CCR Perspectives in Drug Approval

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CCR Perspectives in Drug Approval

Enzalutamide for Treatment of Patients with Metastatic Castration-Resistant
Prostate Cancer Who Have Previously Received Docetaxel: U.S. Food and Drug
Administration Drug Approval Summary

Yangmin M. Ning1, William Pierce1, V. Ellen Maher1, Stella Karuri2, Sheng-Hui Tang2, Haw-Jyh Chiu1, Todd
Palmby1, Jeanne Fourie Zirkelbach3, Dhananjay Marathe3, Nitin Mehrotra3, Qi Liu3, Debasis Ghosh4, Christy L.
Cottrell1, John Leighton1, Rajeshwari Sridhara2, Amna Ibrahim1, Robert Justice1, and Richard Pazdur1

Abstract

This article summarizes the regulatory evaluation that led to the full approval of enzalutamide
(XTANDI®, Medivation Inc.) by the U. S. Food and Drug Administration (FDA) on August 31,
2012, for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC)
who have previously received docetaxel. This approval was based on the results of a randomized,
placebo-controlled trial which randomly allocated 1199 patients with mCRPC who had received
prior docetaxel to receive either enzalutamide 160 mg orally once daily (N=800) or placebo
(N=399). All patients were required to continue androgen deprivation therapy. The primary
endpoint was overall survival. At the pre-specified interim analysis, a statistically significant
improvement in overall survival was demonstrated for the enzalutamide arm compared to the
placebo arm [HR=0.63 (95% CI: 0.53, 0.75), p < 0.0001]. The median overall survival time was
18.4 and 13.6 months in the enzalutamide and placebo arms, respectively. The most common
adverse reactions (≥10%) included asthenia or fatigue, back pain, diarrhea, arthralgia, hot flush,
peripheral edema, musculoskeletal pain, headache, and upper respiratory infection. Seizures
occurred in 0.9% of patients on enzalutamide compared to no patients on the placebo arm. Overall,
the FDA’s review and analyses of the submitted data confirmed that enzalutamide had a favorable
benefit-risk profile in the study patient population, thus supporting its use for the approved
indication. The recommended dose is 160 mg enzalutamide administered orally once daily.
Enzalutamide represents the third product that FDA has approved in the same disease setting within
a period of 2 years.

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Authors' Affiliation: 1Office of Hematology and Oncology Products, Office of New Drugs; 2Office of Biostatistics;
3
  Office of Clinical Pharmacology; 4Office of New Drug Quality Assessment; Center for Drug Evaluation and Research,
U.S. Food and Drug Administration, Silver Spring, Maryland

Note: YM Ning and W Pierce reviewed the clinical efficacy and safety of enzalutamide in the NDA, respectively.

Corresponding Author: Yang-Min Ning, M.D., Ph.D. Office of Hematology and Oncology Products, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Building 22, Room 2139,
Silver Spring, MD 20993; E-mail: ningy@cder.fda.gov

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Introduction

Docetaxel in combination with prednisone was the first FDA-approved chemotherapy that improves
survival in patients with metastatic castration-resistant prostate cancer (mCRPC). It received full
approval in 2004 based on a 2.4 month improvement in median overall survival (OS) for docetaxel
compared to mitoxantrone [HR=0.76 (95% CI: 0.62, 0.94), p
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Enzalutamide is an androgen receptor inhibitor. Its clinical development was initiated by
Medivation Inc. in 2007. A Phase 1-2 study of enzalutamide (formerly named MDV3100) at oral
doses ranging from 30 to 600 mg daily demonstrated promising antitumor activity in 133 patients
with mCRPC who were either chemotherapy-naïve or previously treated with docetaxel (9, 10).
Although this study determined that the maximum tolerated dose of enzalutamide was 240 mg once
daily, an additional evaluation of the dose-related activity and safety data, particularly of the 3 cases
of seizure occurring at the doses greater than 240 mg, led to the choice of using enzalutamide 160
mg once daily for further clinical studies. To evaluate whether the antitumor activity of
enzalutamide could be translated into a tangible clinical benefit, the applicant conducted a
randomized, placebo-controlled trial (CRPC2) in patients with mCRPC previously treated with
docetaxel (11, 12). Patients with conditions that could predispose to seizure were excluded from this
randomized trial.

