bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinically significant events associated with metastatic castration-resistant prostate cancer (mCRPC) treatments.
Authors: Moses Kelvin A. , Wallace Katrine L , Landsteiner Adrienne , Bunner Scott H , Engel-Nitz Nicole , Lal Lincy S. , Golsorkhi Tony 
Published: March 2021

61 Background: We describe the association between clinically significant events (CSEs) and mCRPC treatments in US-insured patients using an administrative claims database. Methods: Adult men in a large administrative claims database from Jan 2008 to Mar 2019 with ≥1 claim for prostate cancer, codes for pharmacologic or surgical castration, and incident metastatic disease during the identification period were included in the study. Patients who had ≥6 months of continuous enrollment before and after the index date (first metastatic claim) were included. Patients were followed until death, end of study, or disenrollment. Claims-based algorithms were used to identify patients with mCRPC, lines of therapy (LOTs), and CSEs of interest. CSEs were assessed in the first LOT in which an mCRPC regimen was used. Time on treatment was used as a person-time denominator to assess rates of CSEs per 365 days (treatment year) to control for differing times on treatment regimens. Results: Overall, we identified 3690 patients with mCRPC, of which 3150 (85%) received ≥1 LOT, among whom 1680/3150 (53%) received a regimen indicated for mCRPC. Average follow-up time was 705 days. CSEs occurred in 664/1680 (40%) patients, an average of 1.15 CSE per treatment year (Table). Patients had an average of 2 CSEs. The most common CSEs were anemia (14%), fatigue (15%), and back pain (10%). CSE rates per treatment year were highest among patients who received a taxane (1.7 per treatment year), taxane + gonadotropin-releasing hormone (GnRH) modulator (1.6 per treatment year), and other chemotherapy (1.6 per treatment year). Conclusions: Among treatments for patients with mCRPC, chemotherapy-based regimens showed the highest CSE rates per treatment year. These data indicate the burden of treatment for patients and can inform treatment decisions. [Table: see text]
Comparative cardiotoxicity of the novel hormonal agents abiraterone and enzalutamide in metastatic castration-resistant prostate cancer using real-world data.
Authors: Hu Jason , Aprikian Armen G. , Vanhuyse Marie , Dragomir Alice 
Published: March 2021

62 Background: Novel hormonal agents (NHAs) such abiraterone (ABI) and enzalutamide (ENZA) have demonstrated similar survival benefits against placebo groups in their respective clinical trials leading to their regulatory approval in both the pre- and post-chemotherapy settings in metastatic castration-resistant prostate cancer (mCRPC). Despite the overall tolerable risk profile, certain signals of cardiovascular toxicity were reported for these agents in clinical trials but little is known about their incidence in clinical practice. The objective was to assess the comparative cardiovascular safety of ABI and ENZA in patients with mCRPC in the real-world. Methods: A retrospective population-based cohort was extracted from Quebec public healthcare administrative databases. Patients were selected on the basis of having received androgen deprivation therapy prior to initiating a novel hormonal agent (ABI or ENZA) between 2012 and 2016. The primary outcome of interest was cardiovascular-related hospitalization (composite outcome that included acute coronary disease, cerebrovascular disease, heart failure, arrhythmia and other cardiovascular causes). Inverse probability of treatment weighting (IPTW) with the propensity score was used to adjust for measured baseline confounders including pre-existing cardiovascular disease. Results: The cohort comprises 2,183 patients, with 1,773 (81.2%) in the ABI group and 410 (18.8%) in the ENZA group. Before IPTW, mean age of the ENZA group was higher than the ABI group (78 vs 76). There were more ENZA patients with pre-existing arrythmia (ABI: 10.7%, ENZA: 15.1%) and diabetes (ABI: 21.5%, ENZA: 25.1%). Crude incidence rates of cardiovascular-related hospitalization were of 10 events per 100 person-years (PYs) and of 7 events per 100 PYs for the ABI and ENZA groups, respectively. After applying IPTW, all baseline variables were well balanced across both groups with standardized differences < 0.05. The ABI group was at greater risk of cardiovascular-related hospitalization compared to the ENZA group (IPTW-hazard ratio (HR): 1.79, 95% confidence interval (95%CI): 1.04-3.09). The risk of hospitalization for heart failure was greater in ABI (IPTW-HR: 3.02, 95%CI: 1.17-7.78). Conclusions: In our study population, there was a greater risk of cardiovascular-related hospitalizations for ABI users relative to ENZA users, in particular for hospitalization for heart failure. Given the lack of evidence from randomized head-to-head comparisons of both agents, these results provide clinicians with additional insight on the cardiovascular risks of mCRPC patients treated with NHAs in the real-world and further large studies are required to corroborate these findings.
Health-related quality-of-life (HRQoL) analysis from a randomized phase II trial of androgen signaling inhibitors with or without androgen deprivation therapy (ADT) for castration-sensitive prostate cancer: LACOG 0415.
Authors: Soares Andrey , Bastos Diogo Assed , Schutz Fabio A. B. , Cronemberger Eduardo , Luz Murilo , Martins Suelen P. S. , Muniz David Queiroz Borges , Carcano Flavio Mavignier , Smaletz Oren , Peixoto Fábio A , Gomes Andrea Juliana , Cruz Felipe Melo , Franke Fabio Andre , Herchenhorn Daniel , Gidekel Rosemarie , Rebelatto Taiane Francieli , Gomes Rafaela , Souza Vinicius Carrera , Fay Andre P. , Maluf Fernando C. 
Published: March 2021

