Men with nonmetastatic, castration-resistant prostate cancer and a rapidly rising prostate-specific antigen (PSA) level are at high risk for metastasis. We hypothesized that enzalutamide, which ...prolongs overall survival among patients with metastatic, castration-resistant prostate cancer, would delay metastasis in men with nonmetastatic, castration-resistant prostate cancer and a rapidly rising PSA level.
In this double-blind, phase 3 trial, we randomly assigned, in a 2:1 ratio, men with nonmetastatic, castration-resistant prostate cancer and a PSA doubling time of 10 months or less who were continuing androgen-deprivation therapy to receive enzalutamide (at a dose of 160 mg) or placebo once daily. The primary end point was metastasis-free survival (defined as the time from randomization to radiographic progression or as the time to death without radiographic progression).
A total of 1401 patients (median PSA doubling time, 3.7 months) underwent randomization. As of June 28, 2017, a total of 219 of 933 patients (23%) in the enzalutamide group had metastasis or had died, as compared with 228 of 468 (49%) in the placebo group. The median metastasis-free survival was 36.6 months in the enzalutamide group versus 14.7 months in the placebo group (hazard ratio for metastasis or death, 0.29; 95% confidence interval, 0.24 to 0.35; P<0.001). The time to the first use of a subsequent antineoplastic therapy was longer with enzalutamide treatment than with placebo (39.6 vs. 17.7 months; hazard ratio, 0.21; P<0.001; such therapy was used in 15% vs. 48% of patients) as was the time to PSA progression (37.2 vs. 3.9 months; hazard ratio, 0.07; P<0.001; progression occurred in 22% vs. 69% of patients). At the first interim analysis of overall survival, 103 patients (11%) receiving enzalutamide and 62 (13%) receiving placebo had died. Adverse events of grade 3 or higher occurred in 31% of the patients receiving enzalutamide, as compared with 23% of those receiving placebo.
Among men with nonmetastatic, castration-resistant prostate cancer with a rapidly rising PSA level, enzalutamide treatment led to a clinically meaningful and significant 71% lower risk of metastasis or death than placebo. Adverse events were consistent with the established safety profile of enzalutamide. (Funded by Pfizer and Astellas Pharma; PROSPER ClinicalTrials.gov number, NCT02003924 .).
Enzalutamide, a potent oral androgen receptor inhibitor, improves survival in men with metastatic castration-resistant prostate cancer (CRPC) before and after chemotherapy. Bicalutamide, a ...nonsteroidal antiandrogen, is widely used to treat men with nonmetastatic or metastatic CRPC. The efficacy and safety of these drugs were compared in this randomized, double-blind, phase II study of men with CRPC.
A total of 396 men with nonmetastatic (n = 139) or metastatic (n = 257) CRPC were randomly assigned to enzalutamide 160 mg per day (n = 198) or bicalutamide 50 mg per day (n = 198). Androgen deprivation therapy was continued in both arms. The primary end point was progression-free survival (PFS).
Enzalutamide reduced the risk of progression or death by 76% compared with bicalutamide (hazard ratio HR, 0.24; 95% CI, 0.18 to 0.32; P < .001). Median PFS was 19.4 months with enzalutamide versus 5.7 months with bicalutamide. Enzalutamide resulted in significant improvements in all key secondary end points: time to prostate-specific antigen progression (HR, 0.19; 95% CI, 0.14 to 0.26; P < .001); proportion of patients with a ≥ 50% prostate-specific antigen response (81% v 31%; P < .001); and radiographic PFS in metastatic patients (HR, 0.32; 95% CI, 0.21 to 0.50; P < .001). Beneficial effects with enzalutamide were observed in both nonmetastatic and metastatic subgroups. The observed adverse event profile was consistent with that from phase III enzalutamide trials.
Enzalutamide significantly reduced risk of prostate cancer progression or death compared with bicalutamide in patients with nonmetastatic or metastatic CRPC.
