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Visual Abstract. Enzalutamide Monotherapy vs Active Surveillance in Patients With Low-Risk or Intermediate-Risk Localized Prostate Cancer
Enzalutamide Monotherapy vs Active Surveillance in Patients With Low-Risk or Intermediate-Risk Localized Prostate Cancer
Figure 1.  Patient Disposition
Patient Disposition

Patients could discontinue a study period yet remain in the study. AE indicates adverse event; AS, active surveillance.

aThe full analysis set (FAS) comprised all randomized patients.

bThe safety analysis set (SAF) comprised all randomized patients who received study treatment. Two patients randomized to the enzalutamide treatment arm were excluded from the SAF; 1 patient did not receive the study drug but remained in the study and 1 patient withdrew from the study after randomization and before taking the study drug.

Figure 2.  Time to Pathological or Therapeutic Prostate Cancer Progression and Prostate-Specific Antigen (PSA) Progression
Time to Pathological or Therapeutic Prostate Cancer Progression and Prostate-Specific Antigen (PSA) Progression

Pathological progression was defined as an increase in primary or secondary Gleason pattern by 1 or more or a higher proportion of cancer-positive cores (≥15% increase). Therapeutic progression was defined as the earliest occurrence of primary therapy for prostate cancer (prostatectomy, radiation, focal therapy, or systemic therapy). Prostate-specific antigen progression was defined as a secondary rise in serum PSA levels of 25% or more of the baseline, an increase of 25% or more than the nadir, or an absolute increase of 2 or more ng/mL (to convert to μg/L multiply by 1). AS indicates active surveillance; NR, not reached.

aPatients with no prostate cancer progression at the time of study completion, discontinuation, or death were censored at the last assessment date. Patients who switched therapy during the study were censored at the time of the initial therapy switch, and patients who discontinued receiving therapy were censored at the time of study discontinuation.

bCalculated using a 2-sided, log-rank test.

cCalculated using a Cox regression model assuming proportional hazards, with treatment group, stratification factors, age, race, and time since prostate cancer diagnosis as fixed effects, and study site and patient as random effects. A hazard ratio (HR) of less than 1 favored enzalutamide.

dCalculated using a 2-sided, stratified, log-rank test.

ePatients with no PSA progression at the time of study completion, discontinuation, or death were censored at the last assessment date. Patients who switched therapy during the study were censored at the time of the initial therapy switch, and patients who discontinued receiving therapy were censored at the time of study discontinuation.

Table 1.  Baseline Demographic and Disease Characteristics
Baseline Demographic and Disease Characteristics
Table 2.  Secondary Efficacy End Points
Secondary Efficacy End Points
Table 3.  AEs Reported During the 1-Year Treatment Period by Gradea
AEs Reported During the 1-Year Treatment Period by Gradea
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    5 Comments for this article
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    Scrutiny in the study aspects
    Saeed Taheri, M.D. | NLMJ; Lahijan
    Despite the HIGH importance of the study, it did not evaluate the hard outcome measures (i.e. survival/metastases) between the two groups (maybe because there was no difference). Moreover, the lack of placebo use in the control group inevitably unblinds the study, and makes patients in the control arm prone to leave the study. It might also confer a placebo effect in the experiment arm.
    One death was due to cerebral hemorrhage, which was reported unrelated to the experiment drug, nonetheless it actually can be due to antiandrogenic therapy (stroke, unusual bleeding and cerebral hemorrhage are among the documented side
    effects of this drug class, including enzalutamide itself [PMID: 30610805]).
    Despite employing MRI/transrectal ultrasonography, no radiological progression reports has been provided. Wad it because of no difference detected?
    Genetic evaluations of the tumor is of extreme interest. Special point mutations in the androgen receptors totally alter response to therapies. In case of enzalutamide, F876L point mutation has been proposed to confers resistance; it might be selected under the treatment and result in attenuation of the therapy effects at the 2nd year. Existence of variant androgenic receptors e.g. AR-V7-positivity have also been shown to confer less PSA responsiveness to androgen deprivation therapy (enzalutamide or abiraterone) and lower overall survival. Likewise, androgen receptor amplification is another factor that confers resistance to androgen deprivation and deserves evaluations. Furthermore, expression of NCOA2 has been associated with androgen deprivation therapy resulting in castration-resistant prostate cancer and metastasis. All these are of particular interest in this study, considering the rapid decline in PSA response at month 15 post treatment as well as the significant difference in the differential rates of secondary PSA rise in the 2nd year versus that for the 1st year (table 2).
    CONFLICT OF INTEREST: None Reported
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    Which is more appropriate, “House of cards” or “Armchair analysis”?
    Takeshi Takehashi, M.D, Ph.D | Health and Welfare Bureau, Kitakyushu City, Japan
    The authors report the results of an RCT comparing Enzaltamide monotherapy with active surveillance (AS) in the treatment of “early prostate cancer”. Unfortunately, they should have checked for basic and essential data before planning such an RCT.