The new drug application (NDA) for enzalutamide was submitted and received by the FDA on May
22, 2012. This NDA was designated for a 6-month priority review and was approved on August 31,
2012, three months after submission. This article summarizes key findings from FDA’s
multidisciplinary review teams, with a focus on the clinical review findings that support the
approved indication. For more details, see the reviews of enzalutamide at Drugs@FDA (13).

Chemistry

Enzalutamide has a chemical designation as 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-
dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro-N-methylbenzamide. Its molecular
formula is C21H16F4N4O2S, with a molecular weight of 464.44. Enzalutamide is a white crystalline
non-hygroscopic solid that is practically insoluble in water.

The inactive ingredients of XTANDI include caprylocaproyl polyoxylglycerides, butylated
hydroxyanisole, butylated hydroxytoluene, gelatin, sorbitol sorbitan solution, glycerin, purified
water, titanium dioxide, and black iron oxide.

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XTANDI is provided as liquid-filled soft gelatin capsules. Each capsule contains 40 mg of
enzalutamide as a solution in caprylocaproyl polyoxylglycerides.

Nonclinical pharmacology and toxicology

In vitro, enzalutamide inhibited androgen binding to androgen receptors, androgen-dependent
androgen receptor nuclear translocation, androgen-dependent androgen receptor association with
DNA, and decreased proliferation and induced cell death of prostate cancer cells. In vivo,
enzalutamide decreased tumor volume in a mouse xenograft model of human prostate cancer.

Major target organ systems of toxicity that were identified in repeat-dose toxicity studies with
enzalutamide in rats and dogs were the reproductive organs and central nervous system. Consistent
with the pharmacological activity of enzalutamide, major toxicity findings were noted in male
reproductive organs. In a 26-week study in rats, decreased organ weights were correlated with
atrophy of the prostate and seminal vesicles, which were observed at systemic exposures similar to
the human exposure based on AUC. In 4- and 13-week studies in dogs, decreased organ weights
were correlated with hypospermatogenesis and atrophy of the prostate and epididymides, which
were observed at 0.3 times the human AUC. Convulsions were noted in repeat-dose studies in mice
and dogs. A dose-dependent increase in convulsions was observed in mice at 0.6 times the human
AUC, and a convulsion was observed in one dog at 3.3 times the human AUC. Other nonclinical
findings of minimal severity and without significant clinical correlations were noted in the liver
(hepatocellular hypertrophy), pituitary (hypertrophy and hyperplasia), and kidney (chronic
progressive nephropathy) following repeat-dose administration of enzalutamide to rats.

Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not
genotoxic in either the in vitro mouse lymphoma tk gene mutation assay or the in vivo mouse bone
marrow micronucleus assay. Carcinogenicity studies with enzalutamide were not conducted or
required to support approval for use in the indicated patient population.

Enzalutamide is not indicated for use in female patients. Reproductive and developmental
toxicology studies with enzalutamide were not required to support approval for use in the indicated
patient population. However, based on its mechanism of action and findings from repeat-dose

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toxicity studies in rats and dogs, enzalutamide may impair male fertility. In addition, enzalutamide
can cause fetal harm when administered to a pregnant woman based on its mechanism of action.
Enzalutamide was assigned pregnancy category X and is contraindicated for use in pregnant
women.

Clinical pharmacology

Following oral administration of enzalutamide, the median time to reach maximum plasma
enzalutamide concentrations is 1 hour (range 0.5 to 3 hours). The mean terminal half-life for
enzalutamide is 5.8 days. Enzalutamide steady state is achieved by Day 28, and the accumulation
ratio is 8.3 fold. At steady state, enzalutamide showed approximately dose proportional
pharmacokinetics over the daily dose range of 30 to 360 mg. Enzalutamide is primarily eliminated
by hepatic metabolism. Following oral administration of 14C-enzalutamide, 71% and 14% of
radioactivity were recovered in urine and feces, respectively. The major metabolite of
enzalutamide, N-desmethyl enzalutamide, has similar in vitro activity to enzalutamide. The mean
terminal half-life for N-desmethyl enzalutamide is 7.8 days.

