bluuebunny/crossref_metadata_2025_split huggingface dataset:
Eltanexor (KPT-8602), a second-generation selective inhibitor of nuclear export (SINE) compound, in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Zhang Jingsong , Chism David D. , Tagawa Scott T. , Monk Paul , Alter Robert S. , Reichman William , Senapedis William , Baloglu Erkan , Shacham Sharon , Kauffman Michael G. 
Published: March 2019

197 Background: Overexpression of exportin 1 (XPO1) in malignant cells increases the nuclear export/inactivation of tumor suppressor proteins (eg. p53), and promotes the translation of eIF4E-bound oncoprotein mRNAs (eg. c-MYC). XPO1 inhibition reduces total androgen receptor levels, including ARv7, and may re-sensitize prostate cancer (PC) cells to androgen deprivation therapy. Selinexor, the first-in-human SINE compound, showed anticancer activity in patients (pts) with mCRPC. Eltanexor (ELTA), a second-generation SINE compound, showed promising anticancer activity in preclinical models of PC, including in abiraterone (ABI) resistant cell lines. Therefore, ELTA ± ABI was evaluated in mCRPC. Methods: This was part of a phase 1/2 study to determine the safety, preliminary efficacy, and recommended phase 2 doseof ELTA in pts with advanced cancers. Pts with mCRPC received oral ELTA once daily for 5 days per week over a 28-day cycle in 4 cohorts: single-agent (20 mg; n=7 or 30 mg; n=6) or in combination with ABI (20 mg; n=13 or 30 mg; n=4). Pts may have prior exposure to chemotherapy. Pts receiving ELTA + ABI had prior response to ABI then progressed. Response was evaluated by PCWG3 / RECIST v1.1. Results: As of 17 Sept 2018, 30 pts were treated with ELTA ± ABI with a median age of 71 and a median of 4 prior regimens; (87% ABI, 60% enzalutamide, and 57% chemotherapy). Twenty-one pts with mCRPC were evaluable for efficacy: 2 partial response (10%), 15 stable disease (71%), and 4 progressive disease (19%). The median treatment duration is 75.5 days; 4 pts still on treatment. Treatment-related adverse events (TRAEs) occurring in ≥30% of the pts: fatigue (67%; 13% Gr≥3), nausea (63.3%; 0% Gr≥3), decreased appetite (57%; 0% Gr≥3), diarrhea (47%; 3% Gr≥3), weight decreased (43%; 3% Gr≥3), vomiting (37%; 7% Gr≥3), anemia (33%; 7% Gr≥3), and dysgeusia (33%; 0% Gr≥3). The 2 Gr4 TRAEs were neutropenia and elevated AST. Conclusions: ELTA± ABI is well-tolerated with AEs mostly limited to Gr 1/2 and demonstrates preliminary anti-tumor activity in patients with mCRPC. With enrollment complete, these results warrant further investigation of ELTA ± ABIin mCPRC. Clinical trial information: NCT02649790.
Outcomes of the patients with pT0 on first protocol biopsy during active surveillance for early prostate cancer: From the PRIAS-JAPAN study.
Authors: Kato Takuma , Sugimoto Mikio , Kakehi Yoshiyuki , Yamaguchi Akito , Yokomizo Akira , Shinohara Nobuo , Matsumoto Ryuji , Mitsuzuka Koji , Kume Haruki , Nakamura Masaki , Egawa Shin , Sasaki Hiroshi ,   PRIAS JAPAN Study Group
Published: March 2019

20 Background: We assessed the outcomes of the patients with pT0 on first protocol biopsy during active surveillance(AS) from the analysis Japanese cohort forming part of the Prostate Cancer Research International: Active Surveillance (PRIAS) study. Methods: PRIAS-JAPAN started in January 2010. 39 institutions are participating in this study. The inclusion criteria for the PRIAS study are as follows: clinical stage T1c/T2, PSA ≤ 10 ng/ml, PSA density (PSAD) < 0.2 ng/ml per milliliter, one or two positive biopsy cores, and Gleason score (GS) ≤ 6 at initial diagnostic biopsy.In this analysis, we defined the patients presenting no reclassification with cancer after first protocol biopsy as NR-CA group and the patients presenting no reclassification showing pT0 as NR-noCA group. We compared AS remaining rate, pathological outcomes in extra biopsy and second protocol biopsy at 4 years between two groups. Results: First protocol biopsy was performed on 514 patients. 191 patients were in NR-noCA group and 199 patients were in NR-CA group. Patients background of NR-noCA group was as follows: Median age was 68, median PSA was 5.6ng/ml, and median prostate volume was 38.4cc. T1c were in 183 and T2a were in 8. At the time of first protocol biopsy, there was no significant differences about PSA parameters and pathological factors between NR-noCA group and NR-CA group. Also, extra biopsy performing rate (NR-noCA group vs NR-CA group; 5.75% vs 7.53%) and implementation rate of second protocol biopsy at 4 years (75.6% vs 63.6%) showed no significant differences. On second protocol biopsy, number of cancer positive cores were significantly smaller and rate of pT0 was higher in NR-noCA group. After five years, both group showed comparable AS remaining rate (76.9 vs 75.3%). Thirty eight patients of NR-noCA group selected definitive therapy and surgery was the most frequently chosen treatment option. Conclusions: Although rate of pT0 on second biopsy was higher in NR-noCA group, there was no significant difference between both groups in AS remaining rate. The patients in NR-noCA group tended to choose surgery as a definitive therapy. Clinical trial information: UMIN000002874.
Prostate cancer-derived anti-GRP78 autoantibodies compromise the blood-brain barrier and accelerate atherosclerosis progression in vivo.
Authors: Al-Hashimi Ali , Shayegan Bobby , Austin Richard , Won Kevin Doyoon 
Published: March 2019

205 Background: Pathological conditions of prostate cancer (PCa) drive the translocation of the endoplasmic reticulum-resident chaperone, GRP78, to the cell surface (cs) where it acts as an antigenic protein with signaling properties. In PCa, csGRP78 drives the production of anti-GRP78 autoantibodies (AutoAbs) that engage csGRP78 and promote PCa survival/progression. New studies now demonstrate csGRP78 expression on endothelial cells (EC) that line the arterial vasculature and the blood-brain barrier (BBB) suggesting that these AutoAbs can affect other systems in the body. Based on this, we investigated how the engagement of anti-GRP78 AutoAbs to csGRP78 on EC can contribute to EC-dysfunction that can promote atherosclerosis and compromise the integrity of the BBB. Methods: Anti-GRP78 AutoAbs were purified from PCa patients (St. Joseph’s Healthcare Hamilton); human aortic EC and the ApoE -/- mouse model were used for in vitro and in vivo investigations, respectively. EC or mice were treated with anti-GRP78 AutoAbs or IgG control (60µg/mL); EC-dysfunction was investigated by measuring attachment protein expression, in vitro. In vivo evaluation was carried out by studying atherosclerotic plaque progression (immunohistochemistry; aorta); the BBB integrity was examined using the Evans Blue dye. Results: Mice injected with anti-GRP78 AutoAbs, and not human IgG, demonstrated larger atherosclerotic plaque volume and hallmarks of a leaky BBB. In terms of a mechanism, in vitro studies demonstrated that treating EC with anti-GRP78 AutoAbs resulted in activation of the NFκB pathway that led to increased expression of attachment proteins. All these effects were reversed by using a recombinant molecule that interfere with the binding of the AutoAb to csGRP78. Conclusions: We have identified anti-GRP78 AutoAb as a driver of EC-dysfunction that promote atherosclerotic plaque progression and damage to the BBB. Our results indicate that interfering with anti-GRP78 AutoAb:csGRP78 complex can reverse the pathological effects of the AutoAbs. This novel data suggests that patient-derived anti-GRP78 autoantibodies systemically drive pathologies, other than cancer, in vivo.
Overall survival by race in chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone acetate or enzalutamide.
Authors: McNamara Megan Ann , George Daniel J. , Ramaswamy Krishnan , Lechpammer Stanislav , Mardekian Jack , Schultz Neil M. , Wang Li , Baser Onur , Huang Ahong , Freedland Stephen J. 
Published: March 2019

212 Background: Prostate cancer (PC) is the most common malignancy among US men and the 2nd leading cause of cancer-related death. African Americans (AAs) have higher mortality from mCRPC than Whites (W). Despite this disparity, a small prior study suggested AAs may have better PSA response to abiraterone acetate (ABAC) than Ws, though radiographic progression did not differ. We evaluated overall survival (OS) in AA vs W chemotherapy-naïve (CN) mCRPC patients (Ps) treated with ABAC or enzalutamide (ENZ). Methods: This was a retrospective study that used the Veterans Health Administration (VHA) database. Male PC Ps (≥18 years) who had surgical or medical castration were identified from Apr 1, 2013 to Mar 31, 2018. The index date was the first prescription claim date for ABAC or ENZ following castration. Ps had no chemotherapy for 12 months pre-index date and had continuous VA health plan enrollment for ≥12 months pre- and post-index date. Ps were followed until death or disenrollment. Unadjusted and Kaplan-Meier survival analyses adjusted for demographic and clinical characteristics were used to calculate survival time, and multivariate Cox proportional hazards models assessed the relationship between race and OS. Results: This study included 2,123 W and 787 AA mCRPC Ps with mean ages of 74 and 71 years, respectively. The median follow‐up time was 570 days and 561 days for AA and W, respectively. AA were more prone to comorbid hypertension (77.1% vs 67.1%; p<.0001), type II diabetes (38.1% vs 29.3%; p<.0001), and liver damage or abnormality (8.8% vs 5.2%; p=0.0003) than W . From the unadjusted analysis, the median Kaplan-Meier estimated OS was 910 days for AAs and 784 days for Ws; AAs had better OS than Ws (HR=0.887; 95%CI [0.790-0.996]). From the adjusted analysis, the median Kaplan-Meier estimated OS was 918 days for AAs and 781 days for Ws; AAs still had better OS (HR=0.826; 95%CI [0.732-0.933]). Conclusions: This large retrospective study provides the first evidence that AA CN mCRPC Ps may have better OS with ABAC or ENZ than W Ps. Trials are needed to validate this finding and explore the mechanisms of racial disparities in outcomes with new hormonal therapies.
Pembrolizumab for metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel: Updated analysis of KEYNOTE-199.
Authors: Antonarakis Emmanuel S. , Goh Jeffrey C. , Gross-Goupil Marine , Vaishampayan Ulka N. , Piulats Josep M. , De Wit Ronald , Alanko Tuomo , Fukasawa Satoshi , Tabata Kenichi , Feyerabend Susan , Berger Raanan , Wu Haiyan , Kim Jeri , Poehlein Christian Heinrich , De Bono Johann S. 
Published: March 2019

216 Background: Previously presented data from cohorts (C) 1-3 of the phase 2 KEYNOTE-199 study (n = 258; NCT02787005) showed that pembrolizumab monotherapy had antitumor activity and acceptable safety in patients (pts) with mCRPC previously treated with next-generation hormonal agents (NHAs; eg, abiraterone, enzalutamide) and docetaxel. Activity was observed for both PD-L1–positive and negative cohorts and in RECIST-measurable and bone-predominant disease. We present data from KEYNOTE-199 C1, C2, and C3 based on longer-follow-up. Methods: C1 enrolled 133 pts with RECIST-measurable, PD-L1–positive disease, C2 enrolled 66 pts with RECIST-measurable, PD-L1–negative disease, and C3 enrolled 59 pts with nonmeasurable, bone-predominant disease. All pts had ECOG PS 0-2 and received ≥1 NHA and 1-2 prior chemotherapies including docetaxel. Pembrolizumab 200 mg Q3W was given for 35 cycles or until PD or intolerable toxicity. Response was assessed Q9W in yr 1, then Q12W. Primary end point was ORR per RECIST v1.1 by central review. Key secondary end points included DCR (CR + PR + SD ≥6 mo), duration of response (DOR), OS, and safety. Results: Median follow-up as of Aug 21, 2018, was 9.5 mo in C1, 7.9 mo in C2, and 14.1 mo in C3. ORR (95% CI) was 5% (2-11) in C1 and 3% ( < 1-11) in C2. DCR was 10% in C1, 9% in C2, and 22% in C3 per RECIST v1.1. Median (range) DOR was not reached (1.9-21.8+ mo) in C1 and 10.6 mo (4.4-16.8) in C2; KM estimates of DOR ≥12 mo were 71% and 50%. Median (95% CI) OS was 9.5 mo (6.4-11.9) in C1, 7.9 mo (5.9-10.2) in C2, and 14.1 (10.8-17.6) in C3. 12-mo OS rates were 41% in C1, 35% in C2, and 62% in C3; 18-mo rates were 30%, 21%, and 36%. Grade 3-5 drug-related AE rates were 15% in C1, 14% in C2, and 17% in C3. There were 2 drug-related deaths (n = 1 each sepsis and pneumonitis). Conclusions: Pembrolizumab shows antitumor activity and disease control with acceptable safety in RECIST-measurable and bone-predominant mCRPC previously treated with NHAs and docetaxel. Responses are durable, and the observed OS benefit is promising. Clinical trial information: NCT02787005.
