El valor de la experiencia en el nuevo entorno del CPRC

Daniel Castellano

Oncología Médica. Unidad de Tumores GenitoUrinarios

Hospital Universitario 12 de Octubre

I + 12 Research Institute

Overview of treatment strategies for

mCSPC and CRPC

Docetaxel or

Cabzaitaxel?

Docetaxel Abiraterone [A] Enzalutamide [A]

1st -

line

Sipuleucel-T [P3]† Abiraterone [A] Enzalutamide [A] Cabazitaxel [A]

Po

st

-do

c

Post-abirateronePost-docetaxel

& abiraterone

Post-docetaxel

& enzalutamide

Docetaxel [EP] Enzalutamide [EP] Cabazitaxel [EP] Abiraterone [A]

Su

bse

qu

e

nt lin

es

Patients with mCRPCmCRPC + bone mets

BP

s ±

sta

nd

ard

an

tic

an

cer

the

rap

y [

A]

Dm

ab

* ±

sta

nd

ard

an

tic

an

cer

the

rap

y [

A]

Ra

diu

m-2

23‡

[A]

Antiresorptive bone-targeting agent (dmab)

Antiresorptive bone-targeting agent (BP)

mCSPC

Docetaxel [A] Apalutamida Abiraterone [A] Enzalutamide [A]

nmCRPC

Docetaxel ? Apalutamida Darolutamida [A] Enzalutamide [A]

DYNAMIC PROGRESSION OF PROSTATE CANCER

Treatment Options

Localized disease

Local treatment

Non metastatic

relapsed

Metastatic relapsed

Hormone-Naive

Non Metastatic

Castration resistant

Metastatic castration

resistant

Metastatic disease

Hormone-Naive

Abi-Enza-

DOX-CBZ-

Radium-Sipuleucel

Zoled-Denos

27-53%

10-

20%

5-10%

33% in 2 years

Fizazi K, Ann Oncol 2015

Crawford DE, J Urol 2014

Median time to

metastases 8-10y1-3 y

10-15%Abiraterona

Docetaxel

Enzalutamida

Apalutamida

Abiraterona

Docetaxel

Apalutamida

Enzalutamida

Darolutamida

Docetaxel (TAX-327)

Dox vs Caba (FIRSTANA) Cabazitaxel (TROPIC)

Cabazitaxel (PROSELICA)

Docetaxel + ADT (CHAARTED)

Docetaxel + ADT (STAMPEDE)

Localiz. High risk PC

RT + ADT + Docetaxel

(RTOG-0521)

Landscape of Systemic

Treatment in Prostate Cancer

Apalutamide

Enzalutamide

Darolutamide

Abiraterone

Enzalutamide

Apalutamide

Abiraterone

Enzalutamide

Apalutamide ?

A phase III protocol of androgen suppression and radiotherapy vs AS and RT followed by chemotherapy with docetaxel and prednisone for localized, high-risk prostate cancer

<br />(NRG Oncology/RTOG 0521)

Presented By Howard Sandler at 2015 ASCO Annual Meeting

Slide 3

Presented By Howard Sandler at 2015 ASCO Annual Meeting

Rosenthal et al J Clin Oncol. 2019 Mar 12:JCO1802158

Median follow-up 5,7 years

Four years OS rate: 89% RT+ADT vs 93% RT+ADT+ DTX

high-risk nmCRPC

Median Overall Survival in nmCRPC is 2,5 years.

PSA DT=8-10 months has a higher risk of death

There are no approved drugs in this setting

MFS is a reasonable endpoint.

