BACKGROUND: Results of this double-blind, phase 2 trial showed patients with metastatic castration-resistant prostate cancer given olaparib plus abiraterone versus placebo plus abiraterone had significantly improved progression-free survival. Here, we present an exploratory analysis of pain and health-related quality of life (HRQOL). METHODS: This double-blind, randomised, placebo-controlled, phase 2 trial was conducted across 41 urological oncology sites in 11 countries in Europe and North America. Eligible patients were aged 18 years or older, had metastatic castration-resistant prostate cancer, and had previously received docetaxel and up to one additional line of previous chemotherapy. Metastatic castration-resistant prostate cancer was defined as increasing prostate-specific antigen (PSA) concentration or other signs of disease progression despite androgen-deprivation therapy and serum testosterone concentrations at castrate levels (≤50 ng/dL), and with at least one metastatic lesion on bone scan, CT, or MRI. Eligible patients were randomly assigned (1:1) to receive oral olaparib (300 mg twice per day) plus oral abiraterone (1000 mg once a day) and oral prednisone or prednisolone (5 mg twice a day) or placebo plus abiraterone (1000 mg once a day) and prednisone or prednisolone (5 mg twice a day). Randomisation was done without stratification and by use of an interactive voice or web response system. A randomised treatment kit ID number was assigned sequentially to each patient as they became eligible. The primary endpoint (radiographic progression-free survival) has previously been reported. HRQOL was a prespecified exploratory patient-reported outcome. Patients were asked to complete the Brief Pain Inventory-Short Form (BPI-SF), single-item worst bone pain, Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire, and EuroQol-5 five-dimension five level (EQ-5D-5L) assessment at baseline, at weeks 4, 8, and 12, then every 12 weeks until treatment discontinuation. Prespecified outcomes were change from baseline in BPI-SF worst pain, single-item worst bone pain and FACT-P Total Outcome Index (TOI) scale scores, time to deterioration in BPI-SF worst pain and worst bone pain, and assessment of the EQ-5D-5L pain and discomfort domain. All analyses were exploratory and done in the full analysis set (all randomly assigned patients, including patients who were randomly assigned but did not subsequently go on to receive study treatment), with the exception of mean baseline and total change from baseline analyses, for which we used the population who had a valid baseline and at least one post-baseline assessment. This trial is registered with Clinicaltrials.gov, NCT01972217, and is no longer recruiting patients. FINDINGS: Between Nov 25, 2014, and July 14, 2015, 171 patients were assessed for eligibility. 29 patients were excluded, and 142 were enrolled and randomly assigned to receive olaparib and abiraterone (n=71) or placebo and abiraterone (n=71). Data cutoff was Sept 22, 2017. Median follow-up was 15·9 months (IQR 8·1-25·5) in the olaparib plus abiraterone group and 24·5 months (8·1-27·6) in the placebo plus abiraterone group. Questionnaire compliance was generally high (43-100%). Least-squares mean changes from baseline in BPI-SF worst pain, single-item worst bone pain, and FACT-P TOI remained stable across all visits for patients in both treatment groups. Adjusted mean change in FACT-P TOI from baseline across all visits was -0·10 (95% CI -2·50 to 2·71) in the olaparib plus abiraterone group and -1·20 (-4·15 to 1·74) in the placebo plus abiraterone group (difference 1·30, 95% CI -2·70 to 5·30; p=0·52). Time to deterioration in pain was similar in both groups (BPI-SF worst pain HR 0·90 [95% CI 0·62-1·32], p=0·30; worst bone pain HR 0·85 [0·59-1·22], p=0·18). Improvement rates in the pain and discomfort domain of the EQ-5D-5L were similar in both groups from baseline to week 48, beyond which a higher proportion of patients in the olaparib plus abiraterone arm reported an improvement compared to the placebo plus abiraterone group. INTERPRETATION: In these prespecified exploratory analyses, there was no significant difference in pain or HRQOL when olaparib was added to abiraterone. In this phase 2 trial, a statistically significant radiographic progression-free survival benefit was observed with the olaparib plus abiraterone combination. These results suggest that the improved survival benefits observed when combining olaparib with abiraterone does not result in different HRQOL compared with placebo plus abiraterone. Phase 3 studies are required to validate these results. FUNDING: AstraZeneca and Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

• MeSH
• androgeny MeSH
• androsteny MeSH
• antagonisté androgenů terapeutické užití   MeSH
• bolest chemicky indukované   MeSH
• docetaxel škodlivé účinky   MeSH
• dvojitá slepá metoda MeSH
• ftalaziny MeSH
• hodnocení výsledků péče pacientem MeSH
• kvalita života MeSH
• lidé MeSH
• nádory prostaty rezistentní na kastraci * patologie   MeSH
• piperaziny MeSH
• prednisolon MeSH
• prednison MeSH
• prostatický specifický antigen * terapeutické užití   MeSH
• protokoly antitumorózní kombinované chemoterapie škodlivé účinky   MeSH
• testosteron MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• abiraterone MeSH Prohlížeč
• androgeny MeSH
• androsteny MeSH
• antagonisté androgenů MeSH
• docetaxel MeSH
• ftalaziny MeSH
• olaparib MeSH Prohlížeč
• piperaziny MeSH
• prednisolon MeSH
• prednison MeSH
• prostatický specifický antigen * MeSH
• testosteron MeSH

BACKGROUND: Enzyme replacement therapy (ERT) with recombinant human α-galactosidase has been available for the treatment of Fabry disease since 2001 in Europe and 2003 in the USA. Treatment outcomes with ERT are dependent on baseline patient characteristics, and published data are derived from heterogeneous study populations. METHODS: We conducted a comprehensive systematic literature review of all original articles on ERT in the treatment of Fabry disease published up until January 2017. This article presents the findings in adult male patients. RESULTS: Clinical evidence for the efficacy of ERT in adult male patients was available from 166 publications including 36 clinical trial publications. ERT significantly decreases globotriaosylceramide levels in plasma, urine, and in different kidney, heart, and skin cell types, slows the decline in estimated glomerular filtration rate, and reduces/stabilizes left ventricular mass and cardiac wall thickness. ERT also improves nervous system, gastrointestinal, pain, and quality of life outcomes. CONCLUSIONS: ERT is a disease-specific treatment for patients with Fabry disease that may provide clinical benefits on several outcomes and organ systems. Better outcomes may be observed when treatment is started at an early age prior to the development of organ damage such as chronic kidney disease or cardiac fibrosis. Consolidated evidence suggests a dose effect. Data described in male patients, together with female and paediatric data, informs clinical practice and therapeutic goals for individualized treatment.

• Klíčová slova
• ACEi, angiotensin-converting enzyme inhibitor, ANS, autonomic nervous system, ARB, angiotensin receptor blocker, BPI, Brief Pain Inventory, CES-D, Center for Epidemiologic Studies Depression Scale, CNS, central nervous system, CR, case report, CT, clinical trial, ECG, electrocardiogram/electrocardiography, EOW, every other week, ERT, enzyme replacement therapy, Fabry disease, GFR, glomerular filtration rate, GI, gastrointestinal, GL-3, globotriaosylceramide, IENFD, intra-epidermal nerve fibre density, IVST, intraventricular septum thickness, LPWT, left posterior wall thickness, LVEDD, left ventricular end-diastolic diameter, LVEF, left ventricular ejection fraction, LVH, left ventricular hypertrophy, LVM, left ventricular mass, LVMi, left ventricular mass index, LVWT, left ventricular wall thickness, MG, mixed gender, MRI, magnetic resonance imaging, MWT, maximal wall thickness, NYHA, New York Heart Association, OS, observational study, PNS, peripheral nervous system, QoL, quality of life, RCT, randomized controlled trial, SF-36, 36-item Short Form Health Survey, TIA, transient ischaemic attack, WMH, white matter hyperintensities., adult male patients, agalsidase alfa, agalsidase beta, eGFR, estimated glomerular filtration rate, enzyme replacement therapy, lyso-GL-3, globotriaosylsphingosine, systematic literature review,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

INTRODUCTION: Abiraterone acetate plus prednisone (AAP) and enzalutamide (ENZ) are commonly prescribed for metastatic castration-resistant prostate cancer (mCRPC). Data comparing their effects on patient-reported outcomes (PROs) from routine clinical practice are limited. METHODS: AQUARiUS (NCT02813408) is an ongoing, two-cohort, prospective, observational, non-randomised, multicentre, phase IV European study assessing the effects of AAP and ENZ on PROs in 211 patients with mCRPC over 12 months. Patients receive AAP or ENZ per routine clinical practice. Data on cognition, fatigue, pain and health-related quality of life are measured using the Functional Assessment of Cancer Therapy-Cognitive Function, Brief Fatigue Inventory-Short Form, Brief Pain Inventory-Short Form and European Organization for Research and Treatment of Cancer Quality of Life-C30 questionnaires, respectively. RESULTS: This 3-month analysis was conducted in 105 patients; 46 received AAP and 59 received ENZ. There were statistically significant differences in mean change from baseline favouring AAP over ENZ at months 1, 2 and 3 for perceived cognitive impairments and cognitive functioning. At each time-point, ENZ-treated patients had a significantly higher risk of experiencing clinically meaningful worsening in perceived cognitive impairments versus those receiving AAP.Statistically significant differences in mean change from baseline favouring AAP over ENZ were seen for usual level of fatigue and fatigue interference at months 2 and 3 and for current fatigue and worse level of fatigue at month 3. Differences favouring AAP versus ENZ were seen for the fatigue scale of the QLQ-C30 questionnaire (months 1 and 3). There was a significantly higher risk of clinically meaningful worsening in usual level of fatigue with ENZ versus AAP at month 3.No significant differences between cohorts were observed for pain (BPI-SF) at any time-point. CONCLUSION: This analysis suggests more favourable outcomes with AAP versus ENZ for cognition and fatigue in the first 3 months of treatment initiation for mCRPC. These findings require confirmation from future analyses of data from AQUARiUS from a larger number of patients with a longer follow-up period.

• Klíčová slova
• abiraterone acetate, enzalutamide, metastatic castration-resistant prostate cancer, patient-reported outcomes,
• Publikační typ
• časopisecké články MeSH

BACKGROUND: This phase II study was conducted to assess clinical efficacy of tasquinimod maintenance therapy in patients with metastatic castrate-resistant prostate cancer not progressing during first-line docetaxel-based therapy. PATIENTS AND METHODS: Patients were randomly assigned (1 : 1) to receive tasquinimod (0.25-1.0 mg/day orally) or placebo. The primary end point was radiologic progression-free survival (rPFS); secondary efficacy end points included: overall survival (OS); PFS on next-line therapy (PFS 2) and symptomatic PFS, assessed using the Brief Pain Inventory (BPI) questionnaire and analgesic use. Quality of life was measured by the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire and by the EuroQol-5 Dimension Quality of Life Instrument (EQ-5D). Adverse events were recorded. RESULTS: A total of 219 patients were screened and 144 patients randomized. The median duration of treatment was 18.7 weeks (range 0.6-102.7 weeks) for the tasquinimod arm and 19.2 weeks (range 0.4-80.0 weeks) for the placebo arm. Median (90% CI) rPFS was 31.7 (24.3-53.7) and 22.7 (16.1-25.9) weeks in the tasquinimod and placebo arms, respectively [HR (90% CI) 0.6 (0.4-0.9), P = 0.0162]. The median OS was not reached because only 14 deaths occurred by the cut-off date. No statistically significant differences between treatment arms were noted for symptomatic PFS, PFS 2, BPI score, FACT-P score, or EQ-5D. The incidence of any treatment emergent adverse event (TEAE) was similar in the tasquinimod and placebo arms (97.2% versus 94.3%, respectively), whereas severe TEAEs (NCI-CTC Grade 3-5) incidence was higher in the tasquinimod group (50.7% versus 27.1%). CONCLUSIONS: Randomized trials testing new drugs as maintenance can be successfully conducted after chemotherapy in castrate-resistant prostate cancer. Maintenance tasquinimod therapy significantly reduced the risk of rPFS by 40%. CLINICALTRIALS: gov identifier NCT01732549.

• Klíčová slova
• castrate-resistant, docetaxel, maintenance therapy, prostate cancer, tasquinimod,
• MeSH
• chinolony aplikace a dávkování   MeSH
• docetaxel MeSH
• dvojitá slepá metoda MeSH
• kvalita života * MeSH
• lidé středního věku MeSH
• lidé MeSH
• management nemoci MeSH
• mezinárodní agentury MeSH
• míra přežití MeSH
• nádory prostaty rezistentní na kastraci farmakoterapie   sekundární   MeSH
• následné studie MeSH
• prognóza MeSH
• protokoly antitumorózní kombinované chemoterapie terapeutické užití   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• taxoidy aplikace a dávkování   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• chinolony MeSH
• docetaxel MeSH
• tasquinimod MeSH Prohlížeč
• taxoidy MeSH

BACKGROUND: In the CARD study, cabazitaxel significantly improved radiographic progression-free survival and overall survival versus abiraterone or enzalutamide in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel and the alternative androgen signalling-targeted inhibitor. Here, we report the quality-of-life outcomes from the CARD study. METHODS: CARD was a randomised, multicentre, open-label, phase 4 study involving 62 clinical sites across 13 European countries. Patients (aged ≥18 years, Eastern Cooperative Oncology Group (ECOG) performance status ≤2) with confirmed metastatic castration-resistant prostate cancer were randomly assigned (1:1) by means of an interactive voice-web response system to receive cabazitaxel (25 mg/m2 intravenously every 3 weeks, 10 mg daily prednisone, and granulocyte colony-stimulating factor) versus abiraterone (1000 mg orally once daily plus 5 mg prednisone twice daily) or enzalutamide (160 mg orally daily). Stratification factors were ECOG performance status, time to disease progression on the previous androgen signalling-targeted inhibitor, and timing of the previous androgen signalling-targeted inhibitor. The primary endpoint was radiographic progression-free survival; here, we present more detailed analyses of pain (assessed using item 3 on the Brief Pain Inventory-Short Form [BPI-SF]) and symptomatic skeletal events, alongside preplanned patient-reported outcomes, assessed using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire and the EuroQoL-5 dimensions, 5 level scale (EQ-5D-5L). Efficacy analyses were done in the intention-to-treat population. Pain response was analysed in the intention-to-treat population with baseline and at least one post-baseline assessment of BPI-SF item 3, and patient-reported outcomes (PROs) were analysed in the intention-to-treat population with baseline and at least one post-baseline assessment of either FACT-P or EQ-5D-5L (PRO population). Analyses of skeletal-related events were also done in the intention-to-treat population. The CARD study is registered with ClinicalTrials.gov, NCT02485691, and is no longer enrolling. FINDINGS: Between Nov 17, 2015, and Nov 28, 2018, of 303 patients screened, 255 were randomly assigned to cabazitaxel (n=129) or abiraterone or enzalutamide (n=126). Median follow-up was 9·2 months (IQR 5·6-13·1). Pain response was observed in 51 (46%) of 111 patients with cabazitaxel and 21 (19%) of 109 patients with abiraterone or enzalutamide (p<0·0001). Median time to pain progression was not estimable (NE; 95% CI NE-NE) with cabazitaxel and 8·5 months (4·9-NE) with abiraterone or enzalutamide (hazard ratio [HR] 0·55, 95% CI 0·32-0·97; log-rank p=0·035). Median time to symptomatic skeletal events was NE (95% CI 20·0-NE) with cabazitaxel and 16·7 months (10·8-NE) with abiraterone or enzalutamide (HR 0·59, 95% CI 0·35-1·01; log-rank p=0·050). Median time to FACT-P total score deterioration was 14·8 months (95% CI 6·3-NE) with cabazitaxel and 8·9 months (6·3-NE) with abiraterone or enzalutamide (HR 0·72, 95% CI 0·44-1·20; log-rank p=0·21). There was a significant treatment effect seen in changes from baseline in EQ-5D-5L utility index score in favour of cabazitaxel over abiraterone or enzalutamide (p=0·030) but no difference between treatment groups for change from baseline in EQ-5D-5L visual analogue scale (p=0·060). INTERPRETATION: Since cabazitaxel improved pain response, time to pain progression, time to symptomatic skeletal events, and EQ-5D-5L utility index, clinicians and patients with metastatic castration-resistant prostate cancer can be reassured that cabazitaxel will not reduce quality of life when compared with treatment with a second androgen signalling-targeted inhibitor. FUNDING: Sanofi.

• MeSH
• androgeny genetika   MeSH
• androsteny aplikace a dávkování   škodlivé účinky   MeSH
• antagonisté androgenů aplikace a dávkování   škodlivé účinky   MeSH
• benzamidy MeSH
• fenylthiohydantoin aplikace a dávkování   škodlivé účinky   analogy a deriváty   MeSH
• kvalita života MeSH
• lidé středního věku MeSH
• lidé MeSH
• metastázy nádorů MeSH
• nádory prostaty rezistentní na kastraci farmakoterapie   epidemiologie   patologie   MeSH
• nitrily MeSH
• přežití po terapii bez příznaků nemoci MeSH
• senioři MeSH
• taxoidy aplikace a dávkování   škodlivé účinky   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze IV MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• abiraterone MeSH Prohlížeč
• androgeny MeSH
• androsteny MeSH
• antagonisté androgenů MeSH
• benzamidy MeSH
• cabazitaxel MeSH Prohlížeč
• enzalutamide MeSH Prohlížeč
• fenylthiohydantoin MeSH
• nitrily MeSH
• taxoidy MeSH