64 Background: LACOG0415 is a 3-arm randomized trial evaluating ADT with abiraterone acetate plus prednisone (ADT+AAP), apalutamide alone (APA) or apalutamide with AAP (APA+AAP) for patients with locally-advanced, high-risk biochemical recurrence or metastatic castration-sensitive prostate cancer (ASCO 2020). In this trial, ADT+AAP and APA+AAP achieved the primary endpoint of percentage of patients with PSA ≤ 0.2 ng/mL at week 25. Apalutamide alone showed a high PSA decline > 50% rate, but did not achieve the pre-specified PSA threshold. Here we report patient-reported outcome data using Functional Assessment of Cancer Therapy-Prostate (FACT-P). Methods: HRQoL was measured in the overall population using the FACT-P questionnaire, comprising 5 subscales: physical wellbeing (PWB), functional wellbeing (FWB), emotional wellbeing (EWB), social/family wellbeing (SFWB), and prostate cancer subscale (PCS). Scores for each patient were measured at baseline and every four weeks until week 25. Questionnaire completion was defined as ≥ 1 question answered at an assessment time point. Analysis of HRQoL change from baseline and deterioration included only patients with baseline and ≥ 1 postbaseline score. Differences greater than 10-points in FACT-P total score and differences greater than 3-points in PWB, FWB, EWB, SFWB, and PCS scores were considered clinically significant. The time-to-event endpoint was estimated by Kaplan-Meier method and compared by stratified log-rank test. Results: 128 patients were included in LACOG0415 trial and 122 of them completed the HRQoL assessments (ranging from 95.3% at baseline to 79.7% at week 25). FACT-P and all subscales scores were similar for all three arms at baseline. There were no meaningful differences in FACT-P scores at baseline and at week 25 between the 3 arms. The subscales scores also showed no statistically differences at baseline and at week 25. Time to FACT-P deterioration did not show any statistically difference between three arms ( P=0.3371). Conclusions: ADT free alternatives with APA alone or APA+AAP did not show meaningful differences in HRQoL in patients with advanced castration-sensitive prostate cancer compared to ADT+AAP. The short follow-up period limited the ability to explore differences in HRQoL after 25 weeks. Larger studies with longer follow-up are needed to further evaluate HRQoL with ADT-free strategies. Clinical trial information: NCT02867020. [Table: see text]
Common genetic and clinical risk factors: Association with fatal prostate cancer in the Cohort of Swedish Men.
Authors: Huynh-Le Minh-Phuong , Karunamuni Roshan , Fan Chun Chieh , Thompson Wesley K , Muir Kenneth , Lophatananon Artitaya , Tye Karen , Wolk Alicja , Niclas Hakansson , Mills Ian G. , Andreassen Ole A , Dale Anders M , Seibert Tyler M , Consortium The PRACTICAL 
Published: March 2021

