bluuebunny/crossref_metadata_2025_split huggingface dataset:
Degarelix/bicalutamide combination versus degarelix alone as initial androgen-deprivation therapy
Authors: Nozawa Masahiro , Sugimoto Koichi , Nagai Yasuharu , Sugiyama Takahide , Hatanaka Yuji , Oki Takashi , Tahara Hideo , Matsuda Hisao , Yamamoto Yutaka , Uemura Hirotsugu 
Published: February 2017

183 Background: Antiandrogens have been used to prevent symptoms due to testosterone surge in the early phase of treatment with gonadotropin-releasing hormone (GnRH) agonist as well as to add antitumor efficacy. Degarelix, an antagonist of GnRH does not introduce testosterone surge, however, the combination of degarelix and antiandrogen can exert a stronger antitumor effect than degarelix alone. We conducted a phase II study to investigate the early-phase efficacy and safety of combination of degarelix and bicalutamide compared with degarelix alone in patients with prostate cancer (PCa). Methods: Patients with histologically proven adenocarcinoma in the prostate indicated for androgen-deprivation therapy (ADT) were randomly assigned to a treatment group with either combination of degarelix and bicalutamide or degarelix alone. Degarelix was administered subcutaneously with an initial dose of 240 mg followed by 80 mg thereafter every four weeks. Bicalutamide was taken 80 mg every day. The primary endpoint was the percentage of patients whose serum prostate-specific antigen (PSA) declined with greater than 90% of the baseline at Day 28. Secondary endpoints were the transition of serum PSA and testosterone during treatment of 12 weeks, safety, and quality of life. Results: A total of 93 patients were evaluable in this final analysis. Median age was 75 years. Median baseline serum PSA was 10.2ng/ml. Baseline patient characteristics were well-balanced in both arms. The percentage of patients with serum PSA declines greater than 90% from baseline was 34% and 27% in the combination group and the degarelix monotherapy group, respectively (P= 0.503). The transition of serum PSA and testosterone levels were similar in both groups. No grade 3 or greater adverse event was observed in both groups. Conclusions: Adding bicalutamide on degarelix as initial ADT does not produce a greater impact on serum PSA decline in the early-treatment phase compared to degarelix alone. Clinical trial information: UMIN000011506.
The impact of statin use on abiraterone acetate (AA) treatment duration in patients with castration-resistant prostate cancer (CRPC).
Authors: Harshman Lauren Christine , Werner Lillian , Nakabayashi Mari , Tripathi Abhishek , McKay Rana R. , Wang Xiaodong , Pomerantz Mark , Mucci Lorelei A. , Taplin Mary-Ellen , Sweeney Christopher , Lee Gwo-Shu Mary , Kantoff Philip W. 
Published: February 2017

196 Background: Statins compete with DHEAS for influx through the transporter SLCO2B1 and may prolong time to progression (TTP) on androgen deprivation therapy (ADT). The androgen biosynthesis inhibitor, AA, may also undergo SLCO-mediated transport. We hypothesized that statins may compete with AA for influx by SLCO2B1, which could negatively impact drug efficacy. Methods: We queried our institutional clinical database for patients treated with AA for CRPC. Data on statin use including on-therapy dates were retrospectively collected from the medical record. Time on AA was used as a surrogate for TTP. Duration of AA was defined as the time from AA initiation to time to when AA was discontinued or censored on the last known alive date. The association between statin use and AA duration was estimated using the Kaplan-Meier method. Multivariable Cox regression adjusted for known prognostic factors (e.g, prior docetaxel (D) or enzalutamide (E) use, and sites of metastases (mets) specifically bone or lymph node versus liver or other viscera. Results: Of the 224 patients eligible for analysis, the majority (96%) had metastatic disease at time of AA initiation. 26% had prior D and 7% E. Nearly half were statin users (41%). The median duration on AA was 10.7 months (mo) with a trend to longer duration in statin users: 14.2 vs. 9.2 mo (HR 0.79, 95% CI: 0.57-1.09, p = 0.14). Prior D and E was significantly associated with shorter AA duration while site of mets and age were not. Adjusting for prior use of D, E, and site of mets did not alter the relationship between statin use and AA duration (p = 0.18, HR 0.81, 0.58-1.11). Conclusions: Contrary to our initial hypothesis, there was a trend to longer AA duration in statin users. Given our prior work demonstrating a 10 mo prolonged TTP on ADT in men concurrently taking statins (adjusted HR 0.83), and in vitro findings of inhibition of DHEAS uptake by statins, we postulate that there could be an additive effect of statins and AA by blocking DHEAS uptake. Alternatively, statins may inhibit hepatic AA uptake prolonging drug exposure and increasing effectiveness. Ongoing analyses are evaluating the impact of SLCO SNPs on AA efficacy.