Next generation N-terminal domain androgen receptor inhibitors with improved potency and metabolic stability in castration-resistant prostate cancer models.
Authors: Le Moigne Ronan , Zhou Han-Jie , Mawji Nasrin R , Banuelos C. Adriana , Wang Jun , Jian Kunzhong , Virsik Peter , Andersen Raymond J , Sadar Marianne 
Published: March 2019

220 Background: EPI-506, pro-drug of EPI-002, was a first-in-class oral small molecule from the Aniten family of compounds, which inhibit androgen receptor (AR) activity by binding to the N-terminal domain of the AR. EPI-506 was tested in a Phase 1 study in men with metastatic castration-resistant prostate cancer (mCRPC) resistant to current therapies and demonstrated a favorable tolerability profile with signs of moderate efficacy. Metabolic vulnerabilities in the chemical scaffold of EPI-506 were identified and new Aniten molecules, EPI-7170 and EPI-7245 , with improved potency, metabolic stability and pharmaceutical properties have been generated. Methods: Chemical structure activity relationships were developed in order to increase molecule potency in cellular and in vivo assays, while metabolic stability improvements were assessed in in vitro ADME assays and in animal pharmacokinetic studies. In addition, the on-target activity and selectivity was also optimized using a variety of cellular experiments. Results: Next generation Anitens demonstrated a 10-20 fold improvement on AR-driven cellular potency, with IC50’s of 0.5-1 uM when compared to 10-12 uM for EPI-002. In vitro proliferation assays demonstrated on target activity, with an IC50 ~ 2 uM in LNCaP and > 10 uM in the AR-independent cell model PC-3. EPI-7170 was also active in AR-V7-driven LNCaP95 cells. The antiproliferative effect was in alignment with the inhibitory effect on a subset of AR driven genes. In vivo activity in castrated mice bearing LNCaP tumors showed tumor growth inhibition of approximately 70%. While EPI-7170 represents a major advance, subsequent chemistry efforts led to the generation of EPI-7245 and other next generation Anitens which exhibit IC50’s < 500 nM and favorable ADME and PK profiles. Conclusions: Promising next-generation Aniten compounds have been identified. Major chemistry efforts led to the identification of several Anitens with > 10-20 fold improvements in cellular potency compared to EPI-506 which are also metabolically stable. IND-selection preclinical studies are underway on the most promising Aniten’s with an IND submission planned shortly.
Clinicopathologic and genomic characterization of parenchymal brain metastases (BM) in prostate cancer (PCa).
Authors: Mota Jose Mauricio S. C. , Teo Min Yuen , Knezevic Andrea , Bambury Richard Martin , Hatzoglou Vaios , Autio Karen A. , Abida Wassim , Gopalan Anuradha , Fine Samson , Danila Daniel Costin , Rathkopf Dana E. , Slovin Susan F. , Young Robert J. , Reuter Victor E. , Heller Glenn , Scher Howard I. , Morris Michael J. 
