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

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.

Figure 1.. 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

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.