Addition of Enzalutamide to Standard First-Line Therapy Prolongs Survival in Metastatic Prostate Cancer

22 Jul, 19

Introduction

Addition of docetaxel or abiraterone to testosterone suppression improves survival outcomes in metastatic hormone-sensitive prostate cancer. Enzalutamide is an orally administered, small-molecule inhibitor of the androgen receptor developed to overcome the acquired resistance to first generation non-steroidal antiandrogens. Studies have demonstrated improved survival outcomes with enzalutamide in castration-resistant prostate cancer (CRPC), irrespective of its use before or after docetaxel chemotherapy. However, effects of adding enzalutamide to testosterone suppression, with or without early docetaxel is not known.

Aim

The ENZAMET (Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer) study, evaluated the effects of enzalutamide on the overall survival outcomes when added as the first-line therapy that included testosterone suppression with or without early docetaxel in men with metastatic hormone sensitive prostate cancer.

Method

Study Design

Multinational, open-label, randomized, phase 3 trial
Patients having prostatic adenocarcinoma with metastases and having a score of 2 or less on the Eastern Cooperative Oncology Group (ECOG) performance-status scale were included
The cohort received testosterone suppression plus enzalutamide at a dose of 160 mg daily or a standard non-steroidal antiandrogen drug – bicalutamide, nilutamide or flutamide (standard care group)

Endpoints

Primary Endpoints

Overall survival (OS) measured as the interval from randomization to death from any cause or to the date at which the patient was last known to be alive

Secondary Endpoints

Prostate-specific antigen (PSA) progression-free survival (PFS) defined as interval from randomization to the earliest event of PSA progression
Clinical progression-free survival defined as the earliest sign of radiographic progression
Adverse events (AEs)

Results

A total of 1125 men were assessed for a median follow up period of 34 months
Enzalutamide group comprised of 563 patients and standard-care group included 562 patients
Across both randomized arms, 52% patients had high volume disease and ~45% patients were considered as candidates for early docetaxel treatment
There were fewer deaths in the study group as shown in figure 1; hazard ratio (HR) 0.67, p=0.002

Figure 1. Comparison of mortality

Kaplan-Meier estimates of OS at 3 years were 80% and 72% in the study and standard care groups based on 94 and 130 events respectively
The enzalutamide group had higher PSA PFS (HR 0.39; p<0.001) and clinical progression-free survival (HR 0.40; p<0.001) at 3 years
The comparison of survival outcomes is shown in figure 2.

Figure 2. Comparison of survival outcomes at 3 years

The study group had higher treatment discontinuation rates due to AEs (33 events vs 14 events in the standard care group)
Fatigue was the most commonly reported AE in the enzalutamide group
The incidence of seizures was 1% vs none in the standard care group

Conclusion

Addition of enzalutamide to standard first line therapy significantly prolonged the overall survival, PSA progression-free survival (PFS) and clinical PFS at 3 years than the standard non-steroidal antiandrogen therapy in patients with metastatic hormone-sensitive prostate cancer.
Treatment with enzalutamide was associated with a higher incidence of seizures and other toxic effects, especially in patients treated with early docetaxel.

N Engl J Med. 2018 June. DOI: 10.1056/NEJMoa1903835.