«Προσεγγίζοντας τη θεραπεία του Καρκίνου του Προστάτη με νέα δεδομένα: Οι αποφάσεις του κλινικού ιατρού για κάθε ασθενή χωριστά»

Transcript

1 «Προσεγγίζοντας τη θεραπεία του Καρκίνου του Προστάτη με νέα δεδομένα: Οι αποφάσεις του κλινικού ιατρού για κάθε ασθενή χωριστά» Η θεραπευτική προσέγγιση στον ορμονοευαίσθητο Καρκίνο Προστάτη Ελένη Ισιδώρα Α. Περδικούρη ΕΠΙΜ.Β ΠΑΘΟΛΟΓΙΑΣ ΟΓΚΟΛΟΓΙΑΣ ΠΑΝ/ΚΗ ΟΓΚΟΛΟΓΙΚΗ ΑΠΘ ΓΝΘΠΑΠΑΓΕΩΡΓΙΟΥ

2 Disclosures Honoraria: Sanofi, Janssen Advisory: Pfizer, Leo, Roche

3 Καρκίνος Προστάτη: Επιδημιολογία 2ος συχνότερος συμπαγής όγκος στους άνδρες 4ος συχνότερος ανάμεσα σε όλους τους τύπους καρκίνου: 1 στους 6 στην Αμερική και 1 στους 8 στο UK θα εμφανίσουν Ca προστάτη 5η αιτία θανάτου λόγω κακοήθειας παγκόσμια Η συχνότητα εμφάνισης της νόσου αυξάνεται σταθερά τα τελευταία είκοσι χρόνια GLOBOCAN 2012 (IARC) Section of Cancer Information

4 Επιδημιολογικά δεδομένα μεταστατικής νόσου 15-20% νεοδιαγνωσθέντων PrCa εμφανίζονται με προχωρημένη νόσο 4-5% με απομακρυσμένες μεταστάσεις EU,USA Συχνότητα εμφάνισης de novo ματαστατικής νόσου ποικίλει γεωγραφικά, αναλόγως προγραμμάτων screening, δυνατότητα πρόσβασης σε συστήματα υγείας κ.τ.λ 75-80% ασθενών με μεταστατική νόσο εμφανίζουν υποτροπή μετά από θεραπεία τοπικής νόσου 20% 80% Metastatic Disease M1 Local DIsease M0 Recurrence M1 CPRC_M1 CPRC_M1 Siegel, Ca Cancer J Clin,2017 Buzzoni, Eur Urol, 2015

5 Ρόλος ανδρογόνων-μηχανισμός δράσης T μετατρέπεται σε DHT AR είναι συνδεδεμένος με Heat Shock Proteins AR αλλάζει διαμόρφωση: Φωσφορυλίωση και διμερισμός Διαπυρηνική μετάθεση Επίδραση συνενεργοποιητών και συγκαταστολέων

6 Prostate Cancer Disease States Hormone-Sensitive (Castration-Sensitive) Newly diagnosed localized disease Non-metastatic, biochemical relapse Metastatic hormone-sensitive Castration-Resistant Non-metastatic Metastatic Asymptomatic, pre-docetaxel Symptomatic, chemotherapy-naive Post-docetaxel

7 Prostate Cancer Disease States Hormone-Sensitive (Castration-Sensitive) Newly diagnosed localized disease Non-metastatic, biochemical relapse ADT Metastatic hormone-sensitive ADT Castration-Resistant Non-metastatic Metastatic

8 Survival in metastatic prostate cancer We are making progresses 1990s Today Prednisone (P) alone (M1): 12.6 mo 1 TAX327 (DOC/P M1): 18.9 mo 2 TROPIC (DOC/P CABA/P M1): 29.4 mo 3-4 COU-AA-301 (DOC/P ABI/P M1): 32.6 mo 5 COU-AA-302 (ABI/P pre-doc M1): 34.7 mo 5 X 3 PREVAIL (ENZA pre-doc M1): 35.3 mo 6 CHAARTED (ADT+DOC M1): 57.6 mo 7 STAMPEDE (ADT+DOC/P M1): 65 mo 8 LATITUDE & STAMPEDE (ADT+ABI/P M1): not yet reached Kantoff PW. J Clin Oncol 1999;7: ; 2. Tannock IF. NEJM 2004;351: ; 3. De Bono JS. Lancet 2010;376: ; 4. Sartor O. J Clin Oncol 2011; 29(S15): abst 4525 (podium presentation) ; 5. Fizazi K. Lancet Oncol 2012;13:983-92; 6. Ryan CJ. Lancet Oncol 2015; 16: ; 7. Beer TM. Eur Urol. 2017;71: ; 7. Sweeney C. NEJM 2015;373:737-46; 8. James ND Lancet 2016;387: ; 9. Fizazi K. NEJM 2017; 377:352-60; 10. James ND. NEJM 2017; 377:

9 Prostate Cancer Disease States Hormone-Sensitive (Castration-Sensitive) Newly diagnosed localized disease Non-metastatic, biochemical relapse Metastatic hormone-sensitive De novo Metastatic hormone-sensitive Docetaxel Abiraterone

10 The hope ADT AR-independent clones AR-dependent cells SAEU.CAB (Nov 2015) AR: androgen receptor Sweeney C et al. J Clin Oncol 2014;32(5S):abstract LBA2 (podium presentation)

11 Hit first hit hard

12 Phase III Randomized Trials in Metastatic Hormone-Sensitive PCa CHAARTED 1-2 (N=790) GETUG (N=385) STAMPEDE 2-5 Inclusion period M1 at diagnosis 72,8% 72% 61% Stage at inclusion M1 M1 M0 or M1 High tumor burden at inclusion 65%* 48%** Not collected N DOC cycles Daily prednisone No No Yes DOC at progression in ADT arm 48% 85% 40% *Tumor volume was a stratification factor in CHAARTED; **Tumor volume retrospectively analysed in GETUG Sweeney CJ et al. N Engl J Med 2015;373:737-46; 2. Gravis G et al. Cancer Treat Rev 2016; doi: /j.ctrv ; 3. Gravis G et al. Lancet Oncol 2013;14:149-58; 4. Gravis G et al. Eur Urol 2016;70:256-62; 5. James ND et al. Lancet 2016;387:

13 Rationale for study agent Intracellular conversion of steroid precursors to androgenic steroids by prostate cancer cells is a mechanism of escape from ADT CYP17 is key for this conversion Abiraterone is a selective, irreversible inhibitor of CYP17 Inhibition of CYP17 results in a more effective androgen depletion COU-301 & COU-302 showed adding abiraterone + prednisolone/prednisone to ADT prolonged survival in castrationresistant prostate cancer James N, et al. ASCO LBA5003 and Oral Abstract Session Attard G, et al J Clin Oncol. 2008;26(28): de Bono JS, et al NEJM 2011;364(21): Ryan CJ, et al, NEJM. 2013;368(2):

14 Abiraterone plus Prednisone in Metastatic, Castration- Sensitive Prostate Cancer N Engl J Med June 4 [Epub ahead of print] Summary Karim Fizazi, M.D., Ph.D., 1 NamPhuong Tran, M.D., 2 Luis Fein, M.D., 3 Nobuaki Matsubara, M.D., 4 Alfredo Rodriguez-Antolin, M.D., Ph.D., 5 Boris Y. Alekseev, M.D., 6 Mustafa Özgüroğlu, M.D., 7 Dingwei Ye, M.D., 8 Susan Feyerabend, M.D., 9 Andrew Protheroe, M.D., Ph.D., 10 Peter De Porre, M.D., 11 Thian Kheoh, Ph.D., 12 Youn C. Park, Ph.D., 13 Mary B. Todd, D.O., 14 and Kim N. Chi, M.D., 15 for the LATITUDE investigators* 1 Gustave Roussy, University of Paris Sud, Villejuif, France; 2 Janssen Research & Development, Los Angeles, CA; 3 Instituto de Oncologia de Rosário, Rosário, Argentina; 4 National Cancer Center Hospital East, Chiba, Japan; 5 12 de Octubre University Hospital, Madrid, Spain; 6 P.A. Hertsen Moscow Cancer Research Institute, Moscow, Russian Federation; 7 Cerrahpaşa Medical Faculty, Istanbul University, Istanbul, Turkey; 8 Fudan University Shanghai Cancer Center, China; 9 Studienpraxis Urologie, Nürtingen, Germany; 10 Oxford University Hospitals Foundation NHS Trust, Oxford, UK; 11 Janssen Research & Development, Beerse, Belgium; 12 Janssen Research & Development, San Diego, CA; 13 Janssen Research & Development, Raritan, NJ; 14 Janssen Global Services, Raritan, NJ; 15 BC Cancer Agency, Vancouver, BC, Canada

