A Multinational, Phase 3, Randomized, Double-Blind, Placebo-Controlled, Efficacy and Safety Study of Enzalutamide in Patients With Nonmetastatic Castration-Resistant Prostate Cancer

Prostate cancer progresses through a series of characteristic clinical states
that reflect both the natural history of the disease and response to treatment.
Following the initial evaluation and diagnosis of prostate cancer,
approximately 90% of men undergo primary localized treatment with curative
intent. After initiation of androgen deprivation therapy in men with rising
prostate-specific antigen (PSA) after primary therapy, the next clinical state
in the current model of prostate cancer progression is that of
castration-resistant prostate cancer (CRPC), defined as progression despite
castrate hormone levels (testosterone <= 50 ng/dL). CRPC is present in 10% to
20% of all men with prostate cancer, and is associated with a high risk of bone
metastases, bone pain, pathologic fractures, spinal cord compression, decreased
quality of life, and death from prostate cancer.

PSA doubling time and baseline PSA are useful for identifying the subset of men
who are at high risk for morbidity and mortality from CRPC. For example, an
analysis of 201 patients with nonmetastatic CRPC randomized to the placebo arm
in an aborted randomized controlled trial of zoledronic acid showed that PSA
doubling time and baseline PSA independently predicted risk of time to first
bone metastases, overall survival, and metastasis-free survival (MFS). The
relative risk of a shorter time to first bone metastases for patients with a
PSA greater than 10 ng/mL was 3.18 (95% confidence interval [CI]: 1.74, 5.8)
and the relative risk for a 0.01 increase in PSA velocity was 4.34 (95% CI:
2.30, 8.21).

Currently, although continued use of androgen deprivation therapy is part of
clinical practice, no medicine is approved for treatment of patients with
nonmetastatic CRPC or for prevention of metastasis, and the results of several
studies designed to address these needs have been disappointing. Therefore, no
standard of care is defined for nonmetastatic CRPC and accordingly, patients
are encouraged to participate in clinical trials.

The androgen receptor remains the main driver of prostate cancer progression in
CRPC. Enzalutamide is a potent androgen receptor inhibitor that significantly
prolonged overall survival in men with metastatic CRPC previously treated with
docetaxel. Patients with nonmetastatic CRPC at high risk for metastatic disease
may therefore also derive significant benefit from treatment with enzalutamide.
The Phase 3 study described herein is designed to address this unmet medical
need.

Primary
• To determine the efficacy of enzalutamide compared with placebo as assessed
by metastasis-free survival (MFS).

Secondary:
• To evaluate the benefit of enzalutamide compared with placebo as measured by
the following:
- Time to PSA progression
- Time to first use of new antineoplastic therapy
- Overall survival
- Time to pain progression
- Time to first use of cytotoxic chemotherapy
- Chemotherapy-free disease-specific survival
- Chemotherapy-free survival
- PSA response rates
- Quality of life as assessed by the Functional Assessment of Cancer
Therapy-Prostate (FACT-P) questionnaire, European Quality of Life-5
Dimensions-5 Levels (EQ-5D-5L) health questionnaire, and Quality of Life
Questionnaire-Prostate 25 (QLQ-PR25) module

• To evaluate safety

This multinational, Phase 3, randomized, double-blind, placebo-controlled,
efficacy and safety study will assess the efficacy and safety of enzalutamide
versus placebo in approximately 1560 men with nonmetastatic CRPC. All patients
will be required to maintain androgen deprivation during the study, either
using a gonadotropin-releasing hormone (GnRH) agonist/antagonist or having a
history of bilateral orchiectomy.

Central randomization to enzalutamide or placebo treatments (2:1) will be
stratified by the following factors:
• PSA doubling time (< 6 months vs >= 6 months);
• Baseline use of a bone-targeting agent (yes vs no).

The primary efficacy endpoint is MFS, defined as the time from randomization to
radiographic progression or death on study (death within 112 days of treatment
discontinuation without evidence of radiographic progression), whichever occurs
first. Assessment of bone disease will be done by whole-body radionuclide bone
scan. A bone scan will consist of 5 regions including skull, thorax, spine,
pelvis, and extremities. Radiographic progression for bone disease is defined
as the appearance of 1 or more metastatic lesion on bone scan. Confirmation
with a second imaging modality (plain film, computed tomography [CT], or
magnetic resonance imaging [MRI]) will be required when bone lesions are found
in a single region on the bone scan. Appearance of metastatic lesions in 2 or
more of the 5 regions on a bone scan will not require confirmation with a
second imaging modality. Assessment of soft tissue disease will be done by CT
or MRI. Radiographic progression for soft tissue disease is defined by the
Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1)

All study films should be read locally at the study site and submitted to the
central imaging unit for independent central radiology review. Each study site
should designate a radiologist or investigator as the primary imaging reviewer
to ensure that all images are read consistently as specified in Section 9.1. of
the protocol. Radiographic assessments will be approximately every 16 weeks,
but images may be obtained sooner if progression is clinically suspected.
Radiographic imaging will not be required after radiographic progression is
confirmed by independent central radiology review according to protocol
specifications

In addition to imaging, the following assessments of prostate cancer status
will be made during the course of the study: survival status, pain intensity
and interference using the Brief Pain Inventory Short Form (BPI-SF),opiate use
for prostate cancer pain, PSA values, functional status deterioration as
assessed by the FACT-P questionnaire, and quality of life as assessed by the
EQ-5D-5L and QLQ-PR25 questionnaires. Assessments of safety will include
adverse events, clinical laboratory tests, physical examinations, and vital
signs. An independent Data Monitoring Committee will periodically monitor the
safety data.

