Focus sulla malattia resistente alla castrazione (CRPC )
Trattamento della malattia CRPC metastatica (M+)
Chemioterapia
Giacomo Cartenì
Direttore U.O.S.C. di Oncologia Medica Responsabile del Centro di Riferimento Oncologico Regionale Polispecialistico A.O. A. Cardarelli Napoli
AIOM
Campagna Nazionale importanza chemioterapia
mHDPC mCRPC
HDPC - HSPC DCT sensitive mCRPC DCT Refractory mCRPC
mCRPC
Cabazitaxel Enzalutamide
Zoledronic Acid ?
Alpharadin
± AWS ADT
Mitox. + Pdn Abiraterone Wait & See ?
Docetaxel Abiraterone
Abiraterone
Docetaxel
DCT
Rechallenge
Denosumab ?
Asymptomatic:
- W&S or AA/Enz.
Bone Symptoms:
- DCT
Visceral Mets:
DCT
Enzalutamide
Enzalutamide
Docetaxel
Why Chemoterapy Should be Given
Early in Metastatic Prostate Cancer?
Histologic heterogeneity of prostate cancer
Arora R, et al. Cancer 2004; 100:2362-6
Molecular heterogeneity in CRPC
Gundem G, et al. Nature 2015;520(7547):353-7 4
Natural History of Prostate Cancer
Typical patient presentation as they move through different stages
Under the care of ONCOLOGIST Under UROLOGIST care
Nonmetastatic Metastatic
Local therapy
Androgen deprivation
Therapies after LHRH agonists
and antiandrogens
First-line therapy
Salvage therapy
Death Under ONCOLOGIST care
Burden of disease
Asymptomatic Symptomatic
Castrate sensitive Castrate resistant Castrate sensitive
Castrate resistant
= Neuroendocrine-like cells
Docetaxel
Indicazione terapeutica
• Pazienti asintomatici o sintomatici
• Pazienti malattia ossea e/o viscerale
Docetaxel 75 mg/m2 q3 wks + Prednisone 5 mg bid
Docetaxel 30 mg/m2 wkly 5 of 6 wks + Prednisone 5 mg bid
1:1
R A N D O
M
Mitoxantrone 12 mg/m2 q3 wks + Prednisone 5 mg bid MetastaticCRPC Stratify Pain level
PPI ≥ 2 or AS ≥ 10 vs
PPI < 2 or AS < 10 KPS ≤70 vs ≥ 80
Tannock et al. N Engl J Med 2004; 351: 1502-1512
Docetaxel: TAX 327 (+ update)
Berthold DR, et al. J Clin Oncol 2008;26:242–245
30 mesi 48 mesi
Update 2008:
OS benefit only in the 3 weekly arm
Median Survival (months)
Hazard
ratio p-value Docetaxel q3w: 19.2 0.79 0.004
Docetaxel qw: 17.8 0.87 0.086
Mitoxantrone 16.3 – –
Docetaxel: TAX 327 - Basale
Hormonal Manipulations (%) 1
2 > 2
9 68 23
8 72 21
6 69 25
Median PSA (ng/ml) 114 108 123
Gleason Score (%) ≤ 7
8-10
Not available
42 31 26
40 31 29
42 28 30 Extent of Disease (%)
Bone Metastases Visceral Disease
90 22
91 24
92 22 Docetaxel
Q 3 week
Docetaxel
weekly Mitoxantrone
Randomized 335 334 337
Ineligible*(%) 12 12 12
Median age (range) 68 (42-92) 69 (36-92) 68 (43-86)
≥ 80 Karnofsky PS (%) 88 87 86
Pain level ≥ PPI 2 or
AS ≥ 10 (%) 45 45 46
Prior treatment (%) Prostatectomy Radiotherapy Estramustine
19 52 19
24 44 18
21 51 21
Tannock et al, N Engl J Med 2004; 351: 1502-1512
Pattern of efficacy
Results
Tannock IF et al. N Engl J Med 2004;351:1502-12.
Variable Docetaxel Q3W (%)
Docetaxel Weekly (%)
Mitoxantrone (%)
Pain 35
(P=0.01)
31 (P=0.08)
22
≥50% Reduction in serum PSA 45 (P<0.001)
48 (P<0.001)
32
Tumor response 12 (P=0.11)
8 (P=0.59)
7
Quality of life 22 (P=0.009)
23 (P=0.005)
13
! Il solo PSA non rappresenta un buon surrogato per OS nella malattia avanzata
Docetaxel: TAX 327 - Docetaxel or Mitoxantrone
Weekly
Nessun Vantaggio in OS !
