Improved Survival With Enzalutamide in Patients With Metastatic Hormone-Sensitive Prostate Cancer

Abstract

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.

In primary analysis, enzalutamide plus androgen deprivation therapy (ADT) improved radiographic progression-free survival (rPFS) in patients with metastatic hormone-sensitive prostate cancer (mHSPC); however, overall survival data were immature. In the phase III, double-blind, global ARCHES trial (ClinicalTrials.gov identifier: NCT02677896), 1,150 patients with mHSPC were randomly assigned 1:1 to enzalutamide (160 mg once daily) plus ADT or placebo plus ADT, stratified by disease volume and prior docetaxel use. Here, we report the final prespecified analysis of overall survival (key secondary end point) and an update on rPFS, other secondary end points, and safety. After unblinding, 180 (31.3%) progression-free patients randomly assigned to placebo plus ADT crossed over to open-label enzalutamide plus ADT. As of May 28, 2021 (median follow-up, 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 not reached in either group; hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P < .001). Enzalutamide plus ADT continued to improve rPFS and other secondary end points. Adverse events were generally consistent with previous reports of long-term enzalutamide use. In conclusion, enzalutamide plus ADT significantly prolongs survival versus placebo plus ADT in patients with mHSPC.

INTRODUCTION

Enzalutamide in combination with androgen deprivation therapy (ADT) is approved for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC [also referred to as metastatic castration-sensitive prostate cancer])^1,2 on the basis of proven clinical benefits in the phase III ARCHES trial (ClinicalTrials.gov identifier: NCT02677896). At the time of the primary analysis, enzalutamide plus ADT significantly reduced the risk of radiographic disease progression or death in men with mHSPC; however, overall survival (OS) data were considered immature.³

Herein, we report the final prespecified OS analysis and an update on radiographic progression-free survival (rPFS), other secondary end points, and safety.

METHODS

Study Design

Details of the study design of ARCHES have been published previously.³

Enrolled patients were randomly assigned 1:1 to receive enzalutamide (160 mg once daily) plus ADT or placebo plus ADT, stratified by disease volume and prior docetaxel use. After the primary analysis, ARCHES was unblinded to allow patients randomly assigned to placebo plus ADT to cross over to enzalutamide plus ADT in an open-label extension.

End Points

OS (key secondary end point) was defined as the time from random assignment to death from any cause. We also report an update on rPFS and other key secondary end points. The data cutoff for this report was May 28, 2021.

Statistical analysis methodology is reported in the Data Supplement (online only).

RESULTS

Baseline Demographics and Patient History

From March 21, 2016, to January 12, 2018, 1,150 patients were randomly assigned. Baseline demographics are presented in Table 1. Patient disposition is summarized in the Data Supplement.

TABLE 1.

Patient Demographics and Disease Characteristics (intent-to-treat population)

After study unblinding, 184 patients (31.9%) randomly assigned to placebo plus ADT remained progression-free and consented to cross over, 180 (31.3%) of whom received treatment with enzalutamide plus ADT (median time to crossover, 21.5 months). After a total of 356 deaths (enzalutamide plus ADT, n = 154; placebo plus ADT, n = 202), the data cutoff for the final OS analysis was May 28, 2021; the median follow-up time was 44.6 months.

After treatment discontinuation, 131 patients (23%) randomly assigned to enzalutamide plus ADT and 221 patients (38%) randomly assigned to placebo plus ADT received subsequent life-prolonging therapy; an additional 15 patients (8%) in the crossover group received subsequent life-prolonging therapy after discontinuing enzalutamide plus ADT (Data Supplement). Inclusive of crossover, 401 patients (70%) randomly assigned to placebo plus ADT received subsequent life-prolonging therapy, with 241 (42%) receiving enzalutamide as the first subsequent life-prolonging therapy.

OS

Patients randomly assigned to enzalutamide plus ADT had a 34% reduction in the risk of death versus placebo plus ADT (hazard ratio [HR], 0.66; 95% CI, 0.53 to 0.81; P < .001; Fig 1A); the median OS was not reached in either group. At 24, 36, and 48 months, 86%, 78%, and 71% of patients randomly assigned to enzalutamide plus ADT were estimated to be alive, respectively, compared with 82%, 69%, and 57% of patients randomly assigned to placebo plus ADT.

FIG 1.

Efficacy analyses (intent-to-treat population) showing (A) Kaplan-Meier estimate of final OS analysis, (B) forest plot of OS subgroup analyses, (C) Kaplan-Meier estimates of time to first subsequent antineoplastic therapy, and (D) Kaplan-Meier estimates of rPFS (investigator assessed). ADT, androgen deprivation therapy; E, events; ECOG, Eastern Cooperative Oncology Group; ENZA, enzalutamide; HR, hazard ratio; NE, not evaluable; NR, not reached; OS, overall survival; PBO, placebo; PSA, prostate-specific antigen; RoW, rest of world; rPFS, radiographic progression-free survival.

