Treatment of castration sensitive and resistance prostate cancer

Presentazione sul tema: "Treatment of castration sensitive and resistance prostate cancer"— Transcript della presentazione:

1 Treatment of castration sensitive and resistance prostate cancer
Daniele Santini Università Campus bio-Medico, Roma Napoli, 28 novembre, 2017

2 mHSPC

3 Dimensioni del problema

4 Tumore della prostata metastatico alla diagnosi
Incidenza1-5: ~3% negli USA, in incremento; ~6% in Europa ~4-10% in America Latina ~60% in Asia Storicamente, standard of care è sempre stata la terapia con deprivazione androgenica Narayanan S, et al. Nat Rev Urol. 2016;13:47-60, with permission from Nature Publishing Group. 1. Weiner AB, et al. Prostate Cancer Prostatic Dis. 2016;19: Buzzoni C, et al. Eur Urol. 2015;68: Chen R, et al. Asian J Urol. 2014;1: Ito K. Nat Rev Urol. 2014;11: Nardi AC. Int Braz J Urol. 2012;38:

5 Lo standard degli ultimi anni

6 ADT + docetaxel: nuovo standard dal 2015 nella malattia metastatica con alto volume
Overall Survival ADT + DOC ADT Median (mos) HR (95% CI) P Value GETUG-151 62.1 48.6 0.88 ( ) 0.3 CHAARTED2 57.6 47.2 0.73 ( ) 0.0018 STAMPEDE3 60 45 0.76 ( ) 0.005 1. Gravis G, et al. Eur Urol. 2016:70: Sweeney C, et al. N Engl J Med. 2015;373: ; Sweeney C, et al. Ann Oncol. 2016;27(Suppl 6): James N, et al. Lancet. 2016;387: and Vale C, et al. Lancet Oncol 2016;17: 6

7 Review sistematica e metanalisi
Trial name Overall STAMPEDE (SOC + ZA +/- DOC) STAMPEDE (SOC +/- DOC) GETUG 15 CHAARTED HR=0.77 (0.68, 0.87); P<0.0001 .5 1 2 Heterogeneity:2=4.80, df=3, P=0.187, I2=37.5% Favors SOC + DOC Favors SOC Risultati basati su 2,993 uomini / 1,254 decessi 10% di incremento assoluto della sopravvivenza (dal 40% al 50%) a 4 anni Vale CL et al. Lancet Oncol 2016;17:243-56

8 ADT + docetaxel: a chi? Alto volume, ormono-naive
Paziente giovane, fit In preferenza se metastasi alla diagnosi

9 ….Quest’anno (2017)

10 Questi sono i fatti HS alla M+ diagnosi
Latitude study N Engl J Med June 4 [Epub ahead of print] Stampede study N Engl J Med June 3 [Epub ahead of print]

11 Overall study design of LATITUDE
Patients Newly diagnosed adult men with high-risk mHNPC Stratification factors Presence of visceral disease (yes/no) ECOG PS (0, 1 vs 2) Efficacy end points Co-primary: OS rPFS Secondary: time to pain progression PSA progression next symptomatic skeletal event chemotherapy subsequent PC therapy 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) 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 Presented by: Karim Fizazi

12 38% Risk Reduction for Death
LATITUDE: Co-primary End Points 38% Risk Reduction for Death 53% Risk Reduction for rPFS 20 40 60 80 100 Radiographic progression-free survival (%) 4 8 12 16 24 28 32 36 Months 597 533 464 400 353 316 251 177 102 51 21 602 488 367 289 214 168 127 81 41 17 7 HR, 0.47 (95% CI, ) P < 0.001 ADT + AA + P, mo ADT + Placebos, 14.8 mo 10 30 50 70 90 Patients at risk ADT + AA + P ADT + Placebos 6 12 18 24 30 36 42 20 40 60 80 100 Months Overall survival (%) Patients at risk ADT + AA + P 597 565 529 479 388 233 93 9 602 564 504 432 332 172 57 2 HR, 0.62 (95% CI, ) P < 0.001 ADT + AA + P, NR ADT + Placebos, 34.7 mo ADT + Placebos 10 70 90 50 Figures included with permission, from Fizazi K, et al. N Engl J Med. 2017;377: CI, confidence interval; HR, hazard ratio; NR, not reached; rPFS, radiographic progression-free survival.

