ArticlesEffect 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
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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