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

Metastatic Castration Resistant Prostate Cancer Clinical Trial

— PRESIDE  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02288247
• Other study ID #: 9785-MA-1001
• Secondary ID: 2013-004711-50
• Status: Completed
• Phase: Phase 3
• Start date: December 1, 2014
• Est. completion date: March 13, 2024

Study information

• Verified date: March 2024
• Source: Astellas Pharma Inc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 688
• Est. completion date: March 13, 2024
• Est. primary completion date: April 30, 2020
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

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-a 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

Related Conditions & MeSH terms

• Metastatic Castration Resistant Prostate Cancer
• Prostatic Neoplasms

Intervention

Drug:
• Enzalutamide
Oral
• Docetaxel
intravenous infusion
• Prednisolone
Oral
• Placebo
Oral

Locations

Country	Name	City	State
Austria	Site AT43004	Linz
Austria	Site AT43001	Vienna
Belgium	Site BE32003	Bonheiden
Belgium	Site BE32002	Liege
Belgium	Site BE32004	Ottignies
Czechia	Site CZ42004	Brno
Czechia	Site CZ42003	Olomouc
Czechia	Site CZ42002	Plzen -Lochotín
Czechia	Site CZ42001	Praha 2
France	Site FR33012	Albi
France	Site FR33003	Montpellier
France	Site FR33002	Nîmes
France	Site FR33008	Paris
France	Site FR33014	Paris
France	Site FR33004	Plerin
France	Site FR33013	Quimper
France	Site FR33011	Reims
France	Site FR33005	Suresnes
Germany	Site DE49008	Aachen
Germany	Site DE49010	Bergisch Gladbach
Germany	Site DE49001	Hannover
Germany	Site DE49006	Heidelberg
Germany	Site DE49003	Mannheim
Germany	Site DE49002	Munster
Germany	Site DE49018	Nürtingen	Baden-Württemberg
Germany	Site DE49015	Tübingen
Germany	Site DE49017	Ulm
Germany	Site DE49004	Wuppertal
Greece	Site GR30003	Athens
Greece	Site GR30006	Athens
Greece	Site GR30001	Heraklion	Crete
Greece	Site GR30004	Heraklion	Crete
Greece	Site GR30005	Thessaloniki
Italy	Site IT39001	Arezzo
Italy	Site IT39012	Brescia
Italy	Site IT39003	Milano
Italy	Site IT39008	Naples
Italy	Site IT39010	Pavia
Italy	Site IT39005	Roma
Italy	Site IT39004	Rome
Italy	Site IT39002	Terni
Netherlands	Site NL31002	Amsterdam
Netherlands	Site NL31007	Blaricum
Netherlands	Site NL31004	Hoofddorp
Netherlands	Site NL31010	Nieuwegein
Netherlands	Site NL31003	Rotterdam
Norway	Site NO47005	Drammen
Norway	Site NO47001	Kristiansand
Norway	Site NO47004	Stavanger
Poland	Site PL48004	Gdansk
Poland	Site PL48003	Krakow
Poland	Site PL48002	Lodz
Poland	Site PL48005	Warszawa
Poland	Site PL48006	Warszawa
Russian Federation	Site RU70001	Moscow
Russian Federation	Site RU70002	Moscow
Russian Federation	Site RU70003	Moscow
Russian Federation	Site RU70004	Obninsk	Kaluga
Russian Federation	Site RU70005	St. Petersburg
Russian Federation	Site RU70006	St. Petersburg
Spain	Site ES34005	Lugo
Spain	Site ES34001	Madrid
Spain	Site ES34002	Madrid
Spain	Site ES34003	Madrid
Spain	Site ES34010	Madrid
Spain	Site ES34007	Malaga
Spain	Site ES34009	Murcia
Spain	Site ES34008	Santander
Spain	Site ES34004	Sevilla
Spain	Site ES34006	Valencia
Sweden	Site SE46002	Göteborg
Sweden	Site SE46005	Kalmar
Sweden	Site SE46003	Solna
Sweden	Site SE46004	Uppsala
Switzerland	Site CH41005	Locarno	Tessin
Switzerland	Site CH41009	Zurich
Turkey	Site TR90001	Ankara
Turkey	Site TR90003	Istanbul
Turkey	Site TR90002	Izmir
United Kingdom	Site GB44010	Aberdeen
United Kingdom	Site GB44004	Cambridge
United Kingdom	Site GB44018	Cardiff
United Kingdom	Site GB44014	Exeter
United Kingdom	Site GB44003	London
United Kingdom	Site GB44020	Northwood
United Kingdom	Site GB44015	Norwich
United Kingdom	Site GB44002	Nottingham
United Kingdom	Site GB44017	Swansea
United Kingdom	Site GB44007	Wirral

Sponsors (2)

Lead Sponsor	Collaborator
Astellas Pharma Europe Ltd.	Medivation LLC, a wholly owned subsidiary of Pfizer Inc.

Countries where clinical trial is conducted

Austria,  Belgium,  Czechia,  France,  Germany,  Greece,  Italy,  Netherlands,  Norway,  Poland,  Russian Federation,  Spain,  Sweden,  Switzerland,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression Free Survival (PFS)	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.	From date of randomization to the earliest of either documented disease progression (median duration: 35 weeks)
Secondary	Time to Prostate-specific Antigen (PSA) Progression	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.	From date of randomization to the first PSA value (median duration: 35 weeks)
Secondary	Prostate-specific Antigen (PSA) Response	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.	Randomization, Week 13, any time after randomization in Period 2 (median of 35 weeks)
Secondary	Objective Response Rate (ORR)	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.	From date of randomization up to median duration of 35 weeks
Secondary	Time to Pain Progression	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.	From date of randomization up to median duration of 35 weeks
Secondary	Time to Opiate Use for Cancer-related Pain	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].	From date of randomization up to median duration of 35 weeks
Secondary	Time to First Skeletal-related Event (SRE)	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.	From date of randomization up to median duration of 35 weeks
Secondary	Change From Baseline in Functional Assessment of Cancer Therapy - Prostate (FACT-P)	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.	Period 2: Baseline, weeks 1, 13, 25, 37, 49, 61, 73, 85, 97, 109, 121, 133, 145, 157, 169, 181
Secondary	Change From Baseline in EuroQOL 5-dimension 5-level Questionnaire [EQ-5D-5L] Visual Analog Scale (VAS)	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).	Period 2: Baseline, weeks 1, 13, 25, 37, 49, 61, 73, 85, 97, 109, 121, 133, 145, 157, 169, 181