SPARTAN

Apalutamide

PROSPER

Enzalutamide

ARAMIS

Darolutamide

Smith MR, et al. J Clin Oncol, 2005

At 1 year of randomization= 50% of patients presented bone metastases or died

Small E, et al. Presented at ASCO GU 2018. Abstract#161 Smith MR, NEJM 2018

Small E, et al. Presented at ASCO GU 2018. Abstract#161 Smith MR, NEJM 2018

Small E, et al. Presented at ASCO GU 2018. Abstract#161 Smith MR, NEJM 2018

Small E, et al. Presented at ASCO GU 2018. Abstract#161 Smith MR, NEJM 2018

Small E, et al. Presented at ASCO GU 2018. Abstract#161Smith MR, NEJM 2018

Small E, et al. Presented at ASCO GU 2018. Abstract#161Smith MR, NEJM 2018

PROSPER Study Design

Presented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

Hussain M, et al. Presented at ASCO GU, 2018. Abstract#3

Hussain M, et al. Presented at ASCO GU, 2018. Abstract#3

Hussain M, et al. Presented at ASCO GU, 2018. Abstract#3

Hussain M, et al. Presented at ASCO GU, 2018. Abstract#3

ARAMIS: Efficacy and safety of darolutamide in nonmetastatic castration-resistant prostate cancer

Presented By Karim Fizazi at 2019 Genitourinary Cancers Symposium

ARAMIS trial design

Presented By Karim Fizazi at 2019 Genitourinary Cancers Symposium

Baseline patient characteristics

Presented By Karim Fizazi at 2019 Genitourinary Cancers Symposium

Primary endpoint: Metastasis-free survival<br />59% risk reduction of distant metastases or death

Presented By Karim Fizazi at 2019 Genitourinary Cancers Symposium

MFS benefit was consistent across subgroups

Presented By Karim Fizazi at 2019 Genitourinary Cancers Symposium

Secondary endpoint: Overall survival<br />29% risk reduction of death

Presented By Karim Fizazi at 2019 Genitourinary Cancers Symposium

TEAEs of interest

Presented By Karim Fizazi at 2019 Genitourinary Cancers Symposium

Robinson, D. et al. Cell 161, 1215–1228 (2015).

Necesitamos saber qué mecanismos están conduciendo la resistencia

Mechanism of resistance

PTEN mut

AR gainAR mutant/ AR sv

Neuroendocrine differentiationDNA repair deficient tumors

Other mechanisms

Tissue biopsyPlasma DNA

CTCs

Genetic evolution in Prostate Cancer

Rising PSANo visible metastasis

MetastaticDisease

Invasive disease

Pre-invasive disease (PIN)

No disease

Prevention of the disease

Prevention of invasion

Local treatment (RP or RT) or observation(only selected

pts)

“Prevention” of evident metastatic

disease

Systemic treatment (ADT, HT,

CT)

InflammationOxidative Stress

Telomere shortening

Senescence Castrationresistance

Myc TMPRSS2-ERG

PTEN inactivation

ERK/MAPK activationP53 inactivationRb inactivation

EZH2,P53, Rb inactivation

Systemic treatment (HO + CT) New targeted therapies + IO therapy

Conclusiones

• El tratamiento sistémico tiene un papel relevante en el tratamiento del CP en diferentes etapas de la enfermedad.

• Mantiene su eficacia en pacientes “HO-naive” y “HO-refractarios” .

• El momento exacto de administración está condicionado por factores pronósticos adversos clínicos y bioquímicos.

• Faltan biomarcadores que nos faciliten la identificación de cual es la mejor terapia en cada momento.

• El tratamiento cada vez más temprano de la enfermedad está complicando la toma de decisiones en una secuencia terapéutica futura.

Back-up

Caso clínico

• Varón de 72 años

• 2000. Diagnóstico: Adenocarcinoma de próstata pT3N0M0- Prostatectomía radical

• 2008. Elevación PSA -Inicia bloqueo hormonal.

• Marzo 2010 PSA 6,23

• Julio 2010 PSA 12,13.

• Abril 2012 TAC Adenopatía obturatriz de 9,6 mm.

Opciones

• Radioterapia de rescate

• Apalutamida

• Observación

• Docetaxel

Caso clínico continuación

• Radioterapia desde 19/10/2012 a 11/12/2012 sobre lecho de prostatectomia y adenopatía en iliaca interna derecha (70Gy)

• Continua seguimiento

• Marzo 2014. Nueva adenopatía retroperitoneal de 18mm x 15mm

Opciones

• Abiraterona

• Observación

• Apalutamida

Marzo 2014 Agosto 2014

Marzo 2014 Marzo 2018