Cancer de prostata hormono-sensible

metastasico y alta carga tumoral Dra. Aránzazu González del Alba

Servicio de Oncologia Médica

Hospital Universitario Son Espases

Palma de Mallorca

Formigal, 29 de junio de 2018

Introduction • Aprox 5-20% of new PCa diagnosis present with metastatic disease:

– 4-10% in Europe, US

– Prevalence of metastasis at diagnosis varies geographically, depending on screening programs, access to health system, etc

• 80% patient present without metastatic disease. In Spain up to 50% CRPC-M1 will present after being initially diagnosed with localized disease

Siegel, Ca Cancer J Clin,2017; Castro et al. ESMO

2017

Introduction

• Androgen deprivation has been the standard of care of advanced prostate cancer during the past 7 decades

– Orchiectomy1 Huggins 1941

– Oestrogens

– LHRHa/GnRHa2 Standard of care until recently

– Alternatives:

• High vs low doses antiandrogens

• Maximun Androgen Blockage3

• Intermitent blockage4

• ADT may induce responses >90% of patients, but after a median of 24-36 months progression to CRPC occurs

1. Huggins C, Can Res, 1941;2. Messing EM, N Eng J Med, 1999;

3. Prostate cancer trialists collaborative group, Lancet,2000; 4. Hussain, N Eng J Med, 2013;

Introduction • Since 2015, Docetaxel plus LHRHa has become the standard of care for a

majority of Castration-Sensitive M1 patients AR-independent clones

• However, most men progress to castration-resistant status through reactivation of androgen-signalling

1. Gravis G, et al. Eur Urol. 2016:70:256-262. 2. Sweeney C, et al. N Engl J Med. 2015;373:737-746;

3. James N, et al. Lancet. 2016;387:1163-1177.

What are we learning from long term follow‐up of CHAARTED: Overall Population

Median Follow‐up: 53.7 months

Median Follow‐up 28.9 months

13 months / HR 0.61 10 months / HR 0.73

What are we learning from long term follow‐up of CHAARTED: Overall Population

Median Follow‐up: 53.7 months

Median Follow‐up 28.9 months

13 months / HR 0.61 10 months / HR 0.73

What are we learning from long term follow-up of CHAARTED: Overall Population

Median Follow-up: 53.7 months Median Follow-up 28.9 months

13 months / HR 0.61 10 months / HR 0.73

Sweeney et al NEJM 2015, Sweeney et al ESMO 2016 © Vall d'Hebron Institute of Oncology (VHIO)

Sweeney et al NEJM 2015, Sweeney et al ESMO 2016

What are we learning from long term follow-up of

CHAARTED: High volume

What are we learning from long term follow‐up of CHAARTED: High volume

Median Follow‐up: 53.7 months

Median Follow‐up 28.9 months

17 months / HR 0.6 17 months / HR 0.6

What are we learning from long term follow‐up of CHAARTED: High volume

Median Follow‐up: 53.7 months

Median Follow‐up 28.9 months

17 months / HR 0.6 17 months / HR 0.617 months / HR 0.6 17 months / HR 0.6

Median Follow-up: 53.7 months Median Follow-up 28.9 months

Sweeney et al NEJM 2015, Sweeney et al ESMO 2016 © Vall d'Hebron Institute of Oncology (VHIO)

Sweeney et al NEJM 2015, Sweeney et al ESMO 2016

CHAARTED: Total patient population

HVD LVD

Kiriakopoulos JCO 2018

CHAARTED: De novo metastatic patients

Kiriakopoulos JCO 2018

CHAARTED QOL

CHAARTED – Quality of Life (FACT-P)High volume Low volume

ADT alone ADT + DOC

ADT alone

120

118

116

114

112

FA

CT

-P T

ota

l

0 3 6 9 12

120

116

112

0 3 6 9 12

ADT + DOC

Significant improvement in FACT-Pat 1 year with ADT + DOC

No significant difference at 1 yearbetween both arms

Sweeney CJ et al. Ann Oncol 2016;27(suppl 6):abstract 720FACT-P: Functional Assessment of Cancer Therapy – Prostate (higher values=improvement)

ASCO 2017 No DOC

THE STAMPEDE TRI AL: A MULTI -ARM, MULTI -STAGE DESI GN

ASCO 2015

2:1 randomization against SOC= ADT +/-RT

Slide 10

Presented By Neeraj Agarwal at 2018 ASCO Annual Meeting

STAMPEDE – OS (primary endpoint) (n= 1,776)

• 61% M1; 15% N1M0; 24% N0M0; median follow-up: 43 mo

HR= 0.78 (95% CI: 0.66-0.93)

P= 0.006

Time from randomization (months)

Ov

era

ll s

urv

iva

l1.0

0.8

0.6

0.4

0.2

0.0

0 12 24 36 48 60 72 84

SOC by Kaplan MeierSOC + DOC by Kaplan MeierSOC by flexible parametric modelSOC + DOC by flexible parametric model

SOC

Median 71 mo

SOC + DOC

Median 81 mo

James, ND et al. Lancet. 2016;387:1163-77.