    AS has already been widely used clinically, but its effectiveness has not been validated. Theoretically, it must be scientifically verified that the “early prostate cancer” detected by screening is inferior in OS to the control group, that is, the biopsy negative group or the general public without PSA screening and AS has OS benefits. Then, it is desirable to have positive
    data in small retrospective studies of Enzaltamide with appropriate control group, before planning a RCT.

    The USPSTF systematic review shows no OS benefits for PSA screening, and no differences in OS between treatments such as AS, surgery, and radiation therapy. (1) Neither RCTs nor retrospective studies in the reviews have non-treatment or control arms, and AS data may even be used as a substitute for them. (1) There is no data on the OS and natural history of "Early prostate cancer". In other words, the pathological diagnosis of "Early prostate cancer" has not been scientifically verified.

    The criteria for diagnosis of prostate cancer are: the absence of basal cells, prominent nucleoli, and small acinar formation. (2) Looking at the history of pathology, (2) we can see that the criteria is created for "the Bowery series", (3,4) which has been criticized as an unethical medical practice. The criteria is merely a personal opinion derived from morphological observations of dozens of specimens by a pathologist of 1950s. Urologist Hudson was aware that the criteria had not been scientifically validated, and pathologist Stout was aware that the prostate would be removed on the basis of their diagnosis. (3) When PSA was introduced in the 1990s, urologists and pathologists at that time adopted the criteria without questioning its historical background or scientific validity, and has not been verified, even today. (4,5) The USPSTF's review is regarded as the only scientific validation, and the conclusion is that there is overdiagnosis problem, that is, a problem with the pathological diagnosis. PSA screening is a continuation of “the Bowery series” of the 1951s, because pathological diagnosis remain unchanged. (4)

    The boundary between overdiagnosis and misdiagnosis is sometimes unclear. For early-stage prostate cancer, the term “misdiagnosis” in the first definition, not of individual cases, seems more appropriate, not in the individual diagnosis. A solution for overdiagnosis has already been suggested.(6) Pathologists and urologists should move on to rename “early prostate cancer” to ”IDLE”, “a lesion formerly known as …” or something else.



    REFERENCE
    US Preventive Services Task Force, Grossman DC, Curry SJ, Owens DK, et al. Screening for Prostate Cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2018 May 8;319:1901-1913.
    Young RH, Eble JN. The history of urologic pathology: an overview. Histopathology. 2019;74:184-212.
    Totten RS. Some experiences with latent carcinoma of the prostate. Bull N Y Acad Med. 1953;29:579-82.
    Aronowitz R. "Screening" for prostate cancer in New York's skid row: history and implications. Am J Public Health. 2014;104:70-6.
    Humphrey PA. Histopathology of Prostate Cancer. Cold Spring Harb Perspect Med. 2017;7:a030411.
    Esserman LJ, Thompson IM, Reid B, et al. Addressing overdiagnosis and overtreatment in cancer: a prescription for change. Lancet Oncol. 2014 May;15:e234-42
    CONFLICT OF INTEREST: None Reported
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    Medicalising disease
    Brian Birch, MD (Cantab) | University Hospital Southampton NHS FT
    The results are not unexpected. Enzalutamide has a significant side-effect profile e.g. fatigue in 55.4% and other adverse events (92% vs 55%). However, and most importantly, we do not know if this the reported effects translate into long-term benefit, improved quality of life or improved overall survival. Indeed at 36 months the proportion of patients experiencing pathological progression is almost identical in the 2 groups (see Suppl 3)

    We do know that it will increase treatment costs!

    The first law of medical treatment is primum non nocere - first do no harm. I am not convinced that
    this study has achieved this aim. However, I am afraid that it is yet another example of the unnecessary medicalisation of healthcare for a disease which can be dealt with adequately and safely using current surveillance regimes if properly implemented.

    I would be interested to see what others think.

    Brian Birch Southampton UK
    CONFLICT OF INTEREST: None Reported
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    Alternative Measures to Hazard Ratio: Restricted Mean Survival Time vs Area Above Quantile
    Guosheng Yin, Ph.D. | Department of Statistics and Actuarial Science, The University of Hong Kong
    In clinical trials with survival endpoints, the hazard ratio (HR) is routinely used to compare efficacy between interventions, while inappropriate use of HR might result in misleading interpretations and problematic inference on treatment effect (1). Shore et al. (2) conducted the ENACT trial which enrolled patients with low-risk and intermediate-risk prostate cancer to investigate the efficacy and safety of enzalutamide monotherapy plus active surveillance (AS) versus AS alone. With a covariate-adjusted HR of 0.54 (95% CI [0.33, 0.89]), the authors claimed that enzalutamide significantly reduced the risk of prostate cancer progression by 46%. However, unlike the relative risk which is a ratio of two probabilities, HR cannot be interpreted as risk reduction because hazard is not a probability and HR is the ratio of two instantaneous rates assuming proportional hazards (PH). If the PH assumption is violated, HR loses its meaning and interpretation.

