L’algoritmo terapeutico nella neoplasia della prostata
Tumore della prostata metastatico alla diagnosi
• Incidenza
1-5:
– ~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
1. Weiner AB, et al. Prostate Cancer Prostatic Dis. 2016;19:395-397. 2. Buzzoni C, et al. Eur Urol. 2015;68:885- 890. 3. Chen R, et al. Asian J Urol. 2014;1:15-29. 4. Ito K. Nat Rev Urol. 2014;11:15-29. 5. Nardi AC. Int Braz J Urol. 2012;38:155-166.
Narayanan S, et al. Nat Rev Urol. 2016;13:47-60, with permission from Nature Publishing Group.
Matteo Santoni – L’algoritmo terapeutico nella neoplasia della prostata
Come scegliere la miglior sequenza?
Sequenza terapeutica: Settings
Metastatic HSPC
M0 CRCP
Metastatic CRPC
Elderly patients
Metastatic HSPC
ADT + docetaxel: nuovo standard dal 2015 nella malattia metastatica con alto volume
1. Gravis G, et al. Eur Urol. 2016:70:256-262. 2. Sweeney C, et al. N Engl J Med. 2015;373:737-746; Sweeney C, et al. Ann Oncol.
2016;27(Suppl 6):243-265. 3. James N, et al. Lancet. 2016;387:1163-1177. and Vale C, et al. Lancet Oncol 2016;17:243-256.
62.1 48.6 0.88 (0.68-
1.14) 0.3 57.6 47.2 0.73 (0.59-
0.89) 0.0018 60 45 0.76 (0.62-
0.92) 0.005 ADT +
DOC ADT
Median (mos)
Median
(mos) HR (95% CI) P Value GETUG-15
1CHAARTED
2STAMPEDE
3Overall
Survival
• Risultati basati su 2,993 uomini / 1,254 decessi
10% di incremento assoluto della sopravvivenza (dal 40% al 50%) a 4 anni
Review sistematica e metanalisi
Vale CL et al. Lancet Oncol 2016;17:243-56
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
Alto volume, ormono-naive
Paziente giovane, fit per docetaxel trisettimanale
Con o senza metastasi viscerali alla diagnosi
Sintomatico?
Gleason 10 (5+5)?
ADT + docetaxel: a chi?
CABAZITAXEL
…. 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 RADIUM 223
SCENARIO 2
Paziente CRCP con alto carico sintomatico o progressione in sede viscerale o con breve risposta all’ADT (<18 mesi)
ABIRATERONE/ENZALUTAMI DE
CABAZITAXEL o RADIUM 223
(solo osseo e unfit CT) ADT
+ DOCETAXEL
Latitude study
N Engl J Med. 2017 June 4 [Epub ahead of print]
Stampede study
N Engl J Med. 2017 June 3 [Epub ahead of print]
Questi sono i fatti HS alla M+ diagnosi
ADT alone
ADT+AA+P
In LATITUDE and STAMPEDE addition of AA+P to ADT significantly improved OS
1. Fizazi K, et al. N Engl J Med. 2017 Jul 27;377(4):352-360; 2. James N, et al. ASCO 2017. LBA5003 and Oral Abstract Session; 3. James N, et al. N Engl J Med. 2017 Jul 27;377(4):338-351
LATITUDE1
• STAMPEDE: 39% reduction in the risk of death in patients with mHSPC
Hazard ratio, 0.61 (95% CI 0.49- 0.75)
STAMPEDE - M1 Disease2,3
• LATITUDE: 38% reduction in the risk of death in patients with NDx HR mHSPC
In LATITUDE and STAMPEDE addition of AA+P to ADT significantly delayed progression
1. Fizazi K, et al. N Engl J Med. 2017 Jul 27;377(4):352-360; 2. James N, et al. ASCO 2017. LBA5003 and Oral Abstract Session; 3. James N, et al. N Engl J Med. 2017 Jul 27;377(4):338-351
LATITUDE - rPFS1
• STAMPEDE: 69% reduction in the risk of FFS in patients with mHSPC
Hazard ratio, 0.40 (95% CI 0.34-0.47)
P<0.001
STAMPEDE – FFS 2,3
ADT alone ADT+AA+P
• LATITUDE: 53% reduction in the risk of radiographic
progression or death in patients with NDx HR mHSPC
• Riduzione del rischio di morte del 36% nel braccio ABI
• Mediana OS non raggiunta nel braccio ABI vs 36.7 mesi nel braccio ADT
• Piu’ del 50% dei pazienti ancora in vita a 41.4 mesi di mediana di follow up
FOLLOW UP MEDIANO 41.4 MESI
Fizazi K. et al, Poster presented at ASCO 2018, abstact 5023
Studies comparing AA+P+ADT with Doce+ADT in mHSPC – HRQoL/FACT-P
Feyerabend S, et al. Poster presented at ASCO-GU 2018; abstract 200.
