalutamide Imagin/Bone/SRE AND new Therapy 12 weeks (3 mo) PCWG2vs placebo

29 Differenze nei risultati e durata trattamento Time to PSA progression Time to imaging progression OS Sperimental OS Comparator HRPFSTreatment Cabazitaxel 6.4 mo PSA-r 39% 8.8 mo ORR 14% 15.1 mo Final 12.7 mo Final 0.70 Final 2.8 mo4.5 mo Abiraterone 10.2 mo PSA-r 38% 5.6 mo ORR 14% 14.8 mo IA  15.8 10.9 mo IA  11.2 0.65 IA  0.74 Final 5.6 mo PFS-imag 8 mo Enzalutamide 8.3 mo PSA-r 54% 8.3 mo ORR 29% 18.4 mo IA13.6 mo IA0.63 IA8 mo IA= intermin analysis PSA-r= biochemical response PFS-imag= PFS radiological

30 Treatment Choice Age - Younger than 60 yrs - 60-80 yrs - Older than 80 yrs Performance Status Score - 0/1 - 2 - 3 Pain - None - Moderate - Severe PSA doubling time < 3 mos > 3 mos Comorbidities are the most important prognostic factor for 3-yr survival in pts younger than 70 yrs [1]. Presence of ≥ comorbidities significantly increase the risk of death [2] 1. Hall WH, et al. Prostate Cancer Prostatic Dis 2005; 8:22-30; 2. Houterman S, et al. Crit Rev Oncol Hematol. 2006; 58:60-67. Pt’ Comorbidities - Elevated LFTs - Diabetes - Cardiac Disease - Neuropathy - Anemia/cytopenia PSA DT (t2 - t1)log(2)/log(P2/P1)

31 Cabazitaxel and Abiraterone phase III studies Pts characteristics & Outcome Cabazitaxel (/MP)Abiraterone (/P) Age (years)68 (62-73)69 (42-95) ECOG PS 27%10.7% Pain at baseline46%44.3% Median PSA (ug/L)143.9129 Visceral mets25%24.3% Measurable disease53%69% Number of line of CT > 231%28.2% PSA response rate39.2% (34-44.5)29.1% Pain response rate9.2% (4.9-13.5)NR Tumour response rate14.4% (9.6-19.3)NR PFS (months)cPFS (1.4-2.8 mths)rPFS (3.6-5.6 mths) Overall Survival (months)12.7 —› 15.110.9 —› 14.8

32 Fisazi et al, Lancet Oncol 2012; 13: 983–92 COU-AA-301: Final OS by subgroup analyses

33 De Bono et al, Lancet Oncol 2010; 376: 1147–54 TROPIC: final results

34 Fizazi, Lancet Oncology 2012 La risposta ad abiraterone è indipendente dalla risposta alla prima linea con docetaxel e dalla sua durata I dati dello studio 301 mostrano l’efficacia di abiraterone nei pazienti con Buona risposta alla chemioterapia (>3 mesi prima dell’inizio del nuovo trattamento) Risposta non buona (<3 mesi prima dell’inizio del nuovo trattamento) Breve esposizione precedente al docetaxel (<3 mesi) Più lunga esposizione precedente al docetaxel (>3 mesi)

35 ↑ sopravvivenza Preservare/ Migliorare QoL ….è mandatorio nel CRPC

36

37

38

39 Abiraterone ritarda il tempo al deterioramento della QoL Il tempo mediano al deterioramento della QoL (punteggio totale FACT-P) è stato di 12.1 mesi nel gruppo abiraterone + prednisone e 8.4 mesi nel gruppo placebo + prednisone Harland et al. ECCO 2011: Abstract 7001

40 Palliazione del dolore e tempo alla palliazione Logothetis et al. The Lancet-Oncology 2012 45% 28.8% P = 0.0005 Abiraterone + prednisonePlacebo + prednisone Il braccio Abi+prednisone ha evidenziato una percentuale di palliazione significativamente maggiore rispetto al braccio placebo+prednisone

41 Patient Type 1 Received up to 4 cycles of Taxotere and has never responded to the treatment. Patient Type 2 Responding during the initial cycles of treatment and progresses while on treatment (patient received between 4 to 10 consecutive cycles). Patient Type 3 Responding during all treatment (patient received up to 10 or more cycles). Then patient progresses within 6 months after the last cycle of Taxotere Patient Type 4 Responding during all treatment (patient received up to 10 or more cycles). Then patient progresses more than 6 months after the last cycle of Taxotere Patient Type 0b Discontinued due to toxicity Patient Type 0a Unsuitable for chemotherapy Distribution of 1 st line docetaxel patients Patient segments who are unsuitable for CT 21%27%34%20%

42

43 In the past, present and future... …clinical experience and multidisciplinary