Slide 12

Presented By Neeraj Agarwal at 2018 ASCO Annual Meeting

ADT + docetaxel in mHSPC

Not head-to-head comparison studies. a Data are presented as % (n).

* p value non-significant.

mHSPC, metastatic hormone-sensitive prostate cancer; NE, not evaluable. 1. Gravis G, et al. Lancet Oncol. 2013;14:149-58. 2. Gravis G, et al. Eur Urol. 2016;70:256-62. 3. Sweeney CJ, et al. N Engl J Med. 2015;373:737-46. 4. Sweeney C, et al. Ann Oncol. 2016;27:abstr 720PD. 5. James ND, et al. Lancet. 2016;387:1163-77.

GETUG-151,2 CHAARTED3,4 STAMPEDE5

Accrual 2004–2008 2006–2012 2005–2013

Total sample size, n 385 790 1,776

Patients with mHSPC, % 100 100 61

Patients with high-volume mHSPC, %

48 65 (513)a NE

Patients with de novo M1, % 72 72.8 58

Median follow-up, months 83.9 53.7 43

Median age, years 63 64 65

Treatment duration

Docetaxel cycles ≤ 9 6 6

Prednisone No No Yes

© Vall d'Hebron Institute of Oncology (VHIO)

Dr J Carles

ADT + docetaxel in mHSPC (cont.)

Not head-to-head comparison studies. a Data are presented as % (n).

* p value non-significant

cPFS, clinical progression free survival, FFS, failure-free survival; HR, hazard ratio; HVD, high-volume disease; NA, not available, NE, not evaluated.

1. Gravis G, et al. Lancet Oncol. 2013;14:149-58. 2. Gravis G, et al. Eur Urol. 2016;70:256-62. 3. Sweeney CJ, et al. N Engl J Med. 2015;373:737-46. 4. Sweeney C, et al. Ann Oncol. 2016;27:abstr 720PD. 5. James ND, et al. Lancet. 2016;387:1163-77.

GETUG-151,2 CHAARTED3,4 STAMPEDE5

Patients, n 385 183 790 513 1,776 1,086

All HVD All HVD All M1

OS

Experimental arm (median), months

62.1 39.8 57.6 51.2 81 60

Benefit, months 13.5

(48.6 to 62.1) 4.7

(35.1 to 39.8) 10.4

(47.2 to 57.6) 16.8

(34.42 to 51.2) 10

(71 to 81) 15

(45 to 60)

HR for OS 0.88* 0.78* 0.73 0.63 0.78 0.76

Progression cPFS Time to clinical progression FFS

Experimental arm (median), months

23.5 NE 33.0 27.3 37 NA

Benefit, months 8.1

(15.4 to 23.5) NE

13.2 (19.8 to 33.0)

14.3 (13.0 to 27.3)

17 (20 to 37)

NA

HR for progression 0.75 NE 0.62 0.53 0.61 0.61

© Vall d'Hebron Institute of Oncology (VHIO) Dr J Carles

Efficacy Endpoints

Co-primary:

•OS

•rPFS

Secondary: Time to

•pain progression

•PSA progression

•next symptomatic skeletal event

•chemotherapy

•subsequent PC therapy

ADT + Abiraterone acetate

1000 mg QD + Prednisolone 5 mg QD

(n = 597)

ADT + placebos(n = 602)

Patients

•Newly diagnosed adult men with high-risk mHNPC

Stratification Factors

•Presence of visceral disease (yes/no)

•ECOG PS (0, 1 vs 2)

RANDOMIZED

Fizazi K et al. J Clin Oncol. 2017;35 (suppl; abstr LBA3); Fizazi K et al. N Engl J Med. 2017;377(4):352≤60.

High-risk defined as meeting at least 2 of 3 high-risk criteria:

•G leason score of ≤ 8

•Presence of ≤ 3 lesions on bone scan

•Presence of measurable visceral lesion

LATITUDE: Phase III Trial of Abiraterone in patients with newly diagnosed metastatic prostate cancer (n=1,199)

38% Risk Reduction for Death

00 6 12 18 24 30 36 42

20

40

60

80

100

Months

Ov

era

ll s

urv

iva

l (%

)

Patients at riskADT + AA + P 597 565 529 479 388 233 93 9

602 564 504 432 332 172 57 2

HR, 0.62 (95% CI, 0.51-0.76)P < 0.001

ADT + AA + P, NR

ADT + Placebos, 34.7 mo

ADT + Placebos

10

70

90

50

30

0

20

40

60

80

100

Ra

dio

gra

ph

ic p

ro

gre

ssio

n-fre

e s

urv

iva

l (%

)

0 4 8 12 16 2420 28 32 36 40

Months

597 533 464 400 353 316 251 177 102 51 21602 488 367 289 214 168 127 81 41 17 7

HR, 0.47 (95% CI, 0.39-0.55)P < 0.001

ADT + AA + P, 33.0 mo

ADT + Placebos, 14.8 mo

10

30

50

70

90

Patients at riskADT + AA + P

ADT + Placebos

Fizazi K, et al. N Engl J Med. 2017;377:352-360. CI, confidence interval; HR, hazard ratio; NR, not reached.