Food does not alter the systemic exposure of enzalutamide or N-desmethyl enzalutamide, and
enzalutamide can be administered with or without food.

Co-medications can significantly affect the exposure to enzalutamide. Co-administration of
gemfibrozil (a strong CYP2C8 inhibitor) increased the composite exposure of enzalutamide plus N-
desmethyl enzalutamide by 2.2-fold. The concomitant use of strong CYP2C8 inhibitors should be
avoided if possible. If patients must be co-administered a strong CYP2C8 inhibitor, reduce the
enzalutamide dose to 80 mg once daily. The effects of CYP2C8 inducers on the pharmacokinetics
of enzalutamide have not been evaluated, and co-administration of enzalutamide with strong and
moderate CYP2C8 inducers should be avoided if possible. Co-administration of itraconazole (a
strong CYP3A4 inhibitor) increased the composite exposure of enzalutamide plus N-desmethyl
enzalutamide by 1.3-fold. The effects of CYP3A4 inducers on the pharmacokinetics of
enzalutamide have not been evaluated, and co-administration of enzalutamide with strong or
moderate CYP3A4 inducers should be avoided if possible.

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Enzalutamide can significantly affect the exposure to other co-medications. In vivo, enzalutamide is
a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer. At steady state,
enzalutamide reduced the plasma exposure to midazolam (a CYP3A4 substrate), warfarin (a
CYP2C9 substrate) and omeprazole (a CYP2C19 substrate) by 86%, 56% and 70%, respectively.
Therefore, concomitant use of enzalutamide with narrow therapeutic index drugs that are
metabolized by CYP3A4, CYP2C9 or CYP2C19 should be avoided if possible. If co-
administration with warfarin (a CYP2C9 substrate) is unavoidable, conduct additional INR
monitoring.

No exposure-response relationship for overall survival (OS) could be identified for enzalutamide
within a single fixed dose of 160 mg/day in the phase 3 CRPC2 trial. An exposure-response analysis
for seizure was not possible due to its low incidence in the trial; however, four patients who were
reported to have a seizure and who had available pharmacokinetic data belonged to the higher
exposure quartiles (Q3/Q4) rather than the lower exposure quartiles (Q1/Q2). The recommendation
for dose adjustment when co-administered with strong CYP2C8 inhibitors is intended to keep the
enzalutamide exposures within the concentration range that has been studied.

No starting dose adjustment is needed for patients with creatinine clearance (CrCL) greater than 30
mL/min. Clinical and pharmacokinetic data are insufficient to assess the potential effect of severe
renal impairment (CrCL < 30 mL/min) on enzalutamide pharmacokinetics.

The composite exposure of enzalutamide and N-desmethyl enzalutamide following a single dose of
enzalutamide was similar in subjects with baseline mild or moderate hepatic impairment (Child-
Pugh Class A and B, respectively) versus those with normal hepatic function, and no starting dose
adjustment is needed. Enzalutamide has not been studied in subjects with baseline severe hepatic
impairment (Child-Pugh Class C).

Clinical Studies

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This NDA was primarily based on results from the CRPC2 trial and was supported by data from
two open-label, single-arm Phase 1-2 studies in the same or similar patient populations. The
clinical review found that the two open-label studies showed similar PSA response rates
(approximately 50%) and safety signals.

Study design

The CRPC2 trial was a randomized, double-blind, placebo-controlled, multicenter Phase 3 trial
comparing the efficacy and safety of once daily dosing of enzalutamide to that of placebo in
patients with mCRPC who had previously received docetaxel. The primary endpoint was overall
survival. Key secondary endpoints included radiographic progression-free survival, time to PSA
progression, and the percentage of confirmed PSA declines of ≥50%.