Published: March 2019

227 Background: BM are rarely seen with PCa, but the incidence may be increasing with contemporary therapies. We sought to evaluate the clinical phenotypes associated with BM and their outcomes. Methods: The MSKCC institutional clinical database from 01/2001 through 06/2018 was reviewed to identify pts with PCa and (1) secondary malignant neoplasm of the brain / spinal cord per ICD-9 (198.3), (2) radiation treatment plan targeting the brain, (3) craniotomy, or (3) notes containing the terms “brain metastasis”. Medical charts were reviewed to confirm diagnosis (dx) and extract data. The logrank statistic and the Cox proportional hazards model were used to determine correlations with overall survival (OS). Results: Of 575 pts who met search criteria, 43 had BM and prostate adenocarcinoma. At PCa dx, median age was 60 years (range: 44 –77 years) and 51% had metastasis (mets). Median time from PCa dx to BM was 4.2 years. At the time of BM dx, 36 had metastatic castration-resistant PCa (mCRPC), 55% had liver mets and 66% had lung mets. 45% had ≥3 lines of therapy for mCRPC prior to BM dx (abiraterone/enzalutamide: 47%, chemotherapy: 91%). The median OS from BM dx was 5.8 months (Table). 4/10 pts with sequencing data had germline mutations ( ATM, BRCA1, BRIP1, MUTYH). To date, 4 BM were sequenced, and 3 showed PTEN loss. Conclusions: BM associated with a poor prognosis and occurred after prolonged treatment. Presence of liver/lung mets, 3 or more BM, and surgical resection (SR) prognosticate for OS in univariate analysis; SR in multivariate analysis. Further analysis is needed to determine if germline mutations and/or PTEN loss associate with BM. [Table: see text]
Early 18F-FDHT PET/CT as a predictor of treatment response in mCRPC treated with enzalutamide.
Authors: Hoving Hilde , Palthe Selma , Vallinga Marleen , Dost Rutger , Gietema Jourik A. , Antunes Inez , De Vries Erik F. J. , Glaudemans Andor , de Jong Igle Jan 
Published: March 2019

232 Background: Androgen deprivation is the mainstay in the treatment of metastatic prostate cancer. During treatment, the majority of patients will develop progressive disease despite castrate levels of testosterone; castration-resistant prostate cancer (CRPC). In vivo determination of androgen receptor status by 18F-FDHT PET/CT could be of use to predict treatment response timely and objectively. The objective of this study is to assess the value of early 18F-FDHT PET/CT to predict treatment response of enzalutamide in mCRPC. Methods: This pilot study was performed in 18 chemotherapy naïve men with mCRPC. 18F-FDHT PET/CT was performed at baseline and after 4 weeks of treatment with enzalutamide. Standard Uptake Value (SUV)max and SUVpeak of the 5 most intense and/or all bone, pleura and lymph node metastases were determined per patient. Area under the curve (AUC), sensitivity (Se) and specificity (Sp) of different characteristics of 18F-FDHT PET/CT were performed by ROC analysis. Response was determined at 12 weeks of treatment according to PCCTWG. Results: A total of 477 lesions (411 bone, 3 pleura and 63 lymph node) were found. At 12 weeks, response was seen in 16 patients, whereas 2 patients showed no response. The characteristics of 18F-FDHT PET/CT are shown in table 1. Baseline median SUVpeak of all metastatic lesions showed an AUC of 0.79 to predict response. AUC values using the 5 most intense lesions only or using the delta between baseline and 5 weeks were less accurate. Clinical trial information: NTR4086. Conclusions: Baseline 18F-FDHT PET/CT using SUVpeak of all metastatic lesions predicts treatment response in mCRPC treated with enzalutamide with an AUC of 0.79.[Table: see text]
Association between urinary, bowel, and hormonal treatment-related symptoms and clinical outcomes in nonmetastatic castration-resistant prostate cancer (nmCRPC): PROSPER study.
Authors: Saad Fred , Morlock Robert , Ivanescu Cristina , Sugg Jennifer , TOMBAL Bertrand F. 