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

14 Statistically significant improvement in all secondary end points

15 Immagine ripulita da Office Lens

16 STAMPEDE Study Abiraterone plus prednisone comparison: M0 + M1 patients
James N, et al. ASCO LBA5003 and Oral Abstract Session

17 OS – STAMPEDE “abiraterone plus prednisone comparison”
Events 262 Control | 184 abiraterone plus prednisone SOC+AAP This represents a 37% improvement in survival HR 0.63 95% CI 0.52 to 0.76 P-value James N, et al. ASCO LBA5003 and Oral Abstract Session

18 … Qualità di vita?

19 Benefits of Abiraterone Acetate Plus Prednisone When Added to Androgen Deprivation Therapy in LATITUDE on Patient-Reported Outcomes K. N. Chi,1 A. Protheroe,2 A. Rodriguez-Antolin, G. Facchini,4 H. Suttman,5 N. Matsubara,6 Z. Ye,7 B. Keam,8 T. Li,9 K. McQuarrie,10 B. Jia,11 P. De Porre,12 J. Martin,13 M.B. Todd,14 and K. Fizazi15 1BC Cancer Agency, Vancouver, BC, Canada; 2Oxford University Hospitals NHS Foundation Trust, Oxford, UK; 312 de Octubre University Hospital, Madrid, Spain; 4Istituto Nazionale Tumori – I.R.C.C.S - Fondazione Pascale, Naples, Italy; 5Urologikum Hamburg, Hamburg, Germany; 6National Cancer Center Hospital East, Chiba, Japan; 7Tongji Hospital, Wuhan City, China; 8Seoul National University Hospital, Seoul, South Korea; 9Global Market Access Oncology, Janssen Global Services, Raritan, NJ, USA; 10PRO Team, Janssen Global Services, Raritan, NJ, USA; 11Janssen Research & Development, China; 12Clinical Oncology, Janssen Research & Development, Beerse, Belgium; 13Clinical Oncology, Janssen Research & Development, Buckinghamshire, UK; 14Oncology, Janssen Research & Development, Raritan, NJ, USA; 15Gustave Roussy, University of Paris Sud, Villejuif, France Chi KN et al.ESMO, 2017

20 ADT + AA + P Significantly Improved Fatigue Interference
41% Risk Reduction for Fatigue Interference Progression Mean Change From Baseline Differed from Cycle 5 Onward ADT + Placebos ADT + AA + P Cycle* 3 2 1 7 9 5 15 17 21 19 23 25 27 29 31 33 4 6 8 11 13 10 12 0.4 0.2 0.0 -0.2 -0.4 0.6 Worse Better BPI fatigue interference score Patients without fatigue interference progression (%) 597 602 487 424 399 274 321 186 238 122 131 57 50 15 1 6 HR 0.59 (95% CI, ) P < 12 18 24 30 36 42 ADT + AA + P, NR ADT + Placebos, NR Months 100 80 60 20 40 2 Patients at risk ADT + AA + P ADT + Placebos *1 cycle = 28 days.

21 ADT + AA + P Significantly Improved Pain
PRO: statistically significant and clinically relevant benefits ADT + AA + P Significantly Improved Pain 37% Risk Reduction for Worst Pain Progression Mean Change From Baseline Differed From Cycle 2 Onward 597 602 456 387 356 246 299 162 218 99 115 44 47 10 2 1 Months 6 ADT + Placebos, NR ADT + AA + P, NR 12 18 24 30 36 42 Patients without worst pain progression (%) HR 0.63 (95% CI, ) P < 100 80 60 20 40 Patients at risk ADT + AA + P ADT + Placebos 13 10 8 6 1 2 4 7 Mean change from baseline in worst pain score (BPI-SF) 0.6 0.4 0.2 0.0 -0.2 -0.4 3 5 9 12 ADT + Placebos ADT + AA + P 15 17 21 19 23 25 Cycle* 27 29 31 33 11 Worse Better Patients with metastatic prostate cancer frequently experience negative effects on quality of life that are both disease- and treatment-related1-6 It is important to delay disease progression and extend survival without increasing the symptom burde An understanding of the impact of new therapies from the perspective of the patient experience is needed This analysis was performed to explore health-related quality of life (QoL) differences between ADT + AA + P and ADT + P *1 cycle = 28 days. Chi K, et al. Abstract 783O presented at ESMO 2017