Pharmacokinetic food-effect study of abiraterone acetate (AA) in patients with metastatic castration resistant prostate cancer (mCRPC): The ABIFOOD trial (EudraCt number: 2012-003226-25).
Authors: Espinosa M. , Falcon A , Gutierrez-Valencia A , Cervera A , Rosso-Fernandez CM , Martinez-Lozano E , Perez-Valderrama B , Martinez-Atienza J , Jimenez Gonzalez-Serna L , Sanchez-Simon I , Cruz M , Rodriguez A , Virizuela JA , Maiquez P , Hindi N , Gallego Jimenez I , Lopez-Cortes FL , Paz-Ares Luis G. , Duran Ignacio 
Published: February 2017

227 Background: A.A has been approved for the treatment of mCRPC before and after docetaxel. The standard regime consists on daily A.A. 1.000 mg in a fasting state along with prednisone 10mg q.d. However, data from pharmacokinetic (PK) studies in patients (pts) and healthy volunteers has revealed a significant food-effect with up to 7-10 folder increase in area under plasma concentration-time curve (AUC) when A.A is given with food, specially with fat content, [Chi KN, J Clin Pharmacol 2015]. Methods: ABIFOOD is a phase I, randomized trial to evaluate the short and long-term effect of diet on the PKs of A.A. in pts with mCRPC who have progressed to docetaxel. Eligible pts include men ≥ 18 years old with mCRPC, ECOG performance status (PS) < 2 and an adequate organ function. Pts are randomly assigned to receive 4-weekly cycles of 250 mg A.A with standard meal (Arm A), 250 mg A.A with high-fat meal (Arm B) or 1000 mg A.A in fasting conditions (Arm C). PK analyses are conducted at week 1 (W1) and cycle 5. Results: Fifteen pts (5, 3 and 7 in arms A, B and C respectively) have been included and 6 are still on treatment. Median age is 72, 97% have ECOG-PS 1. Gleason Score is > 8 in 6 (40%) pts.Geometric mean abiraterone [AUC (ng.h/ml) (IQR)] at W1 did not significantly differ between treatment arms [arm A: 404.68 (368.4 - 488.2), arm B: 372 (334.6 - 440.5) arm C: 656.51 (387.8 – 1144.5) p 0.15]. PK data did not influence activity or toxicity. Progression free survival was 8.50, 6.33 and 4.86 months in Arms A, B and C respectively (p 0.53). One patient in arm A is still on treatment after 17 cycles. Conclusions: The administration of lower doses of A.A with food [regardless the fat content], might achieve comparable plasma levels to standard dosing with no detriment in efficacy or toxicity parameters. The study is actively recruiting and data on additional pts and long term PK parameters will be presented. Clinical trial information: EudraCt number: 2012-003226-25.
Analysis of the temporal relationship between patient-reported outcomes (PROs) and overall survival (OS) and radiographic progression-free survival (rPFS) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts).