Summary Background Enzalutamide is an oral androgen-receptor inhibitor that has been shown to improve survival in two placebo-controlled phase 3 trials, and is approved for patients with metastatic ...castration-resistant prostate cancer. The objective of the TERRAIN study was to compare the efficacy and safety of enzalutamide with bicalutamide in patients with metastatic castration-resistant prostate cancer. Methods TERRAIN was a double-blind, randomised phase 2 study, that recruited asymptomatic or minimally symptomatic men with prostate cancer progression on androgen-deprivation therapy (ADT) from academic, community, and private health-care provision sites across North America and Europe. Eligible patients were randomly assigned (1:1) via an interactive voice response system to receive enzalutamide 160 mg/day or bicalutamide 50 mg/day, both taken orally, in addition to ADT, until disease progression. Patients were stratified by a permutated block method (block size of four), by whether bilateral orchiectomy or receipt of luteinising hormone-releasing hormone agonist or antagonist therapy started before or after the diagnosis of metastases, and by study site. Participants, investigators, and those assessing outcomes were masked to group assignment. The primary endpoint was progression-free survival, analysed in all randomised patients. Safety outcomes were analysed in all patients who received at least one dose of study drug. The open-label period of the trial is in progress, wherein patients still on treatment at the end of the double-blind treatment period were offered open-label enzalutamide at the discretion of the patient and study investigator. This trial is registered with ClinicalTrials.gov , number NCT01288911. Findings Between March 22, 2011, and July 11, 2013, 375 patients were randomly assigned, 184 to enzalutamide and 191 to bicalutamide. 126 (68%) and 168 (88%) patients, respectively, discontinued their assigned treatment before study end, mainly due to progressive disease. Median follow-up time was 20·0 months (IQR 15·0–25·6) in the enzalutamide group and 16·7 months (10·2–21·9) in the bicalutamide group. Patients in the enzalutamide group had significantly improved median progression-free survival (15·7 months 95% CI 11·5–19·4) compared with patients in the bicalutamide group (5·8 months 4·8–8·1; hazard ratio 0·44 95% CI 0·34–0·57; p<0·0001). Of the most common adverse events, those occurring more frequently with enzalutamide than with bicalutamide were fatigue (51 28% of 183 patients in the enzalutamide group vs 38 20% of 189 in the bicalutamide group), back pain (35 19% vs 34 18%), and hot flush (27 15% vs 21 11%); those occurring more frequently with bicalutamide were nausea (26 14% vs 33 17%), constipation (23 13% vs 25 13%), and arthralgia (18 10% vs 30 16%). The most common grade 3 or worse adverse events in the enzalutamide or bicalutamide treatment groups, respectively, were hypertension (13 7% vs eight 4%), hydronephrosis (three 2% vs seven 4%), back pain (five 3% vs three 2%), pathological fracture (five 3% vs two 1%), dyspnoea (four 2% vs one 1%), bone pain (one 1% vs four 2%), congestive cardiac failure (four 2% vs two 1%), myocardial infarction (five 3% vs none), and anaemia (four 2% vs none). Serious adverse events were reported by 57 (31%) of 183 patients and 44 (23%) of 189 patients in the enzalutamide and bicalutamide groups, respectively. One of the nine deaths in the enzalutamide group was thought to be possibly related to treatment (due to systemic inflammatory response syndrome) compared with none of the three deaths in the bicalutamide group. Interpretation The data from the TERRAIN trial support the use of enzalutamide rather than bicalutamide in patients with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer. Funding Astellas Pharma, Inc and Medivation, Inc.
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.
Summary Background The androgen receptor inhibitor enzalutamide is approved for the treatment of metastatic castration-resistant prostate cancer that has progressed on docetaxel. Our aim was to ...assess the activity and safety of enzalutamide monotherapy in men with hormone-naive prostate cancer. Methods This trial is an ongoing open-label, single-arm, phase 2 study, done across 12 European sites. Men aged over 18 years, with hormone-naive prostate cancer for whom hormone therapy was indicated, and who had non-castration levels of testosterone and prostate-specific antigen (PSA) of 2 ng/mL or greater at screening, and an Eastern Cooperative Oncology Group score of 0, received oral enzalutamide 160 mg/day. The primary outcome was the proportion of patients with an 80% or greater decline in PSA at week 25. All analyses included all patients who had received at least one dose of the study drug. This study is registered with ClinicalTrials.gov , number NCT01302041. Findings 67 men were enrolled into the study. 62 patients (92·5%, 95% CI 86·2–98·8) had a decline in PSA of 80% or greater at week 25. The most commonly reported treatment-emergent adverse events up to week 25 were gynaecomastia (n=24), fatigue (n=23), nipple pain (n=13), and hot flush (n=12), all of which were of mild to moderate severity. Nine patients had a treatment-emergent adverse event of grade 3 or higher, most of which were reported in one patient each, except for pneumonia (grade 3, two patients) and hypertension (grade 3, four patients). Five patients reported serious adverse events, none of which were deemed to be treatment related. Interpretation Our findings suggest that enzalutamide monotherapy in men with hormone-naive prostate cancer of varying severity provides a level of disease suppression, and was generally well tolerated. These findings provide a rationale for further investigation of clinical response and outcomes with enzalutamide in non-castrate men with prostate cancer. Funding Astellas Pharma Inc, Medivation Inc.
