(2nd UPDATE) Enzalutamide
Updated: Thursday, September 29, 2022
Last updated: October 9, 2020
Commentary by Sandy Srinivas, MD, Prostate Cancer Site Editor for JNCCN 360
Professor of Medicine, Stanford University Medical Center
Since the original approval of enzalutamide in 2012 for patients with metastatic castration-resistant prostate cancer after chemotherapy, there have been expanding indications across the spectrum of disease states in prostate cancer. It has gained approval in metastatic castration-resistant prostate cancer before chemotherapy, nonmetastatic castration-resistant prostate cancer, and metastatic castration-sensitive prostate cancer. This update addresses additional trial results evaluating the efficacy and tolerability of enzalutamide.
Dr. Srinivas has received institutional research support from AstraZeneca Pharmaceuticals, Bayer HealthCare, Bristol Myers Squibb Company, Clovis Oncology, Eisai, Exelixis, Genentech, Merck & Co., Pfizer, and Seattle Genetics and has served on a scientific advisory board or as a consultant or expert witness to AstraZeneca Pharmaceuticals, AVEO Pharmaceuticals, Bayer HealthCare, Bristol Myers Squibb Company, Eisai, Janssen Pharmaceutica Products, Merck & Co., Novartis Pharmaceuticals Corporation, and Seattle Genetics.
Enzalutamide in Combination
Since the fall of 2020, when the enzalutamide spotlight was last updated, much of the recent research has focused on combination regimens. For instance, in the updated results of the phase IIIB PRESIDE trial, patients who experienced disease progression with enzalutamide plus androgen-deprivataion therapy (ADT) were administered docetaxel and prednisone with continued enzalutamide and ADT, which resulted in a statistically significant improvement in progression-free survival compared with placebo plus ADT and docetaxel.1
A meta-analysis of the primary results from two phase III trials of the STAMPEDE platform protocol suggested adding enzalutamide and abiraterone acetate plus prednisolone to ADT may be more toxic than adding abiraterone acetate plus prednisolone alone in patients with high-risk nonmetastatic prostate cancer.2 Furthermore, metastasis-free survival outcomes did not seem to significantly differ between the arms.
Active surveillance in combination with enzalutamide appeared to reduce the risk of disease progression in patients with low- or intermediate-risk localized prostate cancer compared with active surveillance alone, based on the results of the phase II ENACT trial.3 At 1 year, the enzalutamide group experienced a higher rate of negative biopsy results, a reduction in the percentage of cancer-positive cores, and a lower likelihood of a secondary increase in the prostate-specific antigen level.
Updates From ENZAMET and ARCHES Trials
Since the interim analyses of the phase III ENZAMET trial were published in 2019, health-related quality-of-life outcomes and updated overall survival results have been reported. Clinically meaningful improvements in overall survival were observed with the addition of enzalutamide versus a nonsteroidal antiandrogen to testosterone suppression in patients with castration-sensitive prostate cancer. This benefit was found to continue with an additional 3 years of follow-up, and it appeared to be more pronounced in patients with low-volume disease.4
Modest impairments in fatigue, physical function, and self-rated cognitive function, but not overall health and quality of life, were observed with testosterone suppression plus enzalutamide.5 These impairments did not seem to worsen over time, according to the investigators.
The final prespecified overall survival analysis of the phase III ARCHES trial demonstrated a significant benefit with the addition of enzalutamide to ADT in patients with metastatic castration-sensitive prostate cancer.6
Enzalutamide in Comparison With Other Options
Despite the growing body of evidence supporting enzalutamide in the treatment of prostate cancer, other therapies have conferred a comparable or improved clinical benefit in this setting. For example, the phase II TRANSFORMER trial revealed no difference in progression-free survival with bipolar androgen therapy versus enzalutamide in patients with metastatic castration-resistant prostate cancer who experienced disease progression after treatment with abiraterone.7
The PROfound study previously demonstrated significant improvements in radiographic progression-free and overall survival in patients with metastatic castration-resistant prostate cancer with alterations in homologous recombination repair genes who were treated with olaparib versus enzalutamide or abiraterone plus prednisone.8 Based on an additional analysis, olaparib was also found to yield better-preserved health-related quality of life and reduced pain burden.
As with many anticancer therapies, androgen receptor inhibitors are associated with their share of side effects. In a review and meta-analysis, treatment with enzalutamide, apalutamide, or darolutamide seemed to be associated with an increased risk of both falls and fractures in patients with prostate cancer.9
Treatment with enzalutamide in combination with hormone therapy appeared to increase the risk of serious metabolic or cardiovascular issues compared with hormone therapy alone in patients with advanced prostate cancer.10 In particular, those who received enzalutamide were found to be 1.22 times more likely to be admitted to the emergency room or the hospital because of diabetes, hypertension, or heart disease.
