Apalutamide efficacy, safety and wellbeing in older patients with advanced prostate cancer from Phase 3 randomised clinical studies TITAN and SPARTAN.

BACKGROUND: Apalutamide plus androgen-deprivation therapy (ADT) improved outcomes in metastatic castration-sensitive prostate cancer (mCSPC) and non-metastatic castration-resistant PC (nmCRPC) in the Phase 3 randomised TITAN and SPARTAN studies, respectively, and maintained health-related quality of life (HRQoL). Apalutamide treatment effect by patient age requires assessment. METHODS: Post-hoc analysis assessed patients receiving 240 mg/day apalutamide (525 TITAN and 806 SPARTAN) or placebo (527 TITAN and 401 SPARTAN) with ongoing ADT, stratified by age groups. Prostate-specific antigen declines, radiographic progression-free survival, metastasis-free survival, overall survival (OS), HRQoL and safety were assessed using descriptive statistics, Kaplan-Meier method, Cox proportional-hazards model and mixed-effects model for repeated measures. RESULTS: Hazard ratios (95% confidence intervals) generally favoured apalutamide plus ADT versus ADT alone across all endpoints regardless of age; e.g., OS values were 0.57 (0.40-0.80), 0.70 (0.54-0.91) and 0.74 (0.40-1.39) (TITAN) and 0.39 (0.19-0.78), 0.89 (0.69-1.16) and 0.81 (0.58-1.15) (SPARTAN) in patients aged <65, 65-79 and ≥80 years. Regardless of age, apalutamide also maintained HRQoL and was tolerated well with a potential trend in rates of adverse events increasing with age. Limitations include post-hoc nature and variability in sample size of age groups. CONCLUSIONS: Apalutamide plus ADT was an effective and well-tolerated option maintaining HRQoL in patients with mCSPC and nmCRPC regardless of age. CLINICAL TRIAL REGISTRATION: TITAN (NCT02489318); SPARTAN (NCT01946204).

Post Hoc Analysis of Rapid and Deep Prostate-specific Antigen Decline and Patient-reported Health-related Quality of Life in SPARTAN and TITAN Patients with Advanced Prostate Cancer.

BACKGROUND: Adding apalutamide to androgen-deprivation therapy (ADT) resulted in a rapid (at 3- and 6-mo treatment) and deep prostate-specific antigen (PSA) decline (to ≤0.2 ng/ml or ≥90% from baseline), improved overall survival, reduced risk of disease progression, and prolonged health-related quality of life (HRQoL) in nonmetastatic castration-resistant prostate cancer (nmCRPC) in SPARTAN and metastatic castration-sensitive PC (mCSPC) in TITAN. OBJECTIVE: To evaluate the association of a rapid, deep PSA decline at 3 and 6 mo achieved with the addition of apalutamide to ADT with patient-reported outcomes (PROs) in SPARTAN and TITAN. DESIGN, SETTING, AND PARTICIPANTS: A post hoc analysis of SPARTAN and TITAN PRO data was performed. INTERVENTION: Apalutamide versus placebo plus concurrent ADT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PROs were assessed using Functional Assessment of Cancer Therapy-Prostate (FACT-P; SPARTAN and TITAN), Brief Pain Inventory-Short Form (BPI-SF; TITAN), and Brief Fatigue Inventory (BFI; TITAN) at baseline, prespecified cycles during treatment, and after progression for ≤1 yr. The association between a deep PSA decline at landmark 3 or 6 mo of apalutamide and the time to worsening of PROs was assessed using the Kaplan-Meier methodology and Cox proportional-hazard modeling. RESULTS AND LIMITATIONS: Among 806 SPARTAN and 525 TITAN apalutamide-treated patients, the median treatment duration was 32.9 and 39.3 mo, respectively. Patients achieving a deep PSA decline at 3 mo had longer time to worsening in FACT-P total, FACT-P physical well-being, BPI-SF worst pain intensity, or BFI worst fatigue intensity. The 6-mo PSA decline results were similar. Limitations of patient characteristics in clinical studies should be considered. CONCLUSIONS: Attaining a deep and rapid PSA decline at 3 mo with apalutamide plus ADT was associated with longer preservation of overall HRQoL and physical well-being in nmCRPC and mCSPC. PATIENT SUMMARY: Quality of life is maintained in individuals with advanced prostate cancer who achieve a deep prostate-specific antigen decline at 3 mo of apalutamide plus drugs that lower male sex hormones.

Developmentally specified characterization of the irritability spectrum at early school age: Implications for pragmatic mental health screening.