22 Docetaxel o Abiraterone?

23 Wallis, Eur J Urol 2017

24 Abiraterone versus Docetaxel….
vs. ADT alone vs. ADT+DOC LATITUDE (NDx HR mHSPC)1 STAMPEDE (M1)2 Presented at ESMO ADT+AA+P ADT + placebos ADT+AA+P ADT OS HR, 0.61 (95% CI, 0.49 to 0.75) LATITUDE (rPFS, NDx HR mHSPC)1 STAMPEDE (FFS, M1)2 Presented at ESMO ADT+AA+P ADT + placebos ADT+AA+P ADT PFS HR, 0.31 (95% CI, 0.26 to 0.37) 1. Fizazi K, et al. N Engl J Med Jul 27;377(4): ; 2. James et al. N Engl J Med Jul 27;377(4): ; 3. Sydes M, et al. Abstract LBA31 presented at ESMO 2017; 4. Feyerabend S, et al. Poster presented at ESMO Abstract 803P; Vale C, et al. Poster presented at ESMO Abstract LBA33

25 STAMPEDE: CONFRONTO DIRETTO ADT+AA+P vs ADT+DOC
ESMO 2017 Underpowered but the only head-to-head data. Not claiming these data are definitive but they will be helpful in discussions 566 pazienti randomizzati contemporaneamente in ciascuno dei due bracci di trattamento Pazienti: 189 ADT+DOC 377 ADT+AA+P Adapted from: Sydes M, et al. Abstract LBA31 presented at ESMO 2017 Adapted from: Sydes M, et al. Abstract LBA31 presented at ESMO 2017

26 Head-to-head data in 566 pts (Nov-2011 to Mar-2013)
STAMPEDE Favours ADT+AA+P Favours ADT+DOC Failure-free survival Head-to-head data in 566 pts (Nov-2011 to Mar-2013) Progression-free survival Strong evidence favouring AA+P Metastatic progression-free survival Weak evidence favouring AA+P Symptomatic skeletal events No good evidence of a difference Cause-specific survival  Proportionately different time spent in each disease state Survival similar which means spending time in proportionately different disease states Overall survival Hazard ratio Toxicity profiles quite different and well known Sydes M, et al. Abstract LBA31 presented at ESMO 2017

27 Quindi presto nel nostro ambulatorio

28 ADT + Abiraterone: a chi?
Alto volume, ormono-naive Paziente giovane, ma anche anziano, fit ma anche non fit per docetaxel In preferenza se metastasi alla diagnosi

29 …. E quando vedremo i primo pazienti in progressione?

30 o RADIUM 223 (solo osseo e unfit CT) ABIRATERONE/ENZALUTAMIDE
…. nel paziente che progredisce post-docetaxel nel setting HSPC? SCENARIO 1 Paziente CRPC con alto carico asintomatico o poco sintomatico e lunga durata ormonosensibilità (> 18 mesi) ADT + DOCETAXEL ABI/ENZA CABAZITAXEL RADIUM 223 SCENARIO 2 Paziente CRCP con alto carico sintomatico o progressione in sede viscerale o con breve risposta all’ADT (<18 mesi) CABAZITAXEL o RADIUM (solo osseo e unfit CT) ADT + DOCETAXEL ABIRATERONE/ENZALUTAMIDE

31 ….e nel paziente che progredisce post-abiraterone nel setting HSPC?
SCENARIO 1 Paziente CRPC con alto carico asintomatico o poco sintomatico o lunga durata ormonosensibilità ADT + ABI DOCETAXEL CABAZITAXEL O RADIUM 223 (solo osso) ENZALUTAMIDE SCENARIO 2 Paziente CRCP con alto carico sintomatico e/o con breve risposta all’ADT ADT + ABI DOCETAXEL o RADIUM 223 (solo osso) CABAZITAXEL ENZALUTAMIDE