15 Study Design Patients Newly diagnosed adult men with high-risk mhnpc Meets at least 2 of 3 high-risk criteria Gleason score of 8 Presence of 3 lesions on bone scan Presence of measurable visceral lesion Stratification factors Presence of visceral disease (yes/no) ECOG PS (0, 1 vs 2) R A N D O M I Z E D 1:1 ADT + Abiraterone acetate 1000 mg QD + Prednisone 5 mg QD (n=597) ADT + placebos (n=602) Efficacy end points Co-primary: OS rpfs Secondary: time to pain progression PSA progression next symptomatic skeletal event chemotherapy subsequent PC therapy Conducted at 235 sites in 34 countries in Europe, Asia-Pacific, Latin America, and Canada Designed and fully enrolled prior to publication of CHAARTED/STAMPEDE results

16 Demographics and Baseline Disease Characteristics Age (yr), n (%) < Median (range) Gleason score at initial diagnosis, n (%) < Baseline pain score (BPI-SF Item 3), n (%) ADT-Abiraterone- Prednisone (n = 597) 221 (37) 112 (19) 141 (24) 123 (21) 68.0 (38-89) 4 (0.7) 9 (2) 584 (98) 284 (50) 123 (22) 163 (29) ADT-Placebos (n = 602) 233 (39) 134 (22) 115 (19) 120 (20) 67.0 (33-92) 1 (0.2) 15 (2) 586 (97) 288 (50) 137 (24) 154 (27) Patients with 3 bone metastases at screening, n/n (%) 586/597 (98.2) 585/602 (97.2) Patients with high risk at screening, n (%) n Gleason score bone lesions Gleason score 8 + measurable visceral disease 3 bone lesions + measurable visceral disease Gleason score bone lesions + measurable visceral disease (96) 82 (14) 84 (14) 71 (12) (95) 87 (14) 85 (14) 70 (12) 16

17 Overall Survival At a median follow-up of 30.4 months (48% of total deaths), the addition of abiraterone acetate and prednisone to ADT significantly improved OS, with a 38% reduction in the risk of death The 3-year OS rate was 66% in the ADT-abiraterone-prednisone group compared with 44% in the ADT-placebos group 17

18 Overall Survival by Subgroup The treatment effect of ADT-abiraterone-prednisone on OS was consistently favorable across nearly all prespecified subgroups 18

19 Radiographic Progression-free Survival Patients in the ADT-abiraterone-prednisone group had a 53% reduction in the risk of radiographic progression or death compared with patients receiving ADT plus placebos 19

20 Radiographic Progression-free Survival by Subgroup The treatment effect of ADT-abiraterone-prednisone on rpfs was consistently favorable across nearly all prespecified subgroups 20

21 Time to Pain Progression A statistically significant 30% risk reduction of time to pain progression was observed in patients treated with ADT-abirateroneprednisone 21

22 Time to PSA Progression A statistically significant 70% risk reduction of time to PSA progression was observed in patients treated with ADT-abiraterone-prednisone 22

23 Time to Next Symptomatic Skeletal Event A statistically significant 30% risk reduction of time to next symptomatic skeletal event was observed in patients treated with ADT-abiraterone-prednisone 23

24 Time to Cytotoxic Chemotherapy A statistically significant 56% risk reduction of time to cytotoxic chemotherapy was observed in patients treated with ADT-abiraterone-prednisone 24

25 Time to Subsequent Prostate Cancer Therapy A statistically significant 58% risk reduction of time to subsequent prostate cancer therapy was observed in patients treated with ADT-abiraterone-prednisone 25

26 Subsequent Life-prolonging Therapy for Prostate Cancer ADT-Abiraterone- Prednisone (n = 597) ADT-Placebos (n = 602) Agent no of patients (%)* n = 314 n = 469 Abiraterone acetate plus prednisone 10 (3) 53 (11) Cabazitaxel 11 (4) 30 (6) Docetaxel 106 (34) 187 (40) Enzalutamide 30 (10) 76 (16) Radium (4) 27 (6) *Patients who discontinued treatment and were eligible for subsequent therapy. The numbers of patients receiving one or multiple life-prolonging therapies totaled 125 (21%) in the ADTabiraterone-prednisone group and 246 (41%) in the ADT-placebos group More patients in the ADT-placebos group received docetaxel, enzalutamide, abiraterone acetate plus prednisone, cabazitaxel, and radium

27 Summary of Most Common Adverse Events and Adverse Events of Special Interest Adverse Event ADT-Abiraterone- Prednisone (n = 597) ADT-Placebos (n = 602) All Gr 3 Gr 4 All Gr 3 Gr 4 no of patients (%) Hypertension Hypokalemia ALT increased Hyperglycemia AST increased Bone pain Cardiac disorder Atrial fibrillation Anemia Back pain Fatigue Spinal cord compression

28 Conclusions-Latitude In the phase 3 LATITUDE trial σε ασθενείς με high-risk πρόσφατα διαγνωσμένο mhspc, η προσθήκη abiraterone acetate και prednisone στη ADT οδήγησε σε : Βελτίωσε σημαντικά τη συνολική επιβίωσημε μείωση του κινδύνου θανάτου κατά 38% Βελτίωσε σημαντικά το απεικονιστικό (radiographic) progression-free survival (53% μείωση) και όλα τα δευτερεύοντα καταληκτικά σημεία Το προφίλ ασφαλείας της abiraterone acetate με prednisone ADT ήταν συμβατό με το αντίστοιχο προηγούμενων μελετών στο mcrpc, με αυξημένη επίπτωση υπέρτασης και υποκαλιαιμίας Η προσθήκη της abiraterone acetate και της prednisone στο ADT προσφέρει κλινικό όφελος και παράταση επιβίωσης στους ασθενείς με high-risk, πρόσφατα διαγνωσθέντα mcnpc 28

29 Inclusion criteria Newly-diagnosed Any of: Metastatic Node-Positive 2 of: Stage T3/4 PSA 40ng/ml Gleason 8-10 Relapsing after previous RP or RT with 1 of: PSA 4ng/ml and rising with doubling time <6m PSA 20ng/ml Node-positive Metastatic All patients Fit for all protocol treatment Fit for follow-up WHO performance status 0-2 Written informed consent Full criteria James N, et al. ASCO LBA5003 and Oral Abstract Session

30 Outcome measures Primary outcome measure Overall survival FFS definition First of: PSA failure Local failure Lymph node failure Distant metastases Prostate cancer death Secondary outcome measures Failure-free survival (FFS) Toxicity Quality of life Skeletal-related events Cost effectiveness PSA failure definition PSA fall >= 50% 24wk nadir + 50% and >4ng/ml PSA fall of <50% failure at t=0 James N, et al. ASCO LBA5003 and Oral Abstract Session

31 Multi-arm multi-stage (MAMS) design For the abiraterone plus prednisone comparison Allocation ratio of 1 control to 1 research Target 25% relative improvement in overall survival HR=0.75 Interim analysis 3 lack-of-benefit analyses on failure-free survival Main analysis on primary outcome measure Requires ~267 control arm deaths Power and alpha 90% and 0.025, 1-sided 31

32 Accrual Comparison Open: Nov-2011 Closed: Jan-2014 Accrual: 1917 Number of patients 957 A Standard-of-care* (SOC) 960 G SOC + abiraterone acetate + prednisolone (SOC+AAP) *SOC = ADT ± RT James N, et al. ASCO LBA5003 and Oral Abstract Session 32

33 Patient characteristics 1% WHO PS 2 [s] 21% WHO PS 1 [s] 67yr Median age [s] (min 39, max 85) 52% Metastatic [s] (88% Bony mets) 20% N+M0 28% N0M0 99% LHRH analogues [s] 41% Planned for RT [s] (96% of N0M0 pts; 62% of N+M0 pts) 5% Previous local therapy [s] = Stratification factors Also stratified on :: hospital :: NSAID/aspirin Balanced by arm James N, et al. ASCO LBA5003 and Oral Abstract Session 33

34 OS STAMPEDE abiraterone plus prednisone comparison Events 262 Control 184 abiraterone plus prednisone SOC+AAP This represents a 37% improvement in survival SOC HR % CI 0.52 to 0.76 P-value James N, et al. ASCO LBA5003 and Oral Abstract Session

35 OS STAMPEDE abiraterone plus prednisone comparison SOC vs SOC+AAP Subgroup SOC-only Dths/N SOC+AAP Dths/N Interaction p-value Haz. Ratio (95% CI) Mets status M0 M1 44/ /502 34/ / (0.48, 1.18) 0.61 (0.49, 0.75) Nodal status N0 N+ NX 83/ /483 15/36 61/ /484 10/ (0.49, 0.96) 0.61 (0.48, 0.77) 0.68 (0.29, 1.57) Gleason Sum Score (cats) <= unknown 40/ /721 6/13 33/ /715 7/ (0.48, 1.23) 0.59 (0.48, 0.73) 0.47 (0.11, 1.91) Age at randomisation (cats) Under or over 180/596 82/ /603 74/ (0.40, 0.65) 0.94 (0.69, 1.29) WHO PS 0 vs /744 80/ /745 47/ (0.56, 0.87) 0.50 (0.35, 0.72) NSAID/Aspirin use No use Uses either 191/718 71/ /714 52/ (0.47, 0.74) 0.71 (0.50, 1.02) Is radiotherapy planned? No RT planned RT planned 226/561 36/ /564 24/ (0.51, 0.77) 0.64 (0.38, 1.08) Recurrent disease No Yes 254/919 8/38 171/900 13/ (0.50, 0.74) 0.94 (0.35, 2.52) Time period (co-recruiting arms) ABC-E-G /328 ABC-E-GH-- 17/49 A-----GH-- 123/580 95/330 10/47 79/ (0.53, 0.90) 0.60 (0.27, 1.33) 0.59 (0.44, 0.78) Overall 0.63 (0.52, 0.76) James N, et al. ASCO LBA5003 and Oral Abstract Session Favours: abiraterone SOC-only

