Enzalutamide in combination with androgen deprivation therapy (ADT) showed clinical benefits in the phase III ARCHES study for the treatment of men with metastatic hormone-sensitive prostate cancer (mHSPC). At the time of the primary analysis, enzalutamide plus ADT significantly reduced the risk of radiographic disease progression or death in men with mHSPC, but data from a key secondary endpoint, overall survival (OS), were immature. On 14 April 2022, Dr. Andrew J. Armstrong of the Duke Cancer Institute Center for Prostate & Urologic Cancers, Duke University in Durham, NC, US and the ARCHES colleagues reported in the Journal of Clinical Oncology the final prespecified OS analysis and an update on radiographic progression-free survival (rPFS), other secondary endpoints, and safety. They found that enzalutamide plus ADT significantly prolongs survival versus placebo plus ADT in men with mHSPC, including across clinically important subgroups.
In the phase III, double-blind, global ARCHES study, 1150 patients with mHSPC were randomly assigned 1:1 to enzalutamide plus ADT or placebo plus ADT, stratified by disease volume and prior docetaxel use. After unblinding, 180 (31.3%) progression-free patients randomly assigned to placebo plus ADT crossed over to open-label enzalutamide plus ADT. As of 28 May 2021, with a median follow-up of 44.6 months, 154 of 574 patients randomly assigned to enzalutamide plus ADT and 202 of 576 patients randomly assigned to placebo plus ADT had died.
Enzalutamide plus ADT reduced risk of death by 34% versus placebo plus ADT, median was not reached in either group (hazard ratio 0.66, 95% confidence interval 0.53 to 0.81; p < 0.001). Enzalutamide plus ADT continued to improve rPFS and other secondary endpoints.
The authors wrote that the survival benefit of enzalutamide plus ADT became more apparent with additional follow-up. Enzalutamide plus ADT also delayed time to initiation of the first subsequent antineoplastic therapy. In total, 70% of patients who initially received placebo plus ADT went on to receive a life-prolonging treatment and, inclusive of those who crossed over, 42% went on to treatment with enzalutamide. Despite this, a statistically significant survival benefit was observed with enzalutamide plus ADT, highlighting the importance of early enzalutamide use in patients with mHSPC, rather than delaying initiation until the development of castration resistance. Improvement in OS with enzalutamide is unlikely to be the result of patients in the placebo plus ADT group receiving inadequate post-protocol therapy.
Longer-term use of enzalutamide was well tolerated and not associated with any new toxicity concerns, a key consideration for clinicians when choosing a systemic treatment for patients with advanced prostate cancer.
The authors concluded that enzalutamide plus ADT significantly prolongs survival versus placebo plus ADT in men with mHSPC, and thus represents an effective and well-tolerated therapeutic option in this setting.
The findings were previously presented in part at the ESMO 2021 Virtual Congress.
The study was supported by Astellas Pharma Inc and Pfizer Inc, the codevelopers of enzalutamide.
Armstrong AJ, Azad AA, Iguchi T, et al. Improved Survival With Enzalutamide in Patients With Metastatic Hormone-Sensitive Prostate Cancer. Journal of Clinical Oncology; Published online 14 April 2022. DOI: 10.1200/JCO.22.00193