Clinical trial NCT02288247: A Study to Assess the Benefit of Treatment Beyond Progression With Enzalutamide in Men Who Are Starting Treatment With Docetaxel After Worsening of Their Prostate Cancer When Taking Enzalutamide Alone
Official title: A Randomized, Double Blind, Placebo-Controlled, Phase IIIb Study of the Efficacy and Safety of Continuing Enzalutamide in Chemotherapy Naïve Metastatic Castration Resistant Prostate Cancer Patients Treated With Docetaxel Plus Prednisolone Who Have Progressed on Enzalutamide Alone
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Metastatic Castration Resistant Prostate Cancer
Keywords: Metastatic
Castration-resistant
Docetaxel
Chemotherapy- Naïve
Enzalutamide
Prostate Cancer
Chemotherapy Naïve Metastatic Castration Resistant Prostate Cancer
Prednisolone
Xtandi
Metastatic Castration Resistant Prostate Cancer
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
Collaborators: name: Medivation LLC, a wholly owned subsidiary of Pfizer Inc.
First posted: 2014-11-11
Enrollment: 688
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 the study was to understand if there was benefit in continued treatment with a medicine called enzalutamide, when starting treatment with docetaxel and prednisolone (a standard chemotherapy for prostate cancer), after the prostate cancer had gotten worse when treated with enzalutamide alone.

Detailed description: The study was conducted in consecutive periods of open label treatment with enzalutamide followed by randomized double-blind treatment with continued enzalutamide or placebo, in combination with docetaxel and prednisolone.

Open Label (Period 1)

Participants received open label treatment (OL) with enzalutamide. At week 13, all participants were assessed by prostate-specific antigen (PSA) and imaging. Participants with no confirmed PSA response or evidence of radiographic progression were ineligible for participation in Period 2 and typically had safety follow up; however, Period 1 treatment continued for some participants as long as the investigator considered it to be of clinical benefit (stopping on initiation of any new antineoplastic therapy). Participants with confirmed PSA response continued Period 1 until disease progression.

Enrollment to Period 2 ceased after approximately 274 participants had been enrolled or 182 primary endpoint events had been reached, whichever occurred first. Participants who were not randomized into period 2 at this time continued to receive open label treatment in an extension period.

Randomization (Double Blind \[DB\]) (Period 2)

Participants with confirmed disease progression on enzalutamide alone who continued to meet all eligibility criteria proceeded to randomization. Treatment allocation was in a 1:1 ratio, stratified by disease progression in Period 1 to the following treatments:

* Enzalutamide with docetaxel and prednisolone
* Placebo with docetaxel and prednisolone

Any ongoing participants in Period 2 at the point of unblinding in the enzalutamide+docetaxel arm that were still receiving and benefitting from enzalutamide treatment, had the option to continue treatment via an extension period.

Eligibility criteria: Inclusion Criteria:

* Histologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features;
* Ongoing androgen deprivation therapy (ADT) with a luteinizing hormone-releasing hormone (LHRH) agonist or antagonist at a stable dose and schedule within 4 weeks of initiation of investigational medicinal product (IMP), or bilateral orchiectomy (i.e., surgical or medical castration);
* Metastatic disease documented by at least 2 bone lesions on bone scan, or soft tissue disease documented by computed tomography (CT)/magnetic resonance imaging (MRI);
* Progressive disease at study entry defined as the following occurring in the setting of castrate levels of testosterone: Prostate specific antigen (PSA) progression defined by a minimum of three rising PSA levels with an interval of ≥ 1 week between each determination.
* Asymptomatic or minimally symptomatic prostate cancer (Brief Pain Inventory - Short Form (BPI-SF) question 3 score of \< 4);
* Eastern Cooperative Oncology Group (ECOG) performance score of 0-1;
* Estimated life expectancy of ≥ 12 months;
* Be suitable and willing to receive chemotherapy as part of the trial;
* Able to swallow the IMP and comply with study requirements;
* Subject agreed not to participate in another interventional study while on treatment.

