An Efficacy and Safety Study of Enzalutamide Plus Androgen Deprivation Therapy (ADT) Versus Placebo Plus ADT in Chinese Patients With Metastatic Hormone Sensitive Prostate Cancer (mHSPC)

Study Overview
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Brief Summary
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The purpose of this study was to evaluate the efficacy and safety of enzalutamide plus androgen deprivation therapy (ADT) versus placebo plus ADT in Chinese subjects with metastatic hormone sensitive prostate cancer (mHSPC). The study was conducted in two phases: Double-Blind treatment phase and open-label phase.

Official Title
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China ARCHES: A Multicenter, Phase 3, Randomized, Double-blind, Placebo Controlled Efficacy and Safety Study of Enzalutamide Plus Androgen Deprivation Therapy (ADT) Versus Placebo Plus ADT in Chinese Patients With Metastatic Hormone Sensitive Prostate Cancer (mHSPC)

Conditions
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Metastatic Hormone Sensitive Prostate Cancer

Intervention / Treatment
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* Drug: Enzalutamide
* Drug: Placebo
* Drug: Androgen deprivation therapy (ADT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Double Blind treatment Phase: Subject is diagnosed with histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation, signet cell or small cell histology. Subject has metastatic prostate cancer documented by positive bone scan (for bone disease) or measurable metastatic lesions on computed tomography (CT) or magnetic resonance imaging (MRI) scan (for soft tissue). Subjects whose disease spread is limited to regional pelvic lymph nodes are not eligible. Once randomized at day 1, subject must maintain androgen deprivation therapy (ADT) with a luteinizing hormone-releasing hormone (LHRH) agonist or antagonist during study treatment or have a history of bilateral orchiectomy (i.e., medical or surgical castration). Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at screening. Subject has an estimated life expectancy of ≥ 12 months. Subject is able to swallow the study drug and comply with study requirements. A sexually active male subject with female partner(s) who is of childbearing potential is eligible if: Agrees to use a male condom starting at screening and continue throughout the study treatment and for at least 3 months after the last dose of study drug. If the male subject has not had a vasectomy or is not sterile at least 6 months prior to screening his female partner(s) is utilizing 1 form of highly effective birth control per locally accepted standards starting at screening and continue throughout study treatment and for at least 3 months after the male subject receives his last dose of study drug. Subject must agree to abstinence or use a condom throughout the study period and for at least 3 months after the last dose of study drug if engaging in sexual intercourse with a pregnant or breastfeeding partner(s). Subject must agree not to donate sperm from first dose of study drug through 3 months after the last dose of study drug. Subject agrees not to participate in another interventional study while on treatment. Open Label Phase: Before the sponsor's formal determination on study-wide unblinding, includes the subject who has evidence of radiographic progression as confirmed during the double-blind treatment (only apply to the subject in the placebo arm). Subject has not met any of the discontinuation criteria in the main protocol. Subject in the placebo arm who achieved confirmed radiographic progression in the double-blinded period is eligible. Subject is willing to maintain ADT with LHRH agonist or antagonist or has had a bilateral orchiectomy Subject is able to swallow enzalutamide capsules whole and to comply with study requirements throughout the study Subject and subject's female partner agree to follow contraception and sperm donation requirements in main protocol IRB-/IEC-approved written informed consent and privacy language as per national regulations must be obtained from the subject or legally authorized representative prior to any study-related procedures (including withdrawal of prohibited medication, if applicable). Subject is considered an adult according to local regulation at the time of signing informed consent. After the sponsor's formal determination on study-wide unblinding, includes the subject who is randomized to receive treatment in the double-blind period (apply to all subjects). Exclusion Criteria: Double-Blind Treatment Phase: Subject has received any prior pharmacotherapy, radiation therapy or surgery for metastatic prostate cancer (the following exceptions are permitted): Up to 3 months of ADT with LHRH agonists or antagonists or orchiectomy with or without concurrent antiandrogens prior to day 1, with no radiographic evidence of disease progression or rising prostate-specific antigen (PSA) levels prior to day 1; Subject may have 1 course of palliative radiation or surgical therapy to treat symptoms resulting from metastatic disease if it was administered at least 4 weeks prior to day 1; Up to 6 cycles of docetaxel therapy with final treatment administration completed within 2 months of day 1 and no evidence of disease progression during or after the completion of docetaxel therapy; Up to 6 months of ADT with LHRH agonists or antagonists or orchiectomy with or without concurrent antiandrogens prior to day 1 if subject was treated with docetaxel, with no radiographic evidence of disease progression or rising PSA levels prior to day 1; Prior ADT given for < 39 months in duration and > 9 months before randomization as neoadjuvant/adjuvant