bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of prognostic biomarkers of response in patients with metastatic castration-resistant prostate cancer treated with abiraterone: A. C. Camargo Cancer Center experience.
Authors: Silveira Pedro Henrique Ferraro , Corassa Marcelo , Lourenço Abbade Dettino Aldo , Rinck José Augusto , Oliveira Thiago Bueno , Barbosa Luiza Damian Ribeiro , Oliveira Audrey , Formiga Maria Nirvana Cruz
Published: February 2018

335

Background: Despite therapeutic progress in the management of advanced prostate cancer during the past decade, metastatic castration-resistant prostate cancer (mCRPC) remains a disease that causes substantial morbidity and mortality worldwide. A greater understanding of biomarkers permits to guide personalized therapy and can inform clinical trials tailored to men most likely to derive benefit from a given therapy. We aimed to identify prognostic biomarker candidates of Abiraterone Acetate (AA) response in mCRPC patients. Methods: A retrospective clinical records analysis of mCRPC patients treated with AA at A. C. Camargo Cancer Center between January 2012 to December 2016 was realized. Baseline clinical parameters evaluated were: Age, ECOG performance status, metastatic disease at diagnosis, Gleason score, prostate-specific antigen (PSA), Neuroendocrine differentiation, duration of previous androgen-deprivation therapy (ADT), PSA doubling-time (PSAdt), Timing of AA (chemotherapy-naïve or not), PSA response and alkaline phosphatase (ALP) level. Data were analyzed in relation to progression free survival (PFS) stratified by each parameter. Results: We included 141 patients with mCRPC treated with AA to correlate prognostic biomarkers with PFS. Five risk factors individually were associated with poor prognosis and a high risk to progression during AA therapy and were included in the final model: ECOG ≥2 [Relative risk (RR) = 1.52]; PSAdt < 3 months (RR = 2.7); PSA response ( < 50% decline) (RR = 3.03); AA post docetaxel (RR = 1.63) and duration of previous ADT < 12 months (RR = 1.52). The probability to progression free survival in patients receiving AA calculated in 1, 2 and 3 years, was 39,2%, 15,2% and 6,2%, respectively. Conclusions: This analysis identified five factors used to model survival in mCRPC patients treat with AA in our institutional series. Whereas no biomarker has been validated as a predictor of response to a therapy in mCRPC, these those potential clinical biomarkers may help clinicians in distinguishing patients with mCRPC who would obtain the best survival benefit from AA treatment.
Molecular and histopathologic correlates of imaging and biological responses to neoadjuvant GnRH agonist plus enzalutamide for high risk prostate cancer.
Authors: Sowalsky Adam G. , Wilkinson Scott , Ye Huihui , VanderWeele David James , Turkbey Baris , Hennigan S. Thomas , Atway Rayann , Trostel Shana Y. , Lake Ross , Karzai Fatima , Harmon Stephanie , Chun Guinevere , Kelly Kathleen , Pinto Peter A. , Choyke Peter L. , Dahut William L.
Published: February 2018

34

Background: AR directed therapies are standard of care for metastatic prostate cancer, and their use for high-risk localized disease may improve survival. Previous trials showed low rates of complete pathologic responses to neoadjuvant ADT. The underlying biology and molecular features of tumors that fail to respond remain unknown. Methods: Men with localized prostate cancer with high risk features received 6 months of GnRH agonist plus enzalutamide. mpMRI was performed at baseline and prior to RP. MRI-US fusion guided biopsies were performed at study enrollment. RP specimens were sectioned in the same plane as mpMRI. Imaging and anatomical landmarks on pre- and post-treatment mpMRI were used to match targeted biopsies to RPs. IHC stains including AR, GR, and SYP were performed to guide laser capture microdissection (LCM) and characterization of residual disease. DNA was extracted from LCM biopsy and RP tissues. Whole exome sequencing with somatic mutation calling and copy number analysis was performed. Results: Most patients showed incomplete pathologic responses despite reductions in tumor volume. Several patients harbored multiple tumor clones prior to treatment, distinguished by distinct copy number alterations and mutations in biopsies. Alignment of biopsies to pre- and post-treatment mpMRI correlated with imaging response and histopathology of matched RP sections. Minimal genomic divergence from untreated clones on biopsy suggested intrinsic resistance, while extensive divergence indicated selection for pre-existing subclones. Most residual tumor was AR- and GR-positive adenocarcinoma, with some regions of AR-negative Panneth cell-like differentiation positive for synaptophysin. AR-V7 was rare in residual tumor and < 1% cells were positive for KI-67. The most common alteration in all samples was single-copy loss of chromosome 16q overlapping with ZFHX3. Conclusions: Our approach of repeated sampling by matching targeted biopsies to mpMRI demonstrates feasibility in comparing mpMRI response, pathologic treatment response, and the underlying genomic features that drive tumor development versus treatment resistance. Clinical trial information: NCT02430480.
Evolution of neuropsychiatric adverse events of enzalutamide and abiraterone acetate treatments reported in EudraVigilance in metastatic castration resistant prostate cancer patients.
Authors: Moreno Perez Maria Paola , Sanchez Iznaola Miguel , Garcia Angela , Muñoz del Toro Jacobo , Parra Rafael
Published: February 2018