Exclusion Criteria:

* Prior treatment with the following agents for the treatment of prostate cancer: Aminoglutethimide; Ketoconazole; Abiraterone; Enzalutamide or participation in a clinical trial of enzalutamide; 223Ra, 89Sr, 153Sm, 186Re/188Re; Immunomodulatory therapies; Cytotoxic chemotherapy; Participation in a clinical trial of an investigational agent that inhibits the AR or androgen synthesis unless the treatment was placebo;
* Current or prior treatment within 4 weeks prior to initiation of investigational medicinal product (IMP) with the following agents for the treatment of prostate cancer: Antiandrogens; 5-α reductase inhibitors; Estrogens; Anabolic steroids; Drugs with antiandrogenic properties; Progestational agents;
* Subject had received investigational therapy within 28 days or 5 half-lives whichever was longer, prior to initiation of IMP;
* Use of opiate analgesia for pain from prostate cancer within 4 weeks prior to initiation of IMP;
* Radiation therapy to bone lesions or prostatic bed within 4 weeks prior to initiation of IMP;
* Major surgery within 4 weeks prior to initiation of IMP;
* History of seizure or any condition that may predispose to seizures at any time in the past. History of loss of consciousness or transient ischemic attack within 12 months prior to Screening;
* Known or suspected brain metastasis or active leptomeningeal disease;
* History of another malignancy within the previous 5 years other than non-melanoma skin cancer;
* Clinically significant cardiovascular disease;
* Gastrointestinal disorders affecting absorption;
* Medical contraindications to the use of prednisolone or docetaxel;
* Allergies to any of the active ingredients or excipients in the study drugs