Enzalutamide in Older Adults
Although data regarding the effects of androgen receptor inhibition in older adults are limited, recent studies have investigated enzalutamide in this patient population. Based on the results of a post hoc subgroup analysis of the PROSPER trial, overall survival outcomes did not seem to differ between patients older and younger than age 70 with nonmetastatic castration-resistant prostate cancer who were treated with ADT plus enzalutamide. However, older patients were found to experience more exposure-adjusted adverse events per 100 person-years, such as fatigue, falls, and fractures.11 A U.S. Food and Drug Administration pooled analysis revealed that second-generation androgen receptor inhibition with enzalutamide, apalutamide, or darolutamide was associated with survival benefits in patients older than age 80 with nonmetastatic castration-resistant prostate cancer.12 However, older patients seemed to be at an increased risk of adverse events compared with their younger counterparts, irrespective of whether an androgen receptor inhibitor or placebo was administered.
Older patients with metastatic castration-resistant prostate cancer who were treated with either enzalutamide or abiraterone were found to experience a significant decline in Psoas Muscle Index values at 24 months compared with baseline—and thus increased rates of sarcopenia.13 A multicenter, prospective, observational cohort study was conducted to assess physical function, falls, and frailty over time in patients older than age 65 with metastatic castration-resistant prostate cancer who were treated with enzalutamide and other prostate cancer therapies.14 The results demonstrated that, although frail patients had baseline functional deficits compared with fit patients, they experienced greater improvements in physical function and well-being over time.
- Merseburger AS, Attard G, Boysen G, et al. A randomized, double-blind, placebo-controlled, phase 3b study of the efficacy and safety of continuing enzalutamide in chemotherapy-naive, metastatic castration-resistant prostate cancer patients treated with docetaxel plus prednisolone who have progressed on enzalutamide: PRESIDE. 2022 ASCO Genitourinary Cancers Symposium. Abstract 15.
- Attard G, Murphy L, Clarke NW, et al. Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-analysis of primary results from two randomised controlled phase 3 trials of the STAMPEDE platform protocol. Lancet 2022;399:447–460.
- Shore ND, Renzulli J, Fleshner NE, et al. Enzalutamide monotherapy vs active surveillance in patients with low-risk or intermediate-risk localized prostate cancer. JAMA Oncol 2022;8:1128–1136.
- Davis ID, Martin AJ, Zielinski RR, et al. Updated overall survival outcomes in ENZAMET (ANZUP 1304), an international, cooperative group trial of enzalutamide in metastatic hormone-sensitive prostate cancer (mHSPC). 2022 ASCO Annual Meeting. Abstract LBA5004.
- Stockler MR, Martin AJ, Davis ID, et al. Health-related quality of life in metastatic, hormone-sensitive prostate cancer: ENZAMET (ANZUP 1304), an international, randomized phase III trial led by ANZUP. J Clin Oncol 2022;40:837–846.
- Armstrong AJ, Azad AA, Iguchi T, et al. Improved survival with enzalutamide in patients with metastatic hormone-sensitive prostate cancer. J Clin Oncol 2022;40:1616–1622.
- Denmeade SR, Wang H, Agarwal N, et al. TRANSFORMER: a randomized phase II study comparing bipolar androgen therapy versus enzalutamide in asymptomatic men with castration-resistant metastatic prostate cancer. J Clin Oncol 2021;39:1371–1382.
- Thiery-Vuillemin A, de Bono J, Hussain M, et al. Pain and health-related quality of life with olaparib versus physician’s choice of next-generation hormonal drug in patients with metastatic castration-resistant prostate cancer with homologous recombination repair gene alterations (PROfound): an open-label, randomised, phase 3 trial. Lancet Oncol 2022;23:393–405.
- Myint ZW, Momo HD, Otto DE, et al. Evaluation of fall and fracture risk among men with prostate cancer treated with androgen receptor inhibitors. JAMA Netw Open 2020;3:e2025826.
- Lai LY, Oerline MK, Caram MEV, et al. Risk of metabolic and cardiovascular adverse events with abiraterone or enzalutamide among men with advanced prostate cancer. JNCI: Journal of the National Cancer Institute 2022;114:1127–1134.
- De Giorgi U, Hussain MHA, Shore ND, et al. PROSPER subgroup analysis by age and region: overall survival and safety in men with nonmetastatic castration-resistant prostate cancer receiving androgen deprivation therapy plus enzalutamide. 2021 Genitourinary Cancers Symposium. Abstract 84.
- Fallah J, Zhang L, Amatya A, et al. Survival outcomes in older men with non-metastatic castration-resistant prostate cancer treated with androgen receptor inhibitors: a US Food and Drug Administration pooled analysis of patient-level data from three randomised trials. Lancet Oncol 2021;22:1230–1239.
- Naimi MF, Khan M, Carvajal JRB, et al. Comparative analysis of sarcopenia induced by long-term abiraterone versus enzalutamide therapy in men with metastatic castration-resistant prostate cancer. 2021 Genitourinary Cancers Symposium. Abstract 69.
- Yang H, Breunis H, Timilshina N, et al. Impact of treatment and frailty on elder-relevant physical function outcomes in older adults with metastatic castration-resistant prostate cancer. 2021 Genitourinary Cancers Symposium. Abstract 76.