343

Background: Abiraterone acetate plus prednisone (AAP) and enzalutamide (ENZ), oral hormonal treatment of metastatic castration resistant prostate cancer (mCRPC), can have neuropsychiatric impact. Methods: The Proportional Reporting Ratio (PRR) was used to analyze evolution of suspected adverse drug reactions (ADRs) reported in real world, in EudraVigilance from March to August 2017. Results: From the total ADRs of AAP and ENZ reported in Eudra from March to August 2017, 1,162 were related to AAP and 5,101 were related to ENZ. ADRs of ENZ reported in Eudra in August were higher than those reported in March 2017, in all the neuropsychiatry ADRs analyzed. In the case of AAP, 44% of the neuropsychiatric suspected ADRs analyzed did not show new cases reported and 56% of the ADRs shown an increase, although it was not higher than 15 new cases reported. Conclusions: In August 2017, the updated ADRs of AAP and ENZ from Eudra were consistent with those observed in March 2017 (Iznaola et al.). It confirms an increasing trend of reporting neuropsychiatric ADRs of ENZ in mCRPC. Suspected ADRs of AAP reported remained steady.[Table: see text]
Blood-brain barrier penetration of [14C]darolutamide compared with [14C]enzalutamide in rats using whole body autoradiography.
Authors: Zurth Christian , Sandmann Steffen , Trummel Dagmar , Seidel Dietrich , Gieschen Hille
Published: February 2018

345

Background: Darolutamide (ODM-201) (Daro) is an investigational oral and high-affinity androgen receptor antagonist. In preclinical studies, penetration of Daro through the blood–brain barrier (BBB) is negligible and in a retrospective safety analysis of the ARADES database for CNS-related adverse events (AEs), only 1 report of urinary incontinence was linked to Daro (Fizazi K, et al. 2015). Various clinical trials on enzalutamide (Enza) have reported CNS AEs (eg, seizure, falls, fatigue, pain). To understand the differences in CNS outcomes, we report an in vivo tissue distribution study with [14C]-labelled Enza and Daro in a head-to-head study in rats by means of quantitative whole-body autoradiography (QWBA). Methods: Male rats were orally dosed with 10 mg/kg [14C]Daro or [14C]Enza in the same formulation, administration volume, and radioactive dose. The animals were sacrificed at each drug’s specific tmax (time to reach the maximum concentration) in blood and brain and processed for QWBA. Results: At early time points [14C]Daro- and [14C]Enza-derived radioactivity was rapidly absorbed from the gastrointestinal tract and homogenously distributed throughout the body. By 8 h post dose, [14C]Daro was significantly eliminated from almost all organs/tissues, whereas [14C]Enza remained constant within the body. In contrast to [14C]Daro, high and persistent radioactivity was observed in brain for [14C]Enza. At tmax, the brain/blood-ratio of [14C]Enza was ~0.765, while [14C]Daro was about 10-fold lower at ~0.074. Conclusions: Results show that post dose, there was a 10-fold lower BBB penetration of [14C]Daro compared with [14C]Enza. At 8 h, [14C]Daro was rapidly eliminated and almost undetectable in all tissues, including brain, in contrast to [14C]Enza that remained constant. These data suggest that Daro might have a lower risk of inducing CNS-related AEs than Enza. Further clinical studies are ongoing.
Vimentin 3 and endothelin in prostate cancer.
Authors: Kohl Tobias , von Brandenstein Melanie , Stog Andreas , Schlosser Monika , Kuru Timur H. , Pfister David , Fries Jochen , Heidenreich Axel
Published: February 2018

349

Background: An upregulation of vimentin 3, a truncated version of the full length vimentin, with an unknown function, was previously described by our group, in a direct dependency of increased ET-1 levels. We analyzed now vimentin 3 in further genitourinary cancers. Here, we describe our findings how vimentin 3 is part of the signaling pathways from Endothelin-1 (ET-1) and the Endothelin-A-Receptor (ETAR) and how it correlates with aggressive tumor behavior in a PCa cell culture and in human tissue and serum samples from PCa patients. Methods: DU145 cells were cultured. We stimulated with ET-1 with and without artificial downregulation of the ETAR, the ETBR or both receptors. A scratch assay was performed to demonstrate the influence of ET-1. Proteins were then extracted and WB for vimentin full length and vimentin 3 was performed. Additionally we analyzed ET-1 and vimentin 3 in serum from prostate cancer patients using ELISA and we did IF and IHC staining for vimentin 3 in human prostate cancer tissue. Results: Treatment with ET-1 and downregulation of the ETBR lead to a significant increased migration of DU145 cells after 3 and 6 h. The corresponding WB showed increased vimentin 3. ELISA showed increased levels of ET-1 in samples of prostate cancer patients compared to patients with no cancer history. ELISA could also demonstrate elevated levels of vimentin 3 in serum of patients with local disease and significantly elevated values in metastatic prostate cancer patients compared to patients with no cancer history. Conclusions: The data presented shows that ET-1 stimulation leads to overexpression of vimentin 3 in prostate cancer cell cultures and a concomitant aggressive biological behavior. Here we previously described the direct interaction of Vimentin 3 in prostate cancer and the activation mechanism via ET-1 and the ETAR. IHC, IF show an upregulation of the truncated variant Vimentin3 in tissue samples. In an Vimentin 3 ELISA we could show that this truncated variant is increased and therefore represents a potential biomarker. Highest values of vimentin 3 were measured using ELISA in serum of patients with recurrent and metastatic disease also suggesting that vimentin 3 correlates with aggressive tumor behavior.
Effect of a tumor staging template on consistency and clarity of prostate cancer staging.
Authors: Nasseri Ryan , Levy Susan S , Cohen Edward , Dato Paul , Prime Hillary , Dijeh Uchey , Filicko James , Ball Catherine E , Gaylis Franklin
Published: February 2018

