Elsevier

The Lancet Oncology

Volume 15, Issue 10, September 2014, Pages 1147-1156
The Lancet Oncology

Articles
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

https://doi.org/10.1016/S1470-2045(14)70303-1Get rights and content

Summary

Background

In the AFFIRM trial of patients with metastatic castration-resistant prostate cancer after progression with docetaxel treatment, enzalutamide significantly increased overall survival compared with placebo. Here we present the prospectively defined analyses of some secondary endpoints, including occurrence of skeletal-related events, measures of pain control, and patient-reported health-related quality of life (HRQoL).

Methods

In this phase 3, double-blind trial, patients were randomly assigned (2:1) to receive enzalutamide 160 mg/day or placebo orally, stratified by ECOG baseline performance status (0 or 1 vs 2) and mean pain score (Brief Pain Inventory-Short Form [BPI-SF] question 3 worst pain, score ≤3 vs ≥4). Secondary endpoints were time to first skeletal-related event (radiation therapy or surgery to bone, clinically apparent pathological bone fracture, spinal cord compression, or change of antineoplastic therapy to treat bone pain); change from baseline to week 13 in pain severity and interference; pain palliation and progression at week 13; time to pain progression; overall improvement in HRQoL; improvements in HRQoL domains; and time to HRQoL deterioration. Analysis was done on the intention-to-treat population for each endpoint. AFFIRM is registered with ClinicalTrials.gov, number NCT00974311.

Findings

Median time to first skeletal-related event in the enzalutamide (n=800) and placebo (n=399) groups was 16·7 months (95% CI 14·6 to 19·1) and 13·3 months (95% CI 9·9 to not yet reached), respectively (hazard ratio [HR] 0·69 [95% CI 0·57–0·84]; p=0·0001). Pain progression at week 13 occurred in 174 (28%) of 625 evaluable patients in the enzalutamide group versus 101 (39%) of 259 patients in the placebo group (difference −11·2%, 95% CI −18·1 to −4·3; p=0·0018). Median time to pain progression was not yet reached in the enzalutamide group (95% CI not yet reached to not yet reached) versus 13·8 (13·8 to not yet reached) months in the placebo group (HR 0·56 [95% CI 0·41 to 0·78]; p=0·0004). Mean treatment effects for pain severity (mean change from baseline in the enzalutamide group −0·15, 95% CI −0·28 to −0·02, vs placebo 0·50, 0·29 to 0·70; difference −0·65, 95% CI −0·89 to −0·41; p<0·0001) and interference (−0·01, −0·18 to 0·16, vs 0·74, 0·47 to 1·00; respectively, difference −0·74, 95% −1·06 to −0·43; p<0·0001) were significantly better with enzalutamide than with placebo. 22 (45%) of 49 evaluable patients in the enzalutamide group reported pain palliation at week 13 versus one (7%) of 15 in the placebo group (difference 38·2%, 95% CI 19·4–57·0; p=0·0079). Overall improvement in HRQoL was reported in more patients receiving enzalutamide (275 [42%] of 652) than in those receiving placebo (36 [15%] of 248; p<0·0001). Patients in the enzalutamide group had longer median time to HRQoL deterioration than did those in the placebo group (9·0 months, 95% CI 8·3–11·1, vs 3·7 months, 95% CI 3·0–4·2; HR 0·45, 95% CI 0·37–0·55; p<0·0001).

Interpretation

Our results show that, in addition to improving overall survival, enzalutamide improves wellbeing and everyday functioning of patients with metastatic castration-resistant prostate cancer.

Funding

Astellas Pharma and Medivation.