Authors: Traina Shana , Li Tracy , Johnson Kristen , Ho Kai Fai , Molina Arturo , Cella David 
Published: February 2017

240 Background: PROs are used to measure therapeutic impact. The relationship between PROs and clinical outcomes is not well described. Methods: COU-AA-301 (301) and COU-AA-302 (302) were phase 3 trials of abiraterone acetate + prednisone (P) vs P in post-docetaxel and chemotherapy-naïve mCRPC pts, respectively. Using Cox regression models, we explored the association between self-reported fatigue, pain, physical well-being (PWB), functional well-being (FWB), and PC-specific (PCS) signs and symptoms, and OS and rPFS over the first 181 days, regardless of treatment, using data from 301 (N = 1195) and, separately, from 302 (N = 1088). Pts in 301 had more advanced disease and were more symptomatic at entry; pts in 302 were asymptomatic/mildly symptomatic. PRO improvements were assessed for 301 and worsening was assessed for 302. Results: In 301, pts with PRO improvements had reduced risk of death and radiographic progression (p < 0.0001) vs pts with worsening or stable PROs (Table). When all PROs were included in a multivariate (MV) model, all except pain intensity were significantly associated with OS; pain intensity, PWB, and FWB improvements were significantly associated with reduced radiographic progression. Pts in 302 with worsening PROs had greater risk of radiographic progression (p ≤ 0.02) vs pts with improved or stable PROs (Table). When all PRO end points were included in an MV model, worsening PWB remained significantly associated with worse rPFS. There were too few events at cutoff to explore the relationship between PROs and OS in 302. Conclusions: These results reinforce the clinical meaningfulness of self-reported symptoms and suggest that PROs can be used in combination with clinical measures in practice. Clinical trial information: NCT00887198; NCT00638690. [Table: see text]
Radium-223 in metastatic castration resistant prostate cancer: Progression free survival and pain scores—Real-world single-institution experience.
Authors: Challapalli Amarnath , Hilman Serena , Cowley Sue , Masson Susan , Grifiths Dorothy , Persad Rajendra , Mitchell Kathryn , Huckett Rebecca , Greenwood Rosemary , Compton Eleanor , Bahl Amit 
Published: February 2017

250 Background: Radium-223 (Ra223) is a novel alpha-emitting radiopharmaceutical agent approved for use in patients with metastatic castration resistant prostate cancer (mCRPC) and bone metastases based on ALSYMPCA results. We report our early experience in this setting. Methods: 36 patients were treated with Ra223 from Feb 2014 - Aug 2015. The patients were planned to receive 6 injections at a dose of 50 kBq/kg every 4 weekly. The pain was assessed using the visual analogue score (VAS). The effect of 6 cycles of Ra223 on blood counts, serum alkaline phosphatase (SAP), PSA, VAS and progression free survival (PFS) were evaluated. Results: At baseline (BL) median age was 79years; 66% of patients were ECOG 0-1; median VAS was 6. 53% had received prior docetaxel. 18 patients (50%) received all the scheduled 6 cycles of Ra223. In these patients there was a significant reduction in the pain scores both after the first cycle and after 6 cycles compared to the BL score (p < 0.05 & p < 0.001, respectively). A 30% reduction in the SAP levels was seen (p = 0.03). The reduction in pain scores was independent of the PSA response. The treatment was well tolerated with no grade 3,4 toxicity. Discontinuation rate was 50% (18/36) and was due to disease progression. Prior docetaxel use was associated with a higher discontinuation rate (12/18), as was albumin level < 34g/dL (60% vs. 43%). 7 (19%) required blood transfusions during the course. The median PFS was 6.1 months. It was significantly longer in those who completed 6 cycles of treatment and in patients with SAP < 220 U/L (10.97vs.5.2 & 10.33vs.6.4 months, respectively: p < 0.0001). There was a non-significant trend towards longer PFS in patients who had no prior docetaxel (10.33vs.6.5m; p = 0.05) and in patients with Albumin > 34 (8.9vs.6.4m; p = 0.06). Conclusions: Ra223 is a safe and effective treatment for mCRPC with bone metastases. Completion of 6 cycles is associated with a significantly better PFS, reduction in pain scores and in SAP levels. Prior docetaxel use and lower albumin levels were associated with a higher discontinuation rate and this should be considered in the decision process for optimising therapy sequencing.
