bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II, open-label, multi-arm study of TAS-115 for castration-resistant prostate cancer patients with bone metastases.
Authors: Uemura Hiroji , Matsubara Nobuaki , Uemura Hirotsugu , Nagamori Satoshi , Suzuki Hiroyoshi , Kimura Go 
Published: March 2019

164 Background: TAS-115, a novel multi-kinase (eg, MET, VEGFR) inhibitor has also shown to inhibits Feline McDonough Sarcoma oncogene (FMS) kinase, Anti-tumor activity against bone metastases was observed in the preclinical and phase1 study. In this phase 2 study, the efficacy and safety of TAS-115 were evaluated in castration-resistant prostate cancer (CRPC) patients (pts) with bone metastases. Methods: This was a phase 2, open-label, multi-arm study for CRPC pts with bone metastases to evaluate the clinical anti-tumor activity of TAS-115. Pts who had visceral metastases were ineligible for this study. TAS-115 was given orally, once daily, and schedule of 5 days on/2 days off each week was repeated. This study had 2 cohorts (A and B). In cohort A, TAS-115 ranging from 200 to 400 mg/day with abiraterone acetate was given to pts prior to docetaxel. In cohort B, CRPC pts who had symptomatic bone metastases, post or unfit to docetaxel, were randomized in a 1:1 to 400 or 600 mg/day of TAS-115. The primary endpoint was bone scan index (BSI) response rate at week 12, defined as ≥ 30% decrease of BSI from baseline. BSI is a quantitative assessment of bone scan data calculated by software (BONE NAVI). Results: From Nov 2016 to Jul 2018, a total of 50 pts received TAS-115 (24 pts in cohort A and 26 pts in cohort B). BSI response rate at week 12 and best BSI response was 20.8 % and 37.5% in cohort A, and 15.4 % and 19.2% in cohort B, respectively. Any reduction of BSI was observed in 70.8% of cohort A and 61.5% of cohort B. In cohort B, pain was assessed using the Brief Pain Inventory short form and improvement was observed in 61.5% of pts. Furthermore, the reduction of bone-turnover marker (BAP, P1NP, NTx and TRACP-5b) were observed in both cohorts, but not PSA response. The major (≥ 10%) Grade 3/4 treatment-related adverse drug reactions were hypophosphataemia (21%) in cohort A, and anemia (23%), hypophosphataemia (12%) and neutrophil count decreased (12%) in cohort B. Conclusions: Preliminary anti-tumor activity to bone lesion and improved pain were observed in CRPC pts with bone metastases, and safety of TAS-115 was acceptable. TAS-115 could be a novel therapeutic agent with a favorable safety profile for CRPC with bone metastases. Clinical trial information: JapicCTI-163448.
Enzalutamide versus flutamide for castration-resistant prostate cancer after combined androgen blockade therapy with bicalutamide: A multicenter randomized phase II trial (OCUU-CRPC study).
Authors: Iguchi Taro , Tamada Satoshi , Kato Minoru , Yasuda Sayaka , Machida Yuichi , Ohmachi Tetsuji , Ishii Keiichi , Iwata Hiroyuki , Yamamoto Shinji , Kanamaru Tomohiro , Morimoto Kazuya , Hase Taro , Tashiroro Koichiro , Harimoto Koji , Deguhi Takashi , Adachi Takahisa , Iwamoto Katsuki , Takegaki Yoshinori , Nakatani Tatsuya ,   OCUU-CRPC STUDY Group
Published: March 2019

168 Background: In Asia, including Japan, combined androgen blockade (CAB) therapy with bicalutamide is widely administered for metastatic prostate cancer. Alternative anti-androgen therapy (AAT) with flutamide after CAB therapy with bicalutamide was common before the androgen receptor-targeted therapy era. The objective of the OCUU-CRPC study was to compare the efficacy and safety between second-line hormonal therapy of enzalutamide and flutamide as alternative AAT after CAB therapy that included bicalutamide in patients with CRPC. Methods: A total of 104 patients with CRPC with or without distant metastases after disease progression who received CAB therapy with bicalutamide were randomly assigned at a 1:1 ratio according to distant metastases to the enzalutamide (160 mg/day) and flutamide (375 mg/day) groups. The primary endpoint for the drug efficacy was the response rate of prostate-specific antigen (PSA; i.e., declined by ≥50%) at 3 months. Results: Between January 2015 and February 2018, 103 patients were randomly assigned, 52 to enzalutamide and 51 to flutamide. 