Primary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: From date of randomization to the earliest of either documented disease progression (median duration: 35 weeks)
Secondary outcomes:
measure: Time to Prostate-specific Antigen (PSA) Progression
timeFrame: From date of randomization to the first PSA value (median duration: 35 weeks)
measure: Prostate-specific Antigen (PSA) Response
timeFrame: Randomization, Week 13, any time after randomization in Period 2 (median of 35 weeks)
measure: Objective Response Rate (ORR)
timeFrame: From date of randomization up to median duration of 35 weeks
measure: Time to Pain Progression
timeFrame: From date of randomization up to median duration of 35 weeks
measure: Time to Opiate Use for Cancer-related Pain
timeFrame: From date of randomization up to median duration of 35 weeks
measure: Time to First Skeletal-related Event (SRE)
timeFrame: From date of randomization up to median duration of 35 weeks
measure: Change From Baseline in Functional Assessment of Cancer Therapy - Prostate (FACT-P)
timeFrame: Period 2: Baseline, weeks 1, 13, 25, 37, 49, 61, 73, 85, 97, 109, 121, 133, 145, 157, 169, 181
measure: Change From Baseline in EuroQOL 5-dimension 5-level Questionnaire [EQ-5D-5L] Visual Analog Scale (VAS)
timeFrame: Period 2: Baseline, weeks 1, 13, 25, 37, 49, 61, 73, 85, 97, 109, 121, 133, 145, 157, 169, 181
Other outcomes:
Locations:
city: Linz
country: Austria
facility: Site AT43004
city: Vienna
country: Austria
facility: Site AT43001
city: Bonheiden
country: Belgium
facility: Site BE32003
city: Liege
country: Belgium
facility: Site BE32002
city: Ottignies
country: Belgium
facility: Site BE32004
city: Brno
country: Czechia
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city: Olomouc
country: Czechia
facility: Site CZ42003
city: Plzeň -Lochotín
country: Czechia
facility: Site CZ42002
city: Praha 2
country: Czechia
facility: Site CZ42001
city: Albi
country: France
facility: Site FR33012
city: Montpellier
country: France
facility: Site FR33003
city: Nîmes
country: France
facility: Site FR33002
city: Paris
country: France
facility: Site FR33008
city: Paris
country: France
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city: Plerin
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facility: Site FR33004
city: Quimper
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city: Reims
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facility: Site FR33005
city: Nürtingen
country: Germany
facility: Site DE49018
state: Baden-Württemberg
city: Aachen
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facility: Site DE49008
city: Bergisch Gladbach
country: Germany
facility: Site DE49010
city: Hannover
country: Germany
facility: Site DE49001
city: Heidelberg
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city: Mannheim
country: Germany
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city: Munster
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city: Tübingen
country: Germany
facility: Site DE49015
city: Ulm
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facility: Site DE49017
city: Wuppertal
country: Germany
facility: Site DE49004
city: Heraklion
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facility: Site GR30001
state: Crete
city: Heraklion
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facility: Site GR30004
state: Crete
city: Athens
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facility: Site GR30003
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city: Thessaloniki
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city: Arezzo
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city: Brescia
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city: Milano
country: Italy
facility: Site IT39003
city: Naples
country: Italy
facility: Site IT39008
city: Pavia
country: Italy
facility: Site IT39010
city: Roma
country: Italy
facility: Site IT39005
city: Rome
country: Italy
facility: Site IT39004
city: Terni
country: Italy
facility: Site IT39002
city: Amsterdam
country: Netherlands
facility: Site NL31002
city: Blaricum
country: Netherlands
facility: Site NL31007
city: Hoofddorp
country: Netherlands
facility: Site NL31004
city: Nieuwegein
country: Netherlands
facility: Site NL31010
city: Rotterdam
country: Netherlands
facility: Site NL31003
city: Drammen
country: Norway
facility: Site NO47005
city: Kristiansand
country: Norway
facility: Site NO47001
city: Stavanger
country: Norway
facility: Site NO47004
city: Gdańsk
country: Poland
facility: Site PL48004
city: Krakow
country: Poland
facility: Site PL48003
city: Lodz
country: Poland
facility: Site PL48002
city: Warszawa
country: Poland
facility: Site PL48006
city: Warszawa
country: Poland
facility: Site PL48005
city: Obninsk
country: Russian Federation
facility: Site RU70004
state: Kaluga
city: Moscow
country: Russian Federation
facility: Site RU70002
city: Moscow
country: Russian Federation
facility: Site RU70001
city: Moscow
country: Russian Federation
facility: Site RU70003
city: St. Petersburg
country: Russian Federation
facility: Site RU70005
city: St. Petersburg
country: Russian Federation
facility: Site RU70006
city: Lugo
country: Spain
facility: Site ES34005
city: Madrid
country: Spain
facility: Site ES34003
city: Madrid
country: Spain
facility: Site ES34001
city: Madrid
country: Spain
facility: Site ES34002
city: Madrid
country: Spain
facility: Site ES34010
city: Malaga
country: Spain
facility: Site ES34007
city: Murcia
country: Spain
facility: Site ES34009
city: Santander
country: Spain
facility: Site ES34008
city: Sevilla
country: Spain
facility: Site ES34004
city: Valencia
country: Spain
facility: Site ES34006
city: Göteborg
country: Sweden
facility: Site SE46002
city: Kalmar
country: Sweden
facility: Site SE46005
city: Solna
country: Sweden
facility: Site SE46003
city: Uppsala
country: Sweden
facility: Site SE46004
city: Locarno
country: Switzerland
facility: Site CH41005
state: Tessin
city: Zurich
country: Switzerland
facility: Site CH41009
city: Ankara
country: Turkey
facility: Site TR90001
city: Istanbul
country: Turkey
facility: Site TR90003
city: Izmir
country: Turkey
facility: Site TR90002
city: Aberdeen
country: United Kingdom
facility: Site GB44010
city: Cambridge
country: United Kingdom
facility: Site GB44004
city: Cardiff
country: United Kingdom
facility: Site GB44018
city: Exeter
country: United Kingdom
facility: Site GB44014
city: London
country: United Kingdom
facility: Site GB44003
city: Northwood
country: United Kingdom
facility: Site GB44020
city: Norwich
country: United Kingdom
facility: Site GB44015
city: Nottingham
country: United Kingdom
facility: Site GB44002
city: Swansea
country: United Kingdom
facility: Site GB44017
city: Wirral
country: United Kingdom
facility: Site GB44007
Study officials:
affiliation: Astellas Pharma Europe Ltd.
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Merseburger AS, Attard G, Astrom L, Matveev VB, Bracarda S, Esen A, Feyerabend S, Senkus E, Lopez-Brea Piqueras M, Boysen G, Gourgioti G, Martins K, Chowdhury S. Continuous enzalutamide after progression of metastatic castration-resistant prostate cancer treated with docetaxel (PRESIDE): an international, randomised, phase 3b study. Lancet Oncol. 2022 Nov;23(11):1398-1408. doi: 10.1016/S1470-2045(22)00560-5. Epub 2022 Oct 18.