ENZAMET - Enzalutamide for Metastatic Prostate Cancer

Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. [1]

Clinical Question

In patients with metastatic, hormone sensitive prostate cancer, does use of enzalutamide as first line therapy in addition to testosterone suppression +/- docetaxel compared to use of standard non-steroidal antiandrogens improve overall survival and progression free survival.

Bottom Line

Use of enzalutamide improved overall survival and progression-free survival in metastatic hormone sensitive prostate cancer, but associated with higher incidence of seizures and other toxic side effects

Major Points

The ENZAMET trial sets out to examine the use of Enzalutamide, an androgen-receptor inhibitor, in men with metastatic prostate cancer. This study compares enzalutamide with standard nonsteroidal antiandrogen tehrapy and shows a significant benefit in regards to overall survival and PSA progression free survival.

Guidelines

Current guidelines make the following recommendations for this group of men:

EAU

- Offer castration combined with chemotherapy (Docetaxel) to all patients whose first presentation is M1 disease and who are fit enough for docetaxel.

- Offer castration combined with abiraterone acetate plus prednisone to all patients whose first presentation is M1 disease and who are fit enough for regimen.

- Offer castration alone, with or without an anti-androgen, to patients unfit for, or unwilling to consider, castration combined with docetaxel or abiraterone acetate plus prednisone or RT.

NICE guidelines

Offer docetaxel chemotherapy to men who do not have significant comorbidities. The treatment should be started within 12 weeks of starting androgen deprivation therapy with six 3‑weekly cycles at a dose of 75 mg/m2 (with or without daily prednisolone).

Design

• Multicenter, open-label, randomized, controlled trial
• N=1125
  • Enzalutamide (n=563)
  • Standard (n=562)
• Setting: centres across Australia (majority), canada, Ireland, New Zealand, UK and the USA.
• Enrollment: March 2014-March 2017
• Median follow-up: 34 months
• Analysis: Intention-to-treat
• Primary outcome:Overall survival

Population

Inclusion Criteria

• Prostatic adenocarcinoma
• CT confirmed metastases
• ECOG score of 2 or less
• Testosterone supression commenced 12 weeks or less from randomisation
• previsous adjuvant testosterone supression of up to 24 months, if completed more ha 12 months ago

Exclusion Criteria

• Prostate cancer with significant sarcomatoid or spindle cell or neuroendocrine small cell

components

• history of siezures or cardiovascular disease
• Life expectancy less than 12 months
• History of seizures or cardiovascular disease
• Life expectancy less than 12 months
• History of other malignancies
• Participation in other trials for prostate cancer

Baseline Characteristics

• Mean age: 68.9 years
• Planned use of early docetaxel: 45%
• High volume disease: 52%
• Gleason score 8-10: 60%

• Nil significant difference to the baseline characteristics between the 2 groups
• Both groups have similar profiles in terms of disease volume (high 52% vs 53%; low 48% vs 47%; visceral mets 11% vs 12%)
• Some minor difference between previous therapy received by the 2 groups:

1. Adjuvant ADT 10% VS 7%

2. Anti-androgen therapy 51% vs 56%

3. Docetaxel 17% vs 15%

Interventions

Addition of open-label enzatulamide to testosterone suppression and comparison is made between this group and another that received standard non-steroidal antiandrogen drug with testosterone suppression.

Outcomes

Primary Outcomes

● The primary endpoint was overall survival

● 102 deaths in the enzalutamide group vs. 143 deaths in the standard-care group (hazard ratio, 0.67; 95% confidence interval 0.52 - 0.86, P = 0.002).

● Kaplan-Meier estimates of overall survival at 3 years was 80% in the enzalutamide group vs. 72% in the standard-care group.

Secondary Outcomes

● Secondary endpoints included progression-free survival as determined by the PSA level, clinical progression-free survival, and adverse events

● PSA progression-free survival was better in the enzalutamide group compared to the standard-care group (174 events vs. 333 events, hazard ratio 0.39, P<0.001)

● Clinical progression-free survival was better in the enzalutamide group compared to the standard-care group (167 events vs. 320 events, hazard ratio 0.40, P<0.001)

Subgroup Analysis

● Subgroup analyses included bone anti-resorptive therapy, planned early docetaxel treatment and high-volume disease

● The effects of enzalutamide on overall survival were smaller among these groups

● Respective P values for anti-resorptive therapy, planned early docetaxel and high-volume disease: 0.14, 0.14, 0.06

Sidenote: Effect on ongoing treatment

● The number of patients who received anticancer therapies after the trial regimen was lower in the enzalutamide group, reflecting the higher incidence of clinical progression in the standard-care group

● Less patients in the enzalutamide group received subsequent life-prolonging therapies compared to the standard-care group (67% vs. 85%).

Adverse Events

● Adverse events were consistent with the stage of disease, the age of patients and known safety profiles of the trial regimen

● More adverse events were reported by patients in the enzalutamide group (385 serious adverse events vs. 297 serious adverse event). However, the larger number of serious adverse events was in keeping with the longer duration of trial treatment in the enzalutamide group.

● Discontinuation due to adverse events was more frequent in the enzalutamide group.

● Seizures occurred in 7 patients in the enzalutamide group vs. 0 in the standard-care group

● Fatigue was also more common with enzalutamide than in the standard-care group (25% vs. 14%).

● In patients who received early docetaxel, peripheral neuropathy was reported more commonly in the enzalutamide group

Criticisms

- Insufficient African Americans included in study

- Imaging for recurrence not conducted regularly at set times

- Large number of pts discontinued medications

- Testosterone levels not measured

(These criticisms have been published in the NEJM)

Funding

The trial was funded by Astellas Pharma who are the manufacturer for enzalutamide. They provided both the medication and the funding for the trial conduct. Company representatives reviewed drafts of the protocol and trial report but were otherwise not involved in the design or data collection and analysis. Other funding sources included: Candian Cancer society, Cancer Australia, Cancer Trials Ireland, Dana–Farber Cancer Institute and practitioner fellowship and program grants from National Health and Medical Research Council of the Australian Government Department of Health

Further Reading

The CHAARTED trial [2]