65 Background: Clinical variables (age, family history, and genetics) are commonly used for prostate cancer risk stratification. Recently, polygenic hazard scores (PHS46, PHS166) were validated as associated with age at prostate cancer diagnosis. While polygenic scores, including PHS, are associated with all prostate cancer and are not specific for fatal cancers, PHS46 was also associated with age at prostate cancer death. We evaluated if adding PHS to available clinical variables improves associations with prostate cancer death. Methods: Genotype and phenotype data were obtained from a nested case-control subset (n=3,279; 2,163 were diagnosed with prostate cancer, 278 died of prostate cancer) of the longitudinal, population-based Cohort of Swedish Men. PHS and clinical variables (family history, alcohol intake, smoking, heart disease, hypertension, diabetes history, and body mass index) were independently tested via univariable Cox proportional hazards models for association with age at prostate cancer death. Multivariable Cox models were constructed with clinical variables and PHS. Log-likelihood tests compared models. Results: Median age at last follow-up and at prostate cancer death were 78.0 (IQR: 72.3-84.1) and 81.4 (75.4-86.3) years, respectively. On univariable analysis, PHS46 (HR 3.41 [95% CI 2.78-4.17]), family history (HR 1.72 [1.46-2.03]), alcohol intake (HR 1.74 [1.40-2.15]), and diabetes (HR 0.53 [0.37-0.75]) were each associated with prostate cancer death. A multivariable clinical model including PHS46 improved associations for fatal disease ( p<10−15). On multivariable analysis, PHS46 (HR 2.45 [1.99-2.97]), family history (HR 1.73 [1.48-2.03]), alcohol intake (HR 1.45 [1.19-1.76]), and diabetes (HR 0.62 [0.42-0.90]) all remained associated with prostate cancer death. Similar results were found using the newer PHS166. Conclusions: PHS had the most robust association with fatal prostate cancer in a multivariable model with common clinical risk factors, including family history. Adding PHS to clinical variables may improve individualized prostate cancer risk stratification strategies.
The contribution of germline DNA damage response mutations on prostate cancer risk and prognosis: A UK Biobank whole-exome analysis.
Authors: Camacho Niedzica , Matakidou Athena 
Published: March 2021

67 Background: Germline mutations in DNA Damage Response (DDR) genes such as BRCA2 and ATM have been associated with prostate cancer risk and aggressiveness. These associations are largely based on studies that ascertain for cancer diagnosis and family history and provide risk estimates with limited population-level accuracy. Here we evaluate the clinical significance of germline pathogenic variants in 20 DDR genes and a high-risk susceptibility coding variant in HOXB13 using whole exome sequences from (1) the UK Biobank (UKBB), a population-based cohort (300,000 participants) and (2) patients recruited in AZ clinical trials. Methods: Whole exomes from 6,987 prostate cancer patients (5,921 UKBB and 1,066 AZ) and 88,499 cancer-free males were analysed. Known and novel pathogenic variants were identified and associations with disease risk, age of onset, family history, response to hormonal therapy and overall survival were estimated (multiplicity corrected P value < 0.005). Results: HOXB13 G48E (1.36%), ATM (1.03%) and BRCA2 (0.99%) were the largest contributors to prostate cancer risk, each conferring an increase of ~4-fold, followed by CHEK2 with a moderate contribution (0.46%). No significant contributions to prostate cancer risk were observed for any of the other genes analysed. Family history of prostate cancer was not significantly enriched in any of the gene subpopulations of prostate cancer carriers and compared with non-carriers, there was no significant difference in the median age of disease onset. Analysis of clinical outcomes showed that BRCA2 carriers had a 4-fold increased risk of death (Cox PH HR p = 4.11E-12) and poorer overall survival (Log-Rank p = 4.60E-14), with 88% dying from prostate cancer compared to 49% of non- BRCA2 carriers (UKBB analysis). BRCA2 pathogenic mutations were also associated with early failure to hormonal therapy (Cox PH HR 2.38; p = 9.48E-04; AZ cohort analysis). HOXB13, ATM and CHEK2 mutations were not significantly associated with clinical outcomes. Conclusions: This is the largest study to date providing population-based estimates of prostate cancer risk and prognosis, highlighting BRCA2 carriers as a population in clinical need of early identification and targeted intervention. Updated analyses with data from the full 450,000 UKBB participants (9,000 prostate cancers) will be presented.
Adiposity and response to androgen signaling inhibition (ASI) in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Hahn Andrew Warren , Tidwell Rebecca , Surasi Devaki Shilpa , Pilie Patrick Glen , Frigo Daniel , Subudhi Sumit Kumar , Efstathiou Eleni , Zurita Amado J. , Tu Shi-Ming , Chapin Brian Francis , Fogelman David R. , Starbuck Michael W , Corn Paul G. , Aparicio Ana , McQuade Jennifer Leigh , Logothetis Christopher 
Published: March 2021

