Impact of enzalutamide on patient-reported fatigue in patients with prostate cancer: data from the pivotal clinical trials.

BACKGROUND: Fatigue is a multifactorial symptom commonly reported by patients with prostate cancer as a result of disease and treatment. This study assesses the impact enzalutamide has on patient-reported fatigue ("fatigue") by using patient-reported outcomes from four pivotal, placebo-controlled trials of enzalutamide (ARCHES (NCT02677896), PROSPER (NCT02003924), PREVAIL (NCT01212991), and AFFIRM (NCT00974311)). METHODS: Fatigue was assessed in the individual studies using the Functional Assessment of Cancer Therapy-Prostate item GP1 at baseline, weeks 13 or 17, and every 12 weeks until disease progression. Longitudinal changes were assessed using mean scores and mixed-model repeated measures. RESULTS: The fatigue rates at baseline were higher in patients with later-stage disease (metastatic and/or castration-resistant prostate cancer (CRPC)) and among patients who had already received prior treatment lines; rates ranged between 58% in PROSPER (nonmetastatic CRPC) and 86% in AFFIRM (post-docetaxel metastatic CRPC). Irrespective of disease state, initiation of enzalutamide or placebo resulted in an early increase of fatigue (by weeks 13 or 17), with fatigue levels stabilizing thereafter. At last assessment, ≥55% of patients reported fatigue improvement or stabilization in all trials compared to baseline. More patients reported fatigue worsening by ≥1 or ≥2 units with enzalutamide plus androgen deprivation therapy (ADT) than with placebo plus ADT in ARCHES, PROSPER, and PREVAIL, but the between-group difference was <10% in all trials. CONCLUSIONS: The levels of fatigue were greater in mCRPC and lower in earlier states of disease. In all trials, patients reported a small increase in fatigue for the first 13-17 weeks after starting enzalutamide or placebo, with slightly greater fatigue with enzalutamide in all studies except AFFIRM, but fatigue stabilized or improved thereafter. This suggests a role for clinical management of fatigue to help patients cope early in treatment.

Cost-effectiveness analysis of enzalutamide for patients with chemotherapy-naïve metastatic castration-resistant prostate cancer in Japan.

BACKGROUND: We aimed to evaluate cost-effectiveness of enzalutamide in chemotherapy-naïve metastatic castration-resistant prostate cancer patients in Japan. METHODS: A Markov model was developed to capture time spent by patients in various health states: stable, progression and death. Abiraterone acetate and docetaxel were set as active comparators. Clinical outcomes were obtained from the PREVAIL, COU-AA-302 and TAX327 trials. Treatment sequence, concomitant drugs and therapies for adverse events were estimated from responses to a survey by 14 Japanese prostate cancer experts. The analytic perspective was public healthcare payer, with a 10-year time horizon. The incremental cost-effectiveness ratio was estimated from quality-adjusted life-years and Japanese public healthcare costs. Probabilistic sensitivity analysis was performed to assess the robustness of the findings. RESULTS: According to the survey, the most common treatment sequences were (i) enzalutamide â†’ docetaxel â†’ cabazitaxel (enzalutamide-first sequencing), (ii) abiraterone â†’ enzalutamide â†’ docetaxel (abiraterone-first sequencing) and (iii) docetaxel→ enzalutamide â†’ cabazitaxel (docetaxel-first sequencing). In the base-case analysis, enzalutamide-first sequencing saved 1.74 million Japanese Yen versus abiraterone-first sequencing, with a 0.129 quality-adjusted life-year gain (dominant). Enzalutamide-first sequencing had a cost increase of 4.44 million Japanese Yen over docetaxel-first sequencing, with a 0.371 quality-adjusted life-years gain. The incremental cost-effectiveness ratio of enzalutamide-first sequencing versus docetaxel-first sequencing was estimated as 11.94 million Japanese Yen/quality-adjusted life-years. Probabilistic sensitivity analyses demonstrated that, compared with abiraterone-first sequencing, enzalutamide-first sequencing had an 87.4% probability of being dominant. CONCLUSIONS: Results modeled herein suggest that the enzalutamide-first sequencing is more cost-effective than the abiraterone-first sequencing, but less cost-effective than docetaxel-first sequencing for chemotherapy-naïve patients with metastatic castration-resistant prostate cancer.