HRQoL: ITC study showed Bayesian probabilities of AA + P +
ADT being better than Doc + ADT for FACT-P ranging from
92.3% to 99.7%.
Studies comparing AA+P+ADT with Doce+ADT in mHSPC – Pain/BPI
Feyerabend S, et al. Poster presented at ASCO-GU 2018;
abstract 200.
Pain: ITC study showed Bayesian probabilities of AA + P + ADT being better than Doc + ADT for BPI ranging between
88.0% and 100%.
STAMPEDE: CONFRONTO DIRETTO ADT+AA+P vs ADT+DOC
ESMO 2017
Pazienti: 189 ADT+DOC
377 ADT+AA+P
566 pazienti randomizzati contemporaneamente in ciascuno dei due bracci di
trattamento
STAMPEDE
al. Abstract LBA31 presented at ESMO 2017 Adapted from: Sydes M, et al. Abstract LBA31 presented at ESMO 2017
Strong evidence favouring AA+P
Toxicity profiles quite different and well known
Weak evidence favouring AA+P No good evidence of a difference
Favours ADT+AA+P
Favours ADT+DOC
Hazard ratio Metastatic
progression-free survival Progression-free
survival Failure-free survival
Symptomatic skeletal events
Cause-specific survival
Overall survival
Head-to-head data in 566 pts
(Nov-2011 to Mar-2013)
Proportionately different time spent in each disease state
STAMPEDE
Sydes M, et al. Abstract LBA31 presented at ESMO 2017
Alto volume, ormono-naive
Paziente giovane, ma anche anziano, fit ma anche non fit per docetaxel trisettimanale
Con o senza metastasi viscerali alla diagnosi
ADT + Abiraterone: a chi?
….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
ENZALUTAMIDE
DOCETAXEL Non dati con
ENZA
CABAZITAXEL O RADIUM 223
(solo osso)
SCENARIO 2
Paziente CRCP con alto carico sintomatico e/o con breve risposta all’ADT
CABAZITAXEL
DOCETAXEL o RADIUM 223 (solo osso e unfit
per CT) ADT
+ ABI
ENZALUTAMIDE
M0 CRPC
Ongoing Discontinued
and subsequent therapy Discontinued
without subsequent
therapy
61%
19%
20%
Possibilità di ricevere trattamenti successivi con apalutamide?
Primary Endpoint: MFS
Presented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
Ongoing Discontinued
and subsequent
therapy Discontinued
without subsequent
therapy 17%
15% 68%
Possibilità di ricevere trattamenti successivi con enzalutamide?
Metastatic CRPC
48%
20%
0%
20%
40%
60%
80%
100%
1° line 2° line 3°line
% Drop Off Italy
Italy
Drop off in daily clinical practice
20%0%
40%60%
100%80%
1°
line 2°
line 3°
line
% Drop Off USA
USA
20%0%
40%60%
100%80%
1° line2° line3° line
% Drop Off Germany
German y
20%0%
40%60%
100%80%
1°
line 2°
line 3°
line
% Drop Off Spain
Spain
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
Phase 2 randomized cross-over trial of abiraterone vs enzalutamide for patients with mCPRC: Results for 2nd-line therapy. D Khalaf (Abs 5015)
D Khalaf ASCO, 2018
Phase 2 randomized cross-over trial of abiraterone vs enzalutamide for patients with mCPRC: Results for 2nd-line therapy. D Khalaf (Abs 5015)
Despite a PSA reduction of 31% for abiraterone followed by enzalutamide,
median time to PSA progression was relatively limited (2.7 months), suggesting
back to back AR-targeted agents may not be clinically useful
Compliance
Compliance
Remember the “Drop off phenomenon”
FIRSTANA Docetaxel – 1 Line
Post Doc treatment: drop off 23%
Oudard et al. JCO 2017
Ryan CJ et al. Lancet Oncol 2015
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
Systematic Review of 13 Studies
Sonpavde et al. Clinical Genitourinary Cancer 2015
Delanoy N et al. Poster A267 ASCO GU 2017
US Daily Clinical Practice
Flac Study
Maines et al. Critical Reviews in Oncology/Hematology 2015
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
ADT DOCETAXEL o RADIUM 223 (solo se unfit)
CABAZITAXEL (se progressione sintomatica/breve
durata docetaxel)
ABI/ENZA