Patients had to have documented evidence of disease progression by PSA and/or radiographic scans
while maintaining castrate levels of testosterone. Patients with the following conditions were
excluded: prostate cancer with evidence of neuroendocrine differentiation or small cell features, or
with evidence of metastases in the brain or active epidural disease; a history of seizure, including
any febrile seizure, loss of consciousness, or transient ischemia attack within 12 months of
enrollment, or any condition that may pre-dispose to seizure (e.g., prior stroke, brain arteriovenous
malformation, head trauma with loss of consciousness requiring hospitalization); or taking
medicines known to decrease the seizure threshold.

Patients were randomly allocated 2:1 to receive either enzalutamide orally at a dose of 160 mg once
daily or placebo orally once daily. All patients continued androgen deprivation therapy during the
trial. Patients were allowed, but not required to continue or initiate systemic use of glucocorticoids.
Study treatment continued until patients experienced disease progression (evidence of radiographic
progression, a skeletal-related event, or clinical progression), initiation of new treatment for the
disease, unacceptable toxicity, or withdrawal.

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All randomized patients constituted the intent-to-treat (ITT) population, regardless of whether the
actual allocated study treatment was administered or not. Primary efficacy analyses were conducted
in the ITT population. In contrast, the safety population consisted of all patients who received at
least one dose of study treatment.

Patient baseline characteristics

This trial enrolled 1199 patients from 156 study centers in 15 countries, with 800 patients allocated
to the enzalutamide arm and 399 to the placebo arm. Twenty-four percent of the patients were
recruited from the United States. Baseline demographics were balanced between the two arms. The
median age was 69 years (range 41-92) and the distribution by race was 93% Caucasian, 4% Black,
1% Asian, and 2% Other.

Key disease characteristics, as summarized in Table 1, were generally balanced between the two
arms at study entry. Of note, 91% of patients had metastases in bone and 23% had visceral
involvement in the lung and/or liver. The percentage of patients with visceral involvement was 4%
more in the enzalutamide arm than that in the placebo arm, which may favor the placebo arm in
terms of prognosis.

All patients had received prior docetaxel-based chemotherapy and 24% of the patients had received
two cytotoxic chemotherapy regimens. The prior docetaxel usage, including the cumulative dosage
(Table 1) and the time intervals of docetaxel use relative to the initiation of study treatment appears
balanced between the arms (13).

Prior use of the marketed androgen receptor antagonists was examined and found to be balanced
between the two arms. Across the arms, 85% of patients used bicalutamide, 14% used flutamide,
and 10% used nilutamide.

Efficacy results

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Analysis of the primary endpoint OS was conducted according to the pre-specified interim analysis
plan with a total of 520 events (80% of the events required for the planned final analysis). The
analysis demonstrated a statistically significant improvement in OS in patients on the enzalutamide
arm compared to patients on the placebo arm [stratified HR 0.63 (95% CI: 0.53, 0.75), p
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Table 2 summarizes the adverse reactions occurring at a ≥ 2% absolute increase in frequency in the
enzalutamide arm compared to the placebo arm. The most common adverse reactions with an
incidence frequency of ≥10% included asthenia or fatigue, back pain, diarrhea, arthralgia, hot flush,
peripheral edema, musculoskeletal pain, headache, and upper respiratory infection. Other common
adverse reactions (≥5% but
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seizure were excluded from the randomized trial, it is important to assess whether patients with pre-
disposing risk factors for seizure can safely tolerate this medication. The need for a trial to assess
this risk was identified during the review. The trial will be conducted by the applicant as a post-
marketing requirement.

Based on similar PSA response rates with enzalutamide in patients who were chemotherapy-naïve
and in patients who received prior docetaxel (10), a randomized, placebo-controlled Phase 3 trial is
ongoing to investigate the effectiveness and safety of enzalutamide in chemotherapy-naïve patients
with mCRPC (14). Results from this trial may help provide additional information about how to
best use enzalutamide in the treatment of patients with mCRPC.

