K. Skaltsa

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.

Treatment benefit of tivozanib hydrochloride versus sorafenib on health-related quality of life (HRQoL) among patients (pts) with advanced/metastatic renal cell carcinoma (mRCC): TIVO-1 study results.

355 Background: Tivozanib hydrochloride (T) was superior to sorafenib (S) in progression-free survival (medians of 11.9 vs. 9.1 months, respectively; 12.7 vs. 9.1 months, respectively, for metastatic treatment-naïve pts) in the phase III TIVO-1 study in pts with mRCC. T showed a differentiated safety profile with lower rates of dose interruptions/reductions v S (18/12 vs. 35/43, respectively; p<0.001). TIVO-1 also evaluated patient self-reported HRQoL. METHODS Pts with mRCC were randomized 1:1 to receive T (1.5 mg PO once daily for 3 weeks on, 1 week off) or S (400 mg bid, continuously). HRQoL was assessed on Cycle 1/Day1 (baseline [BL]) and at the beginning of each cycle, using the Functional Assessment of Cancer Therapy-General (FACT-G), FACT-Kidney Symptom Index Disease Related Symptoms (FKSI-DRS), and EuroQol 5-dimensional (EQ-5D) questionnaires; EQ-5D scores are not reported here. Pts with BL and ≥1 post-BL evaluable forms were analyzed. Changes from BL in FACT-G and FKSI-DRS scores over 18 treatment cycles were analyzed using repeated measures mixed-effects models. QoL improvement/deterioration was defined as an increase/decrease from BL of ≥3 points for FACT-G subscales and FKSI-DRS total score and 7 points for the FACT-G total score during the study. RESULTS In the mixed effects analyses, no significant differences in HRQoL (FACT-G and FKSI-DRS) were noted between T and S. More pts receiving T vs. S experienced a significant improvement during the study in physical well-being (PWB) (25.7% vs. 16.4%; p=0.011) and a favorable trend in all other FACT-G and FKSI scores (p values: 0.078-0.405). FKSI improvement was greater with T than S in treatment-naïve pts (34.1% vs. 23.6%; p=0.023), pts with ≥2 metastases (32.9% vs. 24.7%; p=0.054), or pts <65 years old (33.0% vs. 22.8%; p=0.022). Median time to QoL deterioration was usually longer with T (3.75-7.66 months) than S (2.04-8.80 months). CONCLUSIONS HRQoL was generally similar for T and S. Non-significant numeric differences usually favored T over S, and PWB improvement occurred significantly more often with T. These results support the previously-reported PFS advantage of T over S. CLINICAL TRIAL INFORMATION NCT01030783.