35

Background: Risk stratification (RS) is central in assessment and treatment of Prostate cancer (PCa). Accurate clinical staging (cT-Stage) based on AJCC criteria is a key component of RS and certain quality measures (PQRS #102). We assessed the potential of a tumor staging template (TST) embedded into an electronic medical record (EMR) to improve consistency and clarity of clinical tumor staging based on digital rectal examination (DRE) near the time of prostate needle biopsy (PNB). Methods: Retrospective analysis before TST implementation followed by prospective analysis after implementation of the TST was performed at Genesis Health Care Partners. Study period was January 1, 2017 through August 23, 2017. TST was implemented into the EMR and physicians were trained in its use on April 1, 2017. CT-Stage was independently categorized based on physicians’ notations. Descriptions of DRE included; confident-explicit (CE) (cT-Stage documented), confident-implicit (CI) (cT-Stage not documented, DRE amply detailed to interpret cT-Stage), and unconfident- inability to discern T-stage (UI). Classification categories prior to and after TST implementation were compared and analyzed using a chi-square test. Two cohorts were evaluated; men at risk for PCa undergoing PNB, and men with diagnosed PCa. Results: 573 PNBs were analyzed: 234/573 before TST (40.2%) and 339/573 after TST (59.8%). 305/573 (53.2%) PNBs were positive for PCa: 118 before TST and 187 after TST. In men at risk of PCa, CE staging increased from 15.8% to 57.8% (p < 0.001) after TST use. Overall staging (CE+CI) increased from 73.5% to 89.1% (p < 0.001), while UI staging decreased from 26.5% to 10.9% (p < 0.001) after TST use. In men with positive PNBs, CE staging increased from 28.8% to 62.6% (p < 0.001) after TST use. Overall staging (CE+CI) increased from 75.4% to 88.8% (p = 0.004), while UI staging decreased from 24.6% to 11.2% (p = 0.003) after TST use. Conclusions: In an era of precision-oriented medicine, accurate clinical tumor assessment, description, and staging is of great importance in RS and treatment recommendation. Our study demonstrates the ability of a standardized EMR-embedded, AJCC based template to improve the consistency and clarity of clinical staging of PCa.
Enhancer of zeste-homolog 2 (EZH2) expression and clinical outcomes in metastatic castrate resistant prostate cancer (mCRPC).
Authors: Giridhar Karthik , Costello Brian Addis , Sosa Carlos , Huang Haojie , Kohli Manish
Published: February 2018

350

Background: In prostate cancer, overexpression of EZH2 is associated with disease recurrence, androgen independent growth, cell invasion, and metastases. We evaluated the prognostic significance of EZH2 gene expression in metastatic biopsies from men with CRPC. Methods: EZH2 (RNA) expression was evaluated in two serial metastatic site biopsies in patients (pts) prior to treatment with abiraterone acetate and prednisone (pre-AA/P) and after 12 weeks of treatment (post-AA/P). All pts were enrolled and prospectively followed for clinical outcomes. The primary endpoint was overall survival (OS), defined as the time from CRPC to death or last follow-up. Cox proportional hazard regression analysis was performed on EZH2 expression using normalized fragments per kilobase million (FPKM) > 1 for association with OS and time to treatment failure (TTF). Results: Of 92 enrolled pts, 59 pts had (pre-AA/P) gene expression using RNA-seq, 45 had paired pre and post-AA/P RNA-seq available for analysis. In pre-AA/P samples, the median EZH2 expression was 4.82 FPKMs (range 1.05-38.8). Elevated expression of EZH2 was associated with shorter OS [hazard ratio (HR) 2.58, p = 0.016]. Radiographic progression at 12 weeks was more frequent in high EZH2 tumors compared to low EZH2 tumors (48% vs 20%, p = 0.03, Fisher’s exact test) No statistically significant associations were identified between EZH2 expression and TTF. In paired post-AA/P biopsies, EZH2 expression increased in 13/45 tumors and decreased in 32/45 tumors. The median log2 fold change in EZH2 expression was -1.38 (range -6.7 to 3.1). In post-AA/P biopsies, no associations were identified between an increase in EZH2 expression and OS or TTF. Conclusions: EZH2 expression represents a potential novel prognostic biomarker in mCRPC and warrants further exploration. Clinical trial information: 01953640.
Independent assessment of TP53 and PTEN as predictors of response to enzalutamide (ENZ) or abiraterone acetate (AA) in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Hahn Andrew W , Rathi Nityam , Gill David Michael , VanAlstine Sidney , Poole Austin , Agarwal Neeraj , Maughan Benjamin Louis
Published: February 2018

351

Background: Alterations in androgen receptor signaling are well-established mechanisms of resistance to medical castration. Pre-clinical studies suggest that alterations to key tumor suppressor genes, such as TP53 or PTEN, may also be associated with development of androgen independence as an alternate mechanism of castration-resistance. Previous studies have shown that TP53 inactivation and PTEN loss are predictive of response to novel androgen axis inhibitors. Here, we independently assess whether TP53 and PTEN genomic alterations are predictive of response to ENZ and AA in men with mCRPC. Methods: Clinical data and samples were analyzed from a prospective prostate cancer registry at the University of Utah (Salt Lake City, UT). Next-generation sequencing (NGS) was performed on predominantly primary tumor tissue for 343 somatic and germline genetic alterations using FoundationOne. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Patients with mCRPC who were treated with any line AA or enzalutamide were included. We performed a univariate analysis to assess the predictive value of TP53 and PTEN. Only patients treated with single-agent therapy were included. Results: Of 141 men with prostate cancer and NGS available, 56 were included. Most patients were treated with abiraterone (n = 50), and only 6 with enzalutamide. 28.6% had PTEN loss and 35.7% had a TP53 mutation. OS and PFS did not differ significantly according to PTEN or TP53 status. Median OS was 40.9 months and not reached for men with and without TP53 mutation (HR 1.85, p = 0.31). Median PFS was 7.5 months and 9.5 months for men with and without TP53 mutation (HR 1.18, p = 0.60). Median PFS was 7.2 months and 9.5 months for men with and without PTEN loss (HR 1.15, p = 0.66). Median OS for PTEN was not mature enough to analyze. Conclusions: In our independent cohort, neither TP53 mutation nor PTEN loss is predictive of response to androgen-directed therapy in men with mCRPC patients. However, this is a relatively small retrospective sample with few events. These results should be considered exploratory only.
A meta-analysis on individual data of bone-targeting radio-isotopes in men with bone metastases from castration-resistant prostate cancer.
Authors: Aarab Terrisse Safae , Parker Chris C. , Eleni Karamouza , Sartor A. Oliver , James Nicholas , Pirrie Sarah , Collette Laurence , Tombal Bertrand F. , Chahoud Jad , Smeland Sigbjørn , Erisktein Bjørn , Pignon Jean-Pierre , Fizazi Karim , Le Teuff Gwénaël
Published: February 2018

352

Background: Among bone-targeted radio-isotopes (RI), Radium-223 (an α-emitter) is the only one with clearly demonstrated overall survival (OS) benefit in men with castration-resistant prostate cancer (CRPC). The aim of this meta-analysis is to estimate the OS impact of RI in men with CRPC. Methods: An individual patient data meta-analysis was carried out from randomized trials with inclusion period 1993-2013. Eligible trials included more than 50 patients, mandated bone metastases from CRPC and randomly evaluated RI. Endpoints were OS (primary), symptomatic skeletal events (SSE) and toxicity. A fixed-effect model was used. The log-rank test stratified by trial was used to estimate individual and overall hazard ratios (HR). Subset analyses were performed by the type of radiation (α vs. β emission) and by trial comparison: RI + Chemotherapy (CT) vs. CT, RI+ External beam radiotherapy (EBRT) vs. EBRT, RI vs. EBRT. Results: From 9 identified trials, data from 6 trials comprising 2081 patients (min: 64, max: 921) were collected with 2 trials representing 80% of data. The data from 3 trials (n = 341) were not available. The overall effect on OS favoured RI with HR = 0.86 [0.77-0.95] but high heterogeneity between trials (p < 0.001, I2= 79.6%). The overall effect of α- emitters on OS (HR = 0.70 [0.58; 0.83], 2 trials, n = 985) significantly differed from that of β-emitters (HR = 0.96 [0.84; 1.10], n = 4 trials, n = 1096) (interaction p = 0.0041). The overall effect on SSE favoured RI with HR = 0.81 [0.69-0.93] (4 trials, n = 1806) with marked between trial heterogeneity (p = 0.08, I² = 55.3%) and a significant difference (p = 0.02) by the type of RI (α-emitters: HR = 0.65 [0.52-0.82]-2 trials, β-emitters: HR = 0.93 [0.77-1.13]-2 trials). Conclusions: In men with metastatic CRPC a significant improvement of OS and SSE was obtained with bone targeted α-emitter radio isotopes, but not with β-emitter. However, some between trial heterogeneity of effects on OS need further investigations.
Progression free survival in patients with castrate resistant metastatic prostate cancer: Does sequence matter?
Authors: Kase Adam McLain , Cook Cheryl , Tan Winston
Published: February 2018

356

Background: Approval of multiple therapeutic agents for castrate resistant prostate cancer (CPRPC) has improved survival and also quality of life. However, how to optimize sequencing is still an ongoing challenge for most clinicians. Methods: A retrospective chart review of patients treated with FDA approved regimens for castrate resistant prostate cancer from 2002 to 2017 at Mayo Clinical Florida was completed. Data on progression free survival of the various treatment sequences including abiraterone, docetaxel, and enzalutamide were reviewed. Results: One hundred patients were included in the study. Those on clinical trial were excluded. All patients were on LHRH agonist /antagonist and were continued while on the subsequent treatments. The first line therapy progression free survival (PFS) was 245 days with abiraterone acetate (AA), 307 days with enzalutamide (E) and docetaxel 285 days, respectively. The second line therapy PFS was 201 days with AA and 166 days with E. When AA was given after E PFS was 97 days and when E was given after AA the PFS was 68 days. E given after docetaxel resulted in a PFS of 390 days for one patient. Conclusions: In this chart review, enzalutamide had the longest PFS when used as the first line therapy and the PFS was improved when used as a second line after docetaxel. This retrospective review suggests therapy sequencing may be optimized to increase progressive free survival in patients with metastatic castrate resistant prostate cancer.
Inherited germline mutations in men with prostate cancer.
Authors: Reid Robert , DiGiovanni Marcie , Bernhisel Ryan , Brown Krystal , Saam Jennifer , Lancaster Johnathon
Published: February 2018

357

Background: Recent studies have demonstrated a high prevalence of pathogenic variants (PVs) in genes that confer hereditary cancer risk among men with metastatic prostate cancer (PC); however, PC does not currently receive attention as an indication for genetic testing. We assessed the clinical features of men with PC who received clinical testing as well as the distribution of PVs identified. Methods: Men with PC who underwent testing with a multi-gene hereditary cancer panel (Myriad Genetic Laboratories) from September 2013–September 2017 were included. Clinical information was obtained from provider-completed test request forms. Individuals with PC only were evaluated separately from those who had ≥1 additional malignancy. Personal/family history was evaluated relative to the 2013 NCCN guidelines for hereditary breast and ovarian cancer (HBOC) testing. Results: Overall, 1004 men with a personal history of PC were identified: 606 (60.4%) with only PC and 398 (39.6%) with PC and ≥1 additional malignancy. The most common additional malignancies were breast (136) and colorectal cancer (134). The median age of diagnosis in men with only PC was 59, which is younger than tested men who had an additional malignancy (63) and the SEER data (2009-2013) for all men with PC (66). HBOC testing criteria were met by 78.0% of men, including 68 (6.8%) who met based only on a personal/family history of PC and 330 (32.9%) who met in part due to a personal/family history of PC. PVs were identified in 12.9% of all men: 11.2% of men with PC only and 15.4% of men with PC and a second malignancy (Table). Conclusions: PC patients selected for genetic testing here were younger than men diagnosed with PC from the general population (SEER), and about a third had a diagnosis of an additional malignancy. They also have a high positive mutation rate across a broad spectrum of genes. [Table: see text]
Real world outcomes of upfront docetaxel for hormone naïve metastatic prostate cancer in an ethnically diverse inner-city population.
Authors: Pathak Surabhi , Thekkekara Romy Jose , Ahmed Ahmed T , Yadav Udit , Mullane Michael Russell , Batra Kumar Kunnal , Lad Thomas E. , Psutka Sarah P
Published: February 2018

359

Background: Upfront docetaxel (UD) in castration-sensitive metastatic prostate cancer (CSPC) has improved failure-free and overall survival in the CHAARTED, GETUG-AFU 15 and STAMPEDE trials, resulting in a paradigm shift in practice patterns. However, the impact of docetaxel-based chemotherapy regimens in minorities and in real-world practice remains to be described. The objective of this study is to evaluate tolerability and response to UD in an inner-city ethnically diverse CSPC cohort. Methods: We retrospectively reviewed clinical data for CSPC patients at Cook County Hospital. Patients treated with UD and androgen deprivation (UD, n = 49, 2013-17) were compared to those receiving androgen deprivation alone (ADT, n = 42, 2010-17) using descriptive statistics and Cox Proportional Hazards analysis. Results: Median age was 59 and 60 years in UD and ADT, respectively. African Americans, Hispanics and Caucasians formed 69%, 18%, and 10% in UD and 64%, 9.5% and 26% in ADT. Median PSA at diagnosis was: UD 536 [72-1110] ng/ml, ADT 229 [54-999] ng/ml (p = 0.3). Gleason score > 7 was present in 89.8% [UD] and 92.8% [ADT]. UD and ADT had similar frequency of bone (91% vs. 95%, p = 0.5), visceral (12.2% vs. 11.9%, p = 0.9) and retroperitoneal nodal metastases (55% vs. 45.2%, p = 0.3). UD was initiated a median of 8 weeks from diagnosis. 94% in UD received > 3 cycles of chemotherapy. CTCAE grade > 3 events included anemia (6%); neutropenia (6%); infection (4%); diarrhea (4%); peripheral neuropathy (6%), and fatigue (2%). Median PSA nadir was 3.2 [0.5-40.1] vs. 3.45 [0.1-36.4] ng/ml and time to nadir was 20 [13-27] vs. 41 [19-69] weeks in UD vs. ADT. Biochemical progression was observed in 34.7% [UD] vs. 40.5% [ADT]. Median time to castration-resistance was UD: 39 [31-67] vs. ADT: 65 [34-76] weeks [HR: 0.9; 95% CI 0.4-1.8; p = 0.7]. There were 12 deaths [UD: 4; ADT: 8] during a median follow-up of 46 [23-86, UD] and 111 [68-157, ADT] weeks. Conclusions: In a diverse underserved population with CSPC, UD was well tolerated but was not associated with improvement in time to castration compared to ADT. These results warrant validation and underscore the importance of ensuring accrual of minorities in clinical trials.
Evaluation of a predefined AS threshold in a large cohort of men with localized prostate cancer.
Authors: Canter Daniel , Reid Julia E. , Latsis Maria , Variano Margaret , Halat Shams , Gurtner Kristen E. , Brawer Michael K. , Stone Steven , Bardot Stephen
Published: February 2018

36

Background: Men with newly diagnosed, localized prostate cancer (PC) have historically been selected for active surveillance (AS) using clinicopathologic features. However, a clinical cell−cycle risk (CCR) score has been developed to include both molecular [cell cycle progression (CCP) RNA signature] and clinical [Cancer of the Prostate Risk Assessment (CAPRA)] features. Previous validations have demonstrated that this combined CCR score provides improved prognostic information relative to molecular or clinical features alone. As such, a CCR threshold score has been recently developed and validated to identify men with low−risk disease who may be candidates for AS. Here, we have evaluated the performance of the AS threshold in a contemporary cohort of men with newly diagnosed localized PC. Methods: Men with localized adenocarcinoma of the prostate who were treated at the Ochsner Clinic between 2006 and 2011 (4 patients were diagnosed in 2012−2014) were evaluated. Formalin−fixed paraffin embedded biopsy tissue and was analyzed for the RNA expression of 46 genes to obtain a CCP score. The CCR score was calculated as (0.57xCCP) + (0.39xCAPRA). A CCR score threshold of 0.8 has been previously validated in a cohort of conservatively managed men. Men with a CCR score equal to the threshold had an estimated 10−year disease−specific mortality risk of 3.3%, while men with scores below the threshold had a 2.7% risk. Results: Complete molecular and clinical information were available for 767 men with a median clinical follow−up time of 5.6 years measured from date of diagnosis. Overall, 217 men had CCR scores ≤ 0.8. Of these, 125 were treated by radical prostatectomy, 61 with radiation, 2 with radiation with hormones, 2 with hormones only, and 19 with watchful waiting. Treatment for eight men was unknown. One patient (0.5%) with a CCR score below the AS threshold progressed to metastatic disease, and was initially treated with radiation. Conclusions: We evaluated the performance of a previously validated AS threshold on a contemporary US cohort. Although the majority of the patients in this study were treated, the observed metastatic event rate of 0.5% supports that the CCR threshold can be safely used to identify candidates for AS.
Is it the time to shift paradigms in castration naïve prostate cancer (CNPC): A meta-analysis of upfront docetaxel and abiraterone in men with CNPC.
Authors: Sun Guangxi , Zhang Xingming , Chen Junru , Liao Banghua , Zhao Jinge , Shen Pengfei , Zeng Hao
Published: February 2018

360

Background: To systematically review the relevant literature evaluating the therapeutic efficacy of upfront docetaxel (Doc) or abiraterone (Abi) plus androgen deprivation therapy (ADT) on oncological outcome in patients with CNPC. An attempt to identify subgroups of patients who will benefit most either from Doc or Abi plus ADT and further compare the efficacy and safety between these two combination therapies. Methods: A comprehensive search of the PubMed/Medline, Embase databases, ICTRP, Clinical Trial and Cochrane Central Register of Controlled Trials to July 2017 was performed. Results: Six studies involving 6480 patients were included in this meta-analysis, consisting of over sixty percent (4462/6480) of patients with metastatic CNPC (mCNPC, M1), and 31.1% (2018/6480) of patients with non-metastatic CNPC (M0). Totally, combination therapies (ADT plus Doc or Abi) significantly improved overall survival (OS) and failure-free survival (FFS) for all CNPC patients. For M1 patients, combination therapies were dramatically associated with improved OS and FFS, but for M0 patients, only with moderate improvement in FFS. M1 patients with age < 70 years, ECOG performance status (ECOG PS) 0-1, Gleason score ( < 8) or visceral metastases could get better survival benefit from either combination therapies. In indirect comparisons, among M1 patients with younger age ( < 70 years), ECOG PS 0-1 or aggressive Gleason score (GS ≥ 8), upfront Abi showed superiority to Doc in prolonging FFS. The incidence of severe adverse events (AEs ≥ 3) was comparable between these two therapeutic regimens. Conclusions: Upfront Doc or Abi plus ADT should be considered as a standard of care for mCNPC patients who are suitable for either or both of these combination therapies.
Preclinical efficacy of dendritic cells derived from bone marrow hematopoietic stem cells for the treatment of syngeneic prostate cancer immune cell therapy.
Authors: Kim Yunlim , Kim Choung-Soo , Kim Bongmin
Published: February 2018

361

Background: PCas are characterized by a primary androgen dependent stage, during which growth is promoted by androgen and suppressed by androgen deprivation or blockade, with even metastatic disease being promptly susceptible to hormonal manipulation; however, despite initial success, androgen deprivation therapy eventually fails because of the development of CRPC. Despite the approval of new clinical trials such as docetaxel, enzalutamide and sipuleucel-T, which is a cell therapy drug, the clinical efficacy is limited. Therefore, there is a desperate need for the limited effectiveness of treatment in an aging society and the development of successful treatments for patients who fail treatment. In this study, we investigated the anticancer effect of prostate cancer using anti-cancer immunity cell vaccine based on the next generation dendritic cell immunotherapy. Methods: FACS and ELISA were performed with stem-DC to analyze phenotype and cytokine expression. To quantify the effect on the tumor growth, we constructed a TRAMP-C1 model and observed for safety, efficacy and induction of antigen-specific immune responses. And we also analyzed proliferation and activation of allogeneic-T cells by therapeutic dendritic cells. Results: From the stem-DC, immune-stimulatory cytokine IL-12 and interferone-gamma was measured higher level than monocyte derived DC (Mo-DC). A DC marker CD11c+CD8a+ cell was higher expression in stem-DC than Mo-DC. After DC injection, tumor size was reduced in stem-DC compared to Mono-DC and vehicle group in TRAMP model. To confirm stem-DC/lysate induce more systemic anti-tumor immunity than Mo-DC/lysate, we checked effector T cells in splenic lymphocytes from prostate cancer bearing mice. The frequency of IFN-γ secreting CD8+ T cells in stem-DC treated group was significantly higher than that in Mo-DC treated group. It shows that the therapeutic responses were associated with induction of IFN-γ secreting CD8+ T cells. Conclusions: Stem-DC, which was developed from hematopoietic stem cells in an optimized manner, proved to be effective and stable as an excellent anti-cancer immunotherapeutic agent for prostate cancer.
A phase II study of itraconazole in biochemically recurrent prostate cancer.
Authors: Lee Mina , Hong Haemin , Kim Won , Friedlander Terence W. , Fong Lawrence , Lin Amy M. , Small Eric Jay , Dhawan Mallika Sachdev , Wei Xiao X. , Rodvelt Tammy J. , Miralda Brigid , Ryan Charles J. , Aggarwal Rahul Raj
Published: February 2018

362

Background: A subset of patients (pts) with biochemically recurrent prostate cancer (BRPC) are at risk for metastasis and lethal outcomes, yet many pts wish to defer or avoid androgen deprivation therapy in this setting. Itraconazole has previously demonstrated anti-tumor activity in castration-resistant prostate cancer independent of modulation of circulating androgen levels. We therefore evaluated itraconazole in a phase 2 study in BRPC as a potentially non-castrating treatment approach. Methods: Pts with BRPC and PSA doubling time (PSADT) ≤ 15 months, without metastases on conventional imaging (whole body bone scan + CT/MRI of the abdomen/pelvis), were enrolled in a single arm phase 2 study. Itraconazole was dosed at 300 mg PO BID until PSA progression by PCWG2 criteria, unacceptable toxicity, or pt withdrawal. The primary endpoint was the proportion of pts who achieved ≥ 50% decline from baseline in serum PSA after 12 weeks of protocol therapy. Secondary endpoints included change in PSADT, adverse events (AEs) by CTCAE version 4.0, and change in serum androgens (including testosterone (T) and androstenedione (ASD) from baseline to week 12. Results: 21 pts were enrolled. The median age was 72 (range 54-76), median baseline PSA was 7.6 ng/mL (range 1.5 – 45.5), and median PSADT was 5.7 months (1.2 – 13.0). Median baseline serum T was 336 ng/dL (165-626). Among the 19 evaluable pts, 9 pts (47%) experienced a PSA decline (mean decline 25.0 %, range 2 – 60 %) by week 12, including one patient (5%) with > 50% PSA decline. Among the 10 pts without a PSA decline, the mean on-treatment vs. pre-treatment PSADT was numerically longer (13.2 vs. 4.8 months, p = 0.17). There was no significant change from baseline to week 12 serum T (mean change = 1.9%, p = 0.77) or ASD levels (mean change = 6.1%, p = 0.83). The most common grade ≥ 3 AE was hypertension (29%); hypokalemia of any grade was also common (24%). Conclusions: Itraconazole can modulate serum PSA levels without lowering serum T in pts with BRPC. However, the magnitude of effect is modest and treatment carries an appreciable risk of toxicities related to mineralocorticoid excess. Exploration of the relationship between mineralocorticoid-related AEs, itraconazole drug levels, and clinical outcomes is ongoing. Clinical trial information: NCT01787331.
Circulating estrogen receptor (ER) mutations and splice variants in men with advanced prostate cancer (APC).
Authors: Qu Liang , Sluka Pavel , Wardan Hady , Davis Ian D. , Pezaro Carmel Jo
Published: February 2018

363

Background: Circulating DNA and RNA have been studied in APC as biomarkers of potential clinical significance. Candidates include androgen receptor amplification or emergence of splice variants. ER signalling has been associated with prostate cancer progression in vitro but blood-based detection of ER variants has not been studied. Methods: Men with APC were recruited for serial blood collection during routine management, from which cell-free DNA (cfDNA) and cell-free RNA (cfRNA) were extracted. Six well-described ERα mutations (E380Q, L536Q, Y537C, Y537S, Y537N & D538G) and six ER splice variants (ERα-66, ERα-36, ERβ1, ERβ2, ERβ4 & ERβ5) were quantitated using droplet digital polymerase chain reaction. These markers were explored in association with clinical and treatment variables using descriptive statistics. Results: 44 men were included for a total of 92 cfDNA and 94 cfRNA samples, with a median of 2 (range: 1-6) sequential samples per patient. Two mutations (E380Q & D538G) were detected in both cfDNA and cfRNA samples, and two (L536Q & Y537S) were detected in cfRNA samples only. The ER splice variants were widely detected in cfRNA samples, including in non-cancer controls. ERα-36 was detected at lower levels than the other splice variants investigated (p < 0.0001). Despite ubiquitous detection, the levels of splice variants altered consistently with analysis of the following clinical variables: during castration therapy; following castration resistance; and with number of previous treatments. No clear patterns of expression were observed for ER mutants. Serial sample analysis associated increased ERα-36 levels with response to docetaxel or abiraterone therapy. ERβ splice variant levels decreased with progression on all studied therapies. Development of E380Q and L536Q mutations was observed in patients with disease progression. Conclusions: We identified circulating ER mutants and splice variants in men with APC. These variants may be associated with previous treatment use, as well as disease progression on castration therapy or other APC treatments. Further work will explore their utility for predicting treatment response.
Contemporary trends in abiraterone and enzalutamide prescription by provider specialty.
Authors: Pucheril Daniel , Wang Ye , Zlatev Dimitar V. , Nguyen Paul L. , Kibel Adam S. , Chang Steven Lee
Published: February 2018

366

Background: Androgen deprivation therapy (ADT) with LHRH-agonists and anti-androgens, is established in the management of prostate cancer and is administered by urologists, medical oncologists, and radiation oncologists. Newer agents for ADT, abiraterone acetate (ABI) and enzalutamide (ENZA) were approved by the FDA in 2011 and 2012, respectively, for the management of metastatic castrate resistant prostate cancer (mCRPC) after failing chemotherapy. We evaluated the contemporary economic burden of ABI and ENZA and their adoption by specialty. Methods: Because a majority of men with mCRPC are > 65 years of age, we utilized Medicare Part D data from 2013-15. The specific outcome variables of interest included the aggregate reimbursement and total number of prescriptions for ABI and ENZA, by specialty. Descriptive statistics and trend analysis were performed. Results: From 2013-15, the total number of prescription rose from 52457 to 81058 for ABI and from 17141 to 69181 for ENZA. Though medical oncologists prescribed more than 75% of ABI/ENZA prescriptions each year, the proportion of prescriptions written by urologists increased annually. The greatest increase in the percentage of prescriptions originating from urology occurred from 2013-2014 for ABI (3.96% to 8.62%) and from 2014-15 for ENZA (5.42% to 15.64%); meanwhile, prescriptions by radiation oncology were negligible throughout the study. Southern states accounted for greater than one third of ABI and ENZA prescriptions. By 2015, the aggregate reimbursement of Part D claims for ENZA and ABI was $790 million each. Among all medication claims, ENZA and ABI represent the 29th and 30th most expensive by aggregate cost. Conclusions: While medical oncologists account for the vast majority of ENZA and ABI prescriptions, the prescriptions by urologists is increasing while prescriptions by radiation oncologists remain negligible. Though approved for mCRPC patients, ENZA and ABI are already among the costliest medications covered by Medicare. As Level 1 indications for the use of these medications increase and now include castrate-sensitive patients, further study should be directed at determining optimal timing and indication for prescription.
Combination of selective polo-like kinase 1 (PLK1) inhibitor PCM-075 with abiraterone in prostate cancer and non-androgen-driven cancer models.
Authors: Patterson Jesse Christopher , Varmeh Shohreh , Erlander Mark G. , Yaffe Michael B.
Published: February 2018

