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Enzalutamide resistance

Yue Zhao, Hao Huang, Changhao Chen, Hao Liu, Hongwei Liu, Feng Su, Junming Bi, Thomas B Lam, Jiaping Li, Tianxin Lin, Jian Huang
Background : Most patients receiving docetaxel-based chemotherapy for castration resistant prostate cancer (CRPC) will eventually progress, and the optimal interventions for these patients are controversial. The objective of our study is to evaluate the clinical efficacy and safety of pharmacological interventions for CRPC patients progressing after docetaxel-based chemotherapy. Methods : A systematic review and Bayesian network meta-analysis of the literature was carried out according to standard methods. Major electronic databases including PubMed, Web of Science and Embase were searched until Jan 2017...
2018: Journal of Cancer
Jonathan Welti, Adam Sharp, Wei Yuan, David I Dolling, Daniel Nava Rodrigues, Ines Figueiredo, Veronica Gil, Antje Neeb, Matthew Clarke, George Seed, Mateus Crespo, Semini Sumanasuriya, Jian Ning, Eleanor Knight, Jeffrey C Francis, Ashley Hughes, Wendy S Halsey, Alec Paschalis, Ram S Mani, Ganesh V Raj, Steve Plymate, Suzanne Carreira, Gunther Boysen, Arul M Chinnaiyan, Amanda Swain, Johann S de Bono
PURPOSE:  Persistent androgen receptor (AR) signaling drives castration resistant prostate cancer (CRPC) and confers resistance to AR targeting therapies. Novel therapeutic strategies to overcome this are urgently required. We evaluated how bromodomain and extra-terminal (BET) protein inhibitors (BETi) abrogate aberrant AR signaling in CRPC. EXPERIMENTAL DESIGN:  We determined associations between BET expression, AR driven transcription and patient outcome; and the effect and mechanism by which chemical BETi (JQ1 and GSK1210151A; I-BET151) and BET family protein knockdown regulates AR-V7 expression and AR signaling in prostate cancer (PC) models...
March 19, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Dana E Rathkopf, Tomasz M Beer, Yohann Loriot, Celestia S Higano, Andrew J Armstrong, Cora N Sternberg, Johann S de Bono, Bertrand Tombal, Teresa Parli, Suman Bhattacharya, De Phung, Andrew Krivoshik, Howard I Scher, Michael J Morris
Importance: Drug development for metastatic castration-resistant prostate cancer has been limited by a lack of clinically relevant trial end points short of overall survival (OS). Radiographic progression-free survival (rPFS) as defined by the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) is a candidate end point that represents a clinically meaningful benefit to patients. Objective: To demonstrate the robustness of the PCWG2 definition and to examine the relationship between rPFS and OS...
March 8, 2018: JAMA Oncology
Tomoaki Hakariya, Yohei Shida, Toshifumi Tsurusaki, Junichi Watanabe, Masataka Furukawa, Fukuzo Matsuya, Yasuyoshi Miyata, Hideki Sakai
OBJECTIVE: To elucidate the effect of prior use of ethinylestradiol on enzalutamide treatment for men with castration-resistant prostate cancer. METHODS: We retrospectively analyzed data from 99 consecutive patients (median age 72 years, range 50-88 years) treated with enzalutamide for castration-resistant prostate cancer between May 2014 and November 2015 after receiving several lines of hormonal therapy. RESULTS: A total of 45 patients were given ethinylestradiol before enzalutamide...
March 8, 2018: International Journal of Urology: Official Journal of the Japanese Urological Association
Megan E V Caram, Jason P Estes, Jennifer J Griggs, Paul Lin, Bhramar Mukherjee
BACKGROUND: Several systemic treatments have been shown to increase survival for patients with metastatic castration-resistant prostate cancer. This study sought to characterize variation in use of the six "focus drugs" (docetaxel, abiraterone, enzalutamide, sipuleucel-T, radium-223, and cabazitaxel) that have been approved by the Food and Drug Administration for the treatment of metastatic castration-resistant prostate cancer during the years 2010-2015. We hypothesized that the use of these treatments would vary over time and by region of the country...
March 6, 2018: BMC Cancer
Takatsugu Okegawa, Naoki Ninomiya, Kazuki Masuda, Yu Nakamura, Mitsuhiro Tambo, Kikuo Nutahara
OBJECTIVE: We examined whether androgen receptor splice variant 7 (AR-V7) in circulating tumor cell(CTC)clusters can be used to predict survival in patients with bone metastatic castration resistant-prostate cancer (mCRPC) treated with abiraterone or enzalutamide. METHODS: We retrospectively enrolled 98 patients with CRPC on abiraterone or enzalutamide, and investigated the prognostic value of CTC cluster detection (+ v -) and AR-V7 detection (+ v -) using a CTC cluster detection - based AR-V7 mRNA assay...
