mCRPC: First andmCRPC: First and Second lineElena VerzoniOncologia Medica Fondazione IRCCS Istituto Nazionale TumoriMilano

Landmarks of disease progression in CRPC

30 months2-10 years

Failed l h h th lli tilocalized 

therapyHormonal therapy chemotherapy palliation

LHRH analogues, antiandrogenis, ADT…

rden

death

Tumou

r bu

r

C t ti i t t P t t CH iti P t t C

diagnosis Symptomatic Asymptomatic PSA rises 

M0 M+

Castration‐resistant Prostate Cancer* (CRPC)

Hormone‐sensitive Prostate Cancer(HSPC)

Castration‐Resistant Prostate Cancer

NONMETASTATIC diseaseNON METASTATIC disease 

OLIGOMETASTATIC disease /asymptomatic or mildly 

symptomatic patientssymptomatic patients

METASTATIC disease/symptomatic 

‐> Chemo‐naïve patients‐> Chemo‐naïve patients

‐> After docetaxel

NON METASTATIC 

CASTRATION‐RESISTANT disease

N t d d t t t• No standard treatment

• Non efficacy data available from docetaxel‐based chemo

CASTRATION‐RESISTANTCASTRATION RESISTANTOLIGOMETASTATIC disease:

A t ti / Mildl S t ti P ti tAsymptomatic/ Mildly Symptomatic Patients

PRE DOCETAXELPRE‐DOCETAXEL

ABIRATERONE –ENZALUTAMIDEABIRATERONE  ENZALUTAMIDEPRE‐DOCETAXEL

PREVAIL

End points di efficaciaPazienti mCRPC chemo-naïve

Enzalutamide 160 mg QD

Co-Primari:• rPFS (central review)

OS

RAND

• Progressione del PSA in

naïvein progressione

(N = 1717)Enzalutamide 160 mg QD

(n=872)• OS

Secondari:Tempo all’uso di oppiacei (dolore

DOMIZ

gaccordo con i criteri PCWG2 o progressione radiologica

• Terapia di deprivazione oppiacei (dolore correlato al tumore)Tempo all’inizio della chemioterapiaPlacebo QD

8 )

ZATIO

p pandrogenica in corso

• ECOG PS di grado 0 o 1 p

Tempo al primo evento scheletricoTempo alla

(n =845)ON

1:1

• Asintomatici o lievemente sintomatici, in accordo con BPI-SF(scores da 0 a 1 [asintomatico] progressione PSA(scores da 0 a 1 [asintomatico]o da 2 a 3 [paucisintomatico])

Enzalutamide: Analisi OS

OS 32.4 mos

OS 30 2 mosOS 30.2 mos

St d t fi t i t i PFS 12 65%

Beer T et al. N Engl J Med 2014;

Stopped at first interim rPFS 12 mo: 65% vs 14%

COU-AA-302

End points di efficaciaPazienti mCRPC chemo-naïve

Abiraterone acetato 1000 mg QDP d i BID

Co-Primari:• rPFS (central review)

efficaciaRAND

• Progressione del PSA in

in progressione(N = 1088)

Prednisone 5 mg BID(n = 546)

• OSSecondari:

Tempo all’uso di oppiacei

OMIZA

Progressione del PSA in accordo con i criteri PCWG2 o progressione radiologica

• Terapia di deprivazione(dolore correlato al tumore)Tempo all’inizio della chemioterapiaT l d t i t

Prednisone 5 mg BIDPlacebo QD

(n = 542)

ATION

• Terapia di deprivazione androgenica in corso

• ECOG PS di grado 0 o 1 Tempo al deterioramento dell’ECOG PSTTPP

( )N

1:1• Asintomatici o lievemente

sintomatici, in accordo con BPI-SF( d 0 1 [ i t ti ](scores da 0 a 1 [asintomatico]o da 2 a 3 [paucisintomatico])

Ryan et al, N Engl J Med 2013

Abiraterone: Analisi OS

Median follow-up of 49.2 monthsAbiraterone treatment effect more pronounced when adjusting for 44% of prednisone patients who received subsequent abiraterone (HR = 0.74)

Ryan C et al. ESMO 2014; Abstract 7530 (oral presentation)

CASTRATION‐RESISTANTCASTRATION RESISTANTOLIGOMETASTATIC disease:

S t ti P ti tSymptomatic Patients

2004: First‐line Docetaxel: Overall Survival

TAX 327 SWOG 9916

Docetaxel therapy led to improved survival and Docetaxel/estramustine improved median survival by 2 monthsDocetaxel therapy led to improved survival and rates of response in terms of pain, PSA level, and quality of life compared with mitoxantrone/prednisone

Docetaxel/estramustine improved median survival by 2 months compared with mitoxantrone/prednisone

1. Tannock IF et al NEJM 20042. Petrylak  DPet al NEJM 2004

I Linea: Docetaxel +?

