Elsevier

The Lancet Oncology

Volume 16, Issue 5, May 2015, Pages 509-521
The Lancet Oncology

Articles
Effect of enzalutamide on health-related quality of life, pain, and skeletal-related events in asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer (PREVAIL): results from a randomised, phase 3 trial

https://doi.org/10.1016/S1470-2045(15)70113-0Get rights and content

Summary

Background

Enzalutamide significantly increased overall survival and radiographic progression-free survival compared with placebo in the PREVAIL trial of asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer. We report the effect of enzalutamide on health-related quality of life (HRQoL), pain, and skeletal-related events observed during this trial.

Methods

In this phase 3, double-blind trial, patients were randomly assigned (1:1) to receive enzalutamide 160 mg/day (n=872) or placebo (n=845) orally. HRQoL was assessed at baseline and during treatment using the Functional Assessment of Cancer Therapy–Prostate (FACT-P) and EQ-5D questionnaires. Pain status was assessed at screening, baseline, week 13, and week 25 with the Brief Pain Inventory Short Form (BPI-SF). The primary analysis of HRQoL data used a mixed-effects model to test the difference between least square means change from baseline at week 61. We assessed change from baseline, percentage improvement, and time to deterioration in HRQoL and pain, the proportion of patients with a skeletal-related event, and time to first skeletal-related event. Analysis was done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01212991.

Findings

Median treatment duration was 16·6 months (IQR 10·1–21·1) in the enzalutamide group and 4·6 months (2·8–9·7) in the placebo group. The mixed-effects model analyses showed significant treatment differences in change from baseline to week 61 with enzalutamide compared with placebo for most FACT-P endpoints and EQ-5D visual analogue scale. Median time to deterioration in FACT-P total score was 11·3 months (95% CI 11·1–13·9) in the enzalutamide group and 5·6 months (5·5–5·6) in the placebo groups (hazard ratio [HR] 0·62 [95% CI 0·54–0·72]; p<0·0001). A significantly greater proportion of patients in the enzalutamide group than in the placebo group reported clinically meaningful improvements in FACT-P total score (327 [40%] of 826 vs 181 [23%] of 790), in EQ-5D utility index (224 [28%] of 812 vs 99 [16%] of 623), and visual analogue scale (218 [27%] of 803 vs 106 of [18%] 603; all p<0·0001). Median time to progression in BPI-SF pain at its worst was 5·7 months (95% CI 5·6–5·7) in the enzalutamide group and 5·6 months (5·4–5·6) in the placebo group (HR 0·62 [95% CI 0·53–0·74]; p<0·0001). Progression of pain at its worst was less common in the enzalutamide group than in the placebo group at week 13 (220 [29%] of 769 vs 257 [42%] of 610; p<0·0001), but not at week 25 (225 [32%] of 705 vs 135 [38%] of 360; p=0·068). 278 (32%) of 872 patients in the enzalutamide group and 309 (37%) of 845 patients in the placebo group had experienced a skeletal-related event by data cutoff. Median time to first skeletal-related events in the enzalutamide group was 31·1 months (95% CI 29·5–not reached) and 31·3 months (95% CI 23·9–not reached) in the placebo group (HR 0·72 [95% CI 0·61–0·84]; p<0·0001).

Interpretation

In addition to improving overall survival relative to placebo, enzalutamide significantly improves patient-related outcomes and delays occurrence of first skeletal-related event in chemotherapy-naive men with metastatic castration-resistant prostate cancer.

Funding

Astellas Pharma and Medivation.

