Clinical trial NCT02677896: A Study of Enzalutamide Plus Androgen Deprivation Therapy (ADT) Versus Placebo Plus ADT in Patients With Metastatic Hormone Sensitive Prostate Cancer (mHSPC)
Official title: A Multinational, Phase 3, Randomized, Double-blind, Placebo-controlled Efficacy and Safety Study of Enzalutamide Plus Androgen Deprivation Therapy (ADT) Versus Placebo Plus ADT in Patients With Metastatic Hormone Sensitive Prostate Cancer (mHSPC)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Metastatic Hormone Sensitive Prostate Cancer
Keywords: Androgen Deprivation Therapy (ADT)
Metastatic hormone sensitive prostate cancer
Xtandi
Enzalutamide
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
Collaborators: name: Medivation LLC, a wholly owned subsidiary of Pfizer Inc.
First posted: 2016-02-09
Enrollment: 1150
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study was to evaluate the efficacy of enzalutamide plus androgen deprivation therapy (ADT) as measured by radiographic progression-free survival (rPFS) based on central review. The study also evaluated the safety of enzalutamide plus ADT in mHSPC.

Detailed description: Following unblinding at the end of the double-blind period and demonstration of a statistically significant advantage of enzalutamide over placebo when added to ADT as assessed by the primary endpoint of rPFS, subjects were eligible to transition to an open-label portion of the study.

Eligibility criteria: Inclusion Criteria:

* Subject is considered an adult according to local regulation at the time of signing informed consent.
* 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 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 ADT with an 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.

Inclusion Criteria for Open-Label Extension:

* Subject received randomized double-blind treatment in ARCHES
* Subject has not met any of the discontinuation criteria in the main ARCHES protocol
* 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

Exclusion Criteria:

* 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 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 AR or androgen synthesis (e.g., TAK-700, ARN-509, ODM-201).
* Subject has known or suspected brain metastasis or active leptomeningeal disease.
* Subject has absolute neutrophil count \< 1500/μL, platelet count \< 100000/μL or hemoglobin \< 10 g/dL (6.2 mmol/L).
* Subject has total bilirubin (TBL) ≥ 1.5 x the upper limit of normal (ULN) (except subjects with documented Gilbert's disease), or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 2.5 x the ULN .
* Subject has creatinine \> 2 mg/dL (177 μmol/L).
* Subject has albumin \< 3.0 g/dL (30 g/L).
* Subject has a history of seizure or any condition that may predispose to seizure.
* Subject has history of loss of consciousness or transient ischemic attack within 12 months prior to day 1.
* Subject has clinically significant cardiovascular disease.
* Subject received bisphosphonates or denosumab within 2 weeks prior to day 1 unless administered at stable dose or to treat diagnosed osteoporosis

Exclusion Criteria for Open-Label Extension:

* Subject has taken commercially available enzalutamide (Xtandi).
* 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: Subjects who progressed radiographically while in the double-blind portion of the study and continued treatment per protocol are allowed to participate in the open label extension.)
* After study-wide 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
* 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

