A Randomized Study of Enzalutamide in Patients With Localized Prostate Cancer Undergoing Active Surveillance (ENACT)

A Randomized Study of Enzalutamide in Patients With Localized Prostate Cancer Undergoing Active Surveillance (ENACT)

The primary purpose of this study was to compare the time to prostate cancer progression (pathological or therapeutic progression) between patients treated with enzalutamide versus patients undergoing active surveillance.

Study Overview

• Status: Completed
• Conditions: Prostate Cancer
• Intervention / Treatment: Drug: Enzalutamide; Other: Active Surveillance

Detailed Description

This was a multicenter, randomized, open label exploratory study, conducted in the US and Canada, evaluating the efficacy and safety of enzalutamide for extension of time to prostate cancer progression (pathological or therapeutic) in patients with clinically localized, histologically proven prostate cancer that is categorized as low risk or intermediate risk and who were under AS.

• Study Type: Interventional
• Enrollment (Actual): 227
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Abbotsford, British Columbia, Canada, V2S 3N6
      • Site CA15005
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 2Y9
      • Site CA15004
  • Ontario
    • Toronto, Ontario, Canada, M4N3M5
      • Site CA15001
    • Toronto, Ontario, Canada, M5G2M9
      • Site CA15003
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35223
      • Site US10034
    • Homewood, Alabama, United States, 35209
      • Site US10024
  • Arizona
    • Tucson, Arizona, United States, 85704
      • Site US10007
    • Tucson, Arizona, United States, 85741
      • Site US10055
  • California
    • Los Angeles, California, United States, 90048
      • Site US10004
    • Sacramento, California, United States, 95670
      • Site US10026
    • San Diego, California, United States, 92123
      • Site US10010
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Site US10051
    • Denver, Colorado, United States, 80211
      • Site US10029
    • Denver, Colorado, United States, 80220
      • Site US10054
  • Florida
    • Bradenton, Florida, United States, 34205
      • Site US10072
    • Lakeland, Florida, United States, 33805
      • Site US10057
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Site US10038
    • Chicago, Illinois, United States, 60612
      • Site US10062
    • Chicago, Illinois, United States, 60612
      • Site US10074
    • Glenview, Illinois, United States, 60026
      • Site US10018
    • Lake Barrington, Illinois, United States, 60010
      • Site US10071
  • Indiana
    • Carmel, Indiana, United States, 46033
      • Site US10046
    • Jeffersonville, Indiana, United States, 47130
      • Site US10009
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Site US10037
    • Shreveport, Louisiana, United States, 71106
      • Site US10006
  • Maryland
    • Towson, Maryland, United States, 21204
      • Site US10001
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Site US10032
  • Michigan
    • Troy, Michigan, United States, 48084
      • Site US10008
  • Nebraska
    • Lincoln, Nebraska, United States, 68516
      • Site US10069
    • Omaha, Nebraska, United States, 68114
      • Site US10044
    • Omaha, Nebraska, United States, 68130
      • Site US10067
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Site US10061
  • New Jersey
    • Morristown, New Jersey, United States, 07962
      • Site US10049
    • Voorhees, New Jersey, United States, 08043
      • Site US10043
  • New York
    • Brooklyn, New York, United States, 11215
      • Site US10068
    • Cheektowaga, New York, United States, 14225
      • Site US10050
    • Garden City, New York, United States, 11530
      • Site US10030
    • Poughkeepsie, New York, United States, 12601
      • Site US10028
    • Syracuse, New York, United States, 13210
      • Site US10021
    • Syracuse, New York, United States, 13210
      • Site US10022
  • North Carolina
    • Gastonia, North Carolina, United States, 28053
      • Site US10047
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Site US10045
    • Middleburg Heights, Ohio, United States, 44130
      • Site US10015
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Site US10053
  • Pennsylvania
    • Bala-Cynwyd, Pennsylvania, United States, 19004
      • Site US10063
    • Lancaster, Pennsylvania, United States, 17604
      • Site US10052
  • Rhode Island
    • Warwick, Rhode Island, United States, 02886
      • Site US10014
  • South Carolina
    • Myrtle Beach, South Carolina, United States, 29572
      • Site US10019
  • Tennessee
    • Nashville, Tennessee, United States, 37209
      • Site US10011
  • Texas
    • Dallas, Texas, United States, 75231
      • Site US10056
    • Houston, Texas, United States, 77027
      • Site US10036
    • San Antonio, Texas, United States, 78229
      • Site US10035
  • Virginia
    • Richmond, Virginia, United States, 23235
      • Site US10058
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Site US10017

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histologically proven adenocarcinoma of the prostate diagnosed (with ≥10 core biopsy) within 6 months of screening. The biopsy that was used for this diagnosis must be submitted for central pathology review.

• Prostate cancer categorized (as determined by central pathology review) as low risk is defined as T1c-T2a, PSA<10, N0, M0 (or presumed N0, M0 if CT/bone scan not done due to low risk of metastases), GS ≤ 6, ECOG status ≤2 and estimated life expectancy >5 years OR intermediate risk is defined as T2b-T2c, PSA<20, N0, M0 (or presumed N0, M0 if CT/bone scan not done), GS ≤7 (3+4 pattern only), ECOG status ≤ 2 and estimated life expectancy > 5 years. Prostate cancer categorized (as determined by central pathology review) to the very low risk category (T1c, GS ≤6, PSA <10 ng/mL, fewer than 3 prostate biopsy cores positive,

  ≤50% cancer in any core, PSA density <0.15 ng/mL/g) is not included.

• Ability to swallow study drugs and to comply with study requirements throughout the study
• Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)-approved written Informed Consent and privacy language as per national regulations must be obtained from the subject or legally authorized representative prior to any study-related procedures

• Throughout study, male subject and a female partner who is of childbearing potential must use two acceptable methods of birth control (one of which must include a condom barrier method of contraception) starting at screening and continuing throughout the study period and for three months after the final study drug administration. Two acceptable methods of birth control thus include the following:

  1. Condom (barrier method of contraception) AND
  2. One of the following is required:

  i. Established use of oral, injected or implanted hormonal methods of contraception by the female partner; ii. Placement of an intrauterine device or intrauterine system by the female partner; iii. Additional barrier method: Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam / gel / film / cream / suppository by the female partner; iv. Tubal ligation in the female partner.

• Must not donate sperm starting at screening throughout the study period and for 90 days after the final study drug administration.

Exclusion Criteria:

• Prior radiotherapy, surgery, chemotherapy, or hormonal therapy for prostate cancer
• Very low risk category (T1c, GS ≤6, PSA <10 ng/mL, fewer than 3 prostate biopsy cores positive, ≤50% cancer in any core, PSA density <0.15 ng/mL/g)
• Prior transurethral resection of the prostate or prior transurethral microwave thermotherapy of the prostate
• Use of oral glucocorticoids within 1 month of screening
• Use of 5 alpha reductase inhibitor within 1 month of screening or total use, within the last two years prior to screening, of >3 months
• Presence of metastatic disease
• 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 of screening
• Absolute neutrophil count < 1,500/μL, platelet count < 100,000/μL, or hemoglobin < 6.2 mmol/L (10 g/dL) at screening
• Total bilirubin >1.5 times the upper limit of normal (ULN) or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 2.5 X ULN at screening
• Creatinine > 177 μmol/L (> 2 mg/dL) at screening
• Albumin < 30 g/L (3.0 g/dL) at screening
• Major surgery within 4 weeks prior to Randomization Visit

• Clinically significant cardiovascular disease including:

  1. Myocardial infarction or uncontrolled angina within 6 months
  2. Congestive heart failure New York Heart Association (NYHA) class 3 or 4
  3. History of clinically significant ventricular arrhythmias
  4. History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place
  5. Hypotension as indicated by systolic blood pressure < 86 millimeters of mercury (mm Hg) at screening
  6. Bradycardia as indicated by a heart rate of < 45 beats per minute on the screening electrocardiogram (ECG) and on physical examination
  7. Uncontrolled hypertension as indicated by at least 2 consecutive measurements of a resting systolic blood pressure > 170 mmHg or diastolic blood pressure > 105 mmHg at the Screening Visit
• Known hypersensitivity to enzalutamide or any of its components.
• Subject has received investigational therapy within 28 days or 5 half lives, whichever is longer, prior to screening

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Enzalutamide; Participants received 160-milligrams (mg) enzalutamide administered as four 40-mg capsules, orally once daily for 1 year of treatment period. Following the 1-year treatment period, all participants were followed for 1 additional year. Post the 1-year follow-up period, participants then started the continued follow-up period, in which, participants were followed up every 3 months for these 2 years, after which follow-up was either every 6 months up to 36 months or until the end of study (total duration of follow up in the study was approximately up to 35.9 months).	Drug: Enzalutamide; Oral; Other Names: Xtandi; MDV3100
Other: Active Surveillance (AS); Participants did not receive any study treatment in this arm but were on continued active surveillance (AS) for 1 year of treatment period. Following the 1-year treatment period, all participants were followed for 1 additional year. Post the 1-year follow up, participants then started the continued follow-up period, in which, participants were followed up every 3 months for these 2 years, after which follow-up was either every 6 months up to 36 months or until the end of study (total duration of follow up in the study was approximately up to 35.9 months).	Other: Active Surveillance

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Prostate Cancer Progression	Time to cancer prostate progression (pathological or therapeutic): time (in months) from date of randomization until the date of cancer progression (pathological or therapeutic). Pathological progression: increase in primary or secondary Gleason pattern by greater than or equal (>=) 1 or higher proportion of cancer positive cores (>=15 percent [%] increase). Therapeutic progression: earliest occurrence of primary therapy for prostate cancer (prostatectomy/radiation/focal therapy/systemic therapy). Medians and 95% CIs were calculated with the Kaplan-Meier (KM) method. Participants with no cancer progression at the time of study completion, discontinuation or death were censored at the last assessment date. Participants switching therapy during the study were censored at the time of the initial therapy switch, and participants discontinuing therapy were censored at the time of study discontinuation.	From the date of randomization until the date of the cancer progression (pathological or therapeutic) (up to study completion date, 28 Aug 2020; approximately 50 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events (AEs)	An AE: any untoward medical occurrence in a participant administered study drug or who underwent study procedures and did not necessarily had a causal relationship with treatment. An abnormality identified during a medical test: an AE only if the abnormality induced clinical signs or symptoms, required active intervention, required interruption, or discontinuation of study medication, or was clinically significant in the opinion of investigator. An AE: serious if it resulted in any of the following outcomes: Death, was life-threatening, Persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, Congenital anomaly, or birth defect, Inpatient hospitalization or prolongation of hospitalization, Other medically important event. Drug-related AEs: assessed by investigator as AEs whose relationship to study drugs could not be ruled out.	From date of first dose of enzalutamide or randomization until end of study (up to study completion date, 28 Aug 2020; approximately 50 months)
Percentage of Participants Reported Negative Biopsies for Cancer	Percentage of Participants who reported negative biopsies for cancer were reported.	At the end of months 12 and 24
Change From Baseline in Percent of Cancer Positive Cores at Month 12 and 24	Percent positive cores were calculated using the number of systemically sampled prostate regions and any targeted regions with at least 1 positive core divided by the total number of systematically sampled regions and targeted regions. This implied that despite the number of samples within a given systematic or targeted region, any positive core indicated that region as positive.	Baseline, months 12 and 24
Time to Prostate-specific Antigen (PSA) Progression	Time to PSA progression was defined as time in months from the date of randomization or first dose enzalutamide untill date of PSA progression (secondary rise in serum PSA >=25% above baseline or >=25% above nadir or absolute increase >= 2 nanogram per mililiter [ng/mL]). Participants with no PSA progression at the time of trial completion, discontinuation or death were censored at the last assessment date. Additionally, participants switching therapy during the study were censored at the time of the initial therapy switch, and participants discontinuing therapy were censored at the time of study discontinuation. Medians and 95% CIs were calculated with the KM method.	From date of randomization or first dose of enzalutamide until date of PSA progression (pathological or therapeutic) (up to study completion date=28 Aug 2020, median duration: 14.82 months for "Enzalutamide", 8.80 months for "Active Surveillance")
Percentage of Participants With Secondary Rise in Serum PSA	Percentage of participants with secondary rise in serum PSA > 25% baseline or > 25% above nadir or absolute increase >2 ng/mL were reported in this measure.	At the end of months 12, 24 and at the end of study (up to study completion date, 28 Aug 2020, approximately 50 months)
Change From Baseline in Brief Fatigue Inventory (BFI) Questionnaire Composite Scores to Months 3, 6, 12, 18 and 24	The BFI is a screening tool designed to assess the severity and impact of fatigue on daily functioning of participants with cancer during the 24 hours. There are 9 items on the scale. The first three questions ask participants to rate their fatigues on a scale from 0 (no fatigue) - 10 (as bad as you can imagine), with higher scores indicating worse outcome. The remaining six questions ask participants to rate how much fatigue has interfered with their daily activities on a scale from 0 (Does not interfere) to 10 (Completely interferes). A composite fatigue score was obtained by averaging all the items on the BFI, ranged between 0 to 10, with a higher BFI fatigue score indicating worse outcome. The composite BFI score was calculated only if at least 5 of the 9 items were answered.	Baseline, months 3, 6, 12, 18 and 24
Change From Baseline in 12-Item Short Form Survey (SF-12) Questionnaire Composite Score to Months 6, 12, 18, 24 - Mental Component Summary	SF-12 is a questionnaire that measures overall health related quality of life using 12 questions. The questions are then scored and weighted into 2 subscales, physical health and mental health. Each yields scores from 0 (representing the worst possible debilitation) to 100 (representing no reduction in quality of life). Scores are transformed and ranges between 0 to 100; higher score indicates improvement.	Baseline, months 6, 12, 18 and 24
Change From Baseline in SF-12 Questionnaire Composite Score to Months 6, 12, 18, 24 - Physical Component Summary	SF-12 is a questionnaire that measures overall health related quality of life using 12 questions. The questions are then scored and weighted into 2 subscales, physical health and mental health. Each yields scores from 0 (representing the worst possible debilitation) to 100 (representing no reduction in quality of life). Scores are transformed and ranges between 0 to 100; higher score indicates improvement.	Baseline, months 6, 12, 18 and 24
Change From Baseline in The Expanded Prostate Cancer Index Composite (EPIC) Hormonal Assessment Scores at Months 6, 12, 18 and 24	The EPIC Hormonal Assessment was a questionnaire used to measure quality of life (QoL) issues in participants with prostate cancer. There were a total of 6 questions related to hormonal function such as hot flashes, breast tenderness, depression, lack of energy, weight fluctuation. The answers ranged from "more than once a day" to "rarely or never" (ranged from 1 to 5, corresponding standardized scores were 100, 75, 50, 25, 0), "no problem" to "big problem" (ranged from 0 to 4, corresponding standardized scores were 100, 75, 50, 25, 0). Score from each answer was converted into standardized score at each visit. Total score was calculated by taking average of standardized scores. Total score was measured on a scale ranged from 0 (worst) to 100 (best) scale with higher scores representing better hormonal function.	Baseline, months 6, 12, 18 and 24
Change From Baseline in EPIC Sexual Assessment Scores at Months 6, 12, 18 and 24	EPIC Sexual Assessment: a questionnaire to measure QoL issues in participants with prostate cancer, included a total of 9 questions on sexual function as level of sexual desire, ability to have an erection, ability to reach orgasm, quality and frequency of erections, frequency of sexual intercourse. Answers ranged from "very poor" to "very good,"(ranged from 1 - 5, corresponding standardized scores:0, 25, 50, 75, 100), "none" to "enough"(ranged from 1 - 4, corresponding standardized scores:0, 33, 67, 100), "no problem" to "big problem"(ranged from 0 - 4, corresponding standardized scores:100, 75, 50, 25, 0), and "never" to "daily"(ranged from 1 - 5, corresponding standardized scores:100, 75, 50, 25, 0). Scores from each answer was converted into standardized score at each visit. Total score = calculated by taking average of standardized scores. Total score was measured on a scale ranged from 0 (worst) to 100 (best), higher scores = better sexual function and satisfaction.	Baseline, months 6, 12, 18 and 24
Change From Baseline in EPIC Urinary Assessment Scores at Month 6, 12, 18 and 24	EPIC urinary assessment: a questionnaire to measure QoL issues in participants with prostate cancer, included a total of 7 questions on urinary function as leaking urine, blood in urine, pain/burning on urination, urinary control and frequency. Answers ranged from "more than once a day" to "rarely or never"(scores from 1 - 5,corresponding standardized scores[CSS]:0, 25, 50, 75, 100), "no urinary control" to "full urinary control"(scores from 1 - 4,CSS:0, 33, 67, 100), "none" to "3 or more pads per day"(scores from 0 - 3, CSS:100, 67, 33, 0), "no problem" to "big problem"(scores from 0 - 4, CSS:100, 75, 50, 25, 0), and "no problem" to "big problem"(scores from 1 - 5, corresponding standardized score:100, 75, 50, 25, 0). Score from each answer was converted into a corresponding standardized score at each visit. Total score was calculated by taking average of standardized scores. Total score ranged from 0(worst) to 100(best), higher scores = better urinary function.	Baseline, months 6, 12, 18 and 24
Change From Baseline in Memorial Anxiety Scale for Prostate Cancer (MAX-PC) Scores at Months 6, 12, 18 and 24	The MAX-PC was a questionnaire used to assess participants' feelings about prostate cancer and PSA tests. There were a total of 18 questions related to understanding how participants cope with aspects of their treatment and medical tests frequently involved in their care; questions such as strong feelings about prostate cancer, scared of PSA tests, trouble sleeping due to thoughts of prostate cancer, unable to plan for the future due to prostate cancer, fear of cancer getting worse. The answers range from "not at all" to "often" and "strongly disagree" to "strongly agree. Total score ranged from 0-54, an increase in the score indicates a worsened anxiety level.	Baseline, months 6, 12, 18 and 24

Collaborators and Investigators

• Sponsor: Astellas Pharma Global Development, Inc.
• Collaborators: Medivation LLC, a wholly owned subsidiary of Pfizer Inc.
• Investigators: Study Director: Medical Director, Astellas Pharma Global Development, Inc.

Publications and helpful links

General Publications

• Shore ND, Renzulli J, Fleshner NE, Hollowell CMP, Vourganti S, Silberstein J, Siddiqui R, Hairston J, Elsouda D, Russell D, Cooperberg MR, Tomlins SA. Enzalutamide Monotherapy vs Active Surveillance in Patients With Low-risk or Intermediate-risk Localized Prostate Cancer: The ENACT Randomized Clinical Trial. JAMA Oncol. 2022 Aug 1;8(8):1128-1136. doi: 10.1001/jamaoncol.2022.1641. Erratum In: JAMA Oncol. 2022 Aug 01;8(8):1225. doi: 10.1001/jamaoncol.2022.3577.

Helpful Links

• Link to results and other applicable study documents on the Astellas Clinical Trials website
• Link to plain language summary of the study on the Trial Results Summaries website

Study record dates

Study Major Dates

• Study Start (Actual): June 9, 2016
• Primary Completion (Actual): August 28, 2020
• Study Completion (Actual): August 28, 2020

Study Registration Dates

• First Submitted: February 29, 2016
• First Submitted That Met QC Criteria: June 10, 2016
• First Posted (Estimated): June 15, 2016

Study Record Updates

• Last Update Posted (Actual): December 6, 2024
• Last Update Submitted That Met QC Criteria: November 19, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: Prostate Cancer; Active surveillance; Enzalutamide; Therapeutic Cancer Progression; Pathological Cancer Progression
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases; Male Urogenital Diseases; Prostatic Neoplasms
• Other Study ID Numbers: 9785-MA-1010

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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 products 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. Further details on Astellas' data sharing policy can be found at https://www.clinicaltrials.astellas.com/transparency/.
• IPD Sharing 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.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No