25 (48%) and 38 (75%) patients, respectively, discontinued their assigned treatment before study end, mainly due to progressive disease. Median follow-up time was 13.4 months (IQR 9.6–23.8) in the enzalutamide group and 17.0 months (9.7–24.4) in the flutamide group. Enzalutamide resulted in significant improvements in the response rate of PSA at 3 months (84.6% vs 31.4%; p< 0.001). Enzalutamide significantly improved in all secondary endpoints: the PSA progression rate at 3 months (HR, 0.17; 95% CI, 0.05 to 0.47; p< 0.01) and at 6 months (HR, 0.22; 95% CI, 0.09 to 0.50; p< 0.01); and PSA response rate at 6 months (75.0% vs 29.4%; p< 0.01); and time to PSA progression (median: not reached vs 6.6 months; HR, 0.29; 95% CI, 0.15 to 0.54; p< 0.01). The observed adverse event profile was consistent with that from phase III enzalutamide trials. Conclusions: Enzalutamide significantly reduced risk of progression compared with flutamide in patients with CRPC after CAB therapy with bicalutamide. This trial is registered with ClinicalTrials.gov, number. Clinical trial information: NCT02346578.
Plasma AR status and cabazitaxel in heavily-treated metastatic castration-resistant prostate cancer (mCRPC).
Authors: Conteduca Vincenza , Castro Elena , Jayaram Anuradha , Wetterskog Daniel , Scarpi Emanuela , Romero-Laorden Nuria , Olmos David , Gurioli Giorgia , Lolli Cristian , Puente Javier , Medina Ana , Querol Rosa , Arranz Jose Angel , Saez Maria Isabel , Fornarini Giuseppe , Basso Umberto , Mellado Begona , Gonzalez-Billalabeitia Enrique , Attard Gerhardt , De Giorgi Ugo 
Published: March 2019

203 Background: Plasma androgen receptor ( AR) copy number status has been identified as a potential biomarker of response in mCRPC patients receiving docetaxel or the AR-targeted therapies abiraterone or enzalutamide. However, the relevance of plasma AR status in the context of cabazitaxel therapy is unknown. Methods: Between September 2011 and January 2018, pre-therapy plasma samples were collected from 155 patients treated with second or third-line cabazitaxel at standard or reduced dose in different biomarker protocols. Droplet digital PCR was used to identify plasma AR gain and normal samples, with the primary objective to evaluate associations of plasma AR status with treatment outcome. In an exploratory analysis, a comparison between plasma AR status and treatment type was investigated by incorporating updated data from our prior study of 85 post-docetaxel patients receiving abiraterone or enzalutamide. Results: We observed a shorter median overall/progression-free survival (OS/PFS) in AR-gained compared to AR-normal patients (OS 10.5 versus 14.1 months, hazard ratio (HR) 1.44, 95% confidence interval (CI) 0.98-2.13, P = 0.064), and (PFS 4.0 versus 5.0 months, HR 1.47, 95%CI 1.05-2.07, P = 0.024). In mCRPC patients receiving second-line therapies, a significant treatment interaction was observed between plasma AR and cabazitaxel versus AR-directed therapies for OS (P = 0.041) but not PFS (P = 0.244). In an exploratory analysis, AR-gained patients treated with initial reduced-dose of cabazitaxel had a significantly shorter median OS (7.3 versus 11.5 months, HR 1.95, 95%CI 1.13-3.38, P = 0.016), and PFS (2.7 versus 5.0 months, HR 2.27, 95%CI 1.39-3.71, P = 0.001). Conclusions: Plasma AR status has a potential clinical utility in patients being considered for cabazitaxel. Validation of these findings in prospective trials are warranted.
A multidisciplinary team-based approach to mitigate the impact of androgen deprivation therapy in prostate cancer: A randomized phase II study.
