In a recently published report in JAMA Oncology, Shore et al evaluated the addition of enzalutamide to the current standard of care for patients with low- or intermediate-risk prostate cancer.1 According to the current National Comprehensive Cancer Network® (NCCN) guidelines, active surveillance (AS) is the current preferred recommendation for patients with very-low-risk and low-risk prostate cancer. For patients with intermediate-risk disease, AS is recommended, but not necessarily preferred over definitive therapy such as surgery or radiation.2
AS has gained significant traction, due to both good long-term oncologic outcomes and, in part, as a strategy to reduce the adverse effects of definitive therapies. The REDEEM trial found that dutasteride, a 5-α-reductase inhibitor, significantly reduced the risk of progression by 38%.3 Shore et al commented that prior to this study, “there are few publications prospectively assessing pharmacological interventions to delay prostate cancer progression in the AS population.”1
Enzalutamide is a potent oral androgen receptor inhibitor that has been shown in numerous studies to be effective in patients with localized4 and advanced prostate cancer.5 This in part inspired the current study. “The ENACT randomized clinical trial compared the efficacy and safety of treatment with enzalutamide monotherapy versus AS alone in patients with clinically localized lowrisk or intermediate-risk prostate cancer.
ENACT was a multicenter, randomized, open label, phase 2 trial that enrolled patients from June 2016 to August 2020 and included patients with low- or intermediate-risk prostate cancer diagnosed on biopsy within 6 months of screening and who were undergoing AS with an expected life expectancy of ≥5 years. In addition, patients needed to not have received prior local or systemic therapy for prostate cancer, oral glucocorticoids within 1 month of screening, or a 5-α-reductase inhibitor within 1 month of screening, or for >3 months within the 2 years before screening. The trial also ensured that patients with very-low-risk prostate cancer were excluded from the study.
Patients were randomized to either receive 1 year of treatment with enzalutamide 160 mg daily or AS alone, stratified by low or intermediate risk, and whether or not biopsy included targeted multiparametric magnetic resonance imaging (mpMRI). Patients were monitored for 24 months. Patients who experienced a grade ≥3 adverse event (AE) were paused from treatment for 1 week or until the AE improved to grade ≤2. At that point, treatment either continued at the regular dose or a reduced dose of 80 to 120 mg daily. Doses were also reduced to manage gynecomastia or breast complications. Transrectal ultrasound–guided prostate biopsies (with or without mpMRI targeted biopsies) were performed at the 12- and 24-month time points.
The primary end points were time to pathological (increase in primary or secondary Gleason pattern by ≥1 or more or a higher proportion of cancer-positive cores with 15% increase) or therapeutic (earliest occurrence of surgery, radiation, focal or systemic therapy) progression. Secondary end points included negative biopsies at 12 and 24 months, percentage of cancer-positive cores at 1 and 2 years, time to prostate-specific antigen (PSA) progression, and incidence of a rise in PSA levels at 1 and 2 years. PSA progression was defined as an increase in PSA of ≥25% above the nadir or an absolute increase of ≥2 ng/mL. Patient-reported outcomes were assessed via questionnaires, and AEs were monitored throughout the study.
The study included 227 patients, of whom 53% had low-risk prostate cancer and 47% had intermediate-risk disease. Most patients (76%) underwent mpMRI targeted follow-up biopsies. A total of 114 patients underwent treatment with enzalutamide; 75% completed 1 year of AS, 61% completed 1 year of follow-up, and 51% had 1 year of continued follow-up. The full trial was completed by 47% of patients in the enzalutamide arm and 35% in the AS arm. Disease progression and patient withdrawal from the study were the most commonly cited reasons for patient discontinuation in both arms. Median follow-up time for patients on enzalutamide was ~500 days, compared with 270 days in the AS arm. The median duration of actively taking enzalutamide was 352 days. Treatment was disrupted in 13% and reduced in 12% of patients, typically owing to AEs.
Disease progression was seen in 28% of patients in the enzalutamide arm versus 37.2% in the AS arm. Although the time to pathological or therapeutic progression was not reached, there was a significant 46% reduced risk of progression in the enzalutamide arm compared with the AS arm. At 1 year, the incidence of pathological or therapeutic progression was 8% with enzalutamide arm versus 23% with AS; however, at 2 years, this difference was not seen (16% vs 16.4%). Odds of a negative biopsy were significantly increased with enzalutamide compared with AS at one year (OR, 3.5; 95% CI, 1.76-6.92; P< .001), but this difference was not appreciated at 2 years. The trend was similar for the percentage of positive cores on biopsy and the secondary rise in serum PSA levels. There was clinically significant sexual and physical function reported in patients taking enzalutamide, but this resolved at 2 years, after ending treatment.
In the enzalutamide arm 92% of patients experienced an AE, compared with 55% of patients in the AS arm. Both arms had decreased numbers of AEs in the second year of the trial compared to the first. Serious AEs were low in both treatment arms. Commonly reported AEs with enzalutamide included fatigue (55%), gynecomastia (37%), nipple pain (30%) or breast tenderness (26%), and erectile dysfunction (18%).
Enzalutamide-associated AEs were seen in 88% of patients, but only 2.7% were considered serious and 7.1% led to patients discontinuing enzalutamide. Only hypertension was noted to occur in ≥5% of patients in the AS arm. A total of 9.8% of enzalutamide-related AEs were grade ≥3, and the authors note that only fatigue was reported by multiple patients. Other grade 3 enzalutamide-attributed AEs were gait disturbance, gynecomastia, myocardial infarction, and syncope. No deaths were considered to be related to treatment or disease progression.
Shore et al began the discussion of their investigation by emphasizing that, “in the phase 2 ENACT randomized clinical trial, treatment with enzalutamide monotherapy significantly reduced the risk of prostate cancer and PSA progression compared to AS in patients with low-risk or intermediate-risk prostate cancer.”1 In addition, there were several secondary end points, including odds of a negative biopsy, reduction in percentage of positive cores, and odds of a secondary rise in PSA at 1 year that also improved with enzalutamide. The drug was well tolerated and consistent with other trials investigating enzalutamide. The observed 46% risk reduction seen in this study was similar to the 38% reduced risk seen with dutasteride in the REDEEM trial. Limitations of the study included generalizability regarding race (90% of patients identified as white) and the results of the additional analyses (not discussed in this review), which should be interpreted with caution, given that the study was not designed or powered for those analyses.
The authors concluded that the ENACT trial is the first of its kind to evaluate a novel androgen receptor antagonist as monotherapy, compared with AS in patients with low- or intermediate-risk prostate cancer. In this study, enzalutamide showed a significant response, was well tolerated, and the “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.”1
David Ambinder, MD, is a urology resident at New York Medical College / Westchester Medical Center. His interests include surgical education, GU oncology, and advancements in technology in urology. A significant portion of his research has been focused on litigation in urology.