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
- Conditions
- Metastatic Castration Resistant Prostate Cancer
- Interventions
- Registration Number
- NCT02288247
- Lead Sponsor
- Astellas Pharma Europe Ltd.
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Male
- Target Recruitment
- 688
- 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.
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Docetaxel Participants received an OL treatment with enzalutamide 160 mg capsules, orally once daily from day 1 in period 1 until randomization to period 2 treatment, confirmation of ineligibility for period 2 treatment, intolerable toxicity, withdrawal, or death, whichever occurred first. Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m\^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, DB in period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle = 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants discontinued the study and received local standard of care. Placebo Placebo Participants received an OL treatment with enzalutamide 160 mg capsules, orally once daily from day 1 in period 1 until randomization to period 2 treatment, confirmation of ineligibility for period 2 treatment, intolerable toxicity, withdrawal, or death, whichever occurred first. Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m\^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, DB in period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle = 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants discontinued the study and received local standard of care. Placebo Prednisolone Participants received an OL treatment with enzalutamide 160 mg capsules, orally once daily from day 1 in period 1 until randomization to period 2 treatment, confirmation of ineligibility for period 2 treatment, intolerable toxicity, withdrawal, or death, whichever occurred first. Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m\^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, DB in period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle = 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants discontinued the study and received local standard of care. Enzalutamide Enzalutamide Participants (Pts) received OL enzalutamide 160 mg QD from Day 1 in Period 1 (P1) until they were either randomized to Period 2 (P2), were ineligible, experienced intolerable toxicity, withdrew, or died. Pts with confirmed disease progression in P1, meeting eligibility, were randomized to receive placebo/enzalutamide 160 mg QD with docetaxel 75 mg/m\^2 in 1hour infusion every 3 weeks \& prednisolone 5mg twice daily in P2. Docetaxel \& prednisolone were administered for upto 10 cycles (1 cycle=3 weeks) or more per investigator discretion, while placebo/enzalutamide continued until progression, toxicity, withdrawal, or death. Extension(EXT) phase was available for Pts in P1\& P2 who were not meeting primary endpoint. Enzalutamide continued until disease progression, intolerable toxicity, withdrawal, or death. Pts not entering EXT discontinued and received local care. Those benefiting from enzalutamide in EXT at study closure continued in study 9785-CL-0123 or via commercial enzalutamide. Enzalutamide Docetaxel Participants (Pts) received OL enzalutamide 160 mg QD from Day 1 in Period 1 (P1) until they were either randomized to Period 2 (P2), were ineligible, experienced intolerable toxicity, withdrew, or died. Pts with confirmed disease progression in P1, meeting eligibility, were randomized to receive placebo/enzalutamide 160 mg QD with docetaxel 75 mg/m\^2 in 1hour infusion every 3 weeks \& prednisolone 5mg twice daily in P2. Docetaxel \& prednisolone were administered for upto 10 cycles (1 cycle=3 weeks) or more per investigator discretion, while placebo/enzalutamide continued until progression, toxicity, withdrawal, or death. Extension(EXT) phase was available for Pts in P1\& P2 who were not meeting primary endpoint. Enzalutamide continued until disease progression, intolerable toxicity, withdrawal, or death. Pts not entering EXT discontinued and received local care. Those benefiting from enzalutamide in EXT at study closure continued in study 9785-CL-0123 or via commercial enzalutamide. Enzalutamide Prednisolone Participants (Pts) received OL enzalutamide 160 mg QD from Day 1 in Period 1 (P1) until they were either randomized to Period 2 (P2), were ineligible, experienced intolerable toxicity, withdrew, or died. Pts with confirmed disease progression in P1, meeting eligibility, were randomized to receive placebo/enzalutamide 160 mg QD with docetaxel 75 mg/m\^2 in 1hour infusion every 3 weeks \& prednisolone 5mg twice daily in P2. Docetaxel \& prednisolone were administered for upto 10 cycles (1 cycle=3 weeks) or more per investigator discretion, while placebo/enzalutamide continued until progression, toxicity, withdrawal, or death. Extension(EXT) phase was available for Pts in P1\& P2 who were not meeting primary endpoint. Enzalutamide continued until disease progression, intolerable toxicity, withdrawal, or death. Pts not entering EXT discontinued and received local care. Those benefiting from enzalutamide in EXT at study closure continued in study 9785-CL-0123 or via commercial enzalutamide.
- Primary Outcome Measures
Name Time Method Progression Free Survival (PFS) From date of randomization to the earliest of either documented disease progression (median duration: 35 weeks) PFS: time from randomization (Period 2 Week 1) to earliest progression event. Progression is defined as radiographic progression, unequivocal clinical progression, or death on study. Radiographic progression is defined for bone disease by appearance of ≥ 2 new lesions on whole-body radionuclide bone scan per Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria (i.e., unconfirmed progressive disease) that needs to be confirmed in the next assessment (i.e., progressive disease in the next assessment) or for soft tissue disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Unequivocal clinical progression is defined as new onset cancer pain requiring chronic administration of opiate analgesia or deterioration from prostate cancer of Eastern Cooperative Oncology Group (ECOG) performance status score to ≥ 3, or initiation of subsequent lines of cytotoxic chemotherapy or radiation therapy or surgical intervention due to complications of tumor progression.
- Secondary Outcome Measures
Name Time Method Time to Prostate-specific Antigen (PSA) Progression From date of randomization to the first PSA value (median duration: 35 weeks) Time to PSA progression, defined as the time from randomization (Period 2 Week 1) to the date of the first PSA value in Period 2 demonstrating progression (Period 2). The PSA progression date is defined as the date that a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the nadir recorded in Period 2 is documented, which must be confirmed by a second consecutive value obtained at least 3 weeks later.
Time to Pain Progression From date of randomization up to median duration of 35 weeks The time to an increase of \>=30% from randomization (Period 2 Week 1) in average BPI-SF item scores (items 3, 4, 5, 6) at two consecutive evaluations \>=3 weeks apart without decrease in analgesic score according to the World health Organization (WHO). Only participants with an average pain intensity item score \>=4 were considered. The BPI-SF was an instrument to document pain-related functional impairment and contains 7 questions which included pain intensity \[(items 3, 4, 5 and 6): worst pain, least pain, average pain and current pain, with scales from 0 (no pain) to 10 (pain as bad as you can imagine)\] and pain interference \](items 9A to 9G): general activity, mood, walking ability, normal work, relations with other people, sleep and enjoyment of life, with scales from 0 (does not interfere) to 10 (completely interferes)\]. The BPI-SF total score for pain intensity was calculated as the mean of the 4 scores for the 4 items of pain intensity.
Prostate-specific Antigen (PSA) Response Randomization, Week 13, any time after randomization in Period 2 (median of 35 weeks) PSA response, defined as a decrease in percentage change from randomization (Period 2 Week 1) of 50% or more. PSA response was derived at Week 13 and at any time after randomization in Period 2. PSA response at any time is defined as a decrease in percentage change from randomization (Period 2 Week 1) at any time after randomization of 50% or more. Percentage of participants with PSA response was reported.
Time to First Skeletal-related Event (SRE) From date of randomization up to median duration of 35 weeks Time to first SRE, defined as the time from randomization (Period 2 Week 1) to radiation therapy or surgery to bone, pathologic bone fracture, spinal cord compression, or change of antineoplastic therapy to treat bone pain.
Change From Baseline in Functional Assessment of Cancer Therapy - Prostate (FACT-P) Period 2: Baseline, weeks 1, 13, 25, 37, 49, 61, 73, 85, 97, 109, 121, 133, 145, 157, 169, 181 FACT-P quality of life questionnaire is a multi-dimensional, self-reported quality of life instrument specifically designed for use with prostate cancer participants. It consists of 27 core items which assess participant function in four domains rated on 0 to 4 Likert-type scale: physical well-being (PWB) (7 items; 0 \[worst\] to 4 \[better\], score range 0-28), social/family well-being (SWB) (7 items; 0 \[worst\] to 4 \[better\], score range 0-28), emotional well-being (EWB) (6 items; 0 \[worst\] to 4 \[better\], score range 0-24), and functional well-being (FWB) (7 items; 0 \[worst\] to 4 \[better\], score range 0-28), which is further supplemented by 12 site-specific items to assess for prostate-related symptoms (Prostate Cancer Subscale \[PCS\] 12 items rated on Likert-type scale 0 \[worst\] to 4 \[better\], score range 0-48). The total domain scores and PCS subscale score are then combined to a global quality of life score ranging between 0 to 156; higher scores representing better quality of life.
Objective Response Rate (ORR) From date of randomization up to median duration of 35 weeks ORR, defined as the best overall radiographic response after randomization (Period 2 Week 1) as per Investigator assessments of response for soft tissue disease per RECIST 1.1, in participants who had a measurable tumor. ORR was reported as the percentage of participants with complete response (CR) or partial response (PR). CR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to \< 10 mm from baseline measurement. PR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters.
Time to Opiate Use for Cancer-related Pain From date of randomization up to median duration of 35 weeks Time to opiate use for cancer-related pain, defined as the time from randomization (Period 2 Week 1) to initiation of chronic administration of opiate analgesia \[parenteral opiate use for ≥7 days or use of WHO Analgesic Ladder Level 3 oral opiates for ≥3 weeks\].
Change From Baseline in EuroQOL 5-dimension 5-level Questionnaire [EQ-5D-5L] Visual Analog Scale (VAS) Period 2: Baseline, weeks 1, 13, 25, 37, 49, 61, 73, 85, 97, 109, 121, 133, 145, 157, 169, 181 The EQ-5D-5L VAS records the participant's self-rated health on a vertical visual analogue scale, where the endpoints are labelled from 0 (worst health imaginable) to 100 (best health imaginable).
Trial Locations
- Locations (89)
Site DE49017
🇩🇪Ulm, Germany
Site ES34003
🇪🇸Madrid, Spain
Site ES34005
🇪🇸Lugo, Spain
Site GR30006
🇬🇷Athens, Greece
Site IT39001
🇮🇹Arezzo, Italy
Site IT39012
🇮🇹Brescia, Italy
Site IT39005
🇮🇹Roma, Italy
Site IT39008
🇮🇹Naples, Italy
Site GR30003
🇬🇷Athens, Greece
Site NO47001
🇳🇴Kristiansand, Norway
Site NO47004
🇳🇴Stavanger, Norway
Site AT43004
🇦🇹Linz, Austria
Site BE32003
🇧🇪Bonheiden, Belgium
Site AT43001
🇦🇹Vienna, Austria
Site BE32002
🇧🇪Liege, Belgium
Site BE32004
🇧🇪Ottignies, Belgium
Site CZ42004
🇨🇿Brno, Czechia
Site CZ42002
🇨🇿Plzeň -Lochotín, Czechia
Site CZ42001
🇨🇿Praha 2, Czechia
Site CZ42003
🇨🇿Olomouc, Czechia
Site FR33012
🇫🇷Albi, France
Site FR33002
🇫🇷Nîmes, France
Site FR33003
🇫🇷Montpellier, France
Site FR33008
🇫🇷Paris, France
Site FR33004
🇫🇷Plerin, France
Site FR33014
🇫🇷Paris, France
Site FR33005
🇫🇷Suresnes, France
Site FR33013
🇫🇷Quimper, France
Site FR33011
🇫🇷Reims, France
Site DE49018
🇩🇪Nürtingen, Baden-Württemberg, Germany
Site DE49008
🇩🇪Aachen, Germany
Site DE49010
🇩🇪Bergisch Gladbach, Germany
Site DE49001
🇩🇪Hannover, Germany
Site DE49006
🇩🇪Heidelberg, Germany
Site DE49003
🇩🇪Mannheim, Germany
Site DE49015
🇩🇪Tübingen, Germany
Site DE49002
🇩🇪Munster, Germany
Site DE49004
🇩🇪Wuppertal, Germany
Site GR30001
🇬🇷Heraklion, Crete, Greece
Site GR30004
🇬🇷Heraklion, Crete, Greece
Site IT39003
🇮🇹Milano, Italy
Site GR30005
🇬🇷Thessaloniki, Greece
Site IT39010
🇮🇹Pavia, Italy
Site IT39002
🇮🇹Terni, Italy
Site NL31007
🇳🇱Blaricum, Netherlands
Site IT39004
🇮🇹Rome, Italy
Site NL31004
🇳🇱Hoofddorp, Netherlands
Site NL31002
🇳🇱Amsterdam, Netherlands
Site NL31003
🇳🇱Rotterdam, Netherlands
Site NL31010
🇳🇱Nieuwegein, Netherlands
Site NO47005
🇳🇴Drammen, Norway
Site PL48002
🇵🇱Lodz, Poland
Site PL48006
🇵🇱Warszawa, Poland
Site PL48004
🇵🇱Gdańsk, Poland
Site PL48003
🇵🇱Krakow, Poland
Site PL48005
🇵🇱Warszawa, Poland
Site RU70004
🇷🇺Obninsk, Kaluga, Russian Federation
Site RU70002
🇷🇺Moscow, Russian Federation
Site RU70006
🇷🇺St. Petersburg, Russian Federation
Site RU70003
🇷🇺Moscow, Russian Federation
Site RU70001
🇷🇺Moscow, Russian Federation
Site RU70005
🇷🇺St. Petersburg, Russian Federation
Site ES34002
🇪🇸Madrid, Spain
Site ES34001
🇪🇸Madrid, Spain
Site ES34010
🇪🇸Madrid, Spain
Site ES34004
🇪🇸Sevilla, Spain
Site ES34006
🇪🇸Valencia, Spain
Site SE46002
🇸🇪Göteborg, Sweden
Site ES34007
🇪🇸Malaga, Spain
Site ES34008
🇪🇸Santander, Spain
Site ES34009
🇪🇸Murcia, Spain
Site SE46005
🇸🇪Kalmar, Sweden
Site SE46003
🇸🇪Solna, Sweden
Site SE46004
🇸🇪Uppsala, Sweden
Site CH41005
🇨🇭Locarno, Tessin, Switzerland
Site CH41009
🇨🇭Zurich, Switzerland
Site TR90001
🇹🇷Ankara, Turkey
Site TR90003
🇹🇷Istanbul, Turkey
Site GB44010
🇬🇧Aberdeen, United Kingdom
Site GB44004
🇬🇧Cambridge, United Kingdom
Site TR90002
🇹🇷Izmir, Turkey
Site GB44014
🇬🇧Exeter, United Kingdom
Site GB44018
🇬🇧Cardiff, United Kingdom
Site GB44003
🇬🇧London, United Kingdom
Site GB44020
🇬🇧Northwood, United Kingdom
Site GB44015
🇬🇧Norwich, United Kingdom
Site GB44007
🇬🇧Wirral, United Kingdom
Site GB44017
🇬🇧Swansea, United Kingdom
Site GB44002
🇬🇧Nottingham, United Kingdom