Authors: Pollock YaoYao Guan , Zhang Li , Rodvelt Tammy J. , Ma Brian , Macaire Greta , Weinberg Rami , Kenfield Stacey , Chan June M. , Topp Kimberly , Van Blarigan Erin , Friedlander Terence W. , Lin Amy M. , Fong Lawrence , Kim Won , Hough Jeffrey , Lee Mina , Ryan Charles J. , Small Eric Jay , Aggarwal Rahul Raj 
Published: March 2019

204 Background: Androgen deprivation therapy (ADT) is associated with numerous metabolic toxicities that are potentially modifiable. We sought to evaluate the impact of participation in a multidisciplinary clinic (MDC) designed to provide individualized lifestyle modification and management of ADT-related side effects. Methods: This phase II study recruited men with prostate cancer who had started ADT < 6 months prior to enrollment, and in whom ADT was planned for at least 12 months following enrollment. Patients were randomized in a 1:1 ratio to either the MDC or standard of care (SOC). Patients randomized to the MDC were provided monthly multidisciplinary assessment and counseling on exercise, nutrition, and symptom management for 12 months on a rotating schedule. Endpoints included feasibility endpoints (proportion of visits completed), and efficacy endpoints, including mean change from baseline to 12 months in blood pressure (BP), weight, waist circumference, percent body fat, hemoglobin A1C (HbgA1C), insulin resistance, and fasting lipids. Results: 25 men were randomized to MDC, and 23 were randomized to SOC. Overall 91% (295/325) of MDC visits were completed. 72% (18/25) of patients completed all 12 months of MDC, and 80% (20/25) completed the first 6 months. Compared to SOC, patients in the MDC arm had a trend towards more favorable mean percent change from baseline to 12-month follow up in systolic BP (6.5% vs. 10.3%), diastolic BP (-3.9% vs.10.0%), waist circumference (2.5% vs. 4.0%), HbA1C (-2.4% vs. -1.7%), insulin resistance (0.5% vs. 1.9%), and fasting lipids (total cholesterol: 7.0% vs. 21.8%; LDL: -2.9% vs. 7.6%; triglyceride: 15.5% vs. 37.2%). Conclusions: Individualized and comprehensive management of toxicities of ADT in a multidisciplinary clinic is feasible, and appears to provide some benefit over SOC. Larger randomized studies are warranted to investigate whether this intervention will provide lasting benefit. Clinical trial information: NCT02168062.
External beam radiation therapy and brachytherapy boost versus radical prostatectomy and adjuvant radiation therapy for high-risk prostate cancer.
Authors: Muralidhar Vinayak , Mahal Brandon Arvin Virgil , Yang David Dewei , Leeman Jonathan Eric , D'Amico Anthony Victor , Nguyen Paul L. , Orio Peter F. , King Martin T. 
Published: March 2019

21 Background: Previous studies have suggested that combination external beam radiation therapy (EBRT) with brachytherapy boost (BT) for high-risk prostate cancer is associated with equivalent overall survival (OS) compared with radical prostatectomy (RP). However, it is not known whether RP with post-operative radiation therapy (PORT) can offer improved OS compared with combination RT (EBRT + BT + androgen deprivation therapy [ADT]) for patients with Gleason 9-10 high-risk disease. Methods: We identified all patients diagnosed with clinical T1-T3, Gleason 9-10, prostate-specific antigen (PSA) 0-40 ng/mL, and clinically node negative disease between 2004 and 2014 from the National Cancer Database. We divided patients into 4 treatment groups: EBRT + ADT, combination RT (EBRT + BT + ADT), RP, and RP + PORT. Only patients who received PORT within 360 days of surgery were included within the RP + PORT group. We compared OS utilizing inverse probability of treatment-weighted multivariable Cox proportional hazards regression modeling after accounting for clinical and demographic factors, including Gleason grade (9 versus 10), T-stage (T1, T2, T3), age, Charlson-Deyo comorbidity score (0, 1, versus 2), education quartile, income quartile, geographic location within the US, insurance status, facility volume, and race. Results: Median follow-up in the entire cohort was 4.5 years. The numbers of patients treated with EBRT + ADT, EBRT + BT + ADT, RP, RP + PORT were 6778, 924, 7111, and 1929, respectively. There were no significant differences in 5-year OS when comparing combination RT to RP (85.0% vs 85.7%, adjusted hazard ratio (AHR) 0.92, 95% confidence interval [CI] 0.77-1.10, p = 0.36) or RP + PORT (85.0% vs 85.6%, AHR 0.89, 95% CI 0.71-1.12, p = 0.34). Combination RT was associated with superior 5-year OS compared to EBRT + ADT alone (without BT boost) (85.0% vs 79.4%, AHR 1.26, 95% CI 1.07-1.48, p < 0.01). Conclusions: Our study suggests that for patients with Gleason 9-10 tumors, multi-modality surgical therapy is equivalent to combination RT.
