A new study has found that enzalutamide given with androgen deprivation therapy significantly reduced the risk of metastatic progression or death in men with metastatic hormone-sensitive prostate cancer versus placebo plus ADT, including patients with low-volume disease and/or prior docetaxel therapy.<br />
Andrew J. Armstrong, MD
A new study has found that enzalutamide (Xtandi) given with androgen deprivation therapy (ADT) significantly reduced the risk of metastatic progression or death in men with metastatic hormone-sensitive prostate cancer (mHSPC) versus placebo plus ADT, including patients with low-volume disease and/or prior docetaxel therapy.1
Results from the ARCHES trial were published in theJournal of Clinical Oncologyand include the finding that enzalutamide plus ADT reduced the risk of radiographic disease progression or death by 61% compared with placebo plus ADT (Hazard Ratio [HR], 0.39; 95% Confidence Interval [CI], 0.30 to 0.50;P< .001). Median radiographic progression-free survival (rPFS), the trial’s primary endpoint, was not reached in the experimental group. Median rPFS in the control group was 19.0 months (95% CI, 16.6 to 22.2 months).
“Importantly, the significant reduction in the risk of radiographic disease progression or death with enzalutamide plus ADT in this study (P< .001) was observed in all prespecified subgroups, including men with or without prior docetaxel chemotherapy and those with a low or high volume of metastatic disease,” wrote the authors, led by Andrew J. Armstrong, MD, ScM, Duke Cancer Institute Center for Prostate and Urologic Cancers, Durham, NC. “These data support the consideration of enzalutamide in addition to ADT for men with mHSPC, including patients with prior docetaxel treatment and regardless of disease volume. Although OS data remain immature, these findings have clear clinical implications for the current management of these patients.”
ARCHES is a multinational, double-blind, randomized, placebo-controlled, phase III trial that enrolled 1,150 patients from 202 centers in North and Latin America, Europe, and Asia. Patients had hormone-sensitive metastatic disease, eitherde novoor after recurrence following prior local therapy and an ECOG performance status of 0 or 1. The trial protocol allowed patients to enroll who had previous ADT and/or up to 6 previous cycles of docetaxel chemotherapy.
Study patients were stratified by low vs high disease volume, which was defined as the presence of visceral lesions or 4 or more bone lesions. Patients were also stratified by prior docetaxel chemotherapy for prostate cancer: 0 cycles, 1-5 cycles, or 6 cycles. Treatment continued until unacceptable toxicity or confirmed radiographic progression. At that point, eligible patients were offered the opportunity to transition to an open-label extension.
In addition to the rPFS primary endpoint, ARCHES had several secondary endpoints. These include time to PSA progression, time to initiation of new antineoplastic therapy (including cytotoxic and hormone therapies), PSA undetectable rate, objective response rate, time to deterioration in urinary symptoms, and overall survival (OS).
Of the 1,150 patients, 727 patients (63.2%) had high-volume disease, and 205 (17.9%) received prior docetaxel chemotherapy. In the enzalutamide group, 34 patients (5.9%) used concomitant antiandrogens as prostate cancer therapy during the study, while 43 patients (7.5%) in the placebo group did so.
Median treatment duration was 12.8 months (range, 0.2 to 26.6 months) in the enzalutamide group and 11.6 months (range, 0.2 to 24.6 months) in the placebo group. As of the October 2018 data cutoff, the median follow-up time was 14.4 months. One third of patients overall discontinued study treatment (n = 377, 32.8%), including 135 in the experimental group (23.5%) and 242 in the placebo group (42.0%). Progressive disease was the primary reason for treatment discontinuation, given by 65 patients in the enzalutamide group (11.3%) and 171 patients in the placebo group (29.7%).
There were 292 radiographic disease progression events or deaths without radiographic disease progression within 24 weeks of treatment discontinuation at data cutoff. This includes 91in the enzalutamide group (15.9%) and 201 in the placebo group (34.9%).
Armstrong et al reported that grade 3 or greater adverse events (AEs), serious AEs, and AEs leading to treatment discontinuation were similar in both treatment groups. In the experimental group, 14 AEs (2.4%) led to death, while 10 AEs (1.7%) did in the placebo group. None of these AEs in the enzalutamide group were found to be treatment-related, but 1 patient’s general physical health deterioration in the placebo group was found to be treatment-related.
Armstrong et al note that both rPFS and metastasis-free survival are accepted by the US Food and Drug Administration as primary efficacy end points in metastatic castration-resistant prostate cancer (CRPC) and nonmetastatic CRPC, respectively. “However, although rPFS has not yet been established as a surrogate for OS in mHSPC, it is an acceptable regulatory end point, and reducing the risk of radiographic progression or death is of clinical importance,” they wrote. “Furthermore, rPFS requires shorter follow-up periods and fewer patients compared with OS as a result of the higher event rate, accelerating trial completion.”
The authors note that OS data from ARCHES are immature and will be analyzed when 342 deaths have occurred. In the meantime, they refer colleagues to ENZAMET, the ongoing phase III trial investigating the addition of enzalutamide versus a first-generation nonsteroidal antiandrogen, such as bicalutamide, to ADT, with or without docetaxel chemotherapy, in men with mHSPC.2
Armstrong et al concluded that enzalutamide plus ADT should be considered as a treatment option for men with mHSPC, including those with low-volume disease or who had received prior docetaxel: “Additional studies are necessary to clarify whether combination or sequential approaches with AR-targeted therapies or chemotherapy are favored for initial management.”