The relationship of B7H3 expression to androgen and prostate cancer outcomes in a large natural history cohort of men undergoing prostatectomy.
Authors: Ross Ashley , Benzon Benjamin , Zhao Shuang , Takhar Mandeep , Haffner Michael , Erho Nicholas , Hurley Paula , Tosoian Jeffrey J. , Alshalalfa Mohammed , Glavaris Stephanie , Simons Brian , Tran Phuoc T. , Davicioni Elai , Karnes Jeffrey , Schaeffer Edward M. , Drake Charles G. , Feng Felix Yi-Chung 
Published: February 2017

256 Background: B7-H3 (CD276), part of the B7 superfamily, has been shown to play an immunomodulatory role, however its regulation, receptor and mechanism of action remain unclear. Protein levels of B7-H3 have been previously shown to relate to prostate cancer outcomes and currently, humanized monoclonal antibodies are being developed for clinical use (MGA271, Macrogenics). Here we use genomic expression data to examine the relationship of B7-H3 to prostate cancer outcomes and molecular subtypes. Methods: Prostatectomy tissue from 905 patients were profiled using the Affymetrix HuEx 1.0 ST microarray. Kruskal-Wallis tests were used to identify significant associations of B7-H3 expression with clinico-pathologic variables, and survival analysis were used to evaluate the prognostic value of B7-H3. Pearson’s correlation analyses were also performed to assess the relationship of B7-H3 expression with molecular subtypes and individual transcripts. Androgen receptor (AR) occupancy of promoter regions was derived in silico from chromosomal immune-precipitation (ChIP) data. Results: B7-H3 expression was positively associated with Gleason score (p < 0.01) and tumor stage (p < 0.01). High B7-H3 expression also correlated with the development of metastasis and prostate cancer specific mortality (HR of 3.4 and 2.4 respectively, p < 0.05 for both), but this was not significant on multi-variable analysis. B7-H3 was positively associated with ERG+ disease (n = 670, r = 0.85, p < 0.05) and AR expression (n = 670, r = 0.46, p < 0.001). B7-H3 was found to be one of the most correlated genes with AR (95th percentile) and ChIP analysis revealed AR binding upstream of B7-H3, suggesting potential androgen dependent regulation. Conclusions: B7-H3 expression correlates with high Gleason grade and advanced prostate cancer stage with higher quartiles of expression portending poor oncologic outcomes in two independent prostatectomy cohorts. B7-H3 expression appears to relate to the androgen receptor.
Chemotherapy in metastatic hormone-naïve prostate cancer: Pooled analysis of randomized clinical trials.
Authors: Fabbri Paolo , Stocchi Lucia , Nicoletti Stefania , Drudi Fabrizio , Tamburini Emiliano , Nicolini Mario , Gianni Lorenzo , Pasini Giuseppe , Montanari Francesco , Tassinari Davide 
Published: February 2017

259 Background: To assess the role of chemotherapy in metastatic, hormone-naïve prostate cancer, we presents the preliminary data of a pooled analysis comparing the outcome of patients with metastatic hormone-naïve prostate cancer. Methods: A pooled analysis of the outcome of randomized clinical trials approaching the role of docetaxel in metastatic hormone-naïve prostate cancer was performed using a random effect model. The final outcome of all the patients enrolled into the trials was the primary end point of our analysis. The pooled final result was reported as pooled Hazard Ratio and 95% Confidence Interval. The between-the trials heterogeneity was assessed using the I2 test. An α-error of 5% was identified as index of statistical significance. Overall survival of the entire population enrolled into the trials was the outcome of the preliminary analysis, while no subgroup analysis was performed in this preliminary phase of a multi-steps analysis. Results: Three trials (the CHAARTED, the STAMPEDE and the GETUG-AFU 15 trial) were considered eligible and included into the analysis. A pooled Hazard Ratio of 0.76 (95% Confidence Interval of 0.59-0.98, p = 0.037) was detected for overall survival, with an I2 of 67.8. The pooled datum was obtained observed the outcome of 951 patients treated with docetaxel plus androgen blockade and 1338 with androgen blockade alone. Conclusions: Although the between-the-trials heterogeneity seems to suggest caution in the final interpretation of the results, a significant reduction of the risk of death can be obtained with docetaxel in the treatment of metastatic hormone-naïve prostate cancer. Our preliminary analysis, including all the patients with metastatic hormone-naïve prostate cancer, seems to suggest a role of docetaxel in all the patients with metastatic disease; further data are probably needed to detect its role in some different subclasses of patients (patients with high burden of the disease, fit or unfit patients, elderly patients).