Final analysis of a phase II study of MRI based functional imaging of bone metastases in men with metastatic castrate-resistant prostate cancer (mCRPC) receiving cabozantinib.
Authors: Desai Arpita , Brewer Jamie Renee , Medved Milica , Oto Aytekin , Gao Guimin , Karrison Theodore , Shevrin Daniel H. , Karczmar Greg S. , Stadler Walter Michael , Szmulewitz Russell Zelig 
Published: March 2019

213 Background: Cabozantinib (C) is a small molecule inhibitor of receptor tyrosine kinases including VEGFR-2, c-MET. C trials have shown significant improvements in bone pain and bone scintigraphy in mCRPC patients (pts). We hypothesized that functional imaging using MRI could elucidate underlying biological processes by demonstrating an early decrease in vascular permeability (decrease in transfer consant - Ktrans) and subsequent decrease in cell density (increase in apparent diffusion coefficient - ADC) within bone metastases. Methods: mCRPC pts received C 60 mg daily. The primary endpoint was change in Ktrans at 2 weeks (wks) of treatment. Secondary endpoints included Ktrans and ADC longitudinal changes, and correlation with bone scan, PSA, RECIST, and changes in reported pain. All pts underwent MRI at baseline, day 0, day 15 and every 12 wks. Results: 17 pts were treated at two sites. Median age: 68 yrs (range:51-83), baseline PSA 94.78 ng/mL (7.4-2971), number of prior CRPC therapies 2 (1-8). Median progression free survival was 5.1 months; 5 pts discontinued therapy for adverse events, and 12 for progressive disease. The most common grades 3/4 toxicities were fatigue (24%) and palmarplantar erythrodysesthesia (12%). 14 pts were evaluable for the primary endpoint. At 2 wks, Ktrans decreased an average 35%, 0.074 to 0.048 min-1 (SD=0.016, p<0.0001). There was no change in Ktrans between wk 2 and end of study. There was an increase in median ADC of 150 at wk 12. There were no RECIST or 50% PSA responses. Conclusions: Ktrans decreased significantly after 2 wks of treatment, consistent with antiangiogenic properties of C. Compared to wk 2, K trans at disease progression is unchanged, which could signify that adaptive vascular change is not the primary mechanism of tumor resistance to the drug. Contrary to our hypothesis, ADC increased during the trial, which perhaps correlates with the short median time to progression. Still, MRI of bone metastases could benefit drug development for other agents in mCRPC or interrogation of bone metastases, notoriously challenging for disease response analysis, in other cancers. Clinical trial information: NCT01599793.
