SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 268,490 new cases of prostate cancer will be diagnosed in 2022, and 34,500 men will die of the disease.
Approximately 70% of patients with a new diagnosis of prostate cancer have localized disease. Active Surveillance (AS) is a recommended management option according to the NCCN treatment guidelines, for patients with clinically localized very low-risk, low-risk, or intermediate-risk prostate cancer. Eligible Active Surveillance patients who opt for definitive therapy, such as radical prostatectomy, external beam radiation therapy, or brachytherapy, may experience adverse effects, including sexual dysfunction and urinary incontinence. The addition of Dutasteride, a 5α-reductase inhibitor as an adjunct to Active Surveillance significantly reduced the risk of progression by 38% in the REDEEM trial, among men with low-risk prostate cancer. Additional systemic therapies are however needed to reduce the risk of disease progression in this patient group.
The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced Prostate cancer and is the first treatment intervention. Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor (AR) inhibitors such as CASODEX® (Bicalutamide), NILANDRON® (Nilutamide) and EULEXIN® (Flutamide) or with second-generation, anti-androgen agents, which include ZYTIGA® (Abiraterone), XTANDI® (Enzalutamide), ERLEADA® (Apalutamide) and NUBEQA® (Darolutamide). Enzalutamide is a potent oral androgen receptor inhibitor with demonstrated efficacy in patients with both localized and advanced prostate cancer.
The ENACT study is a multicenter, randomized, open-label, Phase II exploratory clinical trial, conducted to compare the efficacy and safety of treatment with Enzalutamide monotherapy plus Active Surveillance, versus Active Surveillance alone, in patients with clinically localized low-risk or intermediate-risk prostate cancer. In this study a total of 227 eligible patients were randomly assigned 1:1 to receive 1 year of treatment with Enzalutamide 160 mg orally daily plus Active Surveillance (N=114), or Active Surveillance alone (N=113). Enrolled patients had a diagnosis of histologically proven low-risk or intermediate-risk (defined per National Comprehensive Cancer Network Guidelines) clinically localized adenocarcinoma of the prostate (with 10 or more core biopsies) within 6 months of screening. Patients with very low-risk disease (T1c, PSA less than 10 ng/mL, Gleason score of 6 or less; less than 3 cancer-positive cores, 50% or less cancer in any core, and a PSA density of less than 0.15 ng/mL/g) were not eligible. The mean age was 66 years and baseline characteristics were similar in both treatment groups. Patients were monitored during 1 year of treatment and up to 2 years of follow up. 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% or more increase). Therapeutic progression was defined as the earliest occurrence of primary therapy such as prostatectomy, radiation, focal therapy, or any systemic therapy for prostate cancer. 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, percentage of cancer-positive cores and incidence of a secondary rise in serum PSA levels at 1 and 2 years, as well as time to PSA progression. Median follow up was 492 days for patients receiving Enzalutamide and 270 for patients undergoing Active Surveillance. The median Enzalutamide treatment duration was 352 days.
Treatment with Enzalutamide significantly reduced the risk of prostate cancer progression by 46% versus Active Surveillance (HR=0.54; P=0.02). The odds of a negative biopsy result at 1 year were significantly increased and were 3.5 times higher with Enzalutamide treatment versus Active Surveillance (Odds Ratio=3.5; P<0.001). 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 Enzalutamide treatment, although no significant difference was observed at 2 years. Treatment with Enzalutamide also significantly delayed PSA progression by 6 months vs Active Surveillance (HR=0.71; P=0.03). The most reported adverse events during Enzalutamide treatment were fatigue (55.4%) and gynecomastia (36.6%). Worsening of sexual and physical function resolved by month 24 after treatment cessation.
In a follow up analysis of the ENACT trial, the researchers were able to demonstrate that RNA biomarkers PAM50 (Luminal versus Basal subtypes), Androgen Receptor Activation, and Decipher score were of prognostic value. Higher Decipher signature scores were associated with greater risk of disease progression, thereby providing a better understanding of who would be a better candidate for Active Surveillance versus who would benefit from treatment intervention (Annals of Oncology (2022) 33 (suppl_7): S616-S652. 10.1016/annonc/annonc1070).
It was concluded that Enzalutamide monotherapy was well tolerated and demonstrated a significant treatment response in patients with low-risk or intermediate-risk localized prostate cancer. The authors added that ENACT trial represents the first study to compare the effects of a novel Androgen Receptor antagonist as monotherapy vs Active Surveillance, in patients with low-risk or intermediate-risk localized prostate cancer, 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.
Enzalutamide Monotherapy vs Active Surveillance in Patients with Low-risk or Intermediate-risk Localized Prostate Cancer. The ENACT Randomized Clinical Trial. Shore ND, Renzulli J, Fleshner NE, et al. JAMA Oncol. 2022;8(8):1128-1136. doi:10.1001/jamaoncol.2022.1641.