A prespecified rank-preserving structural failure time sensitivity analysis to adjust for a possible crossover effect demonstrated a 43% reduction in risk of death with enzalutamide plus ADT versus placebo plus ADT (HR, 0.57; 95% CI, 0.45 to 0.70; P < .001; Data Supplement). Median OS was not reached for enzalutamide plus ADT, but was 47.7 months (95% CI, 43.3 to not evaluable) for placebo plus ADT.

The clinical benefit of enzalutamide plus ADT was generally consistent across prespecified subgroups, except in patients with only soft tissue disease at baseline (n = 96; Fig 1B). Further exploratory post hoc subgroup analyses confirmed a survival benefit after enzalutamide plus ADT in all subgroups except for patients with lymph node metastases only and visceral metastases, most likely because of small patient numbers (Data Supplement).

rPFS and Secondary Efficacy End Points

Enzalutamide plus ADT delayed time to first subsequent antineoplastic therapy; median was not reached for enzalutamide plus ADT versus 40.5 months for placebo plus ADT (HR, 0.38; 95% CI, 0.31 to 0.48; Data Supplement; Fig 1C).

Compared with placebo plus ADT, enzalutamide plus ADT reduced the risk of radiographic progression or death by 37%, extending the median rPFS by approximately 11 months (Data Supplement; Fig 1D). A total of 117 patients (20%) randomly assigned to enzalutamide plus ADT had prostate-specific antigen (PSA) progression compared with 259 (45%) randomly assigned to placebo plus ADT, equating to a risk reduction of 72% (Data Supplement). After median time to crossover (21.5 months) was reached, the rate of radiographic and PSA progression slowed over time with placebo plus ADT (Fig 1D; Data Supplement).The reduced risk of radiographic progression or death and PSA progression observed with enzalutamide plus ADT, as compared with placebo plus ADT, was sustained after adjustment for crossover (Data Supplement). Enzalutamide plus ADT also delayed time to first symptomatic skeletal event (Data Supplement) and castration resistance (Data Supplement). Results of other secondary end point analyses are reported in the Data Supplement.

Safety

The median treatment duration was 40.2, 13.8, and 23.9 months in the enzalutamide plus ADT, placebo plus ADT, and crossover groups, respectively. Incidence of treatment-emergent adverse events was consistent with the primary analysis³ (Table 2; Data Supplement), and no new safety signals were identified.

TABLE 2.

Summary of TEAEs and Exposure-Adjusted TEAEs of Special Interest (safety analysis set)

DISCUSSION

In ARCHES, enzalutamide plus ADT significantly reduced the risk of death in patients with mHSPC by 34% versus placebo plus ADT. 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. Importantly, improvement in OS with enzalutamide is unlikely to be the result of patients in the placebo plus ADT group receiving inadequate postprotocol therapy.

The survival benefit with early use of enzalutamide plus ADT was generally consistent across subgroups, with the exception of patients with lymph node metastases only and visceral metastases; however, both subgroups had relatively low patient numbers and statistical analyses were underpowered, as also reported in other large trials of mHSPC.^4-6 Nevertheless, clinicians assessing and prescribing therapy for patients with mHSPC should feel reassured regarding survival benefit with enzalutamide for the majority of patients.

The superiority of enzalutamide plus ADT over placebo plus ADT for other efficacy end points was previously reported³ and maintained with additional follow-up. No new safety signals emerged. Taken together, these data indicate that 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.

In conclusion, enzalutamide plus ADT significantly prolongs survival versus placebo plus ADT in patients with mHSPC, including across clinically important subgroups, and thus represents an effective and well-tolerated therapeutic option for patients with mHSPC.

DATA SHARING STATEMENT

Researchers may request access to anonymized participant-level data, trial-level data, and protocols from Astellas-sponsored clinical trials at www.clinicalstudydatarequest.com. For the Astellas criteria on data sharing, see https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Astellas.aspx.

AUTHOR CONTRIBUTIONS

Conception and design: Andrew J. Armstrong, Arun A. Azad, Taro Iguchi, Francisco Gomez-Veiga, Shunsuke Yamada, Gabriel P. Haas

Administrative support: Arnauld Villers, Neal D. Shore

Provision of study materials or patients: Taro Iguchi, Russell Z. Szmulewitz, Arnulf Stenzl

Collection and assembly of data: Andrew J. Armstrong, Taro Iguchi, Russell Z. Szmulewitz, Jeffrey Holzbeierlein, Arnauld Villers, Antonio Alcaraz, Boris Alekseev, Fabian Zohren, Arnulf Stenzl

Data analysis and interpretation: Andrew J. Armstrong, Arun A. Azad, Taro Iguchi, Russell Z. Szmulewitz, Daniel P. Petrylak, Jeffrey Holzbeierlein, Arnauld Villers, Neal D. Shore, Francisco Gomez-Veiga, Brad Rosbrook, Fabian Zohren, Shunsuke Yamada, Gabriel P. Haas

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Improved Survival With Enzalutamide in Patients With Metastatic Hormone-Sensitive Prostate Cancer

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