«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
Disclosures Honoraria: Sanofi, Janssen Advisory: Pfizer, Leo, Roche
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
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
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
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
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
Survival in metastatic prostate cancer We are making progresses 1990s 2004 2010 2011 2013 2014 2015 2016 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 9-10 1. Kantoff PW. J Clin Oncol 1999;7:2506-13; 2. Tannock IF. NEJM 2004;351:1502-12; 3. De Bono JS. Lancet 2010;376:1147-54; 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: 152 60; 7. Beer TM. Eur Urol. 2017;71:151-154; 7. Sweeney C. NEJM 2015;373:737-46; 8. James ND Lancet 2016;387:1163-77; 9. Fizazi K. NEJM 2017; 377:352-60; 10. James ND. NEJM 2017; 377: 338-51
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
The hope ADT AR-independent clones AR-dependent cells SAEU.CAB.15.10.0092 (Nov 2015) AR: androgen receptor Sweeney C et al. J Clin Oncol 2014;32(5S):abstract LBA2 (podium presentation)
Hit first hit hard
Phase III Randomized Trials in Metastatic Hormone-Sensitive PCa CHAARTED 1-2 (N=790) GETUG 15 2-4 (N=385) STAMPEDE 2-5 Inclusion period 2006-2012 2004-2008 2005-2013 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 6 9 6 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 15 1. Sweeney CJ et al. N Engl J Med 2015;373:737-46; 2. Gravis G et al. Cancer Treat Rev 2016; doi: 10.1016/j.ctrv.2016.09.008; 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;387:1163-77
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 2017. LBA5003 and Oral Abstract Session Attard G, et al J Clin Oncol. 2008;26(28):4563-71. de Bono JS, et al NEJM 2011;364(21):1995-2005. Ryan CJ, et al, NEJM. 2013;368(2):138-48.
Abiraterone plus Prednisone in Metastatic, Castration- Sensitive Prostate Cancer N Engl J Med. 2017 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
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
Demographics and Baseline Disease Characteristics Age (yr), n (%) < 65 65 69 70 74 75 Median (range) Gleason score at initial diagnosis, n (%) < 7 7 8 Baseline pain score (BPI-SF Item 3), n (%) 0 1 2 3 4 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 8 + 3 bone lesions Gleason score 8 + measurable visceral disease 3 bone lesions + measurable visceral disease Gleason score 8 + 3 bone lesions + measurable visceral disease 597 573 (96) 82 (14) 84 (14) 71 (12) 601 569 (95) 87 (14) 85 (14) 70 (12) 16
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
Overall Survival by Subgroup The treatment effect of ADT-abiraterone-prednisone on OS was consistently favorable across nearly all prespecified subgroups 18
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
Radiographic Progression-free Survival by Subgroup The treatment effect of ADT-abiraterone-prednisone on rpfs was consistently favorable across nearly all prespecified subgroups 20
Time to Pain Progression A statistically significant 30% risk reduction of time to pain progression was observed in patients treated with ADT-abirateroneprednisone 21
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
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
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
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
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-223 11 (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-223 26
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 37 20 0 22 10 0.2 Hypokalemia 20 10 0.8 4 1 0.2 ALT increased 16 5 0.3 13 1 0 Hyperglycemia 13 4 0.2 11 3 0 AST increased 15 4 0.2 11 1 0 Bone pain 12 3 0 15 3 0 Cardiac disorder Atrial fibrillation 12 1 3 0.3 Anemia 9 2 0.5 14 4 0.2 Back pain 18 2 0 20 3 0 Fatigue 13 2 0 14 2 0 Spinal cord compression 2 2 0 2 1 0.5 0.8 0 8 0.3 1 0.2 0 0 27
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
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 www.stampedetrial.org James N, et al. ASCO 2017. LBA5003 and Oral Abstract Session
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 2017. LBA5003 and Oral Abstract Session
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
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 2017. LBA5003 and Oral Abstract Session 32
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 2017. LBA5003 and Oral Abstract Session 33