therapy. Subject had a major surgery within 4 weeks prior to day 1. Subject received treatment with 5-α reductase inhibitors (finasteride, dutasteride) within 4 weeks prior to day 1. Subject received treatment with estrogens, cyprotoerone acetate or androgens within 4 weeks prior to day 1. Subject received treatment with systemic glucocorticoids greater than the equivalent of 10 mg per day of prednisone within 4 weeks prior to day 1, intended for the treatment of prostate cancer. Subject received treatment with herbal medications that have known hormonal antiprostate cancer activity and/or are known to decrease PSA levels within 4 weeks prior to day 1. Subject received prior aminoglutethimide, ketoconazole, abiraterone acetate or enzalutamide for the treatment of prostate cancer or participation in a clinical study of an investigational agent that inhibits the androgen receptor or androgen synthesis (e.g., TAK-700, ARN-509, ODM-201). Subject received investigational agent within 4 weeks prior to day 1. Subject has known or suspected brain metastasis or active leptomeningeal disease. Subject has a history of another invasive cancer within 3 years of screening, with the exception of fully treated cancers with a remote probability of recurrence. Subject has absolute neutrophil count < 1500/μL, platelet count < 100000/μL or hemoglobin < 10 g/dL (6.2 mmol/L) at screening. NOTE: May not have received any growth factors within 7 days or blood transfusions within 28 days prior to the hematology values obtained at screening. Subject has total bilirubin ≥ 1.5 x the upper limit of normal (except subjects with documented Gilbert's disease), or alanine aminotransferase or aspartate aminotransferase ≥ 2.5 x the upper limit of normal at screening. Subject has creatinine > 2 mg/dL (177 μmol/L) at screening. Subject has albumin < 3.0 g/dL (30 g/L) at screening. Subject has a history of seizure or any condition that may predispose to seizure (e.g., prior cortical stroke or significant brain trauma, brain arteriovenous malformation). Subject has history of loss of consciousness or transient ischemic attack within 12 months prior to day 1. Subject has clinically significant cardiovascular disease, including the following: Myocardial infarction within 6 months prior to screening; Unstable angina within 3 months prior to screening; New York Heart Association class III or IV congestive heart failure or a history of New York Heart Association class III or IV congestive heart failure unless a screening echocardiogram or multigated acquisition scan performed within 3 months before the randomization date demonstrates a left ventricular ejection fraction ≥ 45%; History of clinically significant ventricular arrhythmias (e.g., sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes); History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place; Hypotension as indicated by systolic blood pressure < 86 mm Hg at screening; Bradycardia as indicated by a heart rate of ≤ 45 beats per minute on the screening electrocardiogram; Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure measurements showing systolic blood pressure > 170 mm Hg or diastolic blood pressure > 105 mm Hg at screening. Subject has gastrointestinal disorder affecting absorption. Subject has any concurrent disease, infection or comorbid condition that interferes with the ability of the subject to participate in the study, which places the subject at undue risk or complicates the interpretation of data. Subject received bisphosphonates or denosumab within 2 weeks prior to day 1 unless administered at stable dose or to treat diagnosed osteoporosis. Subject has shown a hypersensitivity reaction to the active pharmaceutical ingredient or any of the study capsule components. Open-Label Phase: Subject has taken commercially available enzalutamide After unblinding, subject has started any new investigational agent or anti-neoplastic therapy intended to treat prostate cancer Subject has any clinically significant disorder or condition including excessive alcohol or drug abuse, or secondary malignancy, which may interfere with study participation in the opinion of the investigator or medical monitor Subject has current or previously treated brain metastasis or active leptomeningeal disease Subject has a history of seizure or any condition that may increase the risk of seizure Subject's disease has progressed radiographically during the double-blind period of the study and treatment with study drug was stopped prior to study-wide unblinding. (Note: Subject who progressed radiographically while in the double-blind period of the study and continued treatment per protocol is allowed to participate in the open-label phase.)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Enzalutamide Plus Androgen Deprivation Therapy (ADT) (Double Blind Phase)<br>Participants received enzalutamide 160 mg capsules, orally once daily if tolerable, and continued ADT until radiographic disease progression was documented or until they started another investigational agent or new therapy for treatment of prostate cancer. Participants were to remain on study treatment until confirmed radiographic disease progression. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment. | Drug: Enzalutamide<br>* Oral<br>* Other names: MDV3100;Drug: Androgen deprivation therapy (ADT)<br>* All participants were required to maintain ADT during study treatment, either using luteinizing hormone-releasing hormone (LHRH) agonist/antagonist or having a history of bilateral orchiectomy.<br>|