762PDIMPACT OF ENZALUTAMIDE ON SKELETAL RELATED EVENTS (SRES), PAIN AND QUALITY OF LIFE (QOL) IN THE PREVAIL TRIAL

ABSTRACT Aim: Enzalutamide (ENZ) improved overall survival vs. placebo (PL) in PREVAIL, a phase 3 trial in asymptomatic/mildly symptomatic chemotherapy-naive patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) [Beer et al, ASCO GU 2014]. PREVAIL also prospectively evaluated SREs, pain and QoL. Methods: Pts were randomized to ENZ (160mg/day; n = 872) or PL (n = 845). SREs were assessed throughout the study and time to 1st SRE measured. QoL was assessed at baseline (BL) and during treatment (tx) on the FACT-P and EQ-5D; changes from BL over time were compared using repeated measures analyses. Pain was assessed with the BPI-SF at BL, and months (mo) 3 and 6. Pts with BL and ≥1 post-BL score were analyzed using pre-specified criteria for clinically meaningful pain progression (pain severity: increase ≥30% from BL; pain interference: increase ≥50% of BL standard deviation) and QoL deterioration (Cella et al, VIH 2009; Pickard et al, HQOL 2007). Results: Median tx duration was 16.6 (ENZ) and 4.6 (PL) mo; BL pain and QoL scores were similar between arms. Overall, 32% (ENZ) and 37% (PL) of pts reported at least one SRE. Compared to PL, ENZ significantly reduces the risk of 1st SRE occurrence (hazard ratio: 0.72 [0.61, 0.84], p Time to 1st deterioration (mo), median (95% Cl) ENZ (n = 872) PL (n = 845) P-value Hazard ratioa (95% CI) EQ-5D instrument Visual analogue scale 22.14 (19.35;27.66) 13.83 (11.07;16.59) 0.67 (0.56;0.80) FACT-P instrument Physical well-being 10.84 (8.31;11.07) 5.55 (5.49;5.62) 0.74 (0.65;0.85) Functional well-being 8.54 (8.31;11.07) 3.09 (2.86;5.55) 0.72 (0.62;0.82) Emotional well-being 19.48 (16.59;25.07) 11.01 (8.25;11.40) 0.67 (0.57;0.79) Social well-being 24.87 (14.16;NYR) 8.51 (6.01;13.86) 0.74 (0.63;0.86) Prostate Cancer Subscale 5.65 (5.55;8.31) 2.83 (2.79;2.96) 0.69 (0.60;0.78) FACT-P total score 11.30 (11.07;13.86) 5.55 (5.49;5.59) 0.62 (0.54;0.72) Pain progression, n(%) Pain severity 329/802 (41) 317/628 (50) Pain interference 247/788 (31) 255/613 (42) Conclusions: In PREVAIL, in addition to overall survival benefit, ENZ was also associated with clinically significant patient benefits compared to PL, including a delay in time to 1st SRE, superior QoL, a delay in QoL deterioration, and significantly lower proportion of pts with pain. Disclosure: Y. Loriot: Consultant/Advisory: Astellas Research Funding: Astellas Other: Sanofi, Janssen, Bayer, Cellgene; K. Miller: Consulting: Astellas/Medivation Consultancy: Astellas, Amgen, Janssen, Medivation, Novartis, Roche Lectures: Novartis, Janssen, Pierre-Fabre; C.N. Sternberg: Honoraria: Astellas, Johnson & Johnson, Ipsen, Bayer, Millenium; K. Fizazi: Advisory Board: Astellas/Medivation Speaker: Astellas/Medivation; J.S. de Bono: Astellas/Medivation; S. Chowdhury: Advisory Board/Lecture: Astellas, Janssen, Sanofi-Aventis, Dendreon Speaker: GSK; C. Higano: Research funding: Astellas/Medivation, Algeta, Aragon, Dendreon, Sanofi Consultant/Advisory: Astellas/Medivation, Dendreon, Bayer, Johnson & Johnson; S. Noonberg: Employee: Medivation; S. Holmstrom, F.G. Perabo and D. Phung: Employee: Astellas; H. Mansbach: Employee: Medivation; C. Ivanescu: Astellas: payment for writing or reviewing a manuscript, provision of writing assistance or administrative support, consultancy; K. Skaltsa: Astellas: Payment for writing or reviewing a manuscript, provision of writing assistance or administrative support, consultancy; T. Beer: Research Funding: Astellas/Medivation, Janssen Consultant: Janssen; B. Tombal: Advisor: Astellas/Medivation, Ferring Speaker: Astellas, Ferring

Decision Drivers For Brazil: An Analysis of Conitec Recommendations

• In total, 101 publications were identified through Quintiles’ HTA Accelerator database2: 67 assessed drugs, 12 procedures or interventions and 11 medical devices. The remaining 11 were clinical guidelines (not included in the analysis). Overall, 46 recommendations were positive and 44 negative. CONITEC assessed appraisals in 21 different therapeutic areas, out of which cancer (19 reports), cardiovascular diseases (13) and respiratory diseases (11) were the most assessed areas (Figure 1). Objectives

Immature Survival Data From Early Trial Termination - Theory and Hta Practice.

• As surrogate outcomes are often considered the primary endpoint(s) in oncology trials, these RCTs may not be powered and/or patients may not be followed-up long enough to allow detection of OS gains. While this approach may have been agreed upon with regulatory agencies as a requirement to obtain marketing authorisation, healthcare payers usually tend to have a greater focus on hard endpoints. In a recent EUnetHTA guideline, it is explained that decisions on the acceptability of intermediary outcomes are made on a case by case basis and can vary by country, but that PFS alone without data on OS or at least on quality of life or other patient-relevant endpoints is generally considered insufficient to carry out relative effectiveness assessments4. Our analysis of oncology TAs published by NICE since 2011 seems to confirm this statement (Table 1).

Mapping Fact-P To EQ-5D In Metastatic Castration-Resistant Prostate Cancer (MCRPC): Performance Of A Previously Developed Algorithm When Applied On A Sample With A Different Disease Stage

Cristina Ivanescu,1 Louise Longworth,2 Konstantina Skaltsa,3 De Phung,4 Stefan Holmstrom4 1Quintiles, Hoofddorp, The Netherlands; 2Health Economics Research Group, Brunel University London, Uxbridge, UK; 3Quintiles, and Department of Public Health, Faculty of Medicine, University of Barcelona, Barcelona, Spain; 4Astellas Pharma Global Development, Leiden, The Netherlands Poster PRM138 ISPOR-EU 17th Annual Congress | Amsterdam, The Netherlands | 8–12 November 2014