The FDA’s approval of enzalutamide provides a new treatment option for patients with mCRPC
who have received prior docetaxel. Enzalutamide is the third product approved for use in patients
with mCRPC in the last 2 years (4, 5, 13). These three products, cabazitaxel, abiraterone acetate,
and enzalutamide, differ in their mechanism of action and benefit-risk profile, and will provide
more options in the treatment of patients with mCRPC. Nevertheless, choice of a treatment from
the three products will need best assessments of patient’s overall disease condition relative to the
known benefit-risk profile. Comparative effectiveness studies may help define what sequence or
combination of the products is more beneficial to patients.

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Disclosure of Potential Conflicts of Interest

All the authors have no conflicts of interests to disclose.

Authors' Contributions

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References
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  2.        Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus
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  3.        de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, et al. Prednisone
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  4.         Cabazitaxel FDA Medical Review, 2010.
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  5.         Abiraterone Acetate FDA Medical Review, 2011.
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  6.         Attard G, Reid AH, Yap TA, Raynaud F, Dowsett M, Settatree S, et al. Phase I clinical
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  7.        de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN,et al.
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  8.        Chen Y, Clegg NJ, Scher HI. Anti-androgens and androgen-depleting therapies in
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9.        Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, et al. Development of a
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10.       Scher HI, Beer TM, Higano CS, Anand A, Taplin ME, Efstathiou E, et al. Antitumour
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11.       Medivation, Inc. A multinational Phase 3, randomized, double-blind, placebo-controlled
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12.       Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, et al. Increased survival
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14.       Medivation, Inc. A multinational Phase 3, randomized, double-blind, placebo-controlled
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Figure Legend:

Figure 1: Kaplan-Meier curves of overall survival from the CRPC2 trial. XTANDI is the
proprietary name of enzalutamide. Hazard Ratio was derived from a stratified proportional hazards
model. Adapted from the original XTANDI product label, © 2012 Astellas Pharma US, Inc.

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   Table 1: Key Baseline Disease Characteristics in the CRPC2 Trial
                                            Enzalutamide            Placebo
                                               (N=800)              (N=399)
      Disease Progression Type*
       PSA-only Progression                                               326 (41%)                           164 (41%)
       Radiographic Progression                                           470 (59%)                           234 (59%)
      Disease Metastasis Site
       Bone                                                               730 (92%)                           364 (92%)
       Lymph Node                                                         442 (56%)                           219 (55%)
       Viscera (Liver, Lung)                                              196 (25%)                            82 (21%)
      Total Gleason Score at Diagnosis
       ≤7                                                                 359 (45%)                           175 (44%)
        ≥8                                                                366 (46%)                           193 (48%)
        Missing                                                            75 (9%)                            31 (8%)
      Serum PSA Level (ng/mL)
      Median (range)                                             108 (0.4, 11794)                    128 (0.6, 19000)
      ECOG Score
       0                                                                  298 (37%)                           156 (39%)
       1                                                                  432 (54%)                           211 (53%)
       2                                                                   70 (9%)                             32 (8%)
      BPI-SF Pain Score a (Mean)
        ≥4                                                                225 (28%)                           115 (29%)
        0                                                         429 (54%)                           199 (50%)
        =0                                                                146 (18%)                            85 (21%)
      Prior Chemotherapy Use
       Number of Regimens (%)
         1                                                                  72%                                  74%
         2                                                                  25%                                  24%
         ≥3 b                                                                3%                                   2%
      Total Docetaxel Usage c (mg)
        Median (range)                                                      600                                 600
                                                                         (25, 2520)                          (75, 2175)
    * Reported at the time of screening for this trial
    a: Baseline BPI-SF pain score of ≥4 (Average of patient’s reported scores over the 7 days prior to randomization).
    b: Representing a protocol deviation
    c: Reported in 86% patients. Prior docetaxel usage information was collected retrospectively.