| Placebo Comparator: Placebo Plus ADT (Double Blind Phase)<br>Participants received enzalutamide-matching placebo capsules, orally once daily and continued ADT until radiographic disease progression was documented or until they started another investigational agent or new therapy for treatment of prostate cancer. Participants were to remain on study treatment until confirmed radiographic disease progression. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment. | Drug: Placebo<br>* Oral<br>Drug: Androgen deprivation therapy (ADT)<br>* All participants were required to maintain ADT during study treatment, either using luteinizing hormone-releasing hormone (LHRH) agonist/antagonist or having a history of bilateral orchiectomy.<br>|
| Experimental: Enzalutamide Plus ADT (Open-Label Phase)<br>Participants who received placebo in double-blind phase and remaind on study treatment until confirmed radiographic disease progression received enzalutamide and continued ADT in open-label phase. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment. | Drug: Enzalutamide<br>* Oral<br>* Other names: MDV3100;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Prostrate Specific Antigen (PSA) Progression | Time to PSA progression was calculated as the time from the date of randomization to the first observation of PSA progression. PSA progression was defined as a ≥ 25% increase and an absolute increase of ≥ 2 microgram/liter (μg/L) (2 nanogram/milliliter [ng/mL]) above the nadir (i.e., lowest PSA value observed post baseline or at baseline), which was confirmed by a second consecutive value at least 3 weeks later. Time to event analysis was performed using Kaplan-Meier estimates. | From the date of randomization to the first observation of PSA progression (up to 38 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiographic Progression-Free Survival (rPFS) | An rPFS event was defined as the time from randomization to the first objective evidence of radiographic disease progression assessed by investigator or death (defined as death from any cause within 24 weeks from study drug discontinuation), whichever occurred first. Radiographic disease progression was defined as progressive disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for soft tissue disease or by appearance of 2 or more new lesions on bone scan. Time to event analysis was performed using Kaplan-Meier estimates. | up to 38 months | 
| Time to First Symptomatic Skeletal Event (SSE) | Time to first SSE was defined as the time from randomization to the occurrence of the first SSE. SSE was defined as radiation or surgery to bone, clinically apparent pathological bone fracture or spinal cord compression. Time to event analysis was performed using Kaplan-Meier estimates. | Up to 38 months | 
| Time to Castration Resistance | Castration resistance was defined as occurrence of radiographic disease progression, PSA progression or SSE with castrate levels of testosterone (< 50 ng/dL). Time to castration resistance was defined as the time from randomization to the first castration resistant event (radiographic disease progression, PSA progression or SSE), whichever occurred first. PSA progression was defined as a ≥ 25% increase and an absolute increase of ≥ 2 μg/L (2 ng/mL) above the nadir (i.e., lowest PSA value observed post baseline or at baseline), which was confirmed by a second consecutive value at least 3 weeks later. Radiographic disease progression was defined as progressive disease by RECIST version 1.1 for soft tissue disease or by appearance of 2 or more new lesions on bone scan. SSE was defined as radiation or surgery to bone, clinically apparent pathological bone fracture or spinal cord compression. Time to event analysis was performed using Kaplan-Meier estimates. | Up to 38 months | 
| Percentage of Participants With PSA Response (≥ 50%) | The PSA response rate ≥50% is defined as the percentage of participants in the analysis population with maximal PSA declines of at least 50% at any time and at each visit for participants with detectable PSA at baseline and at least 1 post-baseline assessment. | Up to 38 months | 
| Percentage of Participants With PSA Response (≥ 90%) | The PSA response rate ≥90% is defined as the percentage of participants in the analysis population with maximal PSA declines of at least 90% at any time and at each visit for participants with detectable PSA at baseline and at least 1 post-baseline assessment. | Up to 38 months | 
| Time to Initiation of New Antineoplastic Therapy | Time to initiate of a new antineoplastic therapy (including cytotoxic and hormone therapies) was defined as the time interval from randomization to the date of the first dose administration of the first antineoplastic therapy. Time to event analysis was performed using Kaplan-Meier estimates. | Up to 38 months | 
| Percentage of Participants With Undetectable PSA (< 0.2 ng/mL) | The PSA undetectable rate was defined as the percentage of participants with detectable (≥ 0.2 ng/mL) PSA at baseline, which became undetectable (< 0.2 ng/mL) during study treatment. Only participants with detectable PSA at baseline was included in the analysis. | Up to 38 months | 
| Objective Response Rate (ORR) | The ORR was defined as the percentage of participants with measurable disease at baseline who achieved a complete or partial response (CR or PR) in their soft tissue disease using the RECIST version 1.1 criteria, CR was defined as complete disappearance of all target lesions and non-target disease. No new lesions. PR was defined as >=30% decrease on study under baseline of the sum of longest diameters of all target lesions. No unequivocal progression of non-target disease. No new lesions. | Up to 38 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic hormone sensitive prostate cancer, Androgen Deprivation Therapy (ADT), Xtandi, MDV3100, Enzalutamide