Metastatic castration resistant prostate cancer with low baseline prostate specific antigen represents an early stage in the natural history of castration resistant prostate cancer progression (low ...volume disease), low prostate specific antigen producing disease or disease that is less dependent on androgen receptor biology (high volume disease). We analyzed outcomes in men with low prostate specific antigen and a high disease burden who received the oral androgen receptor inhibitor enzalutamide in the PREVAIL (Safety and Efficacy Study of Oral MDV3100 in Chemotherapy-Naive Patients with Progressive Metastatic Prostate Cancer) study.
In this exploratory analysis low baseline prostate specific antigen was defined as less than 10 ng/ml. Post hoc analyses included radiographic progression-free and overall survival in the once daily enzalutamide and placebo arms. Patients were stratified post hoc by high volume disease, defined as more than 4 bone metastases and/or visceral disease, and low volume disease, defined as 4 or fewer bone metastases with no visceral disease.
Of 1,717 patients enrolled in PREVAIL 242 (14.1%) had low baseline prostate specific antigen, including 110 with high volume disease. Enzalutamide decreased the risk of radiographic progression relative to placebo in patients with low baseline prostate specific antigen (HR 0.20, 95% CI 0.10–0.42). This decrease was irrespective of tumor burden (high volume disease HR 0.17, 95% CI 0.06–0.51 and low volume disease HR 0.25, 95% CI 0.09–0.70). Median overall survival was not reached in patients with low baseline prostate specific antigen in either treatment arm.
Chemotherapy naïve men with metastatic castration resistant prostate cancer and low baseline prostate specific antigen irrespective of disease burden may benefit from enzalutamide. This indicates that targeting the androgen receptor signaling pathway is a therapeutic option in similar patients.
Abstract Objectives To develop a mapping algorithm for estimating EuroQol five-dimensional (EQ-5D) questionnaire values from the prostate cancer–specific health-related quality-of-life (HRQOL) ...instrument Functional Assessment of Cancer Therapy–Prostate (FACT-P) instrument. Methods The EQ-5D questionnaire and FACT-P instrument data were collected for a subset of patients with metastatic castration-resistant prostate cancer in a multicenter, randomized, double-blind, placebo-controlled phase 3 trial. We compared three statistical techniques to estimate patients’ EQ-5D questionnaire index scores determined by using the UK tariff: 1) generalized estimating equations, 2) two-part model combining logistic regression and generalized estimating equation, and 3) separate mapping algorithms for patients with poor health defined as a FACT-P score of 76 or less (group-specific model). Four different sets of explanatory variables were compared. The models were cross-validated by using a 10-fold in-sample cross-validation. Results Values for both instruments were available for 236 patients with metastatic castration-resistant prostate cancer. The group-specific model including the FACT-P subscale scores and baseline variables had the best predictive performance with R2 0.718, root mean square error 0.162, and mean absolute error 0.117. The two-part model and the generalized estimating equation model including the FACT-P subdomain scores and baseline variables also had good predictive performance. Conclusions The developed algorithms for mapping the FACT-P instrument to the EQ-5D questionnaire enable the estimation of preference-based health-related quality-of-life scores for use in cost-effectiveness analyses when directly elicited EQ-5D questionnaire data are missing.
Assessment decision-making is an integral part of teacher practice. Issues related to its trustworthiness have always been a major area of concern, particularly variability and consistency of teacher ...judgment. While there has been extensive research on factors affecting variability, little is understood about the cognitive processes that work to improve the trustworthiness of assessment. Even in an educational system like Australia, where teacher-based assessment in mainstream classrooms is widespread, it has only been relatively recently that there have been initiatives to enhance the trustworthiness of teacher assessment of English as a second or additional language (EAL). To date, how teachers make their decisions in assessing student oral language development has not been well studied. This paper reports on the nature and dynamics of teacher decision-making as part of a larger study aimed at exploring variability of teacher-based assessment when using the oral assessment tasks and protocols developed as part of the Victorian project, Tools to Enhance Assessment Literacy for Teachers of English as an Additional Language (TEAL). Employing a mixed-method research approach, this study investigated the assessment judgements of 12 experienced NSW primary and secondary EAL teachers through survey, assessment activity, think-aloud protocols and individual follow-up interviews. The paper highlights the key role of teachers’ first impressions, or judgement Gestalts, in forming holistic appraisals shaping subsequent assessment decision-making pathways. Based on the data, a model identifying three assessment decision-making pathways is proposed which provides a new lens for understanding differences in teachers’ final assessment judgements of student oral language performances and their relative trustworthiness. Implications of the model for assessment theory and practice, teacher education, and future research are discussed.