    Figure 2B shows the two Kaplan-Meier curves for the time to prostate-specific antigen (PSA) progression cross at 15 months (2), indicating a violation of PH with P<0.001 from the Schoenfeld residuals test. Under such a circumstance, robust (assumption-free) clinical measures of the global survival profile would be preferred. For this purpose, the restricted mean survival time (RMST) calculates the area under the survival curve from the baseline to a specified timepoint (3,4,5), which has a clinically meaningful interpretation as the average survival time during the investigated time period. By reanalyzing the data constructed from Figure 2B, the 20-month RMST difference is 3.4 months (95% CI [2.1, 4.7]; P<0.001), significantly favoring enzalutamide plus AS. Compared with patients in the AS alone group, those receiving the combination therapy on average enjoyed extra 3.4 months PSA progression-free time, which contradicts to the claimed 6-month (the median survival difference) delay in PSA progression by enzalutamide.

    Nevertheless, RMST discards the survival information after 20 months. Another measure, called the area above quantile (AAQ), computes the area above a quantile level of interest while projecting the Kaplan-Meier curve to the vertical axis. We set the quantile level as 0.02 and the AAQ difference between the two groups is 2.9 months (95% CI [1.3, 4.5]; P<0.001), which indicates that among patients with survival rates higher than 2%, those under the combination therapy enjoyed 2.9 months more PSA progression-free time than those receiving AS alone. In this study, AAQ yields a more comprehensive evaluation than RMST because it incorporates more information than RMST which ignores survival after 20 months.

    1 Weir IR, Marshall GD, Schneider JI, et al. Interpretation of time-to-event outcomes in randomized trials: An online randomized experiment. Ann Oncol. 2019;30(1):96-102.
    2 Shore ND, Renzulli J, Fleshner NE, et al. Active surveillance plus enzalutamide monotherapy vs active surveillance alone in patients with low-risk or intermediate-risk localized prostate cancer: The ENACT randomized clinical trial. JAMA Oncol. 2022.
    3 Zhao, L., Claggett, B., Tian, L, et al. On the restricted mean survival time curve in survival analysis. Biometrics. 2016:72(1):215-21.
    4 Yin G. Clinical trial design: Bayesian and frequentist adaptive methods. New York, NY: John Wiley & Sons; 2012:151-155, 246-8.
    5 Uno H, Claggett B, Tian L, et al. Moving beyond the hazard ratio in quantifying the between-group difference in survival analysis. J Clin Oncol. 2014;32:2380-5.

    Chenyang Zhang and Guosheng Yin
    CONFLICT OF INTEREST: None Reported
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    The goal?
    Dilipsinh Solanki | Private practice
    This is less than 250 patient study of a Cancer that affected at least 1.3M men Wordwide in 2018. The following are the prostate cancer specific mortalities at 5 and 10 years by risk category derived from the SEER data base. . One is left to wonder, how much these #s would be favorably affected by an expensive drug not without side effects that impacts QOL and how many will be exposed to the drug to benefit 1. And we are not talking cure here.

    “5-year PCSM for men with low, intermediate, and high risk disease was
    0.5%, 1.4%, and 9.4%, respectively, and the 10-year PCSM was 1.6%, 4.0%, and 16.8%. Within 10 years of diagnosis, 6.5% (n = 905) of patients who died of prostate cancer were low risk, 27.4% (n = 3,834) were intermediate risk, and 66.2% (n = 9,278) were high risk. “

    I am disappointed that we would add this to the medical literature.

    I share the sentiment expressed by a colleague: Primum non nocere!
    CONFLICT OF INTEREST: None Reported
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    Original Investigation
    June 16, 2022

    Enzalutamide Monotherapy vs Active Surveillance in Patients With Low-risk or Intermediate-risk Localized Prostate Cancer: The ENACT Randomized Clinical Trial

    Author Affiliations
    • 1Carolina Urologic Research Center, Myrtle Beach, South Carolina
    • 2Yale University, New Haven, Connecticut
    • 3Princess Margaret Cancer Centre, Toronto, Ontario, Canada
    • 4Cook County Health, Chicago, Illinois
    • 5Rush University Medical Center, Chicago, Illinois
    • 6Memorial Healthcare System, Hollywood, Florida
    • 7Astellas Pharma Inc, Northbrook, Illinois
    • 8Pfizer Inc, New York, New York
    • 9University of California, San Francisco
    • 10Departments of Pathology and Urology, Rogel Cancer Center, University of Michigan Medical School, Ann Arbor
    JAMA Oncol. 2022;8(8):1128-1136. doi:10.1001/jamaoncol.2022.1641
    Key Points

    Question  How does the efficacy and safety of treatment with enzalutamide monotherapy compare with active surveillance in patients with clinically localized low-risk or intermediate-risk prostate cancer?

    Findings  In this phase 2, open-label, randomized clinical trial of 227 patients with low-risk or intermediate-risk localized prostate cancer, treatment with enzalutamide was well tolerated. Compared with active surveillance alone, enzalutamide significantly reduced the risk of pathological or therapeutic prostate cancer progression by 46%.

    Meaning  The trial results suggest that enzalutamide monotherapy may offer a potential treatment option for this patient population.

    Abstract

    Importance  There are few published studies prospectively assessing pharmacological interventions that may delay prostate cancer progression in patients undergoing active surveillance (AS).

    Objective  To compare the efficacy and safety of enzalutamide monotherapy plus AS vs AS alone in patients with low-risk or intermediate-risk prostate cancer.