Agent Target Summary of trial StatusBevacizumab VEGF Docetaxel vs

Docetaxel+BevacizumabNEGATIVE

Aflibercept VEGF-trap Docetaxel vs D t l Aflib t

NEGATIVEDocetaxel+Aflibercept

Lenalidomide Antiangiogenic Docetaxel vs Docetaxel+Lenalidomide

NEGATIVE

Atrasentan Endothelin receptor

Docetaxel vs Docetaxel+Atrasentan

OPEN TO ACCRUAL

Zibotentan Endothelin receptor

Docetaxel vs Docetaxel+Zibotentan

NEGATIVEreceptor Docetaxel+Zibotentan

Dasatinib Src kinase, BCR-ABL, ckit, PDGFR

Docetaxel vs Docetaxel+Dasatinib

NEGATIVE

C ti (OGX) Cl t i D t l NEGATIVECustirsen (OGX) Clusterin Docetaxel vs Docetaxel+ Cutrirsen

NEGATIVE

DN-101 Vitamin D receptor Docetexel vs Docetaxel+DN-101 NEGATIVE

GVAX Whole-cell vaccine Docetaxel vs Docetaxel+GVAX NEGATIVE

METASTATIC CASTRATION‐RESISTANT disease

POST‐DOCETAXEL

Post‐docetaxel Options available 

What’s the best sequence to maximize survival?What s the best sequence to maximize  survival?

Abiraterone

ADT Docetaxel CabazitaxelPDPD

CYP 17 i hibiDocetaxel

CYP‐17 inhibitor 

Chemo

rechallenge

Enzalutamide

No data available for the 

New generation antiandrogenEnzalutamide

best sequencing

TROPIC Trial: OSTROPIC Trial: OS

100

80f O

S (%

)

80

60

Prop

ortion

 of

40

P

20

Time (months)

377 299 195 94 31 9

00 6 12 18 24 30

377378

299321

195241

94137

3160

919

De Bono JS et al. Lancet 2010; 

Abiraterone post‐docetaxel: COU‐AA‐301

De Bono NEJM 2011 analisi ad interim studio 301

Fizazi Lancet Oncology 2012 analisi finale studio 301

Logothetis Lancet Oncology 2012S tt li i t di 301 D l SRE

Sternberg Annals of Oncology 2012SECONDARY

Sottoanalisi studio 301 su Dolore e SRE

Sternberg Annals of Oncology 2012Sottoanalisi studio 301 su Fatigue

SECONDARYENDPOINTS

Harland abstract ASCO 2011Sottoanalisi studio 301 su QoL

COU‐AA‐301 Study DesignPhase 3, multinational, multicenter, randomized, double‐blind, placebo‐controlled study 

(147 sites in 13 countries; USA, Europe, Australia, Canada)

FI

ABIRATERONE ACETATO 1000 mg QD

•1195 pts con mCRPC in progressione

•Fallimento 1 o 2 precedenti regimi di CT, uno dei quali a base Docetaxel

NO

A

•Randomizzazione 2:1

•Stratificazione per: •ECOG PS (0‐1 vs. 2)

PROG

Prednisone 5 mg BID

Placebo QD

•Maggior intensità di dolore nelle ultime 24 ore (BPI short form; 0‐3 [assente] vs. 4‐10 [presente]) 

RESSIQ

•Precedente chemioterapia (1 vs. 2)

•Tipo di progressione (solo PSA vs. Rx PD con o senza PSA PD)

IONEPrednisone 5 mg BID

OS Primary Endpoint:

de Bono et al. NEJM 2011; 364:1995‐2005 

(miglioramento del 25%; HR 0.8)

COU AA 301: Overall SurvivalCOU‐AA‐301: Overall Survival 

H d R ti (95% CI) 0 74 (0 638 0 859) P < 0 0001Hazard Ratio (95% CI): 0.74 (0.638-0.859) P < 0.0001

80

100al

(%)

60

80 Abiraterone + prednisone: OS 15.8 mesi

(95% CI; 14.82-17.02)

Braccio Abiraterone+ 4.6 Mesi Su

rviv

a

40

Placebo +

0

20Placebo +

prednisone OS 11.2 mesi

(95% CI; 10.41-13.14)

797 657 473 273 15 0

0

Time to Death (Months)0 6 12 18 24 30

AA/Pdn398 306 183 100 6 0

273 15 0Placebo/Pdn

Fizazi et al. Lancet Oncol 2012; 13(10): 983‐992

MDV3100 Phase 3 AFFIRM study: post docetaxelMDV3100 Phase 3 AFFIRM study: post‐docetaxel  

P ti tPrimary end point:

MDV3100 160mg daily

Patient Population

OS

Secondary endpoints:160mg daily (n=800)1199 patients 

with progressive CRPC

Secondary endpoints:

PSA response

OR

Placebo

CRPC

Failed docetaxel h h

TTPSA progression

rPFS

Time to 1st SRE

(n=399)chemotherapy

Randomised 2:1

QoL

* Glucocorticoids were not required but allowed

Scher HI et al. NEJM 2012; 367:1187‐97

AFFIRM Overall survival: Median benefit 4.8 months

Scher HI et al. NEJM 2012; 367:1187‐97

mOS  18.4 mo vs 13.6 mo (p<0.0001)HR 0.63

Radium‐223 Targets Bone Metastases

ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design

TREATMENT

6 injections at 4‐week intervalsR

PATIENTS4‐week intervals

Radium‐223 (50 kBq/kg) + Best standard of care

RAND

• Confirmed symptomatic CRPC

STRATIFICATION

DOMI

• ≥ 2 bone metastases

• No known

• Total ALP: < 220 U/L vs ≥ 220 U/L

• Bisphosphonate use: Yes vs No

Placebo (saline) + Best standard of care

ISED

visceral metastases

• Post-

Yes vs No• Prior docetaxel: 

Yes vs No

2:1

N = 922

docetaxel or unfit for docetaxel

N = 922

Planned follow‐up is 3 years

ALSYMPCA Time to First Skeletal‐Related Event

90

100

HR 0.610; 95% CI, 0.461‐0.807P = 0.00046

60

70

80

RE

P  0.00046

Radium‐223, n = 541

40

50

60

Witho

ut SR

Median: 13.6 months

20

30

40

% W

Placebo, n = 268Median: 8.4 months

0

10

Month 0 3 6 9 12 15 18 21

Radium-223 541 379 214 111 51 22 6 0

Placebo 268 159 74 30 15 7 2 0

ALSYMPCA Overall Survival

90

100

HR 0.695; 95% CI, 0.581‐0.873P < 0 001

60

70

80 P < 0.001

40

50

60

%Radium‐223, n = 541Median OS: 14.9 months

20

30

40

Placebo, n = 268M di OS 11 3 h

0

10Median OS: 11.3 months

Month 0 3 6 9 12 15 18 21 24 27

Radium- 223 541 450 330 213 120 72 30 15 3 0

Placebo 268 218 147 89 49 28 15 7 3 0

Which drug for which patient?g pDo we have any choice criteria?

Caratteristiche dei pazienti dello studio PREVAIL/COUAA302

Characteristics Enzalutamide(n=872)

Placebo(n=845) Characteristics Abiraterone

(n = 546)Prednisone

(n = 542)

Median age≥75-84≥85

72 (43-93)31.4%4.9%

71 (42-93)28.4%6.2%

Median age, years (range) 71 (44-95) 70 (44-90)

Median time from initial diagnosis to first dose (years) 5.5 5.1

Gleason score ≥8 at initial diagnosis

50.6% 52.4%

Distribution of disease at

diagnosis to first dose (years)

Median PSA (ng/mL) 42.0 37.7

Gleason score (≥ 8) at initial 54% 50%Distribution of disease at screeningBone Lymph nodeVisceral disease (lung or li )

85.0%50.1%11.2%4.6%7 3%

81.7%51.4%12.5%4.0%8 9%

Gleason score (≥ 8) at initial diagnosis 54% 50%

Extent of disease

liver)Visceral liverVisceral lungVisceral lung or liverOther soft tissue†

7.3%0.7%

13.0%

8.9%0.4%

12.4%

Bone metastases 83% 80%

> 10 bone metastases 49% 47%

Other soft tissue†

No. of bone metastases at screening 32.7% 32.2%

Soft tissuea 49% 50%

Pain (BPI-SF)g

>10% %

Baseline pain 0-1 on BPI SF-Q3

66.2% 67.5%

0-1 66% 64%

2-3 32% 33%

Beer T et al. N Engl J Med 2014; epub (Supplementary Data)BPI‐SF, Brief Pain Inventory‐Short Form (scale 0‐10).

Caratteristiche dei pazienti dello studio COUAA301

Cabazitaxel: TROPIC ‐ Caratteristiche dei pazienti al basale

De Bono JS, et al. Lancet 2010; 376: 1147–54

Cabazitaxel: malattia aggressiva (PD: PSA + dolore + radiologia)

Fattori predittivi di efficacia nel CRPC progredito al Docetaxel.

De Bono JS, et al. Lancet 2010; 376: 1147–54

Caratteristiche dei pazienti dello studio AFFIRM

Take home messagesTake home messages

• New drugs are now available in differentsetting ‐> OS improvement!!

• No comparative data

• No data about sequencing

Take home messagesTake home messages

f d• Sites of disease

B d• Burden

S t• Symptoms

Diff t f t fil /• Different safety profile/os‐ev

A PS C bidit• Age, PS, Comorbidity

Multidisciplinary approach is mandatory!!

Grazie dell’attenzione!Grazie dell attenzione! 

elena verzoni@istitutotumori mi itelena.verzoni@istitutotumori.mi.it