Grade 3-4 Hematologic Toxicity (%) Docetaxel Q 3 wk
Docetaxel
wkly Mitoxantrone
Treated (N) 332 330 335
Anemia 5.0 25.0 2.0
Neutropenia 32.0 1.5 22.0
Neutropenic infection 3.0 0.0 0.9
Febrile neutropenia 2.7 0.0 1.8
Septic death 0.0 0.3 0.3
Non hematological Toxicity (%) All Grades 3/4 All Grades 3/4 All Grades 3/4
Alopecia 65 NA 50 NA 13 NA
Fatigue 53 4.5 49 5.5 35 5.1
Nausea 41 2.7 36 2.4 36 1.5
Diarrhea 32 2.1 34 4.8 10 1.2
Neuro-Sensory 30 1.8 24 0.9 7 0.3
Nail Change 30 NA 37 NA 7 NA
Constipation 25 2.1 17 1.5 17 0.6
Docetaxel: TAX 327 – Safety data
Tannock IF et al. N Engl J Med 2004;351:1502-12.
Docetaxel Bi-weekly (PROSTY)
Same Activity but Less Hematological Toxicity
Kellokumpu-Lehtinen P et al. Lancet Oncol. 2013;14:117–124. 15
2013 VENICE Study: docetaxel +/- aflibercept
OS: 22.1 vs 21.2 Months
Confermata OS prolungata
in una popolazione di pz più attuale
Tannock et al 2013
Firstana
Oudard S et al. JCO 2017
Docetaxel
OS = 24.3 (22.18 to 27.60)
Docetaxel
e fattori prognostici
Armstrong AJ, et al. Clin Canc Res 2007;13:6396–6403
0.25 0.50 0.75 1.00
Su rv iv al (% )
0 5 10 15 20 25 30 35 40 45 50
Survival (months)
PSADT <1 month PSADT 1–2 months PSADT 4–6 months
PSADT >6 months
PSADT 2–3 months
Log-rank p<0.001 0
< 1 mo. 13.3 months
6 and 3-6 Med OS NYR
mean OS 25 and 22.5 months
Docetaxel: Pre treatment PSA-DT e OS
PSA DT da TAX327: mediana PSA DT < 55 giorni: malattia a rapido rate di proliferazione:
indicazione chemioterapia
Beneficio di docetaxel
nei pazienti asintomatici/PSA-DT
N died patients 183 183 184
Median survival 23.0 21.1 19.8
Hazard ratio 0.73 0.95
p value 0.009 0.65
N died patients 152 151 153
Median survival 14.9 15.1 12.8
Hazard ratio 0.85 0.8
p value 0.17 0.068
Berthold DR, et al. J Clin Oncol 2008;26:242–45
Docetaxel q3w (n = 335)
Docetaxel q1w (n = 334)
Mitoxantrone (n = 337)
PAIN NO PAIN
No subsequent therapy with established efficacy
Docetaxel: vantaggio in OS nei pts asintomatici
I pazienti senza dolore: prognosi migliore
I pazienti senza dolore: maggior beneficio in OS con docetaxel vs mtx
Docetaxel, efficacia nel paziente asintomatico con PSA-DT > 45 Day
Limitati trattamenti post docetaxel
OS maggiore in pts asintomatici e/o PSA- DT>45 d
Oudard et al, BJUI 2008
OS: 32,4 mesi nei pazienti:
• Asintomatici, minimamente asintomatici
• PSA-DT >45d
Cabazitaxel
II linea di trattamento chemioterapica
Indicazione terapeutica: dopo trattamento con docetaxel in:
• Pazienti asintomatici o sintomatici
• Pazienti malattia ossea e/o viscerale
Taxani: nuove evidenze meccanismo azione
1. Blocco del fuso mitotico
2. Attività in pazienti con ARV7+
3. In vitro: blocco del trasporto intracellulare del recettore androgenico
4. Attività in tumori refrattari a docetaxel 5. Bassa affinità P-gp, maggiore
concentrazione intracellulare vs docetaxel 6. Passaggio barriera ematoencefalica
Cabazitaxel: specificità
No taxano:
migrazione recettore nel nucleo
Taxano:
Il recettore rimane in zona
perinucleare
Cabazitaxel
Cabazitaxel
• Compared to docetaxel,
cabazitaxel likely to be a more potent taxane:
• It suppresses microtubule dynamics instability more potently
• It induces a more sustained G2/M arrest over 72 hours
• It’s uptake into cells is significantly faster
• It shows a prolonged cell retention upon washing the cells
Cabazitaxel mostra una maggiore penetrazione cellulare vs docetaxel
Azarenko O et al. Mol. Cancer Ther 2014; 13: 2092-2103
Cabazitaxel-Studio registrativo fase III TROPIC
Studio di fase III randomizzato, in aperto, internazionale, multicentrico (146 centri, 26 nazioni) su 755 pazienti con mCRPC in progressione durante o dopo trattamento con un regime contenente docetaxel.