    Design, Setting, and Participants  The ENACT study was a phase 2, open-label, randomized clinical trial conducted from June 2016 to August 2020 at 66 US and Canadian sites. Eligible patients were 18 years or older, had received a diagnosis of histologically proven low-risk or intermediate-risk localized prostate cancer within 6 months of screening, and were undergoing AS. Patients were monitored during 1 year of treatment and up to 2 years of follow-up. Data analysis was conducted in February 2021.

    Interventions  Randomized 1:1 to enzalutamide, 160 mg, monotherapy for 1 year or continued AS, as stratified by cancer risk and follow-up biopsy type.

    Main Outcomes and Measures  The primary end point was time to pathological or therapeutic prostate cancer progression (pathological, ≥1 increase in primary or secondary Gleason pattern or ≥15% increased cancer-positive cores; therapeutic, earliest occurrence of primary therapy for prostate cancer). Secondary end points included incidence of a negative biopsy result, percentage of cancer-positive cores, and incidence of a secondary rise in serum prostate-specific antigen (PSA) levels at 1 and 2 years, as well as time to PSA progression. Adverse events were monitored to assess safety.

    Results  A total of 114 patients were randomized to treatment with enzalutamide plus AS and 113 to AS alone; baseline characteristics were similar between treatment arms (mean [SD] age, 66.1 [7.8] years; 1 Asian individual [0.4%], 21 Black or African American individuals [9.3%], 1 Hispanic individual [0.4%], and 204 White individuals [89.9%]). Enzalutamide significantly reduced the risk of prostate cancer progression by 46% vs AS (hazard ratio, 0.54; 95% CI, 0.33-0.89; P = .02). Compared with AS, odds of a negative biopsy result were 3.5 times higher; there was a significant reduction in the percentage of cancer-positive cores and the odds of a secondary rise in serum PSA levels at 1 year with treatment with enzalutamide; no significant difference was observed at 2 years. Treatment with enzalutamide also significantly delayed PSA progression by 6 months vs AS (hazard ratio, 0.71; 95% CI, 0.53-0.97; P = .03). The most commonly reported adverse events during enzalutamide treatment were fatigue (62 [55.4%]) and gynecomastia (41 [36.6%]). Three patients in the enzalutamide arm died; none were receiving the study drug at the time of death. No deaths were considered treatment-related.

    Conclusions and Relevance  The results of this randomized clinical trial suggest that enzalutamide monotherapy was well-tolerated and demonstrated a significant treatment response in patients with low-risk or intermediate-risk localized prostate cancer. Enzalutamide may provide an alternative treatment option for patients undergoing AS.

    Trial Registration  ClinicalTrials.gov Identifier: NCT02799745

    Introduction

    Prostate cancer is the most commonly diagnosed cancer in men in the US,1 with approximately 70% of patients with a new diagnosis having localized disease.2 Based on National Comprehensive Cancer Network treatment guidelines, active surveillance (AS) is a recommended management option for patients with clinically localized very low-risk, low-risk, or intermediate-risk prostate cancer.3 Patients who are undergoing or are eligible to undergo AS who opt for treatment with a definitive therapy, such as radical prostatectomy, external beam radiation therapy, or brachytherapy, may experience adverse effects, including sexual and voiding dysfunction.3 The decision for treatment intervention is influenced by various factors, including pathological upgrading of disease, grade reclassification, and patient well-being. Biopsy type may influence disease assessment, with some studies showing an exclusion of men from AS protocols because of disease reclassification following a multiparametric magnetic resonance imaging (mpMRI)–targeted biopsy.4

    To our knowledge, there are few publications prospectively assessing pharmacological interventions to delay prostate cancer progression in the AS population. Results from the REDEEM trial demonstrated that dutasteride, a 5α-reductase inhibitor, is a beneficial adjunct to AS in men with low-risk prostate cancer, significantly reducing the risk of progression by 38%.5 However, additional pharmacological approaches that may reduce the risks associated with disease progression and interventional treatment are needed. Enzalutamide is a potent oral androgen receptor inhibitor with demonstrated efficacy in patients with localized6 and more advanced stages of prostate cancer,7-12 potentially providing a treatment option for patients undergoing AS. The ENACT randomized clinical trial compared the efficacy and safety of treatment with enzalutamide monotherapy plus AS vs AS alone in patients with clinically localized low-risk or intermediate-risk prostate cancer and to our knowledge is the first trial to assess a known anticancer agent in an AS population.

    Methods
    Study Design

    The ENACT study (NCT02799745) was a multicenter, randomized, open-label, phase 2, exploratory clinical trial conducted in patients with low-risk or intermediate-risk localized prostate cancer in the US and Canada from June 2016 to August 2020 (Supplement 1 and Supplement 2). The study was conducted in accordance with International Council for Harmonization guidelines, applicable local laws, regulations, and guidelines governing clinical study conduct, as well as ethical principles derived from the Declaration of Helsinki. The study was approved by the independent ethics committee or institutional review board at each study site. This article was prepared in accordance with Consolidated Standards of Reporting Trials (CONSORT) guidelines.