Primary outcomes:
measure: Radiographic Progression-Free Survival (rPFS) Based on Independent Central Review (ICR) of Bone Scan According to Prostate Cancer Clinical Trials Working Group 2 (PCWG2) Criteria
timeFrame: From the date of randomization to the first objective evidence of rPD at any time or death (maximum duration was 26.6 months)
measure: rPFS Based on ICR of Bone Scan According to Protocol Assessment Criteria
timeFrame: From the date of randomization to the first objective evidence of rPD at any time or death (maximum duration was 26.6 months)
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: From randomization to death due to any cause (maximum duration was 58.6 months)
measure: Time to Prostate Specific Antigen (PSA) Progression
timeFrame: From the date of randomization to the first observation of PSA progression (maximum duration was 26.6 months)
measure: Time to Start of New Antineoplastic Therapy
timeFrame: From randomization to the date of the first dose administration of the first antineoplastic therapy (maximum duration was 58.6 months)
measure: PSA Undetectable Rate
timeFrame: From baseline to detectable PSA values (maximum duration was 26.6 months)
measure: Objective Response Rate (ORR)
timeFrame: From date of randomization up to 26.6 months
measure: Time to Deterioration in Urinary Symptoms
timeFrame: From date of randomization to the first deterioration in urinary symptoms at any postbaseline visit (maximum duration was 26.6 months)
measure: Time to First Symptomatic Skeletal Event (SSE)
timeFrame: From randomization to the occurrence of the first SSE (maximum duration was 26.6 months)
measure: Time to Castration Resistance
timeFrame: From randomization to the first castration-resistant event (maximum duration was 26.6 months)
measure: Time to Deterioration of Quality of Life (QoL) in Functional Assessment of Cancer Therapy-Prostate (FACT-P)
timeFrame: From the date of randomization to the first date a decline from baseline of 10 points or more in the FACT-P total score (maximum duration was 26.6 months)
measure: Time to Pain Progression Based on Brief Pain Inventory-Short Form (BPI-SF)
timeFrame: From randomization to the first pain progression event (maximum duration was 26.6 months)
Other outcomes:
Locations:
city: Homewood
country: United States
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state: Alabama
city: Anchorage
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city: Brampton
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city: Kingston
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city: Oakville
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city: Toronto
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state: Quebec
city: Montreal
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state: Quebec
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state: IX Region
city: Santiago
country: Chile
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state: RM
city: Providencia
country: Chile
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city: Copenhagen
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state: Nordjylland
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country: Denmark
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state: Etelä-Suomen Lääni
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state: Länsi-Suomen Lääni
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state: Länsi-Suomen Lääni
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country: Finland
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city: Angers
country: France
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state: Maine-et-Loire
city: Creteil
country: France
facility: Site FR33003
state: Val-de-Marne
city: Bordeaux
country: France
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city: Caen Cedex 05
country: France
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city: La Roche sur Yon
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city: Le Mans Cedex 2
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country: France
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city: Freiburg
country: Germany
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state: Baden-Württemberg
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country: Germany
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state: Baden-Württemberg
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country: Germany
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country: Germany
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country: Germany
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city: Kfar-Saba
country: Israel
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state: HaMerkaz
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country: Israel
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country: Italy
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state: Emilia-Romagna
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country: Italy
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city: Milano
country: Italy
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state: Lombardia
city: Milano
country: Italy
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state: Lombardia
city: Novara
country: Italy
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city: Pisa
country: Italy
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city: Trento
country: Italy
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state: Trentino-Alto Adige
city: Padova
country: Italy
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state: Veneto
city: Candiolo
country: Italy
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city: Sakura
country: Japan
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state: Chiba
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country: Japan
facility: Site JP81001
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city: Kita-gun
country: Japan
facility: Site JP81013
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city: Yokohama
country: Japan
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state: Kanagawa
city: Sendai
country: Japan
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city: Abeno-ku
country: Japan
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country: Japan
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state: Osaka
city: Osakasayama
country: Japan
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country: Japan
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state: Tokyo
city: Koto-ku
country: Japan
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country: Japan
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state: Tokyo
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country: Japan
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state: Yamaguchi
city: Chiba
country: Japan
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country: Japan
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city: Fukuoka
country: Japan
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city: Kyoto
country: Japan
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country: Japan
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city: Seongnam-si
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state: Gyeonggi-do
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country: Korea, Republic of
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country: Korea, Republic of