Patients will have safety follow-up approximately 30 days after the last dose
of study drug. If a new antineoplastic treatment is initiated before 30 days
after the last dose of study drug, then safety follow-up will occur immediately
before starting the new treatment. Long-term follow-up assessments will include
monitoring for survival status, new antineoplastic therapies for prostate
cancer, opiate medications, skeletal-related events, and interventions due to
locoregional progression (eg, radiation, transurethral resection of the
prostate, nephrostomy tube placement).

Enzalutamide (160 mg/day) will be administered as four 40-mg soft gelatin
capsules by mouth once daily with or without food. Placebo capsules, identical
in appearance to enzalutamide capsules, will be administered to patients in the
control arm in the same manner.

Study drug administration should continue until radiographic progression.
Investigators are discouraged from obtaining PSA assessments at their local
laboratories during the study and from discontinuing a patient*s study drug
treatment due to PSA rise alone. Initiation of new therapy for prostate cancer
(with the exception of cytotoxic chemotherapy, androgen receptor inhibitors,
and investigational agents) at the time of radiographic progression will not
mandate discontinuation of study drug if the investigator considers continuing
study drug to be beneficial. Prostate cancer is a multiclonal disease, and a
patient with confirmed disease progression may have other clones/foci that may
benefit from continued treatment with study drug. In the ongoing, blinded,
phase 3 PREVAIL study, approximately 34 of 1715 treated patients (2%) received
study drug and antiandrogen or abiraterone after radiographic disease
progression.

Initiation of bisphosphonates or other bone-targeting agents for bone health,
such as denosumab, is not allowed during the study prior to development of bone
metastasis; however, treatment with these agents should continue if initiated
at least 4 weeks before enrollment. Standard of care supplementation with
calcium and vitamin D is encouraged.

In the Phase 3 study CRPC2 (AFFIRM), the prespecified interim analysis at the
time of 520 events demonstrated a statistically significant improvement in
overall survival in patients with metastatic CRPC treated with enzalutamide
versus placebo (hazard ratio [HR] = 0.631; 95% CI: 0.529, 0.752, p < 0.0001).9
The median survival was 18.4 months in the enzalutamide arm and 13.6 months in
the placebo arm (Δ = 4.8 months). The overall survival benefit was consistent
across all subgroups, including age, baseline pain intensity, geographic
region, and type of disease progression at entry. Enzalutamide treatment was
superior to placebo for all secondary endpoints including the proportion of
patients with a reduction in PSA level by 50% or more (54% vs 2%, p < 0.001),
soft tissue response rate (29% vs 4%, p < 0.001), quality of life response rate
(43% vs 18%, p < 0.001), time to PSA progression (8.3 vs 3.0 months; HR 0.25, p
< 0.001), rPFS (8.3 vs 2.9 months; HR 0.40, p < 0.001), and time to first
skeletal related event (16.7 vs 13.3 months; HR 0.69, p < 0.001). Based on the
AFFIRM data, the US FDA approved enzalutamide in August 2012 for men with
metastatic CRPC who previously received docetaxel therapy.
The most common adverse reactions (>= 5%) in patients treated with enzalutamide
(N = 800) in the Phase 3 study CRPC2 (AFFIRM) (N = 1199) were asthenia/fatigue,
back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal
pain, headache, upper respiratory infection, muscular weakness, dizziness,
insomnia, lower respiratory infection, spinal cord compression and cauda equina
syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 1 4
neutropenia occurred in 15% of enzalutamide treated patients (1% grade 3 4) and
in 6% of placebo treated patients (no grade 3 4). Other treatment emergent
adverse events reported in fewer than 5% of patients, but that may have been
associated with enzalutamide treatment, included falls, nonpathologic fracture,
dry skin, and pruritus. A possible cognitive effect of enzalutamide was
reported in a greater proportion of patients in the enzalutamide group for the
following adverse event terms: memory impairment, cognitive disorder, amnesia,
and disturbance of attention. In addition, event terms related to
hallucination (visual hallucination, tactile hallucination, hallucination) were
reported more frequently in the enzalutamide group. Discontinuations due to
adverse events were reported for 16% of enzalutamide treated patients and 18%
of placebo treated patients. The most common adverse reaction leading to
treatment discontinuation was seizure, which occurred in 0.9% of the
enzalutamide treated patients and none (0%) of the placebo treated patients.
The safety and tolerability of enzalutamide were evaluated in an integrated
safety analysis including patients from AFFIRM and 3 open label studies, and
continues to be evaluated on an ongoing basis for all enzalutamide program
studies. No study has been terminated early for safety reasons.
The totality of the efficacy and safety data suggests a positive benefit risk
assessment for the use of enzalutamide in men with metastatic CRPC who have
previously received docetaxel, and for the continued investigation of
enzalutamide in men with earlier stage prostate cancer.