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
References (51)
- et al.
Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial
Lancet
(2010) - et al.
Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study
Lancet Oncol
(2012) - et al.
Updated interim efficacy analysis and long-term safety of abiraterone acetate in metastatic castration-resistant prostate cancer patients without prior chemotherapy (COU-AA-302)
Eur Urol
(2014) - et al.
Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study
Lancet Oncol
(2015) - et al.
Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study
Lancet
(2011) - et al.
The significance of skeletal-related events for the health-related quality of life of patients with metastatic prostate cancer
Ann Oncol
(2005) - et al.
Impact of enzalutamide on quality of life in men with metastatic castration-resistant prostate cancer after chemotherapy: additional analyses from the AFFIRM randomized clinical trial
Ann Oncol
(2015) - et al.
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)
Eur J Cancer
(2009) - et al.
Measuring quality of life in men with prostate cancer using the functional assessment of cancer therapy-prostate instrument
Urology
(1997) - et al.
Defining the clinically important difference in pain outcome measures
Pain
(2000)
Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations
J Pain
Abiraterone acetate plus prednisone versus prednisone alone in chemotherapy-naive men with metastatic castration-resistant prostate cancer: patient-reported outcome results of a randomised phase 3 trial
Lancet Oncol
Assessing and interpreting treatment effects in longitudinal clinical trials with missing data
Biol Psychiatry
New and emerging therapies for bone metastases in genitourinary cancers
Eur Urol
Efficacy, patient-reported outcomes (PROs), and tolerability of the changing therapeutic landscape in patients with metastatic prostate cancer (MPC): a systematic literature review
Value Health
Toxicities following treatment with bisphosphonates and receptor activator of nuclear factor-κB ligand inhibitors in patients with advanced prostate cancer
Eur Urol
EAU guidelines on prostate cancer. Part II: treatment of advanced, relapsing, and castration-resistant prostate cancer
Eur Urol
Castration-resistant prostate cancer: AUA Guideline
J Urol
Effect of abiraterone acetate treatment on the quality of life of patients with metastatic castration-resistant prostate cancer after failure of docetaxel chemotherapy
Eur J Cancer
Management and challenges of corticosteroid therapy in men with metastatic castrate-resistant prostate cancer
Ann Oncol
Effect of enzalutamide on time to first skeletal-related event, pain, and quality of life in men with castration-resistant prostate cancer: results from the randomised, phase 3 AFFIRM trial
Lancet Oncol
Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial
Lancet Oncol
Effect of abiraterone acetate on fatigue in patients with metastatic castration-resistant prostate cancer after docetaxel chemotherapy
Ann Oncol
Estimated cancer incidence, mortality and prevalence worldwide in 2012
Prostate cancer in the elderly: frequency of advanced disease at presentation and disease-specific mortality
Cancer
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