Quality of life (QOL) analysis from E3805, chemohormonal androgen ablation randomized trial (CHAARTED) in prostate cancer (PrCa).
Authors: Patrick-Miller Linda J. , Chen Yu-Hui , Carducci Michael Anthony , Cella David , DiPaola Robert S. , Gartrell Benjamin Adam , Jarrard David Frazier , Liu Glenn , Morgans Alicia Katherine , Wong Yu-Ning , Sweeney Christopher 
Published: February 2017

286 Background: Docetaxel concurrent with androgen deprivation (ADT) for metastatic hormone sensitive prostate cancer (mHSPC) improves overall survival over ADT alone. However, docetaxel as a cytotoxic has an adverse event profile that can diminish QOL. Methods: Patients were randomized to ADT plus 6 cycles of docetaxel every 3 weeks (Arm A, N = 397) or ADT alone (Arm B, N = 393). Validated QOL instruments for PrCa and docetaxel including Functional Assessment of Cancer Therapy (FACT)–Prostate were administered at baseline and 3, 6, 9 and 12 months (mos.) after randomization. Paired t-tests were used to examine QOL changes over time. A mixed effect model compared QOL between arms at each time point (Table). Results: 790 patients were randomized and QOL completed for Arm A and B (91% and 88%, baseline; 87% and 80%, 3 mos.; and 70% and 67%, 12 mos.). Patients in Arm A (ADT + docetaxel) reported -2.7 [Standard Error (SE) 0.9] decline in FACT-P at 3 mos. (p = 0.003), but did not differ significantly from baseline at 12 mos. (-0.7, SE 1.1). In contrast, patients in Arm B (ADT alone), did not differ significantly at 3 mos. [-1.1 (SE: 1.0)], but reported a significant decline [-4.2 (SE: 1.1); p = 0.0001] from baseline to 12 mos. FACT-P scores differed significantly between Arm A and B at 3 mos. (p = 0.02) and 12 mos. (0.04), with Arm A lower at 3 mos. and higher at 12 mos. Conclusions: Docetaxel is associated with decreased QOL on treatment (at 3 mos.) not seen with ADT alone. However, 12 mos. QOL was better for the patients who had docetaxel versus ADT alone, returning to baseline. This suggests that docetaxel + ADT does not confer long-term negative impact on QOL for mHSPC. Clinical trial information: NCT00309985. [Table: see text]
Frequency of BRCA mutations and co-occurring alterations in prostate cancer.
