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.

FIG 1.

CONSORT diagram. (*) Randomization 1:1 was stratified by volume of disease (low v high) and prior docetaxel therapy for prostate cancer (no cycles, one to five cycles, or six cycles); high volume of disease was defined as presence of metastases involving the viscera, or in the absence of visceral lesions, four or more bone lesions, one or more of which must have been in a bony structure beyond the vertebral column and pelvic bone, per CHAARTED (ClinicalTrials.gov identifier: NCT00309985) criteria. (†) Progressive disease types are not mutually exclusive; the same patient may be reported in multiple categories. ADT, androgen deprivation therapy; ITT, intent-to-treat.

FIG 2.

Kaplan-Meier estimate of (A) radiographic progression-free survival (rPFS) and (B) forest plot of rPFS for prespecified subgroups (intent-to-treat population). The dashed line at the 50th percentile indicates the median. Crosses indicate censored data. (*) For patients with no documented progression event, rPFS was censored on the date of the last radiologic assessment performed before the cutoff date. (†) 95% CIs provided are not adjusted for the number of subgroups summarized. ADT, androgen deprivation therapy; E, No. of events; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; NR, not reached; PSA, prostate-specific antigen.

FIG 3.

Kaplan-Meier estimates of time to (A) prostate-specific antigen (PSA) progression, (B) initiation of new antineoplastic therapy, and (C) first symptomatic skeletal event (intent-to-treat population). The dashed line at the 50th percentile indicates the median. Crosses indicate censored data. (*) In patients with no PSA progression, time to PSA progression was censored on the date of the last PSA sample taken. Patients without PSA progression before two or more consecutive missed PSA assessments were censored on the date of last PSA assessment before the assessments missed. (†) In patients with no new antineoplastic therapy initiated for prostate cancer after randomization, time to start of new antineoplastic therapy was censored on the last visit date or the date of randomization, whichever occurred last. The median for the enzalutamide plus androgen deprivation therapy (ADT) group was not a reliable estimate because it resulted from an event observed in the only remaining patient at risk at approximately 30 months, leading to the vertical drop at the end of the Kaplan-Meier curve. The hazard ratio (HR; 95% CI) is a more accurate depiction of the differences between treatment arms. (‡) In patients with no symptomatic skeletal event by the time of the data cutoff point, time to symptomatic skeletal event was censored on the last visit date or the date of randomization, whichever occurred last. HR, hazard ratio; NR, not reached.

FIG A1.

Multiplicity adjustment strategy. (*) Overall survival will be tested at 0.05 only if all the other five secondary end points analyses are statistically significant at 0.01, otherwise it will be tested at 0.04. N, no; Y, yes.