An updated analysis evaluating skeletal related events (SREs) in CTRIAL-IE 13-21: Phase II trial of radium-223 (R223) in combination with enzalutamide (ENZA) for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Greene John Patrick , Lim Marvin Chang Jui , Baird Anne-Marie , Deignan Olwyn , McCaffrey John , Prior Lisa Mary , Parker Imelda , Bowes Alison , Teiserskiene Ausra , Feeney John , Thirion Pierre Guillame , Finn Stephen P. , Kelly Paul J. , McDermott Ray 
Published: March 2019

215 Background: This phase II single arm study, previously reported on the safety and tolerability of the combination of R223 and ENZA in pts with mCRPC. R223 in combination with ENZA was well tolerated with acceptable safety and toxicity profiles. Methods: This study enrolled pts with mCRPC to bone with or without visceral/lymph node involvement progressing on ADT. Pts received 6 cycles of R223 (55 kBq/kg IV Q4W) in combination with ENZA (160mg/day), followed by ENZA alone. Bone health agents were initiated as per treating clinician choice. SREs were defined as: a pathologic fracture, spinal cord compression (SCC), necessity for external beam radiation (EBRT) or surgery to bone. SREs during the combination period and after completion of R223 are reported here. An unplanned retrospective analysis of all scans performed on each patient for any fracture was performed and is included. Results: From July 2015 to July 2017, 45 pts were enrolled. 42 pts (93.3%) received all 6 cycles of combination therapy. 16 pts (35.5%) remain on ENZA alone. In total, 6 pts (13.3%) had SREs. 4 developed pathological fractures (femur = 1, vertebrae = 3) while 3 had EBRT for pain. Of these 6 pts, 2 developed SCC requiring EBRT. The average time from starting R223 to SRE was 615 days. 2/6 pts were not receiving bone protection. One pt who developed a pathological fracture has subsequently died related to progressive disease (time to death = 292 days). In the retrospective analysis, 4 pts (8.8%) developed fractures which were associated with a history of trauma (radius = 1, tibia = 1 ribs = 2). 11 pts (24.4%) developed asymptomatic insufficiency fractures (ankle = 1, femur = 1, sacrum = 2, vertebrae = 4, ribs = 4). The average time to insufficiency fracture was 354 days. No interventions were required. The majority of pts (75.5%) on the study were receiving bone health agents. Conclusions: SREs were in keeping with previously published data. In an unplanned retrospective analysis, there was a higher incidence of asymptomatic insufficiency fractures in this cohort of patients, however no interventions were required. Clinical trial information: NCT02225704.
Circulating tumor (ct) DNA-based genomic profile of prostate cancer (PCa) patients with elevated carcinoembryonic antigen (CEA).
Authors: Malalur Pannaga G. , Gourdin Theodore Stewart , Roberts Ali , Lilly Michael B. 
Published: March 2019

218 Background: Neuroendocrine (aggressive variant) PCa patients often have elevated CEA (40-85%), which is associated with poor outcomes. We used ctDNA analysis to identify a genomic pattern for PCa patients with elevated CEA (CEA+ PCa). Methods: We analyzed ctDNA-based genomic profiles (Guardant 360) from 32 patients with CEA+ PCa. Profiles were compared with genomic profiles from the TCGA database, ctDNA profiles for 50 consecutive PCa patients with normal CEA levels (CEAnl PCa), and ctDNA profiles for GI tumors associated with elevated CEA. Results: CEA+ PCa patient profiles showed concordance with TCGA database genomic profiles for neuroendocrine PCa. There was high similarity in genes amplified; however many more single-nucleotide variants (SNVs) were detected with ctDNA analysis. For ctDNA profiles of CEA+ PCa, the most commonly amplified genes were AR, PIK3CA, MYC, CDK6, BRAF, MET; the most common clonal SNVs were in TP53, PTEN, APC, PIK3CA, and MET. Serial ctDNA analyses were done in 23 CEA+ PCa patients, of which 8 showed conversion from CEAnl to CEA+ PCa. This change was accompanied by emergence of new amplifications (62.5%; AR, MET, MYC, BRAF, EGFR, CDK6) or SNVs (tumor suppressor genes [ APC, TP53] or mitogen signaling pathways [ BRAF, ERBB2, KRAS, MET, PIK3CA]). Clonal mutations present in CEAnl PCa frequently persisted after emergence of a CEA+ phenotype. CEA+ PCa differed from CEAnl PCa by the higher prevalence of AR amplifications (p = 0.033), higher AR copy number (p = 0.004), and lower number of AR clonal mutations (p = 0.0017). AR amplification was significantly more frequent in CEA+ PCa (50%) than in another CEA+ malignancy, colon cancer (3%). AR amplification copy number was also much higher in CEA+ PCa than in colon cancer (p = 0.0023). Conclusions: ctDNA analysis shows AR amplifications as highly associated with CEA+ and neuroendocrine PCa. New amplifications occur during evolution from CEAnl to CEA+ PCa. Genomic profile obtained using ctDNA (within limits) is comparable to TCGA database. AR amplification is characteristic of CEA+ PCA and may distinguish this entity from other cancers with elevated CEA.