Authors: Myers Charles E. , Feldman Rebecca , Abbott Brian L. , Reddy Sandeep K. , Castro Michael 
Published: February 2017

289 Background: Evidence is building for the utility of PARP (oral poly (ADP-ribose) polymerase) inhibitors in BRCA-mutated patients, across solid tumors. We examined the presence of somatic BRCA mutations (detected in tumor), in a population of prostate cancer patients. Comparisons between BRCA-mutated and BRCA-wildtype patients were made to determine potential combination strategies. Methods: 85 advanced prostate cancer patients were included in the study and tested centrally at a CLIA laboratory (Caris Life Sciences, Phoenix, AZ). Tests included one or more of the following: gene sequencing (Sanger or next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]) and gene amplification (C/FISH). Results: Average age of BRCA-mutated patients was 58, compared to 62 in the non-BRCA-mutated cohort. Metastatic (Stage IV) disease was present in 67% in both cohorts (8/12; 49/73). BRCA2 mutations were more frequent (12%; 10/85) than BRCA1 (2%; 2/85). Of the BRCA-mutated patients, 5 variants are classified as having pathogenic effect; the rest consisted of variants of unknown clinical significance. Concurrent mutations in BRCA1 and BRCA2 were found in 17% (2/12) of patients. One patient harbored multiple BRCA mutations (n = 4, c.7977-1G > C, I2068fs, K2077Q, T2337I). Regarding co-occurring alterations, 36% (4/11) and 0% (0/11) exhibited PD1 + TILs and PD-L1+ tumor expression. Amongst theranostic markers tested by IHC, TOPO1 and TUBB3 were differentially expressed in BRCA-mutated vs. BRCA-wildtype groups: 91% (10/11) vs. 59% (41/69); p = 0.04 and 64% (7/11) and 23% (16/70); p = 0.0099. Co-occurring variants detected by NGS, included high rates of TP53: 42% (5/12) compared to BRCA- wildtype (30% 21/71), not significant. Of 3 patients that included expanded NGS analysis (600 genes), each harbored ≥ 39 mutations. Conclusions: The frequency of somatic BRCA mutations observed in prostate cancer, together, with preliminary clinical evidence for the efficacy of targeted therapies for these patients; highlight the potential role of a new class of agents for advanced prostate cancer.
Does androgen deprivation therapy impair renal function in patients with prostate cancer?
Authors: Mitsuzuka Koji , Kyan Atsushi , Sato Tomonori , Orikasa Kazuhiko , Miyazato Minoru , Kakoi Narihiko , Narita Shintaro , Koie Takuya , Habuchi Tomonori , Ohyama Chikara , Arai Yoichi ,   Tohoku Evidence-Based Medicine Study Group and Michinoku Urological Cancer Study Group
Published: February 2017

323 Background: While the adverse effects of androgen deprivation therapy (ADT) in patients with prostate cancer are generally well-known among physicians, it is not clear whether ADT affects renal function. Therefore, the goal of the present study was to assess changes in renal function in response to ADT for 1 year. Methods: Patients with prostate cancer who were hormone-naïve and scheduled to receive long-term ADT were recruited between 2011 and 2013. Body weight and blood testing, including lipid and glucose metabolism and renal function, were recorded every 3 months during 1 year of ADT. Estimated glomerular filtration rate (eGFR) was calculated based on baseline age throughout ADT. Computed tomography (CT) was performed to measure psoas muscle area before and after 1 year of ADT to evaluate the influence of a decrease in lean mass on renal function. ADT was limited to a luteinizing hormone-releasing hormone agonist with or without bicalutamide. Patients who had severe renal dysfunction (eGFR < 30 mL/min/m2) or who had disease progression during 1 year of ADT were excluded from analyses. Results: Of 217 registered patients, renal function data were available from 170 patients who completed 1 year of ADT. Mean changes in serum creatinine and eGFR were 1.3% and 0.2%, respectively. Prostate specific antigen, clinical stage, body mass index, total testosterone, hemoglobin A1c, creatinine, eGFR, and comorbidities (e.g., hypertension, dyslipidemia, diabetes mellitus, cardiovascular disease) at baseline were not associated with a change in renal function. Age < 70 years at baseline was associated with an increase in eGFR in univariate and multivariate analyses (univariate: P = 0.01, multivariate: 95% confidence interval 1.13-4.87, P = 0.03). CT was performed in 72 patients before and after 1 year of ADT. The mean decrease in psoas muscle area was -8.4%. Decrease in psoas muscle area and increase of eGFR were more frequent in patients of age < 70 years than in those of age ≥ 70 years (psoas muscle: -10.2% vs. -7.5%, P = 0.05; eGFR: 6.4% vs. 0.2%, P = 0.03). Conclusions: ADT did not impair renal function in patients with prostate cancer. eGFR was more likely to increase in younger patients, but this increase may be due to a decrease in lean mass. Clinical trial information: UMIN000004709.