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
Neal D. Shore, MD1; Joseph Renzulli, MD2; Neil E. Fleshner, MD3; Courtney M. P. Hollowell, MD4; Srinivas Vourganti, MD5; Jonathan Silberstein, MD6; Rizwan Siddiqui, MD7; John Hairston, MD7; Dina Elsouda, MSc7; David Russell, MD8; Matthew R. Cooperberg, MD9; Scott A. Tomlins, MD10
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Carolina Urologic Research Center, Myrtle Beach, South Carolina
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Yale University, New Haven, Connecticut
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Princess Margaret Cancer Centre, Toronto, Ontario, Canada
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Cook County Health, Chicago, Illinois
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Rush University Medical Center, Chicago, Illinois
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Memorial Healthcare System, Hollywood, Florida
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Astellas Pharma Inc, Northbrook, Illinois
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Pfizer Inc, New York, New York
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University of California, San Francisco
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Departments of Pathology and Urology, Rogel Cancer Center, University of Michigan Medical School, Ann Arbor
Source: Shore N, Renzulli J, Fleshner N 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. Published online June 16, 2022. doi:10.1001/jamaoncol.2022.1641