OS STAMPEDE abiraterone plus prednisone comparison Events 262 Control 184 abiraterone plus prednisone SOC+AAP This represents a 37% improvement in survival SOC HR 0.63 95% CI 0.52 to 0.76 P-value 0.00000115 James N, et al. ASCO 2017. LBA5003 and Oral Abstract Session
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 44/455 218/502 34/460 150/500 0.37 0.75 (0.48, 1.18) 0.61 (0.49, 0.75) Nodal status N0 N+ NX 83/438 164/483 15/36 61/434 113/484 10/42 0.8 0.69 (0.49, 0.96) 0.61 (0.48, 0.77) 0.68 (0.29, 1.57) Gleason Sum Score (cats) <=7 8-10 unknown 40/223 216/721 6/13 33/221 144/715 7/24 0.57 0.76 (0.48, 1.23) 0.59 (0.48, 0.73) 0.47 (0.11, 1.91) Age at randomisation (cats) Under 70 70 or over 180/596 82/361 110/603 74/357 0.0026 0.51 (0.40, 0.65) 0.94 (0.69, 1.29) WHO PS 0 vs 1-2 0 1-2 182/744 80/213 137/745 47/215 0.11 0.69 (0.56, 0.87) 0.50 (0.35, 0.72) NSAID/Aspirin use No use Uses either 191/718 71/239 132/714 52/246 0.35 0.59 (0.47, 0.74) 0.71 (0.50, 1.02) Is radiotherapy planned? No RT planned RT planned 226/561 36/396 160/564 24/396 0.89 0.63 (0.51, 0.77) 0.64 (0.38, 1.08) Recurrent disease No Yes 254/919 8/38 171/900 13/60 0.19 0.61 (0.50, 0.74) 0.94 (0.35, 2.52) Time period (co-recruiting arms) ABC-E-G--- 122/328 ABC-E-GH-- 17/49 A-----GH-- 123/580 95/330 10/47 79/583 0.62 0.69 (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 2017. LBA5003 and Oral Abstract Session.2.4.6.8 1 1.2 1.4 Favours: abiraterone SOC-only
FFS STAMPEDE AA comparison Events 535 Control 248 abiraterone plus prednisone SOC+AAP This represents a 71% improvement in time to failure SOC HR 0.29 95% CI 0.25 to 0.34 P-value 0.377x10-61 James N, et al. ASCO 2017. LBA5003 and Oral Abstract Session
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 142/455 393/502 38/460 210/500 0.085 0.21 (0.15, 0.31) 0.31 (0.26, 0.37) Nodal status N0 N+ NX 184/438 323/483 28/36 69/434 160/484 19/42 0.35 0.26 (0.20, 0.35) 0.29 (0.24, 0.36) 0.44 (0.24, 0.80) Gleason Sum Score (cats) <=7 8-10 unknown 107/223 417/721 11/13 40/221 199/715 9/24 0.73 0.26 (0.18, 0.38) 0.29 (0.25, 0.35) 0.15 (0.05, 0.48) Age at randomisation (cats) Under 70 70 or over 361/596 174/361 165/603 83/357 0.042 0.26 (0.22, 0.32) 0.36 (0.28, 0.47) WHO PS 0 vs 1-2 0 1-2 402/744 133/213 190/745 58/215 0.25 0.30 (0.25, 0.36) 0.25 (0.18, 0.34) NSAID/Aspirin use No use Uses either 394/718 141/239 179/714 69/246 0.29 0.27 (0.23, 0.32) 0.33 (0.25, 0.45) Is radiotherapy planned? No RT planned RT planned 425/561 110/396 224/564 24/396 0.023 0.31 (0.26, 0.36) 0.18 (0.12, 0.28) Recurrent disease No Yes 514/919 21/38 233/900 15/60 0.49 0.29 (0.25, 0.34) 0.32 (0.16, 0.65) Time period (co-recruiting arms) ABC-E-G--- 214/328 ABC-E-GH-- 31/49 A-----GH-- 290/580 110/330 12/47 126/583 0.34 0.33 (0.26, 0.41) 0.21 (0.11, 0.43) 0.27 (0.22, 0.34) Overall 0.29 (0.25, 0.34).2.4.6.8 1 1.21.4 Favours: abiraterone SOC-only James N, et al. ASCO 2017. LBA5003 and Oral Abstract Session
Secondary Outcomes Skeletal-related events James N, et al. ASCO 2017. LBA5003 and Oral Abstract Session
Skeletal related outcomes All patients Events 203 Control 113 abiraterone plus prednisone SOC+AAP SOC HR 0.46 95% CI 0.37 to 0.58 P-value 0.00000000000169 James N, et al. ASCO 2017. LBA5003 and Oral Abstract Session
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 0.45 95% CI 0.36 to 0.58 James N, et al. ASCO 2017. LBA5003 and Oral Abstract Session
Treatment for progression Treatment started since first progression A SOC G SOC+abi Patients randomised 957 960 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-223 24 (5%) 19 (8%) Cabazitaxel 28 (5%) 15 (6%) James N, et al. ASCO 2017. LBA5003 and Oral Abstract Session
Any life-prolonging treatment for progression Treatment started since first progression A SOC G SOC+abi SOC+AAP SOC Patients randomised 957 960 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-223 24 (5%) 19 (8%) Cabazitaxel 28 (5%) 15 (6%) Graph timed from first FFS event James N, et al. ASCO 2017. LBA5003 and Oral Abstract Session
Docetaxel SOC+AAP Treatment started since first progression A SOC G SOC+abi Patients randomised 957 960 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-223 24 (5%) 19 (8%) Cabazitaxel 28 (5%) 15 (6%) SOC SOC+AAP Graph timed from first FFS event James N, et al. ASCO 2017. LBA5003 and Oral Abstract Session
Safety SOC-only SOC+AAP Safety population Patients included in adverse event analysis 960 948 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 2017. LBA5003 and Oral Abstract Session
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 2017. LBA5003 and Oral Abstract Session
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 2017. LBA5003 and Oral Abstract Session
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 100 0.6 80 ADT + AA + P, NR 0.4 60 ADT + Placebos, NR 0.2 Worse 40 0.0 20 0 Patients at risk ADT + AA + P ADT + Placebos HR 0.63 (95% CI, 0.52-0.77) P < 0.0001 0 597 602 6 456 387 12 18 24 30 36 42 Months 356 246 299 162 218 99 115 44 47 10 2 1-0.2-0.4 0 1 2 3 4 5 6 7 8 9 10111213 ADT + AA + P 15 17 19 21 23 25 Cycle* ADT + Placebos 27 29 31 33 Better *1 cycle = 28 days. Chi K, et al. Abstract 783O presented at ESMO 2017
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 100 0.4 80 ADT + AA + P, NR 0.2 Worse 60 40 ADT + Placebos, NR 0.0 20 0 Patients at risk ADT + AA + P ADT + Placebos HR 0.65 (95% CI, 0.53-0.81) P = 0.0001 0 597 602 6 12 18 24 30 36 42 Months 465 407 372 259 305 171 216 118 106 46 44 14 2 1-0.2-0.4 0 1 2 3 4 5 6 7 8 9 10111213 15 17 19 21 23 25 27 29 31 33 Cycle* ADT + AA + P ADT + Placebos Better *1 cycle = 28 days. Chi K, et al. Abstract 783O presented at ESMO 2017
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 0.6 100 0.4 80 60 ADT + AA + P, 12.9 mo 0.2 Better 40 ADT + Placebos, 8.3 mo 0.0 20 0 Patients at risk ADT + AA + P ADT + Placebos 597 602 *1 cycle = 28 days. HR 0.85 (95% CI, 0.74-0.99) P = 0.0322 0 6 12 18 24 30 36 42 Months 338 309 250 192 202 119 135 77 Chi K, et al. Abstract 783O presented at ESMO 2017 65 33 20 7 0 0-0.2 Worse -0.4 0 1 2 3 4 5 6 7 8 910111213 15 17 19 21 23 25 27 29 31 33 Cycle* ADT + AA + P ADT + Placebos
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.
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 2017. Abstract 803P; Vale C, et al. Poster presented at ESMO 2017. Abstract LBA33
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;387:1163-1177; 2. James ND, et al. N Engl J Med. 2017 Jul 27;377(4):338-351; 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): 149 158; 5. Fizazi K, et al. N Engl J Med. 2017 Jul 27;377(4):352-360; 6. Feyerabend S, et al. Poster presented at ESMO 2017. Abstract 803P
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
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
Feyerabend et al. Indirect comparison methods Adapted from: Feyerabend S, et al. Poster presented at ESMO 2017. Abstract 803P AA+P = abiraterone acetate plus prednisone/prednisolone; ADT = androgen-deprivation therapy; DOC = docetaxel 55
Progression-free survival FFS: M0 and M1 combined ADT+AA+P HR (95%CI) P-val All 0.65 (0.48 to 0.88) 0.005 STAMPEDE Interact n test PFS = FFS ignoring PSA failure ADT+DOC M0 0.42 (0.17 to 1.05) 0.06 M1 0.69 (0.50 to 0.95) 0.02 0.32 ADT+DOC ADT+AA+P Event Pts Events Pts s All 72 189 103 377 Key: HR<1 favours ADT+AA+P HR>1 favours ADT+DOC Interact n = test for interaction (heterogeneity of treatment effect) M0 10 74 9 150 M1 62 115 94 227 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
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 M0 1.51 (0.58 to 3.93) 0.40 M1 1.13 (0.77 to 1.66) 0.53 0.69 ADT+DOC ADT+AA+P Events Pts Events Pts All 44 189 105 377 Key: HR<1 favours ADT+AA+P HR>1 favours ADT+DOC M0 6 74 16 150 M1 38 115 89 227 Interact n = test for interaction (heterogeneity of treatment effect) Adapted from: Sydes M, et al. Abstract LBA31 presented at ESMO 2017
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
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)
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;34:1652-1659.
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
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)
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 2015. Abstract 5003.. N = 300 Treatment(s) Serum, plasma, and blood for CTCs collected at baseline, 3 mos after therapy begins, and at progression
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 2015. Abstract 5003. Reprinted with permission.
Survival Probability Intermediate Atypical Carcinoma: Survival 1.0 0.8 0.6 OS by Histology Log-rank P =.041 0.4 0.2 0 Adeno (NR) IAC (11.9 mos) SCNC (6.6 mos) 0 2 4 6 8 10 12 14 16 18 20 22 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 2015. Abstract 5003. Reprinted with permission.
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
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