Symptoms and Impacts in Metastatic Castration-Resistant Prostate Cancer: Qualitative Findings from Patient and Physician Interviews.

BACKGROUND: There is little information available on health-related quality of life in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer. This study aimed to develop a conceptual model that describes patients' experiences of living with this condition. METHODS: This was a cross-sectional, non-interventional qualitative research study. Sixty-minute semi-structured interviews were conducted with physicians experienced in treating metastatic castration-resistant prostate cancer and with chemotherapy-naïve patients with metastatic castration-resistant prostate cancer. Interviews were audio-recorded and transcripts were analysed to identify the key symptoms and impacts on quality of life. Results were used to expand a previously published conceptual model for non-metastatic castration-resistant prostate cancer. RESULTS: Three physicians and 19 patients with metastatic castration-resistant prostate cancer were interviewed. Physicians identified several symptoms frequently mentioned by their patients: fatigue, bone pain, anxiety, stress, depression and interference with daily activities. The most salient symptoms emerging from the patient interviews were urinary frequency and urgency, fatigue, pain/stiffness and sexual dysfunction. The most salient impacts were interference with daily activities, frustration, anxiety and sleep problems. Compared with non-metastatic castration-resistant prostate cancer, some symptoms and impacts in metastatic castration-resistant prostate cancer were more common and rated as more disturbing (e.g. fatigue, pain, urinary frequency, interference with daily activities and frustration). New concepts that were added to the non-metastatic castration-resistant prostate cancer model, to more accurately reflect the experiences of patients with metastatic disease, were enlarged breasts, muscle loss/deconditioning, inability to focus/mental slowing, body image perception, interference with work and lack of ambition/motivation. CONCLUSIONS: Chemotherapy-naïve patients with metastatic castration-resistant prostate cancer experience a substantial burden from their condition. Furthermore, as castration-resistant prostate cancer progresses from the non-metastatic stage to the early metastatic (pre-chemotherapy) stage, certain symptoms become more common and disturb patients' lives to a greater extent. The resulting conceptual model for metastatic castration-resistant prostate cancer highlights areas that are not adequately assessed with current patient-reported outcome instruments.

The association between health-related quality-of-life scores and clinical outcomes in metastatic castration-resistant prostate cancer patients: Exploratory analyses of AFFIRM and PREVAIL studies.

BACKGROUND: Our exploratory analysis examined the association between health-related quality of life (HRQoL) (baseline and change over time) and clinical outcomes (overall survival [OS]/radiographic progression-free survival [rPFS]) in metastatic castration-resistant prostate cancer (mCRPC). METHODS: HRQoL, OS and rPFS were assessed in phase III trials comparing enzalutamide with placebo in chemotherapy-naïve (PREVAIL; NCT01212991) or post-chemotherapy (AFFIRM; NCT00974311) mCRPC. HRQoL was assessed using the Functional Assessment of Cancer Therapy-Prostate (FACT-P). Multivariate analyses evaluated the prognostic significance of baseline and time-dependent scores after adjusting for treatment and clinical/demographic variables. Hazard ratios (HRs) and 95% confidence intervals (CIs) represented the hazard of rPFS or OS per minimally important difference (MID) score change in HRQoL variables. RESULTS: In baseline and time-dependent multivariate analyses, OS was independently associated with multiple HRQoL measures across both studies. In time-dependent analyses, a 10-point (upper bound of MID range) increase (improvement) in FACT-P total score was associated with reductions in mortality risk of 19% in AFFIRM (HR 0.81 [95% CI 0.78-0.84]) and 21% in PREVAIL (HR 0.79 [0.76-0.83]). For baseline analyses, a 10-point increase in FACT-P total score was associated with reductions in mortality risk of 12% (HR 0.88 [0.84-0.93]) and 10% (HR 0.90 [0.86-0.95]) in AFFIRM and PREVAIL, respectively. rPFS was associated with a subset of HRQoL domains in both studies. CONCLUSION: Several baseline HRQoL domains were prognostic for rPFS and OS in patients with mCRPC, and this association was maintained during treatment, indicating that changes in HRQoL are informative for patients' expected survival.