Introduction

Treatment options have changed substantially for patients with castration-resistant prostate cancer over the past 4 years, after five agents with diverse mechanisms of action (sipuleucel-T, abiraterone acetate, enzalutamide, cabazitaxel, and radium-223) were shown to prolong overall survival.1, 2, 3, 4, 5, 6, 7 Survival is one of the measures of clinical benefit; but other measures used to assess how well patients feel and function are also important measures. For patients with prostate cancer, bone is the most common site of spread,8 accounting for about 90% of metastases,7, 9 and results in some of the most painful and functionally compromising complications of the disease. Known collectively as skeletal-related events, major pain, fractures (mainly collapse of the vertebra), and spinal cord compression adversely affect health-related quality of life (HRQoL) and increase risk of mortality.10 HRQoL is crucial to patients in this setting, and is an essential aspect of reported trial results, alongside reporting endpoints that indicate changes in the tumour. In 2008, the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) proposed principles of trial conduct for men with castration-resistant prostate cancer that were designed to align clinical research and practice.11 The focus of these principles was on direct benefits to patients defined as the control, relief, or elimination of disease manifestations present when treatment was initiated, or the delay or prevention of disease manifestations from occurring in the future.

Until recently, the only available and recommended therapy that prolonged life in men with metastatic castration-resistant prostate cancer was docetaxel,12 with palliative therapies given on further progression. The bone-targeting agents zoledronic acid and denosumab are beneficial against skeletal-related events, although these benefits do not translate into increased survival.13, 14 Therapies to palliate pain include the bone-seeking radiopharmaceuticals strontium-89 and samarium-153,15, 16 neither of which has been shown to increase overall survival. New treatments with differing mechanisms of action that have emerged for the treatment of metastatic castration-resistant prostate cancer after docetaxel treatment include cabazitaxel and radium-223 and, based on recognition of the role of androgen-receptor signalling across the prostate cancer continuum, the endocrine treatment options abiraterone and enzalutamide.

Enzalutamide is an androgen-receptor inhibitor that has a higher affinity for this receptor than do anti-androgens such as bicalutamide.17 By contrast with anti-androgens, enzalutamide inhibits nuclear translocation of the androgen receptor and DNA binding, two key mechanisms in the stimulation of prostate cancer cell growth,17, 18 and induces tumour shrinkage in vivo.17, 18 The potential benefits of targeting androgen-receptor signalling with enzalutamide in men with progressive metastatic castration-resistant prostate cancer after docetaxel were assessed in the AFFIRM trial.7 The results of AFFIRM showed significantly increased overall survival with enzalutamide versus placebo (median 18·4 [95% CI 17·3–not reached] months vs 13·6 [11·3–15–8] months, HR 0·63, 95% CI 0·53–0·75, p<0·001). Enzalutamide was significantly superior to placebo in all reported secondary endpoints and was generally well tolerated, with fewer grade 3 or worse adverse events reported than with placebo (45·3% and 53·1%, respectively).7 At the time of the initial analysis, seizures had been reported in five (0·6%) of 800 patients treated with enzalutamide and none in those given placebo.7 One further study patient was identified with an event term syncope with features suggestive of a seizure, and another patient was diagnosed with a seizure after the interim analysis cutoff date. Here, we report the prospectively defined analyses to profile first skeletal-related events and describe several measures of pain control and patient-reported HRQoL in the AFFIRM study population.

Section snippets

Trial design and participants

Study design and eligibility criteria have been described elsewhere.7 Briefly, men with progressive metastatic castration-resistant prostate cancer that had been previously treated with docetaxel were enrolled into a randomised, placebo-controlled, international trial of enzalutamide between Sept 22, 2009, and Nov 15, 2010, at 156 sites in 15 countries.7 Patients were eligible for enrolment if they had: histologically or cytologically confirmed diagnosis of prostate cancer; undergone

Results

As reported previously,7 1199 patients were enrolled; 800 patients were randomly assigned to enzalutamide and 399 to placebo (figure 1), and the trial is ongoing. Patient demographics and characteristics were well balanced in the treatment groups in the intention-to-treat population (table 2). Characteristics of patients included in the current analyses were similar to the intention-to-treat population (appendix).

Overall, 448 (37%) of 1199 patients reported at least one skeletal-related event:

Discussion

Our data show that enzalutamide reduces the risk of skeletal-related events compared with placebo, and also reduces pain and increases time to HRQoL deterioration.

Skeletal-related events associated with metastatic castration-resistant prostate cancer typically include fractures, major bone pain requiring palliative radiotherapy or surgery to the bone, and spinal cord compression. These skeletal-related events are some of the most clinically significant morbidities that directly affect a

References (34)

Cited by (173)

View all citing articles on Scopus
View full text