72 Background: Improved understanding of how host factors influence the efficacy and toxicity of ASI could improve outcomes. Adiposity increases the risk for recurrence and lethal disease in men with localized prostate cancer. Few studies have evaluated the influence of adiposity in metastatic prostate cancer, and in these studies, adiposity was associated with improved outcomes, a potential “obesity paradox”. Herein, we assess whether adiposity is associated with response to maximal ASI in mCRPC and assess how individual body composition measurements interact to influence outcomes. Methods: Men with mCRPC uniformly treated on a prospective clinical trial with abiraterone acetate plus apalutamide were included in this post-hoc analysis (NCT02703623). Responders were defined as those with a decrease in PSA of > 50% after 8 weeks of therapy. Body composition was assessed at the level of L3 on baseline CT scan at trial registration using Slice-O-Matic version 5.0. Body composition indices were normalized for height (m2). Non-parametric Kruskal-Wallis test was used to evaluate associations between continuous baseline measures. A multivariable CART model was used to determine if baseline measures could divide patients into distinct risk groups. Results: In 186 men with mCRPC, responders to maximal ASI (n = 128) had higher subcutaneous adiposity (SATi, 79.3 vs. 67.6, p = 0.02), visceral adiposity (VATi, 76.4 vs. 61.5, p = 0.03), and body mass index (BMI, 30.3 vs. 29.2, p = 0.04). There was a strong correlation between BMI and SAT (r = 0.81). In exploratory multivariable modeling, BMI and VATi had the strongest associations with response to ASI. Specifically, men with a BMI ≥ 26.73 had a higher response rate (75% vs. 46%). For men with a BMI < 26.73, a VATi ≥ 24.7 enriched for response to therapy (86% vs. 26%). Conclusions: Elevated subcutaneous and visceral adiposity is associated with improved response to maximal ASI in men with mCRPC. In hypothesis-generating models, visceral adiposity had the strongest association with response to ASI in men with lower BMI. Further studies need to assess how and when adiposity becomes favorable for outcomes in advanced prostate cancer.
The effects of bright white light therapy on obese frailty in older men with prostate cancer on hormonal therapy: A pilot randomized control trial.
Authors: Bergerot Cristiane Decat , Razavi Marianne , Celis Ashley , Clark Karen L. , Dorff Tanya B. , Pal Sumanta K. , Loscalzo Matthew J. , Dale William 
Published: March 2021

75 Background: Exposure to bright white light (BWL) has been shown to improve outcomes including fatigue, depression, and sleep disturbances among the general older population but the benefit has not been demonstrated as yet in prostate cancer. Older men with prostate cancer on androgen deprivation therapy (ADT) are at risk for obese frailty (components: fatigue, weakness, poor mood, slowness and obesity). In this pilot study, we aimed to determine if BWL, compared to dim white wight (DWL), reduces obese frailty in older prostate cancer patients starting anti-androgens. Methods: Men age ≥ 65 with prostate cancer initiating ADT were randomly assigned to either the BWL (exposure to full spectrum light, 500-1500 lux) or DWL cohort (exposure to low dose white light (<50 lux)) and were blinded to assignment. Men received daily 30-minute morning light session from special glasses (Luminette) for 3 months. Participants were assessed at the beginning of treatment and 3 months later with the Short Physical Performance Battery (SPPB) - including timed 4m walk, tandem balance, and timed chair stands (range: 0 to 12) - energy levels (self-reported 5-point Likert scale), waist circumference (measured via tape (mm)), and muscle strength (handgrip: assessed via dynamometer (kg)). Pre-post outcomes (means differences) were evaluated using paired t-tests with a p-value of 0.05 considered significant. Results: 18 patients (9 per cohort) were recruited. Patients in the BWL arm showed a statistically significant improvement in muscle strength (BWL p=0.012 versus in DWL p=0.22). Compared with DWL, BWL arm showed no decline in energy levels, (BWL p=0.28 vs. DWL p=0.035) nor gain in waist circumference (BWL p=0.51, DWL p=0.046). There were no statistically significant differences in either arm on the SPPB (BWL p=0.44, and in DWL p=0.09). Conclusions: BWL may offset negative effects of ADT for older men with prostate cancer, through improved muscle strength, maintained energy levels, and no waist circumference gain. While a small pilot study, the intervention warrants further research in a larger sample.
A phase II study to evaluate the effects of docetaxel plus lycopene in advanced castrate-resistant prostate cancer.
Authors: Zhuang Eric , Uchio Edward M. , Lilly Michael B. , Fruehauf John P. 
Published: March 2021