    Patients were randomized 1:1 via interactive response technology to receive 1 year of treatment with enzalutamide, 160 mg, monotherapy plus AS or AS alone, as stratified by cancer risk (low vs intermediate) and type of follow-up biopsy (transrectal ultrasonography-guided prostate biopsy [mpMRI-targeted vs non–mpMRI-targeted]) (eFigure 1 in Supplement 3). Enrollment of patients with low-risk prostate cancer was capped to not exceed 80% of the study population. Treatment with oral enzalutamide was administered once daily as 4 × 40-mg capsules per the approved product label. Patients randomized to AS did not receive the study drug. Monitoring continued until the last patient completed the 24-month posttreatment visit (1 year of follow-up and 1 year of continued follow-up).

    Treatment adjustment was permitted in the event of a National Cancer Institute Common Terminology Criteria for Adverse Event (NCI-CTCAE) of grade 3 or higher, for which enzalutamide treatment was paused for 1 week or until the adverse event (AE) reduced in severity to grade 2 or less. Treatment then resumed at the original or reduced dose (120 mg or 80 mg) at the investigator’s discretion. Dose reduction was permitted to manage gynecomastia or breast complications at the investigator’s discretion.

    Patients and Procedures

    Men 18 years or older who received a diagnosis of histologically proven low-risk or intermediate-risk (defined per National Comprehensive Cancer Network Guidelines3) clinically localized adenocarcinoma of the prostate (with ≥10 core biopsies) within 6 months of screening and who were undergoing AS were eligible for inclusion. Enrollment required an Eastern Cooperative Oncology Group status score of 2 or less and estimated life expectancy of more than 5 years. All eligible men were required to provide written informed consent. Information on race was collected to assess differences in baseline demographic characteristics and treatment effects; race was self-identified by the patients.

    Patients who had received prior local or systemic prostate cancer therapy were excluded, as were those who had received treatment with oral glucocorticoids within 1 month of screening or a 5α-reductase inhibitor either within 1 month of screening or for more than 3 months within the previous 2 years. Patients with very low-risk disease (T1c, prostate-specific antigen [PSA] level of <10 ng/mL [to convert to μg/L, multiply by 1]; Gleason score [GS] of ≤6; <3 cancer-positive cores; ≤50% cancer in any core; and a PSA density of <0.15 ng/mL/g) were not eligible.

    Transrectal ultrasonography-guided prostate biopsies (with or without mpMRI targeting) were performed at the 12-month and 24-month visits. Each site was required to be consistent with its method of biopsy throughout the trial, and all biopsies were evaluated by masked central pathology. For mpMRI-targeted biopsies, 2 biopsies were required from each target site, plus 12 systematic biopsies. Serum PSA samples were collected at all visits and analyzed in a central laboratory.

    End Points

    The primary end point was time to pathological or therapeutic prostate cancer progression. Pathological progression was defined as an increase in primary or secondary Gleason pattern by 1 or more or a higher proportion of cancer-positive cores (≥15% increase). Therapeutic progression was defined as the earliest occurrence of primary therapy for prostate cancer (prostatectomy, radiation, focal therapy, or any systemic therapy). Incidence of pathological or therapeutic prostate cancer progression at 1 and 2 years was also assessed.

    Secondary end points included incidence of negative biopsy results at 1 and 2 years; the percentage of cancer-positive cores at 1 and 2 years; time to PSA progression; and incidence of a secondary rise in serum PSA levels at 1 and 2 years. Prostate-specific antigen progression was defined as a secondary rise in serum PSA levels of 25% or more of the baseline, an increase of 25% or more than the nadir, or an absolute increase of 2 or more ng/mL. Patient-reported outcomes (PROs) were assessed as secondary end points via questionnaires, including the Brief Fatigue Inventory (assessing the severity and effect of cancer-related fatigue), 12-item Short Form Survey (measuring health-related quality of life), Expanded Prostate Cancer Index Composite (sexual, urinary, and hormonal domains; measuring function following treatment), and Memorial Anxiety Scale for Prostate Cancer (measuring anxiety).

    Additional analyses of the primary end point, time to prostate cancer progression, were performed by pathological vs therapeutic progression and low (6) vs high (7) GS. Additional analyses of the incidence of prostate cancer progression (secondary analysis of the primary end point) were performed by pathological vs therapeutic progression and by low vs intermediate risk. Additional analyses of all primary and secondary end points were performed for patients with a consistent biopsy type (at screening, month 12, and month 24; screening and month 12; screening and month 24; or just a screening biopsy with no follow-up biopsy).

    Adverse events were monitored from enrollment to study completion to assess safety. All AEs were followed up until they resolved, were no longer considered clinically significant, or were deemed chronic.

    Statistical Analyses

    Sample size was calculated based on an assumed study duration of 3 years with 16% loss to follow-up and a 3-year median time to progression for the AS group (0.23 rate), with an underlying hazard ratio (HR) of 0.52.5 Therefore, 72 events were required to provide a 2-sided type 1 error rate of .05 and power of 80%, resulting in a total sample size of 222 men randomized 1:1, accrued during 1 year.