Published: March 2019

233 Background: PROSPER data were analyzed to assess the relationship between time to worsening of urinary, bowel, and hormonal treatment-related symptoms and prostate-specific antigen (PSA) response, and the longitudinal association between symptom changes and metastasis-free survival (MFS). Methods: 1401 patients (pts) with nmCRPC at high metastasis risk were randomized 2:1 to enzalutamide (ENZA) or placebo. Urinary, bowel, and hormonal treatment-related symptoms were assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-PR25) at baseline (BL) and every 16 weeks. The association between time to first clinically meaningful symptom worsening and PSA response (≥50% decline from BL) was analyzed with stratified Cox regression using treatment as a covariate. Longitudinal symptom changes and MFS were evaluated in joint models using symptom scores as covariates, adjusted for treatment and clinical/demographic variables. The proportion of pts with improvement, no change, or deterioration at metastasis were analyzed by treatment group. Results: 723/1401 (52%) pts were PSA responders, including >90% of ENZA pts. PSA responders were significantly less likely to develop urinary, bowel, and hormone treatment-related symptoms vs. non-responders (hazard ratio [HR] 0.58 [95% confidence interval 0.41, 0.81]; 0.59 [0.43, 0.80]; and 0.70 [0.51, 0.97], respectively). Every 9-point increase in urinary symptom score was associated with a 10% increased metastasis risk (HR 1.1 [1.05, 1.15]). Bowel and hormonal symptoms did not predict metastasis. Most pts reported no EORTC score changes at metastasis and maintained stable urinary/bowel symptoms, with no major observed symptom differences between treatment groups. Conclusions: ENZA delays metastasis and extends time to symptom worsening. A ≥50% PSA reduction from BL is associated with a reduction in risk for urinary, bowel, and hormonal treatment-related symptom worsening; changes in urinary symptoms from BL also predict metastases. Clinical trial information: NCT02003924 (PROSPER).
Health-related quality of life (HRQoL) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with olaparib in combination with abiraterone.
Authors: Clarke Noel W. , Thiery-Vuillemin Antoine , Wiechno Pawel J. , Alekseev Boris , Sala Nuria , Jones Robert , Kocak Ivo , Chiuri Vincenzo Emanuele , Jassem Jacek , Flechon Aude , Redfern Charles , Goessl Carsten Dietrich , Burgents Joseph , Gresty Christopher , Degboe Arnold , Saad Fred 
Published: March 2019

234 Background: A Phase II trial showed that addition of olaparib (O) to abiraterone (A) led to significant radiographic progression-free survival benefit for patients (pts) with mCRPC vs placebo (P) + A (hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.44–0.97). We report predefined exploratory HRQoL analyses. Methods: This randomized, double-blind trial enrolled pts with mCRPC, post-docetaxel. Pts were randomized (71 per arm) to receive either O (300 mg bd, tablets) + A (1000 mg od) or P + A; all received prednisone (5 mg bd). Pts completed Functional Assessment of Cancer Therapy-Prostate (FACT-P total score [TS]; range 0–156, higher score = better HRQoL), Brief Pain Inventory–Short Form (BPI-SF) and worst bone pain (wbp) questionnaires (both range 0–10, higher score = more severe pain). Adjusted mean change from baseline was analysed using a mixed model for repeated measures, improvement by logistic regression and deterioration by log-rank test. Results: Overall compliance rates (O + A vs P + A) were 97% vs 96%, 92% vs 85%, and 96% vs 92% for FACT-P, BPI-SF and wbp, respectively. Best FACT-P TS response of ‘improved’ (increase ≥6 points from baseline at two consecutive visits) was reported by 22/67 (33%) evaluable pts in the O + A vs 18/64 (28%) pts in the P + A arm; the odds ratio (1.32; 95% CI 0.64–2.78) favored the O + A arm. Best FACT-P TS response of ‘worsened’ (decrease ≥6 points from baseline) was reported by 15 (22%) vs 22 (34%) pts. Adjusted mean change from baseline in FACT-P TS across all visits was -0.60 vs -2.09 in the O + A and P + A arms, respectively (difference 1.48; 95% CI -3.96–6.92). Time to deterioration (TTD) results are shown in the table. Clinical trial information: NCT01972217. Conclusions: Whilst not statistically significant, in this study a higher percentage of pts treated with O + A vs P + A had improved HRQoL, with fewer pts negatively affected. Ongoing phase III studies will help elucidate the impact of O on HRQoL in pts with mCRPC. (NCT01972217)[Table: see text]