77 Background: Lycopene, the carotenoid responsible for the red colors seen in tomatoes, grapefruit, and other foods, has demonstrated synergism with docetaxel in prostate cancer cell culture and tumor xenograft models. This phase II study investigated the clinical activity and safety profile of docetaxel plus lycopene in advanced castrate resistant prostate cancer. Methods: Eligible patients had histologically confirmed adenocarcinoma of the prostate, two rising pre-study prostate specific antigen (PSA) values ≥ 1 ng/ml, and no prior treatment with any chemotherapy, biological therapy, or investigational drug. All patients initially received docetaxel 75mg/m2 every 21 days in combination with lycopene 30 mg orally once daily. The primary endpoint was PSA response rate, defined as the proportion of subjects achieving a ≥ 50% reduction in PSA at any point after starting therapy. Secondary endpoints included median time to PSA progression, duration of response (DOR), and overall survival (OS). Results: Fourteen patients were screened, and thirteen patients were initiated on protocol therapy. Median age was 77 years (range 55-90). Twelve patients (92%) had bone metastases. Four patients (30%) had bone and visceral metastases. The PSA response rate was 76.9% [95% confidence interval (CI), 46.2-94.9], comprising of ten PSA responses. Two patients had a best response of stable disease, yielding a disease control rate of 92% [95% CI, 57.2-98.2]. Median time to PSA progression was 8 months [95% CI, 3.5-8.7]. Median duration of response was 7.3 months [95% CI, 4.8-13.2]. On 5-year follow-up, median overall survival was 35.1 months [95% CI, 25.7-57.7]. The most frequently reported ( > 15%) non-hematologic adverse events included diarrhea, nausea, vomiting, peripheral neuropathy, weight loss, fatigue, onycholysis, and alopecia. One patient (7%) experienced febrile neutropenia. No patients experienced grade 3 or above anemia. Conclusions: The combination of docetaxel with lycopene led to improved PSA response rate and tolerability in patients with advanced castrate resistant prostate cancer. Docetaxel plus lycopene merits further research in this patient population. Clinical trial information: NCT01882985.
Outcomes of older men receiving docetaxel for metastatic hormone-sensitive prostate cancer.
Authors: Lage Daniel E , Michaelson M Dror , Lee Richard J. , Greer Joseph A. , Temel Jennifer S. , Sweeney Christopher 
Published: March 2021

82 Background: Most men who die of prostate cancer are older than 70 years, and the impact of therapy in this population is poorly defined. The ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) randomized men of all ages with metastatic hormone-sensitive prostate cancer (mHSPC) to receive androgen deprivation therapy (ADT) with or without docetaxel. Methods: The results of CHAARTED showed an overall survival (OS) benefit for the addition of docetaxel to ADT in men with mHSPC. In a secondary analysis of this trial, we assessed patient characteristics and OS in patients ≥70 years (“older men”) versus <70 years (“younger men”) with Cox proportional hazards models. Additionally, we compared adverse events, therapy completion rate, and subsequent treatment patterns between these two groups using Chi-squared tests. Results: Of the 790 patients enrolled, 177 (22.4%) were ≥70 years. A greater proportion of older men had an impaired performance status (Eastern Cooperative Oncology Group 1-2: 36.7% vs. 28.6%, p=0.038) and prior local therapy (31.7% vs. 25.9%, p<0.001) compared to younger men. Docetaxel + ADT resulted in improved OS in both older and younger men (Hazard Ratio [HR] 0.45, 95%CI: 0.25-0.80 for older men; HR 0.71, 95%CI: 0.53-0.95 for younger men). This treatment benefit was seen for subgroups of older men with high volume disease (HR 0.43, 95%CI 0.23-0.79) and de novo metastatic disease (HR 0.36, 95%CI 0.19-0.69). A similar proportion of older and younger men completed all six cycles of docetaxel (82.6% vs. 87.1%, p=0.28). Rates of grade 3-5 adverse events were similar between older and younger men (36.8% of older men vs. 26.8% of younger men, p=0.69). The rate of any Grade 4-5 adverse events did not differ significantly between older and younger men (14.9% vs. 11.9%, respectively, p=0.46). In the control arm, a smaller proportion of older men received subsequent cancer treatments (34.4% vs. 51.5%, p=0.017) or subsequent docetaxel (25.6% vs. 37.6%, p=0.035) compared to younger men. Conclusions: In summary, older men with mHSPC who were eligible to participate in a clinical trial had similar OS benefit and clinical outcomes compared to younger men when receiving docetaxel chemotherapy + ADT. Oncologists should consider docetaxel chemotherapy as a favorable treatment option for older men with mHSPC who are fit for chemotherapy. Clinical trial information: NCT00309985.