369

Background: The majority of metastatic castration-resistant prostate cancer (mCRPC) patients will become resistant to abiraterone. Drug combinations with abiraterone offer the possibility to extend patient benefit to anti-androgen therapy. PLK1, an essential mitotic kinase for onset of G2/M transition and cytokinesis, is over-expressed in prostate cancer, correlated positively with Gleason grade and PLK1 RNAi induces G2/M arrest and apoptosis in prostate cancer cells. PCM-075 (formerly NMS-1286937) is a potent, highly selective PLK1 inhibitor currently in clinical trials for the treatment of acute myeloid leukemia. Combination of PCM-075 with abiraterone was examined in mCRPC models and other cancer types for synergistic interaction. Methods: We used a variety of tumor cell lines (C4-2, LNCaP, BT-20, AU565, SK-OV-3), animal and computational modeling techniques to elucidate the mechanism and assess the potential clinical utility of synergistic tumor cell killing by PLK1 inhibitors (PLK1i), including PCM-075, with abiraterone. Results: Synergy was observed between abiraterone and PLK1i, including PCM-075, in models of CRPC (C4-2). In addition, PLK1i and abiraterone were synergistic in murine C4-2 xenografts. Unexpectedly, PLK1i sensitized a subset of non-prostate cancer cells to abiraterone, including AR-negative breast and ovarian cancer cells. In contrast to PLK1i, other mitotic arrest agents do not synergize with abiraterone. To elucidate the molecular basis this synergy, we screened a panel of cell lines and implemented a new computational method that links RNA expression patterns to drug combination synergy. This analysis implicated signaling through the retinoic acid (RA) nuclear receptors as a component of this synergy, which was validated experimentally. Increased basal expression of genes involved in RA metabolism in cancer cells is associated with increased synergy. Conclusions: Abiraterone has AR-independent effects that provide a mechanism and biomarkers predictive for synergistic killing when combined with the PLK1i PCM-075. This combination has potential to extend mCRPC patient benefit to abiraterone regardless of AR status.
Initial whole blood-based gene expression profile assays in mCRPC pts.
Authors: Tsumagari Koji , Miller Patrick , Moses Marcus Marie , Ledet Elisa , Sartor A. Oliver
Published: February 2018

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Background: Although second generation androgen receptor (AR) targeting therapy, abiraterone (Abi) and enzalutamide (enza), improve therapeutic effect for patients of mCRPC, acquired resistance occurs. Biomarkers are clearly needed to predict the efficacy of AR targeting drugs for mCRPC patients and much work is occurring on this important issue. Circulating tumor cells are attractive biomaterials because of non-invasive collecting methods. In this study, we assessed whole blood RNA as a non-invasive methodology to access biomarkers of potential interest. Methods: We used whole blood (~5mL) preserved in PAXgene tubes from 10 patients (pts) with mCRPC with acquired resistance following Abi and 11 controls without prostate cancer. Total RNA was extracted followed by qRT-PCR for assessment of 10 transcripts including ARV7, HOXB13, GHLR2, KLK3, KLK2, FOXA1, SchLAP1, KIF2C, MIA, and NCAM1. All amplicons were normalized to β-actin. Results: ARV7 (2/10), GRHL2 (2/10), HOXB13 (4/10), KLK3 (7/10), and KLK2 (4/10) amplicons were detected only in the mCRPC prostate pts. FOXA1 (7/10) and SchLAP1 (3/10) amplicons were detected in mCRPC pts at higher concentrations in mCRPC pts as compared to controls ( p< 0.001 and p = 0.02, respectively). In contrast, KIF2C (5/11), MIA (11/11), and NCAM1 (11/11) amplicons were present in pts but in lower concentrations in mCRPC as compared to controls (p = 0.03, p< 0.001, and p< 0.001, respectively). Conclusions: We identified 5 transcripts that can be detected from whole blood RNA assays only from PCa pts, additional transcripts were expressed at higher or lower concentrations as compared to controls. Although this is a small cohort, these findings highlight the potential role for whole blood RNA to assess mCRPC pts.
Combination of carboplatin (AUC4) and cabazitaxel (25 mg/m2) in mCRPC patients not or no longer responding to cabazitaxel monotherapy.
Authors: Louhanepessy Rebecca , van Rijssen Margriet , van der Noort Vincent , Bergman Andre M.
Published: February 2018

371

Background: Cabazitaxel monotherapy is a second line treatment option for mCRPC patients. However, not all patients have a PSA response on this treatment, while a proportion of patients develop resistance during cabazitaxel treatment. Platinum drugs might be effective in poorly differentiated disease. Ongoing trials suggest effectivity of the combination in mCRPC, however, thus far clinical parameters cannot predict a response. Therefore, we investigated the addition of carboplatin to cabazitaxel in mCRPC patients who do not have a psa response on cabazitaxel monotherapy or have a PSA rise during treatment. Methods: 19 patients (WHO PS ≤2) who were not responding to ≥2 cycles cabazitaxel monotherapy (25 mg/m2) or two rises of PSA during cabazitaxel were included in this prospective cohort study. All patients received the combination of carboplatin (AUC 4) and cabazitaxel (25 mg/m2). Previous therapies, PSA response, WHO performance score, Progression Free Survival (PFS), Overall Survival (OS) and adverse events were monitored. Results: Median age was 66.7 years, 21% of patients had a WHO PS of 2, 68% had a Gleason score ≥8, 74% had bone metastases, 63% lymph node metastases and 26% visceral metastases. All patients received docetaxel prior to cabazitaxel, 6 patients (31,6%) received abiraterone and 15 patients (78,9%) enzalutamide. Combination therapy was initiated after a median of 4.1 cycles monotherapy [IQR 3.0-6.0]. Patients were treated with a median of 3.8 [IQR 2.8-6.3] cycles of combination therapy. Eight patients (42,2%) had a PSA decrease of > 25% and 4 patients (21,1%) had a PSA decrease of ≥50%. One patient had a WHO PS improvement of 2. Median PFS was 8.1 [IQR 6.0-15.1] months and median OS 13.0 months. Anemia was the most common adverse event (≥ grade 2) during combination therapy (62%), while thrombopenia was only found in one patient (5%). Other common adverse events were fatigue (43%), nausea (24%), pain (33%) and constipation (10%). Conclusions: Our data suggests that combination treatment of cabazitaxel and carboplatin might be effective in heavily pretreated patients not, or no longer responding to cabazitaxel monotherapy.