36 FFS STAMPEDE AA comparison Events 535 Control 248 abiraterone plus prednisone SOC+AAP This represents a 71% improvement in time to failure SOC HR % CI 0.25 to 0.34 P-value 0.377x10-61 James N, et al. ASCO LBA5003 and Oral Abstract Session

37 FFS STAMPEDE abiraterone plus prednisone comparison SOC vs SOC+AAP Subgroup SOC-only FFS/N SOC+AAP FFS/N Interaction p-value Haz. Ratio (95% CI) Mets status M0 M1 142/ /502 38/ / (0.15, 0.31) 0.31 (0.26, 0.37) Nodal status N0 N+ NX 184/ /483 28/36 69/ /484 19/ (0.20, 0.35) 0.29 (0.24, 0.36) 0.44 (0.24, 0.80) Gleason Sum Score (cats) <= unknown 107/ /721 11/13 40/ /715 9/ (0.18, 0.38) 0.29 (0.25, 0.35) 0.15 (0.05, 0.48) Age at randomisation (cats) Under or over 361/ / /603 83/ (0.22, 0.32) 0.36 (0.28, 0.47) WHO PS 0 vs / / /745 58/ (0.25, 0.36) 0.25 (0.18, 0.34) NSAID/Aspirin use No use Uses either 394/ / /714 69/ (0.23, 0.32) 0.33 (0.25, 0.45) Is radiotherapy planned? No RT planned RT planned 425/ / /564 24/ (0.26, 0.36) 0.18 (0.12, 0.28) Recurrent disease No Yes 514/919 21/38 233/900 15/ (0.25, 0.34) 0.32 (0.16, 0.65) Time period (co-recruiting arms) ABC-E-G /328 ABC-E-GH-- 31/49 A-----GH-- 290/ /330 12/47 126/ (0.26, 0.41) 0.21 (0.11, 0.43) 0.27 (0.22, 0.34) Overall 0.29 (0.25, 0.34) Favours: abiraterone SOC-only James N, et al. ASCO LBA5003 and Oral Abstract Session

38 Secondary Outcomes Skeletal-related events James N, et al. ASCO LBA5003 and Oral Abstract Session

39 Skeletal related outcomes All patients Events 203 Control 113 abiraterone plus prednisone SOC+AAP SOC HR % CI 0.37 to 0.58 P-value James N, et al. ASCO LBA5003 and Oral Abstract Session

40 Skeletal related outcomes M1 patients Events 203 Control 113 abiraterone plus prednisone SOC+AAP This represents a 55% reduction in skeletal related events SOC HR % CI 0.36 to 0.58 James N, et al. ASCO LBA5003 and Oral Abstract Session

41 Treatment for progression Treatment started since first progression A SOC G SOC+abi Patients randomised Patients with progression 535 (56%) 248 (26%) Reported new treatment 477 (89%) 196 (79%) Reported life-prolonging treatment 310 (58%) 131 (53%) Docetaxel 200 (37%) 115 (46%) Enzalutamide 138 (26%) 25 (10%) Abiraterone plus prednisone 120 (22%) 8 (3%) Radium (5%) 19 (8%) Cabazitaxel 28 (5%) 15 (6%) James N, et al. ASCO LBA5003 and Oral Abstract Session

42 Any life-prolonging treatment for progression Treatment started since first progression A SOC G SOC+abi SOC+AAP SOC Patients randomised Patients with progression 535 (56%) 248 (26%) Reported new treatment 477 (89%) 196 (79%) Reported life-prolonging treatment 310 (58%) 131 (53%) Docetaxel 200 (37%) 115 (46%) Enzalutamide 138 (26%) 25 (10%) Abiraterone plus prednisone 120 (22%) 8 (3%) Radium (5%) 19 (8%) Cabazitaxel 28 (5%) 15 (6%) Graph timed from first FFS event James N, et al. ASCO LBA5003 and Oral Abstract Session

43 Docetaxel SOC+AAP Treatment started since first progression A SOC G SOC+abi Patients randomised SOC Patients with progression 535 (56%) 248 (26%) Reported new treatment 477 (89%) 196 (79%) Reported life-prolonging treatment 310 (58%) 131 (53%) Docetaxel 200 (37%) 115 (46%) Enzalutamide 138 (26%) 25 (10%) abiraterone plus prednisone 120 (22%) 8 (3%) AR-targeting therapy Radium (5%) 19 (8%) Cabazitaxel 28 (5%) 15 (6%) SOC SOC+AAP Graph timed from first FFS event James N, et al. ASCO LBA5003 and Oral Abstract Session

44 Safety SOC-only SOC+AAP Safety population Patients included in adverse event analysis Grade 1-5 AE 950 (99%) 943 (99%) Grade 3-5 AE 315 (33%) 443 (47%) Grade 5 AE 3 9 Grade 3-5 AEs by category (incl. expected AEs) Endocrine disorder (incl. hot flashes, impotence) 133 (14%) 129 (14%) Cardiovascular disorder (incl. hypertension, MI, cardiac dysrhythmia): 41 (4%) 92 (10%) Musculoskeletal disorder: 46 (5%) 68 (7%) Gastrointestinal disorder: 40 (4%) 49 (5%) Hepatic disorder (incl. increased AST, increased ALT): 12 (1%) 70 (7%) General disorder (incl. fatigue, oedema): 29 (3%) 45 (5%) Respiratory disorder (incl. breathlessness): 23 (2%) 44 (5%) Lab abnormalities (incl. hypokalaemia): 21 (2%) 34 (4%) James N, et al. ASCO LBA5003 and Oral Abstract Session

45 Reasons for permanently stopping research abiraterone acetate+prednisolone Target duration to progression Disease progression (52%) Target duration 2 years Treatment complete (69%) Excessive toxicity (21%) Treatment refusal (6%) Comorbidity (6%) Excessive toxicity (17%) Treatment complete (5%) Other reasons <5%: Patient choice, clinician decision, intercurrent illness, death, administrative, withdrawal, ineligible. Note: 1% stopped for disease progression, 4% comorbidity, 3% treatment refusal James N, et al. ASCO LBA5003 and Oral Abstract Session

46 Conclusions- STAMPEDE Σε ασθενείς με ορμονοευαίσθητο καρκίνο προστάτη η προσθήκη abiraterone acetate + prednisolone βελτιώνει: Συνολική επιβίωση κατά 37% Διάστημα εκτός υποτροπής (Failure free survival) κατά 71% Συμπτωματικά σκελετικά συμβάματα κατά 55% Καλή ανοχή της θεραπείας James N, et al. ASCO LBA5003 and Oral Abstract Session

47 Patients without worst pain progression (%) Mean change from baseline in worst pain score (BPI-SF) ADT + AA + P Significantly Improved Pain 37% Risk Reduction for Worst Pain Progression Mean Change From Baseline Differed From Cycle 2 Onward ADT + AA + P, NR ADT + Placebos, NR 0.2 Worse Patients at risk ADT + AA + P ADT + Placebos HR 0.63 (95% CI, ) P < Months ADT + AA + P Cycle* ADT + Placebos Better *1 cycle = 28 days. Chi K, et al. Abstract 783O presented at ESMO 2017

48 Patients without worst fatigue progression (%) Mean change from baseline in worst fatigue score (BFI) ADT + AA + P Significantly Improved Fatigue 35% Risk Reduction for Worst Fatigue Progression Mean Change From Baseline Differed from Cycle 5 Onward ADT + AA + P, NR 0.2 Worse ADT + Placebos, NR Patients at risk ADT + AA + P ADT + Placebos HR 0.65 (95% CI, ) P = Months Cycle* ADT + AA + P ADT + Placebos Better *1 cycle = 28 days. Chi K, et al. Abstract 783O presented at ESMO 2017

49 Patients without degradation in FACT-P total score (%) FACT-P total score ADT + AA + P Significantly Improved HRQoL per FACT-P 15% Risk Reduction for HRQoL Degradation Mean Change From Baseline Differed from Cycle 5 Onward ADT + AA + P, 12.9 mo 0.2 Better 40 ADT + Placebos, 8.3 mo Patients at risk ADT + AA + P ADT + Placebos *1 cycle = 28 days. HR 0.85 (95% CI, ) P = Months Chi K, et al. Abstract 783O presented at ESMO Worse Cycle* ADT + AA + P ADT + Placebos