March 5, 2018: Prostate
Laura Graham, Kalyan Banda, Alba Torres, Brett S Carver, Yu Chen, Katie Pisano, Greg Shelkey, Tracy Curley, Howard I Scher, Tamara L Lotan, Andrew C Hsieh, Dana E Rathkopf
Background MLN0128 is a first-in-class, dual mTOR inhibitor with potential to outperform standard rapalogs through inhibition of TORC1 and TORC2. This phase II study was designed to assess antitumor activity of MLN0128 in metastatic castration-resistant prostate cancer (mCRPC). Methods Eligible patients had mCRPC previously treated with abiraterone acetate and/or enzalutamide. Five patients started MLN0128 at 5 mg once daily, subsequently dose reduced to 4 mg because of toxicity. Four subsequent patients started MLN0128 at 4 mg daily...
March 6, 2018: Investigational New Drugs
Yusuke Ito, Marianne D Sadar
Enzalutamide is a nonsteroidal antiandrogen for the treatment of metastatic castration-resistant prostate cancer (mCRPC) both before and after chemotherapy. Enzalutamide is more effective than its predecessor bicalutamide, which was analyzed in head-to-head studies of patients with CRPC. This family of nonsteroidal antiandrogens is now comprised of four drugs approved by the US Food and Drug Administration with two investigational drugs in clinical trials. Antiandrogens have been employed clinically for more than five decades to provide a rich resource of information...
2018: Research and Reports in Urology
Aishwarya Pawar, Paradesi Naidu Gollavilli, Shaomeng Wang, Irfan A Asangani
BRD4 plays a major role in the transcription networks orchestrated by androgen receptor (AR) in castration-resistant prostate cancer (CRPC). Several BET inhibitors (BETi) that displace BRD4 from chromatin are being evaluated in clinical trials for CRPC. Here, we describe mechanisms of acquired resistance to BETi that are amenable to targeted therapies in CRPC. BETi-resistant CRPC cells displayed cross-resistance to a variety of BETi in the absence of gatekeeper mutations, exhibited reduced chromatin-bound BRD4, and were less sensitive to BRD4 degraders/knockdown, suggesting a BRD4-independent transcription program...
February 27, 2018: Cell Reports
Xiao X Wei, Adam P Siegel, Rahul Aggarwal, Amy M Lin, Terence W Friedlander, Lawrence Fong, Won Kim, Mirela Louttit, Emily Chang, Li Zhang, Charles J Ryan
LESSONS LEARNED: In abiraterone- and/or enzalutamide-refractory metastatic castration-resistant prostate cancer (mCRPC) patients, selinexor led to prostate-specific antigen and/or radiographic responses in a subset of patients, indicating clinical activity in this indication.Despite twice-a-week dosing and maximal symptomatic management, selinexor was associated with significant anorexia, nausea, and fatigue in mCRPC patients refractory to second-generation anti-androgen therapies, limiting further clinical development in this patient population...
February 27, 2018: Oncologist
Kagenori Ito, Takahiro Kimura, Hajime Onuma, Ryuji Tabata, Tatsuya Shimomura, Kenta Miki, Masayuki Tomita, Shin Egawa
BACKGROUND: Guidelines define docetaxel as a first-line therapeutic option for metastatic castration-resistant prostate cancer (mCRPC). However, the role of docetaxel in non-metastatic castration-resistant prostate cancer (nmCRPC) has not been fully investigated. The aim of this retrospective study was to evaluate the potential role of docetaxel in nmCRPC. Clinical outcomes including overall survival were compared between CRPC patients who had docetaxel introduced while in nonmetastatic versus metastatic diseases...
February 23, 2018: Prostate
Alastair H Davies, Himisha Beltran, Amina Zoubeidi
The success of next-generation androgen receptor (AR) pathway inhibitors, such as abiraterone acetate and enzalutamide, in treating prostate cancer has been hampered by the emergence of drug resistance. This acquired drug resistance is driven, in part, by the ability of prostate cancer cells to change their phenotype to adopt AR-independent pathways for growth and survival. Around one-quarter of resistant prostate tumours comprise cells that have undergone cellular reprogramming to become AR-independent and to acquire a continuum of neuroendocrine characteristics...
February 20, 2018: Nature Reviews. Urology
(no author information available yet)
The FDA approved the antiandrogen apalutamide for the treatment of men with nonmetastatic, castration-resistant prostate cancer, the first drug for these patients greenlighted by the agency. Data from the definitive trial of apalutamide, presented at the 2018 Genitourinary Cancers Symposium, showed that the drug prolonged metastasis-free survival by more than 2 years compared with placebo. Data on the related drug enzalutamide, also presented at the symposium, showed that that drug led to dramatic improvements in metastasis-free survival, too...
February 19, 2018: Cancer Discovery
Chao Liang, Shangqian Wang, Chao Qin, Meilin Bao, Gong Cheng, Bianjiang Liu, Pengfei Shao, