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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Enzalutamide
* Other: Active Surveillance


Participation Criteria
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Eligibility Criteria
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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: Condom (barrier method of contraception) AND 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: Myocardial infarction or uncontrolled angina within 6 months Congestive heart failure New York Heart Association (NYHA) class 3 or 4 History of clinically significant ventricular arrhythmias History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place Hypotension as indicated by systolic blood pressure < 86 millimeters of mercury (mm Hg) at screening Bradycardia as indicated by a heart rate of < 45 beats per minute on the screening electrocardiogram (ECG) and on physical examination 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Enzalutamide<br>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<br>* Oral<br>* Other names: Xtandi;|
| Other: Active Surveillance (AS)<br>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<br> <br> |

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Therapeutic Cancer Progression, Pathological Cancer Progression, Enzalutamide, Prostate Cancer, Active surveillance