LATI TUDE: Co-primary End Points

53% Risk Reduction for rPFS

12Median follow up 30.4 m

LATITUDE: Características basales y subgrupos

Slide 13

Presented By Neeraj Agarwal at 2018 ASCO Annual Meeting

HR 0.63

95% CI 0.52 to 0.76P-value 0.00000115

STAMPEDE- OS Abiraterone (n= 1,917)

SOC

SOC+AAP

This represents a 37%

improvement in

survival

Events

262 Control | 184 Abiraterone

mixed population of M1 and

MO patients

James ND et al, N Engl J Med. 2017 Jul 27;377(4):338-351

Slide 15

Presented By Neeraj Agarwal at 2018 ASCO Annual Meeting

Better

Worse

7 9530 15 17 2119 23 25 27 29 31 332 4 6 8 11 1310 121

0.4

0.2

0.0

-0.2

-0.4

0.6

FA

CT

-P t

ota

l sco

re

ADT + PlacebosADT + AA + PCycle*

338

309

250

192

202

119

135

77

65

33

20

7

0

0

ADT + Placebos, 8.3 mo

Pa

tie

nts

wit

ho

ut

de

gra

da

tio

nin

FA

CT

-P t

ota

l sco

re (

%)

100

80

60

20

0

40

597

602

0 6 12 18 24 30 36 42

Months

ADT + AA + P, 12.9 mo

HR 0.85 (95% CI, 0.74-0.99)P = 0.0322

Patients at riskADT + AA + P

ADT + Placebos

ADT + AA + P Significantly Improved HRQoL per FACT-P

15% Risk Reduction for HRQoL Degradation

Mean Change From Baseline Differed from Cycle 5 Onward

23*1 cycle = 28 days.

Summary

Strong evidence favouring AAP

Toxicity profiles quite different and well known

Weak evidence favouring AAP

No good evidence of a difference

FavoursSOC+AAP

FavoursSOC+DocP

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

Safety population SOC+DocP SOC+AAPPatients included in adverse event analysis 172 (91%) 373 (>99%)

Grade 1+ AE 172 (100%) 370 (99%)Grade 3+ AE 86 (50%) 180 (48%)

Grade 3+ AEs by category (incl. expected AEs)Endocrine disorder (incl. hot flashes, impotence) 15 (9%) 49 (13%)Febrile neutropenia 29 (17%) 3 (1%)Neutropenia 22 (13%) 4 (1%)Musculoskeletal disorder: 9 (5%) 33 (9%)Cardiovascular disorder (incl. hypertension, MI, cardiac dysrhythmia): 6 (3%) 32 (9%) Gastrointestinal disorder: 9 (5%) 28 (8%)Hepatic disorder (incl. increased AST, increased ALT): 1 (1%) 32 (9%) General disorder (incl. fatigue, oedema): 18 (10%) 21 (6%)Respiratory disorder (incl. breathlessness): 12 (7%) 11 (3%) Renal disorder 5 (3%) 20 (5%)Lab abnormalities (incl. hypokalaemia): 9 (5%) 11 (3%)

Adverse events – worst toxicity ever

• Implicaciones de las terapias posteriores a Docetaxel

Datos retrospectivos de seguimiento

GETUG-15

First-line Docetaxel in mCRPC setting in <br />GETUG AFU-15 Trial

Presented By Neeraj Agarwal at 2018 ASCO Annual Meeting

SIOG classification for advanced prostate cancer

Droz et al. BJU Int 2010, 106, 462-69 © Vall d'Hebron Institute of Oncology (VHIO)

FÁRMACO

Docet axel

(vial 140 mg) 1 vial

Abiraterona

(comp. 500 mg) 60 comp

Precio unit ario 307, 79 € (PVL)

3. 400 € (PVL)

3. 145 € (* )

Posología 75 mg/m2 iv c/3 sem 1000 mg/día vo

Dosis

(Sc =1, 75 m2)

132 mg 1000 mg = 2 comp/día

Cost e x ciclo

Cost e x mes Coste x mes + pred.

290,2 € (**)

2.935,3 € 1 Ciclo = 28 días

3.145 € 30 días (1 mes)

3. 145, 85 € 30 días (1 mes)

Coste t rat amiento

completo (* * * )

1. 741, 2 € 103. 813, 21 €

(*): PVL -7,5% RDL 8/2010

(**) Con aprovechamiento de viales para el caso de Docetaxel

(***) Calculado para 6 ciclos de docetaxel = 4,5 meses) y 33 meses de tratamiento con Abiraterona (Ensayos CHAARTED y LATITUDE

https:/botplusweb.com/

Cortesia de Jordi Gines

Conclusiones

• Docetaxel y Abiraterona son tratamiento estandar en CPHSm

• En enfermedad de alto volumen ambas opciones han demostrado mismo impacto en SG con diferencias en duración tto, tolerancia y coste

• ¿Que hacer en enfermedad de bajo volumen?

• No disponemos de datos prospectivos para la mejor secuencia posterior

GRACIAS