Drug development for metastatic castration-resistant prostate cancer has been limited by a lack of clinically relevant trial end points short of overall survival (OS). Radiographic progression-free ...survival (rPFS) as defined by the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) is a candidate end point that represents a clinically meaningful benefit to patients.
To demonstrate the robustness of the PCWG2 definition and to examine the relationship between rPFS and OS.
PREVAIL was a phase 3, randomized, double-blind, placebo-controlled multinational study that enrolled 1717 chemotherapy-naive men with metastatic castration-resistant prostate cancer from September 2010 through September 2012. The data were analyzed in November 2016.
Patients were randomized 1:1 to enzalutamide 160 mg or placebo until confirmed radiographic disease progression or a skeletal-related event and initiation of either cytotoxic chemotherapy or an investigational agent for prostate cancer treatment.
Sensitivity analyses (SAs) of investigator-assessed rPFS were performed using the final rPFS data cutoff (May 6, 2012; 439 events; SA1) and the interim OS data cutoff (September 16, 2013; 540 events; SA2). Additional SAs using investigator-assessed rPFS from the final rPFS data cutoff assessed the impact of skeletal-related events (SA3), clinical progression (SA4), a confirmatory scan for soft-tissue disease progression (SA5), and all deaths regardless of time after study drug discontinuation (SA6). Correlations between investigator-assessed rPFS (SA2) and OS were calculated using Spearman ρ and Kendall τ via Clayton copula.
In the 1717 men (mean age, 72.0 range, 43.0-93.0 years in enzalutamide arm and 71.0 range, 42.0-93.0 years in placebo arm), enzalutamide significantly reduced risk of radiographic progression or death in all SAs, with hazard ratios of 0.22 (SA1; 95% CI, 0.18-0.27), 0.31 (SA2; 95% CI, 0.27-0.35), 0.21 (SA3; 95% CI, 0.18-0.26), 0.21 (SA4; 95% CI, 0.17-0.26), 0.23 (SA5; 95% CI, 0.19-0.30), and 0.23 (SA6; 95% CI, 0.19-0.30) (P < .001 for all). Correlations of rPFS and OS in enzalutamide-treated patients were 0.89 (95% CI, 0.86-0.92) by Spearman ρ and 0.72 (95% CI, 0.68-0.77) by Kendall τ.
Sensitivity analyses in PREVAIL demonstrated the robustness of the PCWG2 rPFS definition using additional measures of progression. There was concordance between central and investigator review and a positive correlation between rPFS and OS among enzalutamide-treated patients.
clinicaltrials.gov Identifier: NCT01212991.
The effect of enzalutamide on health-related quality of life (HRQoL) in the PREVAIL trial in chemotherapy-naïve men with metastatic castration-resistant prostate cancer was analyzed using the generic ...EQ-5D instrument.
Patients received oral enzalutamide 160 mg/day (n = 872) or placebo (n = 845). EQ-5D index and EQ-5D visual analogue scale (EQ-5D VAS) scores were evaluated at baseline, week 13, and every 12 weeks until week 61 due to sample size reduction thereafter. Changes on individual dimensions were assessed, and Paretian Classification of Health Change (PCHC) and time-to-event analyses were conducted.
With enzalutamide, EQ-5D index and EQ-5D VAS scores declined more slowly versus placebo and time to diverge from full health was prolonged. Average decline in EQ-5D index (-0.042 vs. -0.070; P < .0001) and EQ-5D VAS (-1.3 vs. -4.4; P < .0001) was significantly smaller with enzalutamide. There were significant (P < .05) between-group differences favoring enzalutamide in Pain/Discomfort to week 37, Anxiety/Depression at week 13, and Usual Activities at week 25, but no significant differences for Mobility and Self-care. The PCHC analysis showed more enzalutamide patients reporting improvement than placebo patients at weeks 13, 25, and 49 (all P < .05) and week 37 (P = .0512). Enzalutamide was superior (P ≤ .0003) to placebo for time to diverge from full health and time to first deterioration on Pain/Discomfort and Anxiety/Depression dimensions.
This in-depth post hoc analysis showed that enzalutamide delayed HRQoL deterioration and had beneficial effects on several HRQoL domains, including Pain/Discomfort and the proportion of patients in full health, compared with placebo, and may help to support future analyses of this type.
NCT01212991.
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