ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer

Abstract

PURPOSE Enzalutamide, a potent androgen-receptor inhibitor, has demonstrated significant benefits in metastatic and nonmetastatic castration-resistant prostate cancer. We evaluated the efficacy and safety of enzalutamide in metastatic hormone-sensitive prostate cancer (mHSPC). METHODS ARCHES (ClinicalTrials.gov identifier: NCT02677896 ) is a multinational, double-blind, phase III trial, wherein 1,150 men with mHSPC were randomly assigned 1:1 to enzalutamide (160 mg/day) or placebo, plus androgen deprivation therapy (ADT), stratified by disease volume and prior docetaxel chemotherapy. The primary end point was radiographic progression-free survival. RESULTS As of October 14, 2018, the risk of radiographic progression or death was significantly reduced with enzalutamide plus ADT versus placebo plus ADT (hazard ratio, 0.39; 95% CI, 0.30 to 0.50; P < .001; median not reached v 19.0 months). Similar significant improvements in radiographic progression-free survival were reported in prespecified subgroups on the basis of disease volume and prior docetaxel therapy. Enzalutamide plus ADT significantly reduced the risk of prostate-specific antigen progression, initiation of new antineoplastic therapy, first symptomatic skeletal event, castration resistance, and reduced risk of pain progression. More men achieved an undetectable prostate-specific antigen level and/or an objective response with enzalutamide plus ADT ( P < .001). Patients in both treatment groups reported a high baseline level of quality of life, which was maintained over time. Grade 3 or greater adverse events were reported in 24.3% of patients who received enzalutamide plus ADT versus 25.6% of patients who received placebo plus ADT, with no unexpected adverse events. CONCLUSION Enzalutamide with ADT significantly reduced the risk of metastatic progression or death over time versus placebo plus ADT in men with mHSPC, including those with low-volume disease and/or prior docetaxel, with a safety analysis that seems consistent with the safety profile of enzalutamide in previous clinical trials in castration-resistant prostate cancer.

Dynamics of the cell-free DNA methylome of metastatic prostate cancer during androgen-targeting treatment

“…As a result, the treatment landscape of mCRPC is complex and continues to focus primarily on the order/sequencing of therapies. For instance, recent trials demonstrated early treatment with Abiraterone or Enzalutamide in the hormone-sensitive state could be beneficial (13–15). However, there is a diverse array of molecular drivers contributing to disease heterogeneity amongst mCRPC patients (16, 17), leading to variable response to current treatment strategies.…”

Optimizing the role of androgen deprivation therapy in advanced prostate cancer: Challenges beyond the guidelines

“…The panel's recommendation was made irrespective of metastatic burden (86% consensus). Recent data from the ARCHES, ENZAMET, and TITAN studies suggest clinical benefit with enzalutamide and apalutamide in this setting as well 61–63 . US FDA approval for these agents in mHSPC is pending.…”

“…9 The panel felt that T levels should be ENZAMET, and TITAN studies suggest clinical benefit with enzalutamide and apalutamide in this setting as well. [61][62][63] US FDA approval for these agents in mHSPC is pending.…”

Identification of genes required for enzalutamide resistance in castration-resistant prostate cancer cellsin vitro

“…First, we have focused on genes that are already expressed in castration-resistant prostate cancer cell lines rather than those that have emerged because of treatment with enzalutamide. We have also only focused on castration-resistant prostate cancer treated with enzalutamide, as at the initiation of our studies, enzalutamide treatment was not yet approved in the metastatic hormone-sensitive setting [47]. In addition, our study has been limited to 5,043 genes that are involved in signal transduction and are drug targets, which has left out a considerable number of potential drivers, like transcription factors, that likely play an important role in enzalutamide resistance.…”