Fulvestrant: recuperando una alternativa

terapéutica

Dr. José Ángel García Sáenz

Estrogen Receptor & Anti-estrogen Therapy

Antiestrogen Therapy

LHRH agonists

Aromatase inhibitors

SERMs

SERDs

SERD Phase of development

Fulvestrant Approved

GDC-0810 Phase 1/2

GDC-0927 Phase 1

AZD9496 Phase 1

SERDs: Ongoing phase 1/2 trials

Estradiol OH

Fulvestrant OH

7

HO HO (CH2)9SO(CH2)3CF2CF3

Meta-analysis of chemotherapy vs endocrine RX for MBC HR for overall mortality

Wilcken N. Cochrane Datbase Syst, 2011

For postmenopausal women, 1st line letrozole improves TTP

Mouridsen H. JCO 2003

Letrozole 9.4m

Tamoxifen 6.0m

Second-line setting after NS-AIs Low-Dose Fulvestrant = Exemestane

Chia S. JCO 2008

Johnston SR. Lancet Oncol 2013

EFECT SoFEA

Fulvestrant 500 mg versus 250 mg improves PFS and OS CONFIRM Trial

Di Leo A. JCO 2010

Di Leo A. JNCI 2014

5.5m

6.5m

26.4 m

22.3 m

Fulvestrant 500 ↑ TTP & OS vs Anastrozole in 1st-line

FIRST Trial

Robertson . Breast Cancer Res Treat 2012

Ellis M. JCO 2015

TTP: 23.4 vs 13.1 mo OS: 54.1 vs 48.4 mo

1st Line: Fulvestrant 500 vs Anastrozol

FALCON

n= •Postmenopausal HR+/HER2- MBC •1st Line

Fulvestrant 500 plus placebo

Placebo plus Fulvestrant

1

1

PFS analisis: 306 events

OS analisis: 50% survival

¿cuál va ser la primera línea en CMM RE+?

Paloma 2

MonaLEEsa 2

FALCON

FLIPPER

Mehta. NEJM 2012

Bergh M. JCO 2012

Fulvestrant + AIs in 1st-line Conflicting data

SWOG0226 FACT

¿por qué es más apropiado FULVESTRANT,

y no EXEMESTANO en aquellas pacientes

previamente expuestas a NSAI?

Mechanisms of endocrine therapy resistence

Activation of signaling pathways

Alteration of survival and cell cycle pathways

ESR1 activation mutations

ESR1 mutations

Jeselsohn R. Nat Rev Clin Oncol. 2015

Toy. AACR 2016

Clinical significance of ESR1 mutations in Breast cancer

Chandarlapaty S. 2016 ASCO Annual Meeting

1. What is the clinical prevalence of mutation among patient subsets?

– Which group of patients are at risk for mutation?

2. What are the outcomes of patients with muts?

– Implication of mutation for overall survival?

– Implication of mutation for specific endocrine therapies?

What is the prevalence of mutation?

Which group of patients are at risk for mutation?

Turner. ASCO 2016

Prognostic implication for mutation?

Augusto. ASCO 2016 Chandarlapaty. SABC 2015

Implication for AI or SERD monotherapy

(SOFEA)?

Turner. ASCO 2016

Implications for SERD monotherapy

(FERGI)?

Spoerke et al. Nat Comm 2016

Implications for CDK4inh efficacy?

Turner. ASCO 2016

¿Debe incorporarse el estudio de mutaciones

de ESR1 a la práctica asistencial?

¿Debe de abandonarse los IA como un

tratamiento estándar en 2L ?

¿Deben incorporarse

2nd line Trials Cohorts

BELLE2 Fulvestrant +/- Buparlisib

SOLAR-1 Fulvestrant +/- Alpelisib

PALOMA-3 Fulvestrant +/- Palbociclib

PEARL Fulvestrant +Palbociclib vs XEL

Monarch-3 Fulvestrant +/- Abemaciclib

MANTA Fulvestrant +/- AZ dual mTOR-in

TAKEDA Fulvestrant +/- ML dual mTOR-in

First line

Single agent

Combination therapy

Non-steroidal AIS

Anastrozole + Fulvestrant

Letrozole + Palbociclib

2nd line

Single agent

Combination therapy

Fulvestrant + Palbociclib

Exemestane + Everolimus

Fulvestrant

Fulvestrant

Letrozole + Ribociclib