OBJECTIVES: Developmentally specified measures that identify clinically salient irritability are needed for early school-age youth to meaningfully capture this transdiagnostic risk factor for psychopathology. Thus, the current study modeled the normal:abnormal irritability spectrum and generated a clinically optimized screening tool for this population. METHODS: The irritability spectrum was modeled via the youth version of the Multidimensional Assessment Profile Scales-Temper Loss Scale (MAPS-TL-Youth) in children (n = 474; 6.0-8.9 years) using item response theory (IRT). Both cross-cutting core irritability items from the early childhood version and new developmentally specific items were included. Items uniquely associated with impairment were identified and used to derive a brief, clinically optimized irritability screener. Longitudinal data were then utilized to test the predictive utility of this clinically optimized screener in preadolescence (n = 348; 8.0-12.9 years). RESULTS: Most children exhibit irritability regularly, but daily occurrence was rare. Of the top 10 most severe items from the IRT analyses, 9 were from the developmentally specific items added for the MAPS-TL Youth version. Two items associated with concurrent impairment were identified for the clinically optimized irritability screener ("Become frustrated easily" and "Act irritable"). The MAPS-TL-Youth clinically optimized screener demonstrated good sensitivity (69%) and specificity (84%) in relation to concurrent DSM 5 irritability-related diagnoses. Youth with elevated scores on the screener at early school age (ESA) had more than 7x greater odds of irritability-related psychopathology at pre-adolescence. CONCLUSIONS: The MAPS-TL-Youth characterized the developmental spectrum of irritability at ESA and a clinically optimized screener showed promise at predicting psychopathology risk. Rigorous testing of clinical applications is a critical next step.

Health-related quality of life in GALAHAD: A multicenter, open-label, phase 2 study of niraparib for patients with metastatic castration-resistant prostate cancer and DNA-repair gene defects.

BACKGROUND: Niraparib is a highly selective poly (adenosine diphosphateribose) polymerase-1 and poly (adenosine diphosphate-ribose) polymerase-2 inhibitor indicated for select patients with ovarian, fallopian tube, and primary peritoneal cancer. The phase 2 GALAHAD trial (NCT02854436) demonstrated that niraparib monotherapy is tolerable and efficacious in patients with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations, particularly those with breast cancer gene (BRCA) alterations who had progressed on prior androgen signaling inhibitor therapy and taxane-based chemotherapy. OBJECTIVE: To report the prespecified patient-reported outcomes analysis from GALAHAD. METHODS: Eligible patients with alterations to BRCA1 and/or BRCA2 (BRCA cohort) and with pathogenic alterations in other HRR genes (other HRR cohort) were enrolled and received niraparib 300 mg once daily. Patient-reported outcome instruments included the Functional Assessment of Cancer Therapy-Prostate and the Brief Pain Inventory-Short Form. Changes from baseline were compared using a mixed-effect model for repeated measures. RESULTS: On average, health-related quality of life (HRQoL) improved in the BRCA cohort by cycle 3 (mean change = 6.03; 95% CI = 2.76-9.29) and was maintained above baseline until cycle 10 (mean change = 2.84; 95% CI = -1.95 to 7.63), whereas the other HRR cohort showed no early change in HRQoL from baseline (mean change = -0.07; 95% CI = -4.69 to 4.55) and declined by cycle 10 (mean change = -5.10; 95% CI = -15.3 to 5.06). Median time to deterioration in pain intensity and pain interference could not be estimated in either cohort. CONCLUSIONS: Patients with advanced mCRPC and BRCA alterations treated with niraparib experienced more meaningful improvement in overall HRQoL, pain intensity, and pain interference compared with those with other HRR alterations. In this population of castrate, heavily pretreated patients with mCRPC and HRR alterations, stabilization, and improvement in HRQoL may be relevant to consider when making treatment decisions. DISCLOSURES: This work was supported by Janssen Research & Development, LLC (no grant number). Dr Smith has received grants and personal fees from Bayer, Amgen, Janssen, and Lilly; and has received personal fees from Astellas Pharma, Novartis, and Pfizer. Dr Sandhu has received grants from Amgen, Endocyte, and Genentech; has received grants and personal fees from AstraZeneca and Merck; and has received personal fees from Bristol Myers Squibb and Merck Serono. Dr George has received personal fees from the American Association for Cancer Research, Axess Oncology, Capio Biosciences, Constellation Pharma, EMD Serono, Flatiron, Ipsen, Merck Sharp & Dohme, Michael J. Hennessey Association, Millennium Medical Publishing, Modra Pharma, Myovant Sciences, Inc., NCI Genitourinary, Nektar Therapeutics, Physician Education Resource, Propella TX, RevHealth, LLC, and UroGPO; has received grants and personal fees from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, and Pfizer; has received personal fees and nonfinancial support from Bayer and UroToday; has received grants from Calithera and Novartis; and has received grants, personal fees, and nonfinancial support from Exelixis, Inc., Sanofi, and Janssen Pharma. Dr Chi has received grants from Janssen during the conduct of the study; has received grants and personal fees from AstraZeneca, Bayer, Astellas Pharma, Novartis, Pfizer, POINT Biopharma, Roche, and Sanofi; and has received personal fees from Daiichi Sankyo, Merck, and Bristol Myers Squibb. Dr Saad has received grants, personal fees, and nonfinancial support from Janssen during the conduct of the study; and has received grants, personal fees, and nonfinancial support from AstraZeneca, Astellas Pharma, Pfizer, Bayer, Myovant, Sanofi, and Novartis. Dr Thiery-Vuillemin has received grants, personal fees, and nonfinancial support from Pfizer; has received personal fees and nonfinancial support from AstraZeneca, Janssen, Ipsen, Roche/Genentech, Merck Sharp & Dohme, and Astellas Pharma; and has received personal fees from Sanofi, Novartis, and Bristol Myers Squibb. Dr Olmos has received grants, personal fees, and nonfinancial support from AstraZeneca, Bayer, Janssen, and Pfizer; has received personal fees from Clovis, Daiichi Sankyo, and Merck Sharp & Dohme; and has received nonfinancial support from Astellas Pharma, F. Hoffman-LaRoche, Genentech, and Ipsen. Dr Danila has received research support from the US Department of Defense, the American Society of Clinical Oncology, the Prostate Cancer Foundation, Stand Up to Cancer, Janssen Research & Development, Astellas Pharma, Medivation, Agensys, Genentech, and CreaTV. Dr Gafanov has received grants from Janssen during the conduct of the study. Dr Castro has received grants from Janssen during the conduct of the study; has received grants and personal fees from Janssen, Bayer, AstraZeneca, and Pfizer; and has received personal fees from Astellas Pharma, Merck Sharp & Dohme, Roche, and Clovis. Dr Moon has received research funding from SeaGen, HuyaBio, Janssen, BMS, Aveo, Xencor, and has received personal fees from Axess Oncology, MJH, EMD Serono, and Pfizer. Dr Joshua has received nonfinancial support from Janssen; consulted or served in an advisory role for Neoleukin, Janssen Oncology, Ipsen, AstraZeneca, Sanofi, Noxopharm, IQvia, Pfizer, Novartis, Bristol Myers Squibb, Merck Serono, and Eisai; and received research funding from Bristol Myers Squibb, Janssen Oncology, Merck Sharp & Dohme, Mayne Pharma, Roche/Genentech, Bayer, MacroGenics, Lilly, Pfizer, AstraZeneca, and Corvus Pharmaceuticals. Drs Mason, Liu, Bevans, Lopez-Gitlitz, and Francis and Mr Espina are employees of Janssen Research & Development. Dr Mason owns stocks with Janssen. Dr Fizazi has participated in advisory boards and talks for Amgen, Astellas, AstraZeneca, Bayer, Clovis, Daiichi Sankyo, Janssen, MSD, Novartis/AAA, Pfizer, and Sanofi, with honoraria to his institution (Institut Gustave Roussy); has participated in advisory boards for, with personal honoraria from, Arvinas, CureVac, MacroGenics, and Orion. Study registration number: NCT02854436.

Convergent Validity of the Patient Reported Outcome Measurement Information System-Pediatric Physical Activity Instrument (PROMIS®-PA) with Wearable Devices in Adolescents.

The study was conducted mainly to examine the convergent validity of the Patient Reported Outcome Measurement Information System-Pediatric Physical Activity instrument (PROMIS®®®-PA) with step counts from wearable devices and another validated self-reported outcome measure. As a secondary aim, we explored the effect of different recall time frames (7-day, end-of-day [EoD], and ecological momentary assessment [EMA] time frames during the day) in terms of their feasibility and associations with each other and with step counts. This was a prospective cohort study that examined the associations between measures of PA in school-age children and adolescents (n = 84, aged 10-20). The participants wore Fitbit devices for 7 consecutive days, and then completed the 7-day-recall PROMIS-PA short form and Youth Activity Profile (YAP). Additional analyses were completed in a sub-sample (n = 25, aged 11-18 years) using the PROMIS-PA for the EMA at five intervals during the day (shorter form) and at the EoD. In the total sample, the PROMIS-PA results showed positive moderate correlations with the YAP and average daily steps (r = 0.533, p < 0.001 and r = 0.346, p = 0.002, respectively). In the sub-sample, the 7-day PROMIS-PA was highly correlated with the averaged EMA or EoD ratings for the week, and moderately correlated with the daily step counts. These findings support the validity of the PROMIS-PA as a measure of self-reported physical activity. Adolescents demonstrated higher compliance rates and preference for the 7-day recall and EoD assessments compared to more frequent EMA reporting.

Psychometric Evaluation of the Parent Effort Scale.

Objective: The Parent Effort Scale (PES) is a parent report questionnaire designed to quantify the level of effort required of caregivers to assist their children in developmentally appropriate home- and community-based activities. This manuscript describes the psychometric evaluation of the PES. Method: Data collected from 304 parents of children ages 2-7 years (167 parents of a children with autism spectrum disorder and 137 parents of neurotypical children) were factor analyzed, calibrated using item response theory, and evaluated for construct validity. Results: The final PES scales are reliable and valid measures of the level of parental effort required to assist children in dressing, personal hygiene, sleep, socialization at home, participation in community events, and access to healthcare. A total score reflects overall parental effort. Conclusion: The PES can be used to plan and evaluate the effectiveness of interventions that aim to help parents enhance children's participation opportunities and thus, support their cognitive and social development.

Enhancing the Content Validity of Self-Reported Physical Activity Self-Efficacy in Adolescents: A Qualitative Study.

PURPOSE: This study's primary purpose was to enhance the content validity of a self-reported measure of self-efficacy for physical activity (PA) in adolescents. This was addressed through assessment of younger and older adolescents' understanding of the construct of self-efficacy for PA, coupled with assessment of the content coverage and comprehensibility of items derived from existing measures. METHODS: Participants completed individual semistructured and cognitive debriefing interviews as well as 3 PA self-efficacy questionnaires. RESULTS: Thematic analysis identified personal and environmental facilitators and barriers to PA self-efficacy. The major categories were physical; psychological; interaction with surroundings; support and relationships; attitudes; and services, systems, and natural environments. Cognitive interviews resulted in the retention of 52 final items: 24 for self-efficacy with perceived facilitators and 28 for self-efficacy to overcome barriers. CONCLUSIONS: This study provides a PA self-efficacy instrument with expanded content coverage that is relevant to adolescents as young as 11 years. With further validation testing in future studies, this instrument will enable pediatric physical therapists and researchers to assess PA self-efficacy and design effective intervention strategies to improve PA.

Measuring PROMIS® Social Relationships in Early Childhood.

OBJECTIVE: Apply the Patient-Reported Outcome Measurement Information System (PROMIS®) mixed-methods approach to develop and validate new parent-report measures of young children's (1-5 years) family and peer relationships that conceptually align to those for 5-17 year olds. METHODS: Expert input, parent interviews, and reviews of theoretical and empirical literature were used to develop draft item pools, which were administered in two waves of panel surveys (N = 1,750). Psychometric evaluation was conducted using item response theory-based methods. Scores were normed to the general U.S. population. Initial validation analyses were conducted using Pearson's correlations and analysis of variance to examine known-group differences between children with various health conditions. RESULTS: Experts and parents confirmed the content validity of existing PROMIS family and peer relationships domain frameworks and suggested adding child-caregiver interactions and empathic behaviors, respectively. Bi-factor model analysis supported sufficient unidimensionality where family and peer relationships were modeled as distinct subdomains of a broader concept, Social Relationships. The new measure was robust in discriminating young children with poor social relationships. Correlational and known-group analyses revealed positive associations with general health and well-being and negative associations with emotional and physical distress. CONCLUSIONS: The PROMIS Early Childhood Parent-Report Social Relationships item bank enables clinicians and researchers a brief, efficient, and precise way to evaluate early relational health. Subdomain short forms also offer the ability to assess specific components (i.e., child-caregiver, family, and peer) for more targeted interventions and analyses.

Measuring PROMIS® Well-Being in Early Childhood.

OBJECTIVE: Expand the current Patient-Reported Outcome Measurement Information System (PROMIS®) well-being measures to early childhood (1-5 years) using best practices from PROMIS and developmental science. METHODS: Qualitative methods included expert input, literature and measure review, and parent interviews to confirm measure frameworks, item understandability, and developmental appropriateness. Quantitative methods included two waves of field testing and item response theory (IRT)-based psychometric evaluation of reliability and validity, as well as IRT centering and item calibration. Correlational analyses with other PROMIS Early Childhood (EC) Parent Report measures and known-group differences analyses by health status were conducted to evaluate construct validity. All measures were normed to the general U.S. population. RESULTS: Qualitative results suggested three primary early childhood well-being domains: Positive Affect, Engagement, and Self-Regulation. Quantitative results revealed a unidimensional factor structure for Positive Affect and multidimensional factor structures for Engagement and Self-Regulation, both of which had two factors accounting for >10% of modeled variance reflecting unique unidimensional domains. This resulted in five final PROMIS EC well-being measures: Positive Affect, Engagement-Curiosity, Engagement-Persistence, Self-Regulation-Flexibility, and Self-Regulation-Frustration Tolerance. Correlations and known-groups differences analyses showed robust construct validity across a range of chronic health conditions. CONCLUSIONS: The new PROMIS EC Parent Report well-being measures offer clinicians and researchers a brief, efficient, and precise way to evaluate young children's well-being. All five measures include only positively valanced item content, which pushes the field to evaluate the presence of children's positive assets rather than the absence of problems.

Health-related Quality of Life at the SPARTAN Final Analysis of Apalutamide for Nonmetastatic Castration-resistant Prostate Cancer Patients Receiving Androgen Deprivation Therapy.

BACKGROUND: In SPARTAN, apalutamide improved metastasis-free and overall survival for patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) with a prostate-specific antigen doubling time of ≤10 mo. OBJECTIVE: We evaluated health-related quality of life (HRQoL) at the final analysis of the SPARTAN study. INTERVENTION: Patients received apalutamide (240 mg/d) or placebo in 28-d cycles. All patients continued androgen deprivation therapy (ADT). DESIGN, SETTING, AND PARTICIPANTS: A total of 1207 patients with nmCRPC were randomized 2:1 to apalutamide or placebo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: HRQoL was assessed using Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EQ-5D-3L questionnaires at day 1 of cycle 1 (predose/baseline), cycles 2-6, every two cycles during cycles 7-13, every four cycles thereafter, at the end of treatment, and every 4 mo after progression to 1 yr. Results are presented using descriptive statistics. A mixed model for repeated measures was fitted to estimate the mean scores at each scheduled visit during treatment. RESULTS: At final analysis, with 52 mo follow-up for survival, the median treatment duration was 32.9 mo for apalutamide and 11.5 mo for placebo. Patients had good baseline HRQoL. At each scheduled collection during treatment, >90% per group completed the questionnaires. The change in FACT-P total score from baseline to cycles 21 and 25 significantly favored apalutamide over placebo (p = 0.0138 and 0.0009, respectively). The apalutamide group generally maintained favorable FACT-P (total and subscales) and EQ-5D-3L scores, while placebo scores tended to decline over time (starting in cycles 11-13 and pronounced by cycles 21-25). Notably, patient-reported fatigue did not worsen with apalutamide. Most patients reported being "not at all bothered" by side effects, and bother did not increase over time with apalutamide or placebo. Patients receiving apalutamide had minimal change in side-effect bother following symptomatic adverse events. CONCLUSIONS: Final analysis of SPARTAN confirms that HRQoL is preserved in patients with nmCRPC receiving apalutamide plus ADT, but declines in patients receiving placebo plus ADT after approximately 1 yr. PATIENT SUMMARY: Responses from patients with prostate cancer who were included in the SPARTAN study indicated that treatment with apalutamide, even after the most extensive follow-up time possible, did not reduce their quality of life. These results, along with improved survival and longer time to the development of metastases (reported separately), confirm the benefits of apalutamide for patients with nonmetastatic castration-resistant prostate cancer.

Development and equivalence of new faces for inclusion in the Childhood Asthma Control Test (C-ACT) response scale.

BACKGROUND: Accurate symptom monitoring is vital when managing pediatric asthma, providing an opportunity to improve control and relieve associated burden. The CHILDHOOD ASTHMA CONTROL TEST (C-ACT) has been validated for asthma control assessment in children; however, there are concerns that response option images used in the C-ACT are not culturally universal and could be misinterpreted. This cross-sectional, qualitative study developed and evaluated alternative response option images using interviews with children with asthma aged 4-11 years (and their parents/caregivers) in the United States, Spain, Poland, and Argentina. Interviews were conducted in two stages (with expert input) to evaluate the appropriateness, understanding and qualitative equivalence of the alternative images (both on paper and electronically). This included comparing the new images with the original C-ACT response scale, to provide context for equivalence results. RESULTS: Alternative response option images included scale A (simple faces), scale B (circles of decreasing size), and scale C (squares of decreasing quantity). In Stage 1, most children logically ranked images using scales A, B and C (66.7%, 79.0% and 70.6%, respectively). However, some children ranked the images in scales B (26.7%) and C (58.3%) in reverse order. Slightly more children could interpret the images within the context of their asthma in scale B (68.4%) than A (55.6%) and C (47.5%). Based on Stage 1 results, experts recommended scales A (with slight modifications) and B be investigated further. In Stage 2, similar proportions of children logically ranked the images used in modified scales A (69.7%) and B (75.7%). However, a majority of children ranked the images in scale B in the reverse order (60.0%). Slightly more children were able to interpret the images in the context of their asthma using scale B (57.6%) than modified scale A (48.5%). Children and parents/caregivers preferred modified scale A over scale B (78.8% and 90.9%, respectively). Compared with the original C-ACT, most children selected the same response option on items using both scales, supporting equivalency. Following review of Stage 2 results, all five experts agreed modified scale A was the optimal response scale. CONCLUSIONS: This study developed alternative response option images for use in the C-ACT and provides qualitative evidence of the equivalency of these response options to the originals.

Accurate monitoring of the symptoms associated with pediatric asthma is important when managing the condition. The CHILDHOOD ASTHMA CONTROL TEST (C-ACT) is a questionnaire widely used to measure asthma severity in young children (aged 4­11 years). Each question answered by the child in the C-ACT has four possible answer choices. To help children answer, each choice is presented alongside an image of a male child's face ranging from sad to happy. However, there are concerns that the images used are not culturally universal and could be misinterpreted­due to difficulties translating to electronic formats and a lack of differentiation between the images used. Through interviewing children with asthma, we aimed to address these concerns by developing and testing new images. Alternative image options developed included simpler faces, circles of decreasing size and squares of decreasing quantity. Children aged 4­11 years old were interviewed to test whether they understood the response scale using the new images and if they answered in the same way as with the original images. Interviews were conducted in two stages, with expert guidance at key stages. Results showed that children can interpret and understand the newly developed images and that they answer the questions the same as they would using the original images. These new images have the advantages of being culturally neutral and easier to implement on an electronic device.

Apalutamide plus abiraterone acetate and prednisone versus placebo plus abiraterone and prednisone in metastatic, castration-resistant prostate cancer (ACIS): a randomised, placebo-controlled, double-blind, multinational, phase 3 study.

BACKGROUND: The majority of patients with metastatic castration-resistant prostate cancer (mCRPC) will have disease progression of a uniformly fatal disease. mCRPC is driven by both activated androgen receptors and elevated intratumoural androgens; however, the current standard of care is therapy that targets a single androgen signalling mechanism. We aimed to investigate the combination treatment using apalutamide plus abiraterone acetate, each of which suppresses the androgen signalling axis in a different way, versus standard care in mCRPC. METHODS: ACIS was a randomised, placebo-controlled, double-blind, phase 3 study done at 167 hospitals in 17 countries in the USA, Canada, Mexico, Europe, the Asia-Pacific region, Africa, and South America. We included chemotherapy-naive men (aged ≥18 years) with mCRPC who had not been previously treated with androgen biosynthesis signalling inhibitors and were receiving ongoing androgen deprivation therapy, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and a Brief Pain Inventory-Short Form question 3 (ie, worst pain in the past 24 h) score of 3 or lower. Patients were randomly assigned (1:1) via a centralised interactive web response system with a permuted block randomisation scheme (block size 4) to oral apalutamide 240 mg once daily plus oral abiraterone acetate 1000 mg once daily and oral prednisone 5 mg twice daily (apalutamide plus abiraterone-prednisone group) or placebo plus abiraterone acetate and prednisone (abiraterone-prednisone group), in 28-day treatment cycles. Randomisation was stratified by presence or absence of visceral metastases, ECOG performance status, and geographical region. Patients, the investigators, study team, and the sponsor were masked to group assignments. An independent data-monitoring committee continually monitored data to ensure ongoing patient safety, and reviewed efficacy data. The primary endpoint was radiographic progression-free survival assessed in the intention-to-treat population. Safety was reported for all patients who received at least one dose of study drug. This study is completed and no longer recruiting and is registered with ClinicalTrials.gov, number NCT02257736. FINDINGS: 982 men were enrolled and randomly assigned from Dec 10, 2014 to Aug 30, 2016 (492 to apalutamide plus abiraterone-prednisone; 490 to abiraterone-prednisone). At the primary analysis (median follow-up 25·7 months [IQR 23·0-28·9]), median radiographic progression-free survival was 22·6 months (95% CI 19·4-27·4) in the apalutamide plus abiraterone-prednisone group versus 16·6 months (13·9-19·3) in the abiraterone-prednisone group (hazard ratio [HR] 0·69, 95% CI 0·58-0·83; p<0·0001). At the updated analysis (final analysis for overall survival; median follow-up 54·8 months [IQR 51·5-58·4]), median radiographic progression-free survival was 24·0 months (95% CI 19·7-27·5) versus 16·6 months (13·9-19·3; HR 0·70, 95% CI 0·60-0·83; p<0·0001). The most common grade 3-4 treatment-emergent adverse event was hypertension (82 [17%] of 490 patients receiving apalutamide plus abiraterone-prednisone and 49 [10%] of 489 receiving abiraterone-prednisone). Serious treatment-emergent adverse events occurred in 195 (40%) patients receiving apalutamide plus abiraterone-prednisone and 181 (37%) patients receiving abiraterone-prednisone. Drug-related treatment-emergent adverse events with fatal outcomes occurred in three (1%) patients in the apalutamide plus abiraterone-prednisone group (2 pulmonary embolism, 1 cardiac failure) and five (1%) patients in the abiraterone-prednisone group (1 cardiac failure and 1 cardiac arrest, 1 mesenteric arterial occlusion, 1 seizure, and 1 sudden death). INTERPRETATION: Despite the use of an active and established therapy as the comparator, apalutamide plus abiraterone-prednisone improved radiographic progression-free survival. Additional studies to identify subgroups of patients who might benefit the most from combination therapy are needed to further refine the treatment of mCRPC. FUNDING: Janssen Research & Development.

Apalutamide in Patients With Metastatic Castration-Sensitive Prostate Cancer: Final Survival Analysis of the Randomized, Double-Blind, Phase III TITAN Study.

PURPOSE: The first interim analysis of the phase III, randomized, placebo-controlled TITAN study showed that apalutamide significantly improved overall survival (OS) and radiographic progression-free survival in patients with metastatic castration-sensitive prostate cancer (mCSPC) receiving ongoing androgen deprivation therapy (ADT). Herein, we report final efficacy and safety results after unblinding and placebo-to-apalutamide crossover. METHODS: Patients with mCSPC (N = 1,052) were randomly assigned 1:1 to receive apalutamide (240 mg QD) or placebo plus ADT. After unblinding in January 2019, placebo-treated patients were allowed to receive apalutamide. Efficacy end points were updated using the Kaplan-Meier method and Cox proportional-hazards model without formal statistical retesting and adjustment for multiplicity. Change from baseline in Functional Assessment of Cancer Therapy-Prostate total score was assessed. RESULTS: With a median follow-up of 44.0 months, 405 OS events had occurred and 208 placebo-treated patients (39.5%) had crossed over to apalutamide. The median treatment duration was 39.3 (apalutamide), 20.2 (placebo), and 15.4 months (crossover). Compared with placebo, apalutamide plus ADT significantly reduced the risk of death by 35% (median OS not reached v 52.2 months; hazard ratio, 0.65; 95% CI, 0.53 to 0.79; P < .0001) and by 48% after adjustment for crossover (hazard ratio, 0.52; 95% CI, 0.42 to 0.64; P < .0001). Apalutamide plus ADT delayed second progression-free survival and castration resistance (P < .0001 for both). Health-related quality of life, per total Functional Assessment of Cancer Therapy-Prostate, in both groups was maintained through the study. Safety was consistent with previous reports. CONCLUSION: The final analysis of TITAN confirmed that, despite crossover, apalutamide plus ADT improved OS, delayed castration resistance, maintained health-related quality of life, and had a consistent safety profile in a broad population of patients with mCSPC.

Generating a Core Set of Outcomes for Hospital-Based Violence Intervention Programs.

Hospital-based violence intervention programs (HVIPs) engage individuals who have experienced violent victimization in postmedical care programming, with the goal of reducing the incidence and impact of future injuries. Although there is some empirical support for HVIPs' impact on violence and crime-related outcomes, proper impact assessment is limited by a lack of systematized research on outcomes that relate to the proximal goals and activities of the programs themselves. To address this critical gap, we conducted a two-stage Delphi method to elicit and prioritize these outcomes using the wisdom and experience of those who are engaged in service delivery (i.e., HVIP community-based practitioners, program coordinators, and embedded researchers; N = 79). Through this process, respondents prioritized outcomes related to posttraumatic stress symptoms, beliefs about aggression, coping strategies, and emotional regulation, which have not been consistently measured using validated or standardized tools. Results suggest that, rather than limiting program outcomes to those related to repeat violent injury or criminality, hospital- and community-based violence prevention programs seek to improve and measure mental health and socioemotional outcomes as a benchmark for healing and recovery after a violent injury. Prioritization of these outcomes broadens the definition of recovery to include psychosocial health and well-being. In addition, inclusion of these outcomes in effectiveness studies will serve to bolster the relevance of findings, and provide support for continued development and refinement of HVIP practice.

Development and Validation of the Pediatric Sleep Practices Questionnaire: A Self-Report Measure for Youth Ages 8-17 Years.

Objective: To develop and evaluate the validity of a self-report measure of sleep practices for youth 8-17 years. Methods: Following recommended guidelines for the development of patient reported outcomes (PROs), sleep practice concepts were identified through expert (n = 8) and child (n = 28) concept elicitation interviews and a systematic literature review. Items were developed based on these concepts and tested in cognitive interviews with children (n = 32). Psychometric analyses were applied to item response data collected from a diverse sample of youth 8-17 years (n = 307). Construct validity was evaluated through tests of associations between sleep practices and sleep disturbance and sleep-related impairment. Finally, clinical validity of the tool was assessed by comparing scores of youth with and without a parent-identified sleep problem. Results: The final Pediatric Sleep Practices Questionnaire (PSPQ) included 15 items that were used to identify 5 sleep practices: sleep timing, sleep routines and consistency, technology use before bedtime, sleep environment, and the need for parental presence to fall asleep. A confirmatory factor analysis supported the hypothesized structure (all factor loadings ≥ 0.72) and PSPQ indices were significantly associated with self-reported sleep disturbances and sleep-related impairment. Finally, children with parent-reported sleep problems had shorter sleep opportunity, later bedtimes, greater need for parental presence, poorer bedtime routines, and more technology use than children without parent-reported sleep problems. Conclusions: The PSPQ was developed using best-practice PRO development methodology. The PSPQ can be used in clinical settings and for research assessment to capture modifiable sleep practices that may promote or interfere with healthy sleep.

Brief Report: What Diagnostic Observation Can Teach Us About Disruptive Behavior in Young Children with Autism.

ABSTRACT: Objective: Approximately 50% of children with autism exhibit severe tantrums, defiance, and/or aggression. We propose that the Disruptive Behavior Diagnostic Observation Schedule (DB-DOS)-a standardized clinical observation modeled after, and complementary to, the Autism Diagnostic Observation Schedule (ADOS)-could enhance earlier identification of disruptive behavior (DB) in autism populations and inform treatment planning. Methods: We adapted the DB-DOS for children with autism based on expert input and preliminary feasibility testing to accommodate varying cognitive and social communication capacities and increase the likelihood of observing DB in this population. Thereafter, we concurrently administered the modified DB-DOS and the ADOS to 12 children with autism aged 36 to 50 months. Results: Overall, children exhibited greater DB, especially behavioral regulation challenges, during the DB-DOS than during the ADOS. Conclusion: The use of a developmentally sensitive standardized observation tool that presses for DB to complement standardized observations such as the ADOS shows promise for enabling more precise research on targeted DB interventions. Such a tool holds promise as a reliable and efficient method of identifying comorbid DB disorders in the autism population.

Using nationally representative percentiles to interpret PROMIS pediatric measures.

PURPOSE: This study's aim was to use a representative sample of the US pediatric population to estimate percentiles for several PROMIS pediatric measures: Anger, Anxiety, Depressive Symptoms, Family Relationships, Fatigue, Global Health, Life Satisfaction, Meaning and Purpose, Pain Behavior, Pain Interference, Physical Activity, Physical Function Mobility, Physical Function Upper Extremity, Physical Stress Experiences, Positive Affect, Psychological Stress Experiences, Sleep Disturbance, Sleep Impairment, and Peer Relationships. METHODS: We used two separate, nationally representative samples of parents and children aged 5-17 years drawn in different years from the GfK Knowledge Panel, a dual-frame online probability panel. RESULTS: All measures that were developed using a representative sample had a median at or near the expected value of 50. For the other measures, the 50th percentile was often 10 points or more from 50. Several domains had high floors or low ceilings. No domain's percentiles completely corresponded to the percentiles associated with a normal distribution with a mean of 50 and standard deviation of 10. CONCLUSIONS: This work allows users to interpret a child's self-reported quality of life relative to children in the US general population. When attempting to evaluate whether a child falls above or below other children in the US, one should use the values presented in this study. In addition, we recommend that users should focus on whether a child's score falls into one of a few broad severity groups rather than on specific percentile scores.

The Free2B Multi-Media Bullying Prevention Experience: An Exemplar of Scientific Edutainment.

OBJECTIVE: The objective of the current article is to highlight an example of a new paradigm, Scientific Edutainment. The manuscript describes how educational researchers and technologists worked together to develop a multi-media bullying prevention experience, called Free2B for middle school students paying particular attention to ensure that the programming was not only relevant to all students but also was appealing and responsive to the needs of urban youth. Bullying is the most common form of aggression experienced among school-aged youth, which impairs students' learning and social-emotional functioning and has financial costs to society. Given that the prevalence of bullying is highest in middle school, finding brief and feasible methods for motivating and sustaining change at this age is critically important, especially in the case of urban, under-resourced schools. METHOD: In response to this challenge, multidisciplinary bullying prevention researchers collaborated with international technologists to develop the Free2B multi-media bullying prevention experience through an iterative Community-Based Participatory Research (CBPR) approach. In addition, the research team conducted a series of pilot studies to iteratively develop and initially evaluate the multi-media program, helping to ensure relevance specifically for urban middle school youth. RESULTS: Results from the pilot studies indicated that the vast majority of middle school students found the Free2B multi-media bullying prevention experience to be enjoyable, relevant to their needs, and addressed important strategies to handle peer bullying and victimization. In addition, the brief prevention experience was associated with increases in problem-solving knowledge, prosocial attitudes about bullying, increased sympathy, and confidence in handling peer conflicts. CONCLUSION: The current paper illustrates the use of a new paradigm, termed Scientific Edutainment, as a way to combine evidenced-based developmental science with the latest in entertainment technology to provide innovative, engaging, and technologically-sophisticated educational programming.

Development of patient-reported outcome measures of children's oral health aesthetics.

OBJECTIVES: To develop and evaluate the psychometric properties of child- and parent-proxy measures of oral health aesthetics. METHODS: Items that describe children's perceptions of their oral attractiveness and its impact on social, emotional, and behavioural functioning were developed based on a systematic review of existing measures, clinician feedback (n = 13) and child semi-structured interviews (n = 27). The tools' content validity was assessed in cognitive interviews with 21 children. Items were administered to socio-demographically diverse samples of 998 children aged 8-17 years and 626 parents of children aged 5-17 years. Psychometric methods were used to finalize and calibrate item banks, generate short questionnaire forms, and evaluate the tools' reliability, precision and validity. RESULTS: The item banks and their short forms provide precise measurement across a wide range of oral health aesthetic states. They measure relevant and meaningful positive and negative experiences using terminology that most children as young as 8 years of age can understand. Known-group comparisons and convergence with existing measures of oral health-related quality of life, global health and body image provide evidence of construct validity. The scores are interpretable relative to the US general population. CONCLUSIONS: The oral health aesthetic item banks and short forms provide precise and valid assessments of children's satisfaction with their oral appearance. They may be useful for targeting and evaluating paediatric dental and orthodontic care in clinical practice and research settings.

Psychometric Evaluation of the Participation and Sensory Environment Questionnaire-Home Scale (PSEQ-H).

IMPORTANCE: The impact of sensory processing challenges on occupational participation is underrepresented by existing measurement tools even though these outcomes are highly prioritized by families. The Participation and Sensory Environment Questionnaire-Home Scale (PSEQ-H) is a parent-report assessment designed to evaluate the impact of the sensory environment on young children's participation in home-based activities. OBJECTIVE: To describe the psychometric evaluation of the PSEQ-H, including the tool's structural validity; item difficulty, discrimination, and bias; reliability; and construct validity. DESIGN: Psychometric field study. SETTING: Community. PARTICIPANTS: Three hundred four parents of children ages 2-7 yr (167 parents of children with autism spectrum disorder). METHOD: Parent-report PSEQ-H data were factor analyzed, calibrated using Item Response Theory, and evaluated for construct validity. RESULTS: The final PSEQ-H is a reliable and valid 15-item parent-report measure of the sensory environment's impact on children's dressing, self-care, sleep, and social and play activities. CONCLUSIONS AND RELEVANCE: The PSEQ-H can be used to plan and evaluate the effectiveness of interventions for reducing the impact of the sensory environment on children's participation in home-based tasks and activities. WHAT THIS ARTICLE ADDS: The PSEQ-H measures how young children's sensory environments influence their participation at home. The measure can be used to plan and evaluate occupational therapy interventions that aim to reduce sensory processing-related barriers to children's completion of developmentally salient activities.