Tuesday, April 15, 2014

Enzalutamide


A pivotal study presented at GU-ASCO 2014 was the
Multinational Phase 3, Randomized, Double-Blind, Placebo-
Controlled Efficacy and Safety Study of Oral MDV3100 in
Chemotherapy-Naive Patients With Progressive Metastatic
Prostate Cancer Who Have Failed Androgen Deprivation
Therapy (PREVAIL) study investigating the utility of enzalutamide
in chemotherapy-naïve patients with CRPC.1 The study
population included a total of 1717 men, enrolled in 22 countries,
including Canada. The subjects were randomized 1:1
to enzalutamide capsules 160 mg/day (n = 872) or placebo
(n = 845). Concomitant steroids were allowed, but were not
required. The co-primary efficacy endpoints were overall survival
(OS) and radiographic progression-free survival (rPFS).
The trial was intended to continue until there were 765 deaths,
with a pre-planned interim analysis planned at 516 deaths (twothirds
of the final number of events).
The baseline characteristics were well-balanced in the 2
groups. Median age was 71 years in the placebo group and 72
in the enzalutamide group. Approximately two-thirds of patients
in each group were either asymptomatic or mildly symptomatic
at initial diagnosis and approximately two-thirds of each group

had an Eastern Cooperative Oncology Group (ECOG) performance
score of 0. Approximately 4% of each group were taking
corticosteroids at baseline.
At the time of the interim analysis, the Data Monitoring
Committee reported statistically significant benefits in both OS
and rPFS in favour of the enzalutamide arm. Because of these
findings, the trial was halted and unblinded at that time; the
planned interim analysis therefore became the trial’s final analysis.
Patients from the placebo arm were subsequently offered
treatment with enzalutamide.
The median duration of treatment among patients in the
enzalutamide arm was 16.6 months, almost 4 times higher than
that of the placebo group (4.6 months). At the time of the trial’s
discontinuation, 42.1% of enzalutamide patients remained on
treatment, as did 7.2% of those in the placebo arm.
Figures 1a and 1b show the curves for the 2 co-primary endpoints.
For OS, enzalutamide significantly reduced the risk by
29% (hazard ratio [HR] 0.706, 95% confidence interval [CI] 0.60
to 0.84, p < 0.0001). Enzalutamide also prolonged mean rPFS,
with an HR of 0.186 (95% CI 0.15 to 0.23, p < 0.0001). The
estimated mean rPFS was 3.9 months with placebo (95% CI 3.7
to 5.4) and was not yet reached (NYR) with enzalutamide (95%
CI 13.8 to NYR). For both co-primary endpoints, the results were
consistent across pre-specified subgroups (e.g., ECOG 0 or 1, age
above or below 75 years, presence or absence of visceral disease
and geographic regions). Overall, the subgroup analyses were
consistent with the benefit observed for the primary analysis of

OS and PFS. Subsequent therapies were used less frequently in
the enzalutamide arm than in the placebo arm: 56.7% of the placebo
group was subsequently treated with docetaxel and 45.6%
with abiraterone. In the enzalutamide group, 32.8% went on to
receive docetaxel and 20.5% received abiraterone.
Objective response rates (complete response [CR] plus partial
response [PR], defined as per RECIST 1.1 criteria) were 58.8%
(19.7% + 39.1%) for enzalutamide and 4.9% (1% and 3.9%) for
placebo (p < 0.0001). Enzalutamide delayed the median time to
chemotherapy by 17 months relative to placebo (p < 0.0001).
Serious adverse events (SAEs) were experienced by 32.0% of
patients in the enzalutamide group and 26.8% of the placebo
group. Discontinuations due to adverse events (AEs) were 5.6%
of the enzalutamide group and 6.0% of the placebo group. AEs
leading to death occurred in 4.2% of the enzalutamide group
and 3.8% of the placebo group. The most common AEs in both
groups were fatigue, back pain, constipation and arthralgia.

One seizure was reported in the placebo group, and 1 seizure
event was subsequently reported in the enzalutamide arm after
the date of data cut-off.
Overall, enzalutamide was well-tolerated compared to placebo;
it demonstrated minimal side effects, with an impressive
29% improvement in OS, and reduced the risk of rPFS by 81%
in those patients who have not received chemotherapy.
Another study of interest with enzalutamide presented at
GU-ASCO 2014 was the data from the extended follow-up
at 49 weeks of the open-label, single-arm, Phase 2 study in
67 patients with histologically-confirmed hormone-naive prostate
cancer requiring hormonal treatment and presenting with
non-castrate testosterone levels (>230 ng/dL), prostate-specific
antigen (PSA) >2 ng/mL, ECOG performance status of 0, and
life expectancy greater than 12 months.2 Enzalutamide was
associated with large reductions in PSA levels, which were
maintained over the duration of the 49-week analysis period
in this study. At week 49, the PSA response rate for all
patients entering the study was 80.6% (54/67) achieving a PSA
decrease of 80% or greater from baseline. Outcomes for all
endpoints at 40 weeks were consistent with those reported at 25
weeks, and no new safety signals were observed.



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