Introduction

About 1·1 million men are diagnosed with prostate cancer every year worldwide (representing 15% of all newly diagnosed cancers in men), and more than 300 000 men die from advanced forms of the disease annually.1 In developed countries, up to 15% of patients have metastatic disease at presentation, which is associated with at least a 75% reduction in life expectancy.2, 3

Development of metastatic castration-resistant prostate cancer has historically been associated with a poor prognosis, a high level of comorbidity, and death expected within 1–2 years.4 During the past 5 years, however, new treatments with wide-ranging methods of action have been developed (eg, sipuleucel-T, abiraterone plus prednisone, enzalutamide, cabazitaxel, and radium-223) that increase survival when used before or after docetaxel chemotherapy.5, 6, 7, 8, 9, 10, 11, 12, 13 As more patients receive these drugs over fairly long periods of time, information about their effects on health-related quality of life (HRQoL) and prostate cancer-related symptom control have become priorities from patient, research, and regulatory perspectives.14

Changes in HRQoL have been previously shown to significantly affect overall treatment satisfaction in survivors of prostate cancer, irrespective of the type of therapy.15 In 2008, the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) identified the following key unmet needs in patients with metastatic castration-resistant prostate cancer who initially do not have major cancer-related symptoms in the chemotherapy-naive setting: (1) prevention of HRQoL decline associated with disease progression; (2) delaying time to skeletal-related events; and (3) delaying time to onset of significant pain.14 PCWG2 advised incorporating validated questionnaires into clinical trials to measure patient-reported outcomes and to monitor these outcomes.14 Findings from the phase 3 PREVAIL study, which enrolled 1717 asymptomatic or minimally symptomatic chemotherapy-naive patients with metastatic castration-resistant prostate cancer, showed that the orally available androgen receptor inhibitor enzalutamide prolonged overall survival and radiographic progression-free survival compared with placebo.5 Enzalutamide was also associated with delaying time to deterioration in HRQoL, indicating that the objective measurements of treatment efficacy (ie, overall and progression-free survival) translated into subjective benefits for the patient.5

Most patients (>80%) with metastatic castration-resistant prostate cancer present with bone metastases and thus have a high likelihood of symptomatic skeletal-related events,16 a variably defined collective term encompassing radiation to bone, pathological fracture, spinal cord compression, surgery to bone, or requirement of different antineoplastic therapy to treat bone pain.17, 18 Skeletal complications of malignancy are a major contributor to worsening HRQoL and pain in patients with metastatic castration-resistant prostate cancer.19, 20 Patients might also experience deterioration in HRQoL and pain status as a result of extraskeletal metastases, locoregional disease progression, systemic effects of cancer, and treatment-associated adverse effects, all of which further complicate disease management.

In view of the importance of patient wellbeing in the management of metastatic castration-resistant prostate cancer,14 we present results of prospectively defined analyses that compare the effects of enzalutamide versus placebo on HRQoL, pain, and skeletal-related events from PREVAIL.

Section snippets

Study design and participants

PREVAIL was a multinational, phase 3, randomised, double-blind, placebo-controlled trial of chemotherapy-naive patients aged 18 years or older with histologically or cytologically confirmed metastatic castration-resistant prostate cancer despite androgen deprivation therapy. Patients had relatively good performance status at trial entry based on an Eastern Cooperative Oncology Group (ECOG) performance status grade 0 (asymptomatic, fully active) or 1 (ambulatory but restricted in strenuous

Results

As reported previously,5 1717 patients were enrolled; 872 were randomly assigned to enzalutamide and 845 to placebo group. A higher proportion of patients randomised to enzalutamide than placebo were available for HRQoL assessment at each time point (figure 1). Patient demographics and baseline characteristics were well balanced between the treatment groups.5 Similar proportions of patients in the enzalutamide (223 [26%] of 872) and placebo (230 [27%] of 845) groups were receiving either

Discussion

Our data show that, relative to placebo, enzalutamide provides significant and clinically meaningful benefits in terms of HRQoL and in time to first skeletal-related event for asymptomatic or minimally symptomatic chemotherapy-naive men with metastatic, castration-resistant prostate cancer (panel). Although the change-from-baseline differences in mean pain scores were also significant in favour of enzalutamide, the effect size was modest. This is not surprising in view of the fact that this

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