    Efficacy analyses were performed on the full analysis set (FAS), defined as all randomized patients. Safety analyses were performed on the safety analysis set, defined as all randomized patients who received study treatment.

    Data were summarized using descriptive statistics for continuous end points and frequency and percentage for categorical end points. There was no imputation for missing data, with the exception of start/stop dates for AEs. Data were analyzed using SAS, version 9.3 or higher (SAS Institute), and all statistical analyses were performed using 2-sided tests with a significance level of .05.

    Time to prostate cancer progression and time to PSA progression were calculated using the Kaplan-Meier method. Patients were censored at the last assessment date in the absence of progression at the time of study completion, discontinuation, or death. Treatment group differences were assessed using a Cox regression model assuming proportional hazards, with treatment group, stratification factors, age, race, and time since prostate cancer diagnosis as fixed effects, and study site and patient as random effects. Treatment group differences in incidence of prostate cancer progression, negative biopsy results, and a secondary rise in serum PSA levels were assessed using logistic regression, with treatment group, stratification factors, age, race, and time since prostate cancer diagnosis as fixed effects and study site and patient as random effects. Treatment group differences in the percentage of cancer-positive cores were analyzed using a mixed-model–repeated-measures model, with treatment group, stratification factors, visit, visit-by-treatment, and baseline score as fixed effects, study site and patient as random effects, and a Bonferroni-Holm test to adjust for multiplicity. Additional analyses of primary and secondary end points were analyzed using the same methods. The PROs were analyzed using descriptive statistics. Adverse events were graded based on the National Cancer Institute Common Terminology Criteria for Adverse Event, version 4.03, and coded using the Medical Dictionary for Regulatory Activities, version 23.0.

    Results

    Patient disposition is presented in Figure 1. Overall, 227 men were randomized across 66 sites. Of the 114 men randomized to receive treatment with enzalutamide, 85 (74.6%) completed 1 year of AS, 70 (61.4%) completed 1 year of follow-up, and 58 (50.9%) completed 1 year of continued follow-up. Of the 113 men randomized to undergo AS, 80 (70.8%) completed 1 year of treatment, 51 (45.1%) completed 1 year of follow-up, and 41 (36.3%) completed 1 year of continued follow-up. Fifty-four patients (47.4%) receiving enzalutamide and 40 patients (35.4%) undergoing AS completed all study periods. Disease progression and patient withdrawal were generally the most commonly reported reasons for discontinuation in both treatment arms throughout the study. Median follow-up was 492.5 days (range, 1.0-1078.0 days) for patients receiving enzalutamide and 270.5 days (range, 1.0-806.0 days) for patients undergoing AS.

    Baseline demographic characteristics and disease characteristics were similar between treatment arms (Table 1). Overall, 121 men (53.3%) had low-risk prostate cancer and 172 (75.8%) underwent non–mpMRI-targeted follow-up biopsies. The median enzalutamide treatment duration was 352 days (range, 1-393 days). During the 1-year treatment period, enzalutamide treatment was interrupted in 15 men (13.2%) and the enzalutamide dose was reduced in 14 men (12.3%), primarily owing to AEs.

    Primary End Point

    Disease progression was observed in 32 patients (28.1%) receiving treatment with enzalutamide and 42 (37.2%) of those undergoing AS. The median time to pathological or therapeutic prostate cancer progression was not reached in either treatment arm (Figure 2A). However, treatment with enzalutamide significantly reduced the risk of prostate cancer progression by 46% vs AS (HR, 0.54; 95% CI, 0.33-0.89; P = .02).

    The incidence of pathological or therapeutic prostate cancer progression was lower with enzalutamide (7.9%) vs AS (23.0%) at 1 year (odds ratio [OR], 0.3; 95% CI, 0.11-0.60; P < .01). At 2 years, incidence was similar between treatment arms (16.0% with enzalutamide vs 16.4% with AS; OR, 0.9; 95% CI, 0.36-2.24; P = .81).

    Secondary End Points

    The odds of a negative biopsy result at 1 year were significantly increased with treatment with enzalutamide vs AS (OR, 3.5; 95% CI, 1.76-6.92; P < .001). At 2 years, although there were more patients with negative biopsy results in the enzalutamide arm than the AS arm, the difference was not statistically significant (Table 2). The mean percentage of cancer-positive cores at 1 year was significantly lower with enzalutamide than AS (difference in least squares mean [SE], −10.07 [2.40]; 95% CI, −14.79 to −5.34; P < .001; Table 2). Although there was no statistically significant difference in cancer-positive cores between the treatment arms at 2 years, there was a statistically significant reduction of 6.7% between baseline and year 2 with enzalutamide (95% CI, −11.36 to −2.00).

    Time to PSA progression was significantly delayed by 6 months with treatment with enzalutamide vs AS (HR, 0.71; 95% CI, 0.53-0.97; P = .03; Figure 2B). The odds of a secondary rise in serum PSA levels at 1 year were significantly reduced with treatment with enzalutamide vs AS (OR, 0.1; 95% CI, 0.08-0.26; P < .001), but not at 2 years (Table 2). Treatment with enzalutamide was not associated with clinically significant worsening of PROs, with the exception of sexual and physical function, which resolved by month 24 after treatment cessation.