Randomizzazione:
n=378 Cabazitaxel 25 mg/m
2ogni tre settimane + prednisone orale 10 mg/die per 10 cicli n=377 Mitoxantrone 12 mg/m
2ogni tre settimane + prednisone orale 10 mg/die per 10 cicli
De Bono JS, et al. Lancet 2010; 376: 1147–54
Study design
N=378 - Cabazitaxel 25 mg/m2 q3 wks + Prednisone 10 mg bid
1:1
R A N D O M I Z A T I O N
N=377 - Mitoxantrone 12 mg/m2 q3 wks + Prednisone 10 mg bid
Eligible patients had an ECOG-PS of 0 to 2.
Patients with measurable disease were required to have documented disease progression by RECIST with at least one visceral or soft-
tissue metastatic lesion
PRIMARY ENDPOINT:
Overall Survival (OS) SECONDARY ENDPOINT:
PSA response
PSA progression
Composite endpoint of progression-free survival
Objective tumour response for patients with measurable disease based on RECIST
Pain response
Pain progression
Time to tumour progression
Cabazitaxel - basale
De Bono JS, et al. Lancet 2010; 376: 1147–54
72% pazienti refrattari/ resistenti a docetaxel
Cabazitaxel: analisi dei risultati - Efficacia
Cabazitaxel prolunga in modo significativo la OS dopo progressione durante o dopo il trattamento con docetaxel
Analisi di Kaplan-Meier per OS
Bahl A, et al. Ann Oncol. 2013 Sep;24(9):2402-8
OS ≥2 anni
(HR 0,72; IC 95%: 0,61–0,84; p <0,0001)
Probabilità di sopravvivenza a 2 anni:
27% vs 16%
Cabazitaxel: OS > 2 anni - caratteristiche pazienti
Bahl A, et al. Ann Oncol. 2013 Sep;24(9):2402-8
Malattia con caratteristiche di mini aggressività: PSA basale, minor carico di malattia viscerale,
asintomaticità, lunga risposta a docetaxel, hanno una OS > 2 anni se trattati con cabazitaxel
Cabazitaxel: analisi dei risultati - Efficacia
De Bono JS, et al. Lancet 2010; 376: 1147–54
Risposta tumorale obiettiva dei pazienti con malattia misurabile secondo i criteri RECIST.
Overall survival in base all’aggressività della malattia alla diagnosi / metastasi viscerali
Patients with poorly differentiated tumour and /or visceral methastases
Lung – liver - adrenal or pancreatic lesions showed significantly improved OS
Cabazitaxel efficacia anche nella malattia scarsamente differenziata / viscerale
Oudard S et a. Poster 933P ESMO 2012. Vienna, Austria.
Cabazitaxel: EAP Italia - Analisi conclusive
Di Lorenzo et al 2015
Cabazitaxel: Assenza di tossicità cumulativa
Cabazitaxel: Safety in senior adults
Safety of cabazitaxel in senior adults with metastatic castration-resistant prostate cancer: Results of the 2014 European compassionate-use programme.
Heidenreich A, et al. European Journal of Cancer. 2014; In Press
Attività di cabazitaxel e dei taxani nei
pazienti mCRPC esprimenti ARV7+
Taxane activity is not influenced by ARv7 in mCRPC patients
Antonarakis ES et al. N Engl J Med 2014;371:1028-38; Antonarakis ES et al. JAMA Oncol 2015;1:582-91
Abiraterone Enzalutamide Taxane
PSA response rate:
AR-V7 positive: 0% (95% CI: 0-26%) AR-V7 negative: 52.6% (95%CI: 29-76%) P=0.004
PSA response rate:
AR-V7 positive: 0% (95% CI: 0-46%) AR-V7 negative: 68.0% (95% CI: 46-85%) P=0.004
PSA response rate:
AR-V7 positive: 41% (95% CI: 18-67%) AR-V7 negative: 65% (95%CI: 41-85%) P=0.19
AR-V7 positive AR-V7 negative
PS A cha nge, %
100 5 0
–50 –100
*
†
* * *
†
†
†
100 50 0 –50 –100
†
*
†
*
†
* †
† †
†
† † † †
† †
† †
† † †
† †
100 50
0
–50
–100
*Docetaxel, N=30 Cabazitaxel, N=7
CTC: circulating tumour cell
Best PSA Response
mod. nach Antonarakis, E.S., et al., presented at ASCO GU 2015..