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      Table 2: Adverse Reactions in the CRPC2 Trial
                                                       Enzalutamide                                     Placebo
                                                         (N=800)                                        (N=399)
                                 Grade 1-4 (%) Grade 3-4(%)                              Grade 1-4 (%)         Grade 3-4 (%)
General Disorders
  Asthenic Conditionsa               50.6          9.0                                          44.4                   9.3
  Peripheral Edema                   15.4          1.0                                          13.3                   0.8
Musculoskeletal And Connective Tissue Disorders
  Back Pain                          26.4          5.3                                          24.3                   4.0
  Arthralgia                         20.5          2.5                                          17.3                   1.8
  Musculoskeletal Pain               15.0          1.3                                          11.5                   0.3
  Muscular Weakness                   9.8          1.5                                           6.8                   1.8
  Musculoskeletal Stiffness           2.6          0.3                                           0.3                   0.0
Gastrointestinal Disorders
  Diarrhea                           21.8          1.1                                          17.5                   0.3
Vascular Disorders
  Hot Flush                          20.3          0.0                                          10.3                   0.0
  Hypertension                        6.4          2.1                                           2.8                   1.3
Nervous System Disorders
  Headache                           12.1          0.9                                          5.5                    0.0
  Dizzinessb                          9.5          0.5                                          7.5                    0.5
  Spinal Cord Compression and         7.4          6.6                                          4.5                    3.8
  Cauda Equina Syndrome
  Paresthesia                         6.6          0.0                                          4.5                    0.0
  Mental Impairment Disordersc        4.3          0.3                                          1.8                    0.0
  Hypoesthesia                        4.0          0.3                                          1.8                    0.0
Infections And Infestations
  Upper Respiratory Tract             10.9         0.0                                          6.5                    0.3
  Infectiond
  Lower Respiratory Tract And          8.5         2.4                                          4.8                    1.3
  Lung Infectione
Psychiatric Disorders
  Insomnia                            8.8          0.0                                          6.0                    0.5
  Anxiety                             6.5          0.3                                          4.0                    0.0
Renal And Urinary Disorders
  Hematuria                           6.9          1.8                                          4.5                    1.0
  Pollakiuria                         4.8          0.0                                          2.5                    0.0
Injury, Poisoning And Procedural Complications
  Fall                                4.6          0.3                                          1.3                    0.0
  Non-pathologic Fractures            4.0          1.4                                          0.8                    0.3
Skin And Subcutaneous Tissue Disorders
  Pruritus                            3.8          0.0                                          1.3                    0.0
  Dry Skin                            3.5          0.0                                          1.3                    0.0
Respiratory Disorders
  Epistaxis                           3.3          0.1                                          1.3                    0.3
a Includes asthenia and fatigue. Discontinuations due to fatigue were reported for 0.6% of enzalutamide-treated patients and 0.5%
of placebo-treated patients.
b Includes dizziness and vertigo.
c Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention.
d Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis.
e Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.
 Note: all adverse reactions were graded using the NCI Common Terminology Criteria for Adverse Events version 4

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Author Manuscript Published OnlineFirst on October 18, 2013; DOI: 10.1158/1078-0432.CCR-13-1763
  Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

          Figure 1:

                                     100%

                                     80%

                                     60%
                      Survival (%)

                                     40%
                                                      XTANDI (n = 800)
                                                      Median 18.4 months
                                                      Placebo (N = 399)
                                                      Median 13.6 months
                                     20%
                                                      Hazard ratio = 0.63
                                                      95% CI (0.53, 0.75)
                                                      P < 0.0001

                                      0%
                                            0     3           6        9       12     15    18   21   24
                                                                             Months
               XTANDI                       800   775        701       627     400    211   72    7    0
               Placebo                      399   376        317       263     167    81    33    3    0

Downloaded from clincancerres.aacrjournals.org on March 14, 2021. © 2013 American Association for Cancer
                                               Research.
Author Manuscript Published OnlineFirst on October 18, 2013; DOI: 10.1158/1078-0432.CCR-13-1763
              Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

Enzalutamide for Treatment of Patients with Metastatic
Castration-Resistant Prostate Cancer Who Have Previously
Received Docetaxel: U.S. Food and Drug Administration Drug
Approval Summary
Yangmin M Ning, William Pierce, V Ellen Maher, et al.

Clin Cancer Res Published OnlineFirst October 18, 2013.

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                         doi:10.1158/1078-0432.CCR-13-1763

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