    Additional Analyses

    Results of additional analyses of time to prostate cancer progression by pathological vs therapeutic progression were consistent with the FAS results, with a median time to prostate cancer progression not reached in either treatment arm or group (eFigure 2 in Supplement 3). The HRs were not statistically significant because of the small sample size.

    For time to pathological or therapeutic prostate cancer progression by low (6) vs high (7) GS (eFigure 3 in Supplement 3), data were generally consistent with the FAS. The median time to prostate cancer progression was not reached in either treatment arm in patients with a low GS. However, among patients with a high GS, the median time to prostate cancer progression was 30 months with AS, for whom the number of progression events nearly doubled compared with enzalutamide (40.4% vs 21.7%; median not reached with treatment with enzalutamide). Analyses of the incidence of prostate cancer by risk indicated that, regardless of whether receiving enzalutamide or undergoing AS, pathological progression was higher in patients with low-risk disease, whereas therapeutic progression was higher in patients with intermediate-risk disease (eTable 1 in Supplement 3).

    Results of the analyses in patients with a consistent biopsy type (eTable 2 in Supplement 3) were consistent with the FAS, further strengthening the findings in the overall study population. The risk of prostate cancer progression was reduced by 55% with treatment with enzalutamide vs AS, and the odds of disease progression were 80% lower at 1 year. In patients treated with enzalutamide, the odds of having a negative biopsy result were 3.5 times higher at 1 year, the mean percentage of cancer positive cores was 8.4% lower at 1 year, time to PSA progression was 6 months longer, and the odds of having a secondary rise in serum PSA levels at 1 year were 80% lower vs AS.

    Safety

    During the 1-year treatment period, the incidence of AEs was higher in patients receiving enzalutamide (92.0%) compared with AS (54.9%). During the 1-year follow-up period, the corresponding numbers were 39.3% and 23.0%, respectively, further decreasing to 14.3% and 10.6%, respectively, during the 1-year continued follow-up period (eTable 3 in Supplement 3). The incidence of serious AEs was low across treatment arms and periods (eTable 3 in Supplement 3).

    The most commonly reported AEs during treatment with enzalutamide were fatigue (62 [55.4%]), gynecomastia (41 [36.6%]), nipple pain (34 [30.4%]), breast tenderness (29 [25.9%]), and erectile dysfunction (20 [17.9%]); the only AE that occurred in 5% or more of patients in the AS arm was hypertension (8 [7.1%]; Table 3). Drug-related AEs were reported in 99 men (88.4%) during treatment with enzalutamide, of which only 2.7% were considered serious and 7.1% led to study drug discontinuation (eTable 3 in Supplement 3).

    Most AEs experienced during the 1-year treatment period were grade 1 or 2 (Table 3). Of the 9.8% of AEs experienced by men in the enzalutamide treatment arm that were grade 3 or higher, only grade 3 fatigue was reported by more than 1 patient (reported by 2 patients). No grade 4 AEs were experienced during treatment with enzalutamide, and only 1 grade 5 AE (homicide) was reported. Six grade 3 AEs (5.4%) in the enzalutamide arm were considered to be drug related (1 occurrence each of gait disturbance, gynecomastia, myocardial infarction, and syncope and 2 occurrences of fatigue). In the AS arm, 9 grade 3 AEs and 1 grade 4 AE were reported, with only grade 3 hypertension reported by more than 1 patient (reported by 3 patients).

    During the study, 3 men (2.7%) in the enzalutamide treatment arm died (eTable 3 in Supplement 3); none were receiving enzalutamide at the time of death. One death was because of homicide during the 1-year treatment period after the patient had discontinued enzalutamide treatment because of noncompliance with the study drug, and 2 deaths occurred during the continued follow-up period (intracranial hemorrhage and metastatic cholangiocarcinoma). No deaths were considered by the investigators to be related to treatment or disease progression.

    Discussion

    In the phase 2 ENACT randomized clinical trial, treatment with enzalutamide monotherapy significantly reduced the risk of prostate cancer and PSA progression vs AS in patients with low-risk or intermediate-risk localized prostate cancer. Patients receiving enzalutamide also had a significant improvement in the odds of a negative biopsy result, as well as significant reductions in the percentage of cancer-positive cores and odds of a secondary rise in serum PSA levels at 1 year compared with AS. Enzalutamide monotherapy was well-tolerated, with the observed AE data consistent with the known safety profile of enzalutamide.

    The REDEEM trial was the first to assess the efficacy and safety of any pharmacological treatment in men with low-risk prostate cancer who were undergoing AS.5 Dutasteride was found to significantly reduce the risk of pathological or therapeutic prostate cancer progression by 38% during the 3-year treatment period vs AS (P = .01). The observed 46% risk reduction (P = .02) in ENACT is consistent with this finding. Similar to REDEEM, AEs related to sexual function and breast disorders were among the most commonly reported treatment-related AEs in ENACT. In contrast to REDEEM, ENACT used a treatment with proven clinical benefit in more advanced prostate cancer and included men with intermediate-risk prostate cancer.