50 CHAARTED: Long term efficacy and QoL data Results: Secondary analysis QoL Docetaxel is associated with decreased QOL on treatment (at 3 mos.) not seen with ADT alone. However, at 12 mos. QoL was better for the patients who had docetaxel versus ADT alone, returning to baseline. Conclusion: The clinical benefit in patients who were prospectively defined and stratified as high volume was preserved with long term follow up in all measures of time to CRPC, clinical progression and OS and FACT-P at 12 months. The clinical benefit in patients who were prospectively defined and stratified as low volume was limited to only an improvement in time to CRPC (which was mostly PSA rise) but not clinical progression, OS or FACT-P at 12 months. The treatment burden for DOC as measured by FACT-T was similar for high volume and low volume. Overall, recognizing limitations of subgroup analyses, there is a clear clinical benefit to use of early DOC in high volume patients, which justifies the treatment burden of early DOC. The clinical benefit is not clearly defined in patients with low volume hormone naïve metastatic prostate cancer. Sweeney C, et al. Ann Oncol 2016;27(suppl 6):Abstract (and poster) 720PD.

51 Comparison of ADT+AA+P and ADT+DOC in mhspc Direct randomised comparison from STAMPEDE (Sydes et al.) Indirect comparisons (Feyerabend et al. and Vale et al.) Sydes M, et al. Abstract LBA31 presented at ESMO 2017; Feyerabend S, et al. Poster presented at ESMO Abstract 803P; Vale C, et al. Poster presented at ESMO Abstract LBA33

52 Patient populations STAMPEDE 1,2 M1 HSPC (with distant metastasis) Low volume High volume Locally advanced, M0 (No distant metastasis) LATITUDE 5,6 (Newly diagnosed, high-risk mhspc) HR and HV HR and LV Newly diagnosed Prior local tx CHAARTED 3 and GETUG-AFU15 4 HR = high risk; HV = high volume; mhspc = metastatic hormone sensitive prostate cancer; tx = treatment 1. James ND, et al. The Lancet. 2016;387: ; 2. James ND, et al. N Engl J Med Jul 27;377(4): ; 3. Sweeney C J et al. N Engl J Med. 2015;373(8):737 46; 4. Gravis G, et al. Lancet Oncol 2013; 14(2): ; 5. Fizazi K, et al. N Engl J Med Jul 27;377(4): ; 6. Feyerabend S, et al. Poster presented at ESMO Abstract 803P

53 STAMPEDE: ADT+AA+P vs ADT+DOC STAMPEDE ESMO 2017 Recruitment: Nov-2011 to Mar-2013 Reported: ESMO 2017 Published: (paper in development) Patients: 189 ADT+DOC 377 ADT+AA+P 566 patients randomised contemporaneously to either research arm AA+P = abiraterone acetate plus prednisone/prednisolone; ADT = androgen-deprivation therapy; DOC = docetaxel; SOC = standard of care (STAMPEDE terminology for ADT) Adapted from: Sydes M, et al. Abstract LBA31 presented at ESMO 2017

54 Feyerabend et al. Indirect comparison Naïve comparison is biased Comparing RELATIVE treatment effects (hazard ratio) Bayesian interpretation Kiefer C, et al. Dtsch Arztebl Int 2015; 112: 803 8

55 Feyerabend et al. Indirect comparison methods Adapted from: Feyerabend S, et al. Poster presented at ESMO Abstract 803P AA+P = abiraterone acetate plus prednisone/prednisolone; ADT = androgen-deprivation therapy; DOC = docetaxel 55

56 Progression-free survival FFS: M0 and M1 combined ADT+AA+P HR (95%CI) P-val All 0.65 (0.48 to 0.88) STAMPEDE Interact n test PFS = FFS ignoring PSA failure ADT+DOC M (0.17 to 1.05) 0.06 M (0.50 to 0.95) ADT+DOC ADT+AA+P Event Pts Events Pts s All Key: HR<1 favours ADT+AA+P HR>1 favours ADT+DOC Interact n = test for interaction (heterogeneity of treatment effect) M M AA+P = abiraterone acetate plus prednisone/prednisolone; ADT = androgen-deprivation therapy; DOC = docetaxel; FFS = failure-free survival; HR = hazard ratio; PFS = progression-free survival; PSA = prostate-specific antigen Adapted from: Sydes M, et al. Abstract LBA31 presented at ESMO 2017

57 STAMPEDE Overall survival [primary outcome measure] OS: M0 and M1 combined ADT + DOC ADT+AA+P HR (95%CI) P-val All 1.16 (0.82 to 1.65) 0.40 Interact n test M (0.58 to 3.93) 0.40 M (0.77 to 1.66) ADT+DOC ADT+AA+P Events Pts Events Pts All Key: HR<1 favours ADT+AA+P HR>1 favours ADT+DOC M M Interact n = test for interaction (heterogeneity of treatment effect) Adapted from: Sydes M, et al. Abstract LBA31 presented at ESMO 2017

