mCSPC: Quem precisa de tratamento sistêmico? Quando postergar ADT ou indicar ADT isolada?

Igor Morbeck, MD, MSc

Professor de Medicina– PUC – Brasília

Oncologista Titular do Centro de Oncologia– Hospital Sírio-Libanês – Brasília

Disclosures:

• Speaker: Astellas, Janssen, Roche, BMS, MSD, Dr Reddys, Ipsen

• Advisory Board: Astra-Zeneca, Roche, BMS, MSD, Astellas, Janssen

• Clinical Research: Astellas, BMS, MSD

ADT:Where we have come from

• 1780 John Hunter, castration

• 1938 Acid phosphatase

• 1940 Huggins, Orchiectomy and estrogen (Nobel Prize)

• 1965 Synthetic estrogens

• 1977 First generation non-steroidal anti-androgens

• 1989 2nd generation non-steroidal AA (bicalutamide)

• 1985 Schally, LHRH agonists (Nobel Prize)

• 2003 LHRH antagonist (Zoladex)

• 2008 Degarelix

• 2009 Abiraterone

• 2010 Sawyer, Enzalutamide

• 2012 Apalutamide

• 2018 Daralutamida

Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Why it isimportant todo this reviewin 2019?

This review is an update of the Cochrane Reviewtitled ‘Early versus deferred androgensuppression in the treatment of advancedprostatic cancer’ published by Nair andcolleagues in 2002

Since 2002, several randomised controlled trialshave been published assessing the effects ofprimary therapy with early versus deferredandrogen suppression therapy in men withadvanced hormone-sensitive prostate cancer(EORTC 30846; EORTC 30891; Granfors 2006)

However, there is still controversy concerningthe ideal timing as to when to introducehormonal therapy in asymptomatic metastaticpatients (EAU 2017).

Early AST probably reduces the risk of death from prostate cancer over time (HR 0.69, 95% CI 0.57 to 0.84; moderate-certainty evidence).

Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Early versus deferred AST may makes little or no difference in serious adverse events (RR 1.05, 95% CI 0.95 to 1.16) ; 5 RCTs; 10,575 participants.

However, there were increased individual non-serious adverse events.

Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Acute and late side effects of ADT

The Past: Ten-Year Survival in Patients with MetastaticProstate Cancer

• SWOG (S8894): 1286 eligible patients

• 794 pts followed for > 10.5 ys

• 16% lived 5 up to 10 years

• 7% lived > 10 ys

• Indepedent predictors of survival (p< 0.05):

• Lower PSA, very low volume, no symptoms, lower Gleason

Tangen C., Faulkner J, Crawford E, et al. Clin Genitourinary Cancer 2003

The Present: Development and Validation of a Novel PrognosticModel for Predicting Overall Survival in Treatment-naïve mCSPC

• Retrospective review of 304 patients treated at Kyoto University Hospital

• A prognostic model was created using clinical parameters associated with OS

• Multivariable analysis was performed to identify the clinical parameters associated

with OS

• Over 80% of the cohort had a GS > 8

• Independent factors associated with OS were extent of disease; liver metastasis; lactate

dehydrogenase >250U/L; and a primary Gleason score of 5.

• Median OS for the high-risk: 28mo. Intermediate-risk: 59mo and low-risk: not reached

Akamatsu A, Kubota M, et al. European Urology Oncology, may 2019

The Past: mCSPC

The presente: mCSPCComparator

ARMN

rPFS(HR)

rPFS*

Months

OS (HR)

mOS months

CHAARTED ADT + Docetaxel 790 0.61 33.0 vs 19.8 (P<0.001) 0.72 57.6 vs 47.2 (P=0.0018)

STAMPEDE

DocetaxelADT + Docetaxel 2,962 0.62 37.0 vs 21.0 (P<0.001) 0.76 77 vs 67 (P=0.003)

STAMPEDEAbiraterone

ADT + Abiraterone 1,917 0.2943.9 vs 30.0 (P<0.001)

3yr-rPFS: 68% vs 41%0.63

NE vs NE (P<0.001)

3yr-OS: 83% vs 76%

LATITUDE ADT + Abiraterone 1,199 0.47 33.0 vs 14.8 (P<0.001) 0.66 53.3 vs 36.5 (P<0.0001)

ARCHES ADT + Enzalutamide 1,150 0.39NE vs 19.4 (P<0001)

1yr-rPFS: 84% vs 64% 0.81

NE vs NE (P= 0.3361)

* not mature (84 events)

ENZAMET ADT + Enzalutamide 1,125 0.40

NE vs 26 (P<001)

3yr-rPFS: 68% vs 41% 0.67NE vs NE (P= 0.0016)

3yr-OS: 80% vs 72%

TITAN ADT + Apalutamide 1,052 0.48NE vs 22.1 (P<0.0001)

2yr-rPFS: 68% vs 48%0.67

NE vs NE (P= 0.0053)

2yr-OS: 82% vs 74%

Definition of Oligometastatic Disease

Latitude: Secondary endpoints

TITAN: Secondary endpoints

R.B.A.B, 81 y/o,retired Lawyer, Hypertension

• Pelvic CT: Hydronephrosis

• TUR: Colo-vesical Biopsy: Adenocarcinoma Gleason 4+5

• iPSA: 52

• Jan/17: PET-PSMA: No positive lymph nodes e no distant mets

• T3bN0M0

• S/P ADT + Bicalutamide “neoadjuvant”

• February 2017: s/p Hypofractioned Rxt

• Maintenance Gosserelin 10,8 mg

August/2016: Urinary obstruction

May/2017: Asymptomatic. PSA: 0,1 ng/ml

•PET-PSMA: 3 Pelvic positive lymph nodes e no distant mets

•s/p SBRT

Nov/2018: PSA 1,69 ng/ml

Feb/2019: PSA 0,22 ng/ml

Nov/2019: PSA 0,82 ng/ml

Conclusions

• Early ADT probably reduces the risk of death from prostate cancer

• In 2019 is hard to identify patients who don’t benefit of ADT combination

• We need to balance between pro and cons to associate or not ADT with new agentes• Elderly, comorbidities, PS

• New research are warranted with new generation AA monotherapyand dose reductions (ex. Abiraterone 250 mg)