    Limitations

    The ENACT PSA progression analysis results were potentially confounded by the effect of enzalutamide on PSA levels and the definition of PSA progression, which resulted in a potential bias toward AS. The PSA rebound was observed following cessation of enzalutamide treatment, although the mean PSA levels in this arm remained less than baseline throughout the study. In addition, the findings may not be generalizable to all racial and ethnic minority groups. While the additional analyses by pathological vs therapeutic progression, low vs high GS, low-risk vs intermediate-risk disease, and in patients with consistent biopsy types provided results that support those from the overall ENACT study population, these findings should be interpreted with caution, given that the study was not designed or powered for such analyses.

    Conclusions

    This randomized clinical trial found that enzalutamide monotherapy was well tolerated and demonstrated a significant treatment response in patients with low-risk or intermediate-risk localized prostate cancer. To our knowledge, ENACT represents the first trial to compare the effects of a novel androgen receptor antagonist as monotherapy vs AS in patients with low-risk or intermediate-risk localized prostate cancer. Results suggest that enzalutamide may offer an alternative short-term treatment option for this patient population, potentially reducing the need for more aggressive treatment approaches.

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    Article Information

    Accepted for Publication: March 18, 2022.

    Published Online: June 16, 2022. doi:10.1001/jamaoncol.2022.1641

    Corresponding Author: Neal D. Shore, MD, Carolina Urologic Research Center, 823 82nd Parkway, Myrtle Beach, SC 29572 (nshore@auclinics.com).

    Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2022 Shore ND et al. JAMA Oncology.

    Correction: This article was corrected on August 18, 2022, to fix the article title.

    Author Contributions: Ms Elsouda had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Shore, Renzulli, Vourganti, Silberstein, Siddiqui, Hairston, Elsouda, Cooperberg.

    Acquisition, analysis, or interpretation of data: Shore, Renzulli, Fleshner, Hollowell, Vourganti, Siddiqui, Hairston, Elsouda, Russell, Cooperberg, Tomlins.

    Drafting of the manuscript: Shore, Hollowell, Vourganti, Siddiqui, Hairston, Elsouda, Russell.

    Critical revision of the manuscript for important intellectual content: Shore, Renzulli, Fleshner, Hollowell, Vourganti, Silberstein, Siddiqui, Hairston, Elsouda, Cooperberg, Tomlins.

    Statistical analysis: Siddiqui, Hairston, Elsouda.

    Obtained funding: Hairston, Elsouda.

    Administrative, technical, or material support: Renzulli, Siddiqui, Hairston.

    Supervision: Shore, Renzulli, Fleshner, Hollowell, Silberstein, Hairston, Elsouda, Russell, Cooperberg.

    Conflict of Interest Disclosures: Dr Shore reported personal fees from Astellas and Pfizer during the conduct of the study as well as personal fees from Bayer, AstraZeneca, Janssen, Dendreon, Sanofi, Myovant, and Merck outside the submitted work. Dr Renzulli reported research support from Astellas during the conduct of the study as well as personal fees from Astellas, Pfizer, and Dendreon outside the submitted work. Dr Fleshner reported grants from Astellas during the conduct of the study as well as grants from Ferring, Astellas, Amgen, Janssen, and Bavarian Nordic; personal fees from Amgen, Janssen, Astellas, Bayer, Sanofi, AbbVie, and Ferring; and being the chief medical officer of Point Biopharma and Verity Pharmaceuticals outside the submitted work. Dr Hollowell reported grants from Astellas during the conduct of the study. Dr Vourganti reported research support from Astellas during the conduct of the study. Dr Silberstein reported personal fees from Astellas during the conduct of the study as well as personal fees from Janssen and Pfizer outside the submitted work. Drs Siddiqui and Hairston and Ms Elsouda reported being employees of Astellas Pharma Inc during the conduct of the study. Dr Russell reported being an employee of Pfizer Inc during the conduct of the study. Dr Cooperberg reported personal fees from Astellas during the conduct of the study as well as personal fees from Dendreon, Bayer, Janssen, Exact Sciences, Verana Health, VeraCyte, Exosome Diagnostics, and ConcertAI outside the submitted work. Dr Tomlins reported grants and personal fees from Astellas during the conduct of the study, being an equity holder in Strata Oncology and Javelin Oncology, and having a patent for ETS gene fusions in prostate cancer issued to the University of Michigan (also being included in the royalty distribution stream) that has been licensed to LynxDx (previously Ventana/Roche and Gen-Probe/Hologic) outside the submitted work.

    Funding/Support: This study was funded by Astellas Pharma Inc and Pfizer Inc, the codevelopers of enzalutamide.

    Role of the Funder/Sponsor: The study sponsors supported the design and conduct of study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Meeting Presentation: This paper was presented at the American Urological Association 2021 Annual Meeting, Las Vegas, Nevada; September 10-13, 2021.

    Data Sharing Statement: See Supplement 4.

    Additional Contributions: We thank the patients and investigators who participated in the ENACT trial. Medical writing assistance was provided by Lianne Young, BSc (Hons), and editorial support was provided by Lauren Smith, BA (Hons), Complete HealthVizion, which were funded by the study sponsors.

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