58 STAMPEDE Failure-free survival Favours ADT+AA+P Favours ADT+DOC Head-to-head data in 566 pts (Nov-2011 to Mar-2013) Progression-free survival Metastatic progression-free survival Strong evidence favouring AA+P Weak evidence favouring AA+P Symptomatic skeletal events No good evidence of a difference Cause-specific survival Overall survival Proportionately different time spent in each disease state Hazard ratio Toxicity profiles quite different and well known AA+P = abiraterone acetate plus prednisone/prednisolone; ADT = androgen-deprivation therapy; DOC = docetaxel Adapted from: Sydes M, et al. Abstract LBA31 presented at ESMO 2017

59 Conclusions Απουσία head to head σύγκρισης (Bayesian network meta analysis) ADT+AA+P το ίδιο αποτελεσματική και ίσως καλύτερο από ADT+DOC στη μείωση του κινδύνου προόδου της νόσου και θανάτου από τη νόσο Περιορισμοί έμμεσης σύγκρισης: Μόνο 1 μελέτη έχει δεδομένα rpfs Οι πληθυσμοί των μελετών διαφορετικοί (CHAARTED, GETUG-AFU15 and STAMPEDE όχι ασθενείς με high risk disease)

60

61 Pattern of Spread in CRPC Associated With Prognosis Expected survival of men with lung metastases is similar to that of men with bone metastases Men with liver metastases have the poorest survival Node only men have the best survival Halabi S, et al. J Clin Oncol. 2016;34:

62 AR negative Neuroendocrine-like AR/PSA-low, p53 and RBdefective., Chromogranin A+, Synaptophysin+,NSRE+ Small-cell like (Anaplastic) Sharing clinical features with small-cell cancers AVPC MOLECULAR Combined tumor suppressor defects >2alterations in Tp53,RB1, and/or PTEN by IHC or genomic analyses PTEN Tp53 RB1 Beltran et al Clin Cancer Res 2014

63 Υψηλό Gleason Score (8-10) Οι αποφάσεις του κλινικού ιατρού για κάθε ασθενή χωριστά Βραχύς χρόνος διπλασιασμού του PSA (PSADT <4-6mo) Σπλαγχνικές μεταστάσεις Bulky λαμφαδενική νόσος >5cm Λυτικές οστικές μεταστάσεις Δυσανάλογο χαμηλό PSA για το φορτίο της νόσου Β συμπτωματολογία (πυρετός, απώλεια βάρους, νυχτερινοί ιδρώτες) Παραγωγή άλλων δεικτών (CEA, Ca125, NSE, Chromogranin A)

64 Radiology Guided Biopsy Optional Biopsy at Progression West Coast Prostate Cancer Dream Team Project and Trial Design Consortium of 6 academic medical centers, sought to identify adaptive pathways in metastatic abiraterone- and enzalutamide-resistant prostate cancer Every-3-Mo Clinical Assessment Metastatic CRPC Amenable to biopsy Progressive Disease: After novel AR targeted Rx Aggressive phenotype On a WCDT trial N = 300 Small EJ, et al. ASCO Abstract N = 300 Treatment(s) Serum, plasma, and blood for CTCs collected at baseline, 3 mos after therapy begins, and at progression

65 Biopsy: Histology Results 2% 1% 13% 1% 3% 2% Histology of 124 Evaluable Biopsies 26% 35% 51% 26% 13% 27% Bone (n = 89) Lymph node (n = 47) Liver (n = 22) Lung (n = 2) Adrenal (n = 3) Soft tissue (n = 6) Brain (n = 1) Bladder (n = 3) Mixed histology Intermediate atypical carcinoma* Pure adenocarcinoma Pure small-cell neuroendocrine cancer *Novel subtype of pure cell population distinct from adenocarcinoma and small-cell neuroendocrine cancer. Small EJ, et al. ASCO Abstract Reprinted with permission.

66 Survival Probability Intermediate Atypical Carcinoma: Survival OS by Histology Log-rank P = Adeno (NR) IAC (11.9 mos) SCNC (6.6 mos) Mos Pts with IAC have poor survival, similar to that seen in pts with SCNC and distinct from that seen in pts with adenocarcinoma (P =.041) 24 Small EJ, et al. ASCO Abstract Reprinted with permission.

67 Pathology Gleason Score Differentiation Neuroendocrine features Οι αποφάσεις του κλινικού ιατρού για κάθε ασθενή χωριστά TREATMENT Serology PSA ( vs ) CEA NSE CA125 LDH Clinical course Short PSA doubling time (< 4-6 mo) Site of metastases Type of Bone mets Presence of B symptoms

68 Σας ευχαριστώ πολύ!