Discovery of targetable mutational signatures in advanced prostate cancer (aPC) using machine learning and next-generation sequencing (NGS) of circulating tumor DNA (ctDNA).
Authors: Lin Edwin , Hahn Andrew W , Sonpavde Guru , Lilly Michael B. , Nussenzveig Roberto , Ledet Elisa , Pal Sumanta K. , Grivas Petros , Rich Thereasa A. , Raymond Victoria M. , Sartor A. Oliver , Yandell Mark , Agarwal Neeraj 
Published: March 2019

226 Background: Alterations (alts) of the AR gene are common in aPC and are associated with reduced responses to AR-axis inhibitors; optimal treatment is unknown. Genomic sequencing of ctDNA from aPCs may recapitulate truncal and branching alts across metastatic sites in heavily pretreated progressive aPC and facilitates identification of AR and other alts that contribute to aPC progression. Such data could lead to better understanding of aPC molecular biology and guide development of novel treatments. Methods: Two unsupervised machine learning algorithms, hierarchical clustering and principal components analysis, were used to evaluate mutational profiles of 2,679 plasma samples from 2,309 men with aPC. Samples were assessed by a validated ctDNA NGS panel that sequences 73 clinically relevant cancer genes (Guardant360, Redwood City, CA). Indels, amplifications, and fusions are evaluated in a subset of genes with high sensitivity and specificity. Chi-squared residual analysis and gene ontology enrichment were used to identify significantly co-altered molecular pathways. Results: Distinct, non-overlapping mutational signatures were observed in tumors with only AR amplification (amp) vs. only AR mutation (mut). Tumors with only AR amp, and those with both AR amp and mut, were strongly enriched for amps in the MAPK pathway (P = 3.62E-10, 4.92E-05, resp.). Tumors with only AR mut, and those with no AR alts, were strongly enriched for muts in negative regulators of cell proliferation (P = 1.09E-05, 3.30E-09, resp.). Muts further stratified to oxidative stress response in AR mut (P = 4.37E-05), and cell aging in no AR alts (P = 8.31E-07). Conclusions: In men with aPC, machine learning of ctDNA NGS data revealed recurrent mutational signatures that stratified according to the type of AR alts. These hypothesis-generating data require external validation but suggest that aPC may progress due to distinct mechanisms dependent on AR status. Future efforts to develop novel therapeutic approaches for aPC may need to consider the impact of the type of AR alt present and explore the interplay of AR with other altered pathways identified in this analysis.
TP53 mutations in circulating tumor DNA in men with metastastic castration-resistant prostate cancer mCRPC.
Authors: Chapman Lynne , Ledet Elisa , Ranasinghe Lahiru , Manogue Charlotte , Cotogno Patrick , Moses Marcus Marie , Christensen Bryce Raymon , Steinwald Peter , Layton Jodi Lyn , Lewis Brian E. , Sartor A. Oliver , Barata Pedro C. 
Published: March 2019

249 Background: Genes involved in mCRPC, including the tumor suppressor gene TP53, can be monitored with ctDNA but implications are unclear. Methods: Between 8/6/15 to 9/19/18, patients with mCRPC with available ctDNA genomic data using Guardant360 (Guardant360, Redwood City, CA) were included. Relationships between various lines of therapy and TP53 mutational status were analyzed. Patients positive for TP53 mutants were categorized using mutant allelic fraction of > 0%, ≥0.5%, ≥1% and ≥5%. Results: This study included 215 patients with mCRPC, median age 70 (41-90), and 80% Caucasians who had ctDNA after one line treatment for CRPC that included abiraterone (55%), enzalutamide (22%), and sipuleucel T (21%). Frequent co-alterations with TP53 mutants after 1 line of CRPC therapy included AR (14%), NF1 (5%), EGFR (4%), and PIK3CA (4%). See Table for relationships between lines of therapy and mutant TP53 allelic fraction. Conclusions: In this cohort of men with mCRPC, a higher mutational burden of TP53 in ctDNA was frequent and particularly associated with multiple lines of therapy. [Table: see text]