ARCHES is a randomized, multinational, double-blind, placebo-controlled, phase III study of enzalutamide combined with androgen deprivation therapy (ADT) in metastatic hormone-sensitive prostate cancer (mHSPC) versus placebo plus ADT that was conducted from March 21, 2016, to January 12, 2018. Other trials that were done prior to this had shown that ADT combined with chemotherapy or abiraterone led to improvements in overall survival.

Most men with prostate cancer are treated with hormonal therapy, and ADT is the gold standard; however, most patients with prostate cancer will progress to metastatic castrate-resistant prostate cancer (mCRPC) within a few years, if not sooner. Current treatment includes using chemotherapy such as docetaxel and other oral chemotherapy such as abiraterone. Enzalutamide is used in mCRPC per National Comprehensive Cancer Network guidelines, so ARCHES has demonstrated a new niche for the use of enzalutamide in prostate cancer.

The ARCHES trial assigned 1,150 men with mHSPC in a 1:1 ratio to either enzalutmide 160 mg by mouth once a day plus ADT versus placebo plus ADT. All of the men had already received ADT for 3 months and may or may not have had up to six cycles of chemotherapy in the past. If patients had disease progression on ADT or chemotherapy, they were excluded from the trial since it included mHSPC. Men were also stratified by low- versus high-volume disease. High-volume disease was defined by the presence of metastases in the viscera or four or more bone lesions in the absence of viscera, one or more of which must have been in a bony structure beyond the vertebral column and pelvic bone (as defined by the CHAARTED trial).

The primary endpoint was progression-free survival, and the median follow up time was 14.4 months. In the study, 377 patients discontinued treatment (135 from the enzalutamide arm and 242 from the placebo arm), with the main reason being disease progression and then patient withdrawal. The ARCHES trial showed that enzalutamide, when combined with ADT therapy, reduced the risk of progression by 61% (hazard ratio 0.39, 85% CI, 0.30-0.50, P <.01). The median treatment duration was 12.8 months in the enzalutamide group and 11.6 months in the placebo group. Grade 3 or higher adverse events were similar in both groups.

Enzalutamide was generally well tolerated, with a preliminary safety analysis consistent with the medication’s established safety profile. Enzalutmide improved secondary endpoints as well as time to prostate-specific antigen progression (81% for enzalutmide, P <.0001), and the objective response rate was 83.1% for enzalutamide versus 63.7% for placebo, P <.0001).

Overall survival and quality-of-life analyses are pending. However, this opens up more treatment options in patients with mHSPC, including abiraterone, docetaxel, enzalutamide, and apalutamide. The ARCHES trial is the first one in the group to demonstrate the benefits of ADT after receiving docetaxel in some patients and low-volume disease. Further studies should look at combination versus sequential therapy for initial management.

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