38 AR-V7 (+): 7/17 = 41% (95% CI: 18-67%)
AR-V7 (-): 13/20 = 65% (95% CI: 41-85%) P = 0.194
Best PSA Response (% Change)
100
50
-100 -50 0
Negative Positive AR-V7 Status
Attività nei pazienti resistenti/refrattari a
docetaxel
100 90 80 70 60 50 40 30 20 10 0
0 6 12 18 24 30 Time (Months)
P ropor tion of O ver all Su rviv al
Number at Risk
MTX + PRED CBZ + PRED
230 239
172 194
98 130
33 44
2 9
1 0
MTX + PRED CBZ + PRED
Symbols = Censors
MTX CBZ 10.9 13.8
De Bono JS et al. 47° ASCO Annual Meeting. G.U.CANCER. ASCOSCANNER n°2 del 4/06/2011.
Cabazitaxel in patients progressing during docetaxel
Median OS (Months)
100 90 80 70 60 50 40 30 20 10 0
0 6 12 18 24 30 Time (Months)
P ropor tion of O ver all Su rviv al
Number at Risk MTX + PRED CBZ + PRED
147 139
128 127
90 101
34 46
9 19
0 4
MTX + PRED CBZ + PRED
Symbols = Censors
MTX CBZ
15.6 18
Cabazitaxel in patients progressing after docetaxel
De Bono JS et al. 47° ASCO Annual Meeting. G.U.CANCER. ASCOSCANNER n°2 del 4/06/2011.
Cabazitaxel efficacy in primary docetaxel refractory patients
G. Di Lorenzo et al.
Pazienti con resistenza primaria a docetaxel, definita come progressione di malattia entro 3 mesi dall’introduzion di docetaxel.
N= 33 pazienti TERAPIA ORMONALE CABAZITAXEL Hazard Ratio (IC
95%) Valore di P
Seconda linea: terapia ormonale vs cabazitaxel
3,22 (1,19–8,68) 0,02
Terza Linea: terapia ormonale vs cabazitaxel 0,36 (0,14–0,93) 0,03
Elaborazione grafica di dati da testo
Di Lorenzo G. Eur Urol. 2014;65(2):505-7
Maggiore attività nei pazienti asintomatici
Cabazitaxel benefit in TROPIC according to baseline Pain vs No Pain
No Pain HR 0.57 (43%) Vs Pain HR 0.76 (24%)
De Bono JS et al. Lancet 2010; 376: 1147–54
TROPIC: cabazitaxel double benefit in patients without Pain
Overall Survival
Cabazitaxel activity after doce confirmed in 3 Phase III Tropic – Affinity - Proselica
TROPIC
AFFINITY
PROSELICA
Tropic: Bahl A et al. Annals Oncology 2013 Affinity: Beer T et al. Lancet Oncology 2017 Proselica: Eisemberger M et al. JCO 2017
PROSELICA
C20/25, cabazitaxel 20/25 mg/m2;DOC, docetaxel; mCRPC, metastatic castration-resistant prostate cancer; Q3W, once every 3 weeks.
1. Eisenberger M, et al. J Clin Oncol. 2017; ePub August 15.
2. PROSELICA Clinical Study Report May 2016.
PROSELICA: Study design 1,2
Patients with mCRPC progressing during or after treatment with DOC
N = 1200 patients 172 centers worldwide
C20
Cabazitaxel 20 mg/m² Q3W + prednisone 10 mg/day
10 cycles n = 598 R
A N D O M I Z E
C25
Cabazitaxel 25 mg/m² Q3W + prednisone 10 mg/day
10 cycles
n = 602
Phase III, open-label study
PROSELICA: Results
Eisenberger M, et al. J Clin Oncol. 2017; ePub August 15
Tumor Response
Docetaxel rechallenge?
Docetaxel rechallenge in mCRPC
Oudard et al, 2014
GETUG 15 in mHSPC
Low activity of docetaxel after progression
Lavaud P et al. J Clin Oncol 2016;34(suppl):abstract 5080
PFS with DOC in mCRPC
ADT arm ADT + DOC arm
Modest PSA response and PFS in patients initially treated with ADT + DOC and rechallenged with DOC at disease progression
LHRH: luteinizing hormone-releasing hormone; PFS: progression-free survival; PSA: prostate-specific antigen