Health-related quality of life effects of enzalutamide in patients with metastatic castration-resistant prostate cancer: an in-depth post hoc analysis of EQ-5D data from the PREVAIL trial.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. TRIAL REGISTRATION: NCT01212991.

Symptoms and Impacts in Non-Metastatic Castration-Resistant Prostate Cancer: Qualitative Study Findings.

OBJECTIVES: We developed a conceptual model to define key concepts associated with patients' experiences with the signs, symptoms, and impacts of non-metastatic castration-resistant prostate cancer (M0-CRPC). METHODS: A targeted review of peer-reviewed literature, and other publicly available information, identified and categorized symptoms and impacts related to early-stage prostate cancer. Semi-structured interviews with five clinical experts helped determine the most relevant and important concepts for patients with M0-CRPC. Qualitative interviews with 17 patients with M0-CRPC identified the most frequently experienced symptoms and impacts, and their degree of interference with patients' lives. The findings from these three lines of evidence were summarized in a conceptual model. RESULTS: Literature searches identified mainly urinary, intestinal, and sexual symptoms. Experts noted the symptoms most frequently mentioned by patients include erectile dysfunction, loss of sexual desire or interest, incontinence/leaking, urgency, and hot flashes. Patient interviews confirmed the high frequency of erectile dysfunction, loss of libido, urinary urgency, and incontinence. The most frequently mentioned impacts expressed by patients were the need to monitor/plan for urinary frequency, interference with/restriction of daily activities, and frustration or anxiety over diagnosis, symptoms, or treatment. Symptoms and impacts most frequently experienced by patients were typically not those with the greatest effects on their lives; rather, those with the greatest consequences were related to treatment. CONCLUSIONS: The leading concerns associated with M0-CRPC were related to voiding and sexual dysfunction. The most relevant symptoms and impacts expressed by patients may be a consequence of therapy rather than of the disease.

Adjusting Overall Survival Estimates after Treatment Switching: a Case Study in Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: If patients in oncology trials receive subsequent therapy, standard intention-to-treat (ITT) analyses may inaccurately estimate the overall survival (OS) effect of the investigational product. In this context, a post-hoc analysis of the phase 3 PREVAIL study was performed with the aim to compare enzalutamide with placebo in terms of OS, adjusting for potential confounding from switching to antineoplastic therapies that are not part of standard metastatic castration-resistant prostate cancer (mCRPC) treatment pathways in some jurisdictions. METHODS: The PREVAIL study, which included 1717 chemotherapy-naïve men with mCRPC randomized to treatment with enzalutamide 160 mg/day or placebo, was stopped after a planned interim survival analysis revealed a benefit in favor of enzalutamide. Data from this cutoff point were confounded by switching from both arms and so were evaluated in terms of OS using two switching adjustment methods: the two-stage accelerated failure time model (two-stage method) and inverse probability of censoring weights (IPCW). RESULTS: Following adjustment for switching to nonstandard antineoplastic therapies by 14.8 (129/872 patients) and 21.3% (180/845 patients) of patients initially randomized to enzalutamide and placebo, respectively, the two-stage and IPCW methods both resulted in numerical reductions in the hazard ratio (HR) for OS [HR 0.66, 95% confidence interval (CI) 0.57-0.81 and HR 0.63, 95% CI 0.52-0.75, respectively] for enzalutamide compared to placebo versus the unadjusted ITT analysis (HR 0.71, 95% CI 0.60-0.84). These results suggest a slightly greater effect of enzalutamide on OS than originally reported. CONCLUSION: In the PREVAIL study, switching to nonstandard antineoplastic mCRPC therapies resulted in the ITT analysis of primary data underestimating the benefit of enzalutamide on OS.

Impact of Enzalutamide Compared with Bicalutamide on Quality of Life in Men with Metastatic Castration-resistant Prostate Cancer: Additional Analyses from the TERRAIN Randomised Clinical Trial.

BACKGROUND: Improving health-related quality of life (HRQoL) is an important goal in metastatic castration-resistant prostate cancer (mCRPC). OBJECTIVE: To examine the impact of enzalutamide versus bicalutamide on HRQoL in mCRPC. DESIGN, SETTING, AND PARTICIPANTS: TERRAIN is a multinational, phase 2, randomised, double-blind study in asymptomatic/mildly symptomatic men with mCRPC (ClinicalTrials.gov, NCT01288911). Patients were randomised (1:1) via an interactive voice and web response system to enzalutamide 160mg/d (n=184) or bicalutamide 50mg/d (n=191), with androgen deprivation therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: HRQoL was assessed using Functional Assessment of Cancer Therapy-Prostate (FACT-P), European Quality of Life 5-Domain Scale (EQ-5D), and Brief Pain Inventory, Short-form questionnaires every 12 wk. Primary and secondary analyses utilised mixed models for repeated measures and pattern mixture models, respectively. RESULTS AND LIMITATIONS: At 61 wk, 84 (46%) enzalutamide and 39 (20%) bicalutamide patients in the study were assessed. At 61 wk, changes from baseline favoured enzalutamide versus bicalutamide on three FACT-P domains in mixed models for repeated measures analyses and seven in pattern mixture models analyses. There were no differences in changes for EQ-5D index/visual analogue scale scores. Risk of first deterioration was lower with enzalutamide for FACT-P total (hazard ratio: 0.64, 95% confidence interval: 0.46-0.89, p=0.007), FACT-G total (hazard ratio: 0.70, 95% confidence interval: 0.50-0.98, p=0.04), PCS pain (hazard ratio: 0.74, 95% confidence interval: 0.54-1.00, p=0.048), and EQ-5D index (hazard ratio: 0.66, 95% confidence interval: 0.47-0.93, p=0.02) scores versus bicalutamide. Brief Pain Inventory, Short-form scores increased in both groups. There was no difference in time-to-pain progression. Study limitations include the exploratory nature of the HRQoL analyses, lack of multiple comparisons corrections, and unknown effects of anxiety/depression on HRQoL. CONCLUSIONS: In patients with asymptomatic/mildly symptomatic mCRPC, enzalutamide provides HRQoL benefit versus bicalutamide. PATIENT SUMMARY: Enzalutamide treatment was associated with better health-related quality of life in several domains versus bicalutamide in asymptomatic/mildly symptomatic metastatic castration-resistant prostate cancer. This likely relates to previously reported lower rates of symptomatic disease progression.

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.

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.

Mapping the FACT-P to the preference-based EQ-5D questionnaire in metastatic castration-resistant prostate cancer.

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 R(2) 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.

A Markov modelled pharmacoeconomic analysis of bimatoprost 0.03% in the treatment of glaucoma as an alternative to filtration surgery in Italy.

OBJECTIVE: Glaucoma is generally managed by decreasing the intraocular pressure (IOP) to a level believed to prevent further damage to the optic disc and loss of visual field. This may be achieved medically or surgically. The objective of this pharmacoeconomic analysis was to investigate the 4-year costs of bimatoprost 0.03% (Lumigan) eye drops as an alternative to filtration surgery (FS) for glaucoma patients on maximum tolerable medical therapy (MTMT). RESEARCH DESIGN AND METHOD: A Markov model was designed using effectiveness and resource use data from a randomized clinical trial and expert statements (Delphi panel). The RCT covered 83 patients on MTMT. The Model compared bimatoprost with FS. In the bimatoprost model arm patients began treatment with bimatoprost. If target IOP (-20%) was not reached using medical therapy the patient proceeded with FS. In the FS model arm, FS was performed after the first ophthalmologist visit. Unit costs were obtained from an Italian chart and tariffs review (healthcare sector perspective). RESULTS: The RCT showed that 74.7% of the patients delayed the need for FS by 3 months. The Markov model forecasted that 64.2% of the patients could delay the need for FS by 1 year, and forecasted 34.0% could avoid FS after 4 years. The 4-year cost per patient in the bimatoprost and FS arms was E3438 and E4194, respectively (incremental costs of E755). The major cost drivers for the bimatoprost arm were patients who needed combination therapy or FS if the target IOP was not reached. In the FS arm, the major cost drives were the initial surgery costs and pressure-lowering medications used as add-on therapy after FS. CONCLUSIONS: The analysis shows that in a 4-year perspective bimatoprost is cheaper compared to FS. In addition, the postponement of FS associated with bimatoprost may have important implications for waiting list planning.