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.

Systematic Review and Network Meta-Analysis of Treatments for Chemotherapy-Naive Patients with Asymptomatic/Mildly Symptomatic Metastatic Castration-Resistant Prostate Cancer.

OBJECTIVES: To estimate the relative effectiveness of enzalutamide in chemotherapy-naive metastatic castration-resistant prostate cancer by conducting a systematic literature review and a network meta-analysis (NMA). METHODS: A systematic literature review identified randomized controlled trials comparing enzalutamide, abiraterone/prednisone, radium-223, sipuleucel-T, or docetaxel with each other or placebo in chemotherapy-naive or mixed populations (with and without prior chemotherapy) with asymptomatic/mildly symptomatic metastatic castration-resistant prostate cancer. Feasibility assessment evaluated the trials' suitability for NMA inclusion. The main outcomes were hazard ratios (HRs) for overall survival (OS) and radiographic progression-free survival (rPFS). RESULTS: Searches of relevant bibliographic databases, trial registers, Web sites, and conference abstracts conducted in October 2014 identified 25,712 records. Ten randomized controlled trials were eligible for the NMA. Enzalutamide was superior to placebo for OS and rPFS (fixed-effects model). NMA results (fixed-effects model) showed no evidence of a difference between enzalutamide and abiraterone/prednisone (HR 0.95 [95% CrI 0.77-1.16]), sipuleucel-T (HR 1.07 [95% CrI 0.84-1.37]), or radium-223 (HR 1.10 [95% CrI 0.87-1.37]) for OS. HRs were similar for the random-effects model. Nevertheless, results (fixed-effects model) suggested that enzalutamide was superior to abiraterone/prednisone (HR 0.59 [95% CrI 0.48-0.72]) and sipuleucel-T (HR 0.32 [95% CrI 0.25-0.42]) for rPFS. Results also suggested superiority of enzalutamide versus placebo, abiraterone/prednisone, or sipuleucel-T for time to chemotherapy. CONCLUSIONS: For rPFS, the NMA suggests that enzalutamide is superior to abiraterone/prednisone and sipuleucel-T. There is no evidence of a statistically significant difference in OS between enzalutamide and abiraterone/prednisone, sipuleucel-T, or radium-223. Given the limitations in network construction and underlying assumptions made to complete these analyses, results should be interpreted with caution.

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.