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country: Korea, Republic of
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country: Korea, Republic of
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city: Seoul
country: Korea, Republic of
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country: Netherlands
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state: Friesland
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country: Netherlands
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state: Gelderland
city: Nijmegen
country: Netherlands
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state: Gelderland
city: Eindhoven
country: Netherlands
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state: Noord-Brabant
city: Alkmaar
country: Netherlands
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state: Noord-Holland
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country: Netherlands
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state: Noord-Holland
city: Zwolle
country: Netherlands
facility: Site NL31009
state: Overijssel
city: Rotterdam
country: Netherlands
facility: Site NL31006
state: Zuid-Holland
city: Tauranga
country: New Zealand
facility: Site NZ64003
state: Bay Of Plenty
city: Kensington
country: New Zealand
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state: Northland
city: Dunedin
country: New Zealand
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state: South Island
city: Nelson
country: New Zealand
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state: Tasman District
city: Hamilton
country: New Zealand
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city: Wroclaw
country: Poland
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state: Dolnoslaskie
city: Krakow
country: Poland
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state: Malopolskie
city: Warszawa
country: Poland
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state: Mazowieckie
city: Gdańsk
country: Poland
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state: Pomerania
city: Slupsk
country: Poland
facility: Site PL48010
state: Pomorskie
city: Myslowice
country: Poland
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city: Cluj-Napoca
country: Romania
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state: Cluj
city: Cluj-Napoca
country: Romania
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state: Cluj
city: Floresti
country: Romania
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state: Cluj
city: Timisoara
country: Romania
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state: Timis
city: Brasov
country: Romania
facility: Site RO40007
city: Bucharest
country: Romania
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city: Bucharest
country: Romania
facility: Site RO40006
city: Ivanovo
country: Russian Federation
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city: Moscow
country: Russian Federation
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city: Moscow
country: Russian Federation
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city: Moscow
country: Russian Federation
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city: Omsk
country: Russian Federation
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city: St. Petersburg
country: Russian Federation
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city: St. Petersburg
country: Russian Federation
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city: St. Petersburg
country: Russian Federation
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city: St. Petersburg
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city: St. Petersburg
country: Russian Federation
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city: Bratislava
country: Slovakia
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city: Kosice
country: Slovakia
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city: Michalovce
country: Slovakia
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city: Nitra
country: Slovakia
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city: Poprad
country: Slovakia
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city: Trencin
country: Slovakia
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country: Slovakia
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city: Salamanca
country: Spain
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state: A Coruña
city: Oviedo
country: Spain
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state: Asturias
city: Sabadell
country: Spain
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state: Barcelona
city: Barcelona
country: Spain
facility: Site ES34012
state: Cataluña
city: Barcelona
country: Spain
facility: Site ES34014
state: Cataluña
city: Valencia
country: Spain
facility: Site ES34013
state: Comunidad Valenciana
city: Pamplona
country: Spain
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state: Navarra
city: Avila
country: Spain
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city: Barcelona
country: Spain
facility: Site ES34007
city: Madrid
country: Spain
facility: Site ES34004
city: Madrid
country: Spain
facility: Site ES34019
city: Örebro
country: Sweden
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state: Orebro Län
city: Malmö
country: Sweden
facility: Site SE46001
state: Skåne Län
city: Stockholm
country: Sweden
facility: Site SE46006
state: Sodermanlands Lan
city: Sundsvall
country: Sweden
facility: Site SE46004
state: Vasternorrlands Lan
city: Goteborg
country: Sweden
facility: Site SE46007
state: Vastra Gotalands Lan
city: Kaohsiung
country: Taiwan
facility: Site TW88601
city: Taichung
country: Taiwan
facility: Site TW88606
city: Taipei
country: Taiwan
facility: Site TW88605
city: Taoyuan
country: Taiwan
facility: Site TW88607
city: Withington
country: United Kingdom
facility: Site GB44002
state: Manchester
Study officials:
affiliation: Astellas Pharma Global Development, Inc.
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Armstrong AJ, Szmulewitz RZ, Petrylak DP, Holzbeierlein J, Villers A, Azad A, Alcaraz A, Alekseev B, Iguchi T, Shore ND, Rosbrook B, Sugg J, Baron B, Chen L, Stenzl A. ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol. 2019 Nov 10;37(32):2974-2986. doi: 10.1200/JCO.19.00799. Epub 2019 Jul 22.
citation: Cella D, Ganguli A, Turnbull J, Rohay J, Morlock R. US Population Reference Values for Health-Related Quality of Life Questionnaires Based on Demographics of Patients with Prostate Cancer. Adv Ther. 2022 Aug;39(8):3696-3710. doi: 10.1007/s12325-022-02204-3. Epub 2022 Jun 22.
citation: Armstrong AJ, Azad AA, Iguchi T, Szmulewitz RZ, Petrylak DP, Holzbeierlein J, Villers A, Alcaraz A, Alekseev B, Shore ND, Gomez-Veiga F, Rosbrook B, Zohren F, Yamada S, Haas GP, Stenzl A. Improved Survival With Enzalutamide in Patients With Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol. 2022 May 20;40(15):1616-1622. doi: 10.1200/JCO.22.00193. Epub 2022 Apr 14.
citation: Stenzl A, Dunshee C, De Giorgi U, Alekseev B, Iguchi T, Szmulewitz RZ, Flaig TW, Tombal B, Morlock R, Ivanescu C, Ramaswamy K, Saad F, Armstrong AJ. Effect of Enzalutamide plus Androgen Deprivation Therapy on Health-related Quality of Life in Patients with Metastatic Hormone-sensitive Prostate Cancer: An Analysis of the ARCHES Randomised, Placebo-controlled, Phase 3 Study. Eur Urol. 2020 Oct;78(4):603-614. doi: 10.1016/j.eururo.2020.03.019. Epub 2020 Apr 23.