32 mCRPC

33 Potential clinical settings in mCRPC
ADT Doce How to move on PD Abi / Enza Docetaxel PD Docetaxel PD

34 How to choose the first line The “drop off phenomenon”

35 Remember the “Drop off phenomenon”
FIRSTANA Docetaxel – 1 Line Post Doc treatment: drop off 23% Oudard et al. JCO 2017 COU AA 302 – 1 Line drop off 33% Post AA treatment: 67% Docetaxel 48% of ITT AA 2,4%, Enza 3,7%, Keto 6,6 % of ITT Ryan CJ et al. Lancet Oncol 2015

36 Drop off in daily clinical practice
Analisi Q – Property of

37 How to choose the first line The “ARTA primary refractoriness”

38 How to identify primary ARTA refractory patients?
Short duration of ADT period? Rapid and symptomatic progression of disease? Visceral metastases? Lack of early PSA response during ARTA? (Attention to dissociation between radiologic and PSA! ) ! Even without clinical signs of progression…. Do not restaging before 3 months but not after !

39 How to choose the first line The “ARTA cross resistance”

40 Cross-Resistance Between AR-Targeted Agents
Poor response to Enza if progression on Abi Poor response to Abi if progression on Enza NICE (UK) does not permit the use of sequential ART if there is progression on first ART

41 The skeletal effects of abiraterone and enzalutamide

42 Docetaxel IS NOT able to resensitize ormonal resistant tumors
1 HT - 2 HT: PSA response 1 HT: PSA response 1 HT- CT- 2 HT PSA response Miyake et al. Clinical Genitourinary Cancer 2017

43 How to choose the first line The “docetaxel rechallenge phenomenon””

44 GETUG 15 in mHSPC Low activity of docetaxel after progression
PFS with DOC in mCRPC Docetaxel PSA response after progression Modest PSA response and PFS in patients initially treated with ADT + DOC and rechallenged with DOC at disease progression ADT + DOC arm ADT arm LHRH: luteinizing hormone-releasing hormone; PFS: progression-free survival; PSA: prostate-specific antigen Lavaud P et al. J Clin Oncol 2016;34(suppl):abstract 5080

45 How to choose the first line The “right sequence phenomenon”

46 Systematic Review of 13 Studies
US Daily Clinical Practice Sonpavde et al. Clinical Genitourinary Cancer 2015 Maines et al. Critical Reviews in Oncology/Hematology 2015 Flac Study Delanoy N et al. Poster A267 ASCO GU 2017

47 Dato un paziente mCRPC con
specifiche caratteristiche (iniziali), è possibile pianificare una sequenza prestabilita? E’ un approccio artificioso, non rispecchia la pratica quotidiana Non tiene conto dell’evoluzione della malattia (sede e carico di malattia; aggressività biologica) nel tempo Non tiene conto dell’evoluzione delle condizioni del paziente (sintomi, PS, comorbidità) nel tempo Non tiene conto dei possibili cambiamenti (mutazioni, resistenze, ecc.) indotti dai vari trattamenti in sequenza Courtesy by my Friend G. Pappagallo

48 …. Insomma alla fine lunedi in ambulatorio Possiamo basarci su un algoritmo terapeutico?

49 Algoritmo potenziale mCRPC nel patiente in progressione con ADT
SCENARIO 1 mCRPC asintomatico o poco sintomatico e malattia non aggressiva dopo ADT standard (>12 mesi) ADT ABI/ENZA DOCETAXEL CABAZITAXEL ABI/ENZA SCENARIO 2 mCRPC sintomatico dopo ADT standard o breve durata ADT Sipuleucel-T approvazione EMA (Provenge) Settembre 2013 Cabazitaxel approvazione AIFA (Jevtana) Dicembre 2011 indicaz. Solo Nel post CHT Abiraterone approvazione AIFA (Zytiga) Marzo 2013 nel post-CHT approvazione EMA Gennaio 2013 pre-cht Pubblicazione determina in G.U settembre 2014 Enzalutamide approvazione EMA (Xtandi)nel Post-CHT giugno 2013. AIFA ottobre classe C(nn) Orteronel Giugno 2014 Takeda annuncia stop sviluppo farmaco sperimentale orteronel Alpharadin approvazione EMA (Xofigo) Novembre 2013 AIFA Gennaio 2014 classe C(nn) DOCETAXEL o RADIUM 223 (solo se unfit) CABAZITAXEL (se progressione sintomatica/breve durata docetaxel) ABI/ENZA ADT

50 Grazie per la Vostra Attenzione