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 (PRESIDE)

• ClinicalTrials.gov Identifier: NCT02288247
• Recruitment Status: Completed
• First Posted: November 11, 2014
• Results First Posted: December 15, 2021
• Last Update Posted: April 5, 2024
• Sponsor: Astellas Pharma Europe Ltd.
• Collaborator: Medivation LLC, a wholly owned subsidiary of Pfizer Inc.
• Information provided by (Responsible Party): Astellas Pharma Inc ( Astellas Pharma Europe Ltd. )

Tracking Information

• First Submitted Date: November 7, 2014
• First Posted Date: November 11, 2014
• Results First Submitted Date: September 29, 2021
• Results First Posted Date: December 15, 2021
• Last Update Posted Date: April 5, 2024
• Actual Study Start Date: December 1, 2014
• Actual Primary Completion Date: April 30, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 17, 2021)

Progression Free Survival (PFS) [ Time Frame: 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.

Original Primary Outcome Measures (submitted: November 7, 2014)

Progression free survival (PFS) [ Time Frame: Until subject discontinuation (up to 3 years) ]

PFS is defined as the time from randomization to the earliest objective evidence of radiographic progression, unequivocal clinical progression, or death on study, whichever occurs first

Current Secondary Outcome Measures (submitted: November 17, 2021)

• Time to Prostate-specific Antigen (PSA) Progression [ Time Frame: 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.
• Prostate-specific Antigen (PSA) Response [ Time Frame: 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.
• Objective Response Rate (ORR) [ Time Frame: 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 Pain Progression [ Time Frame: 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.
• Time to Opiate Use for Cancer-related Pain [ Time Frame: 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].
• Time to First Skeletal-related Event (SRE) [ Time Frame: 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) [ Time Frame: 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.
• Change From Baseline in EuroQOL 5-dimension 5-level Questionnaire [EQ-5D-5L] Visual Analog Scale (VAS) [ Time Frame: 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).

Original Secondary Outcome Measures (submitted: November 7, 2014)

• Time to prostate-specific antigen (PSA) progression [ Time Frame: Until subject discontinuation (up to 3 years) ]
  Time (in months) from randomization to the date of the first PSA value in Period 2 demonstrating progression (Period 2)
• PSA response [ Time Frame: Until subject discontinuation (up to 3 years) ]
  Percentage change in PSA from randomization to Week 13 (or earlier for those that discontinue therapy), as well as the maximum decline in PSA that occurs at any point after treatment
• Objective response rate [ Time Frame: Until subject discontinuation (up to 3 years) ]
  Best overall radiographic response after randomization as per the Investigator assessments of response for soft tissue disease per RECIST 1.1, in subjects who have a measurable tumor
• Time to pain progression [ Time Frame: Until subject discontinuation (up to 3 years) ]
  Time (in months) to an increase of >= 30% from randomization in the mean of Brief Pain Inventory Short Form (BPI-SF) pain intensity item scores
• Time to opiate use for cancer-related pain [ Time Frame: Until subject discontinuation (up to 3 years) ]
  Time (in months) to initiation of chronic administration of opiate analgesia
• Time to first skeletal-related event (SRE) [ Time Frame: Until subject discontinuation (up to 3 years) ]
  Time (in months) from randomization to radiation therapy or surgery to bone, pathologic bone fracture, spinal cord compression, or change of antineoplastic therapy to treat bone pain
• Quality of life [ Time Frame: Until subject discontinuation (up to 3 years) ]
  Assessed using Functional Assessment of Cancer Therapy - Prostate (FACT-P) and EuroQol 5 dimension, 5 level health state utility index (EQ-5D-5L)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Metastatic Castration Resistant Prostate Cancer

Intervention

• Drug: Enzalutamide
  Oral
  Other Names:

  • Xtandi
  • ASP9785
• Drug: Docetaxel
  intravenous infusion
• Drug: Prednisolone
  Oral
• Drug: Placebo
  Oral

Study Arms

• Experimental: Enzalutamide
  Participants received an OL treatment with enzalutamide 160 milligrams (mg) capsules, orally once daily from day 1 in period 1 until randomization to period 2, confirmation of ineligibility for period 2, intolerable toxicity, withdrawal, or death. Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received enzalutamide 160 mg capsules, orally once daily in combination with docetaxel 75 milligrams per square meter (mg/m^2) in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, DB period 2. Docetaxel and prednisolone were administered up to 10 cycles (3 weeks/cycle) or more as assessed by the investigator. Enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death. Participants could continue the extension period, until investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death.
  Interventions:

  • Drug: Enzalutamide
  • Drug: Docetaxel
  • Drug: Prednisolone
• Placebo Comparator: 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, confirmation of ineligibility for period 2, intolerable toxicity, withdrawal, or death. 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, in period 2. Docetaxel and prednisolone were administered up to 10 cycles (3 weeks/cyle) or more as assessed by the investigator. Enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death. Participants could continue the extension period, until investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death.
  Interventions:

  • Drug: Docetaxel
  • Drug: Prednisolone
  • Drug: Placebo

• Publications *: 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 17, 2021): 688
• Original Estimated Enrollment (submitted: November 7, 2014): 650
• Actual Study Completion Date: March 13, 2024
• Actual Primary Completion Date: April 30, 2020 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Austria, Belgium, Czechia, France, Germany, Greece, Italy, Netherlands, Norway, Poland, Russian Federation, Spain, Sweden, Switzerland, Turkey, United Kingdom
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT02288247
• Other Study ID Numbers: 9785-MA-1001; 2013-004711-50 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Access to anonymized individual participant level data collected during the study, in addition to study-related supporting documentation, is planned for studies conducted with approved product indications and formulations, as well as compounds terminated during development. Studies conducted with product indications or formulations that remain active in development are assessed after study completion to determine if Individual Participant Data can be shared. Conditions and exceptions are described under the Sponsor Specific Details for Astellas on www.clinicalstudydatarequest.com.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.
• Access Criteria: Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.
• URL: https://www.clinicalstudydatarequest.com

• Current Responsible Party: Astellas Pharma Inc ( Astellas Pharma Europe Ltd. )
• Original Responsible Party: Same as current
• Current Study Sponsor: Astellas Pharma Europe Ltd.
• Original Study Sponsor: Same as current
• Collaborators: Medivation LLC, a wholly owned subsidiary of Pfizer Inc.

Investigators

• Study Director: Medical Director; Astellas Pharma Europe Ltd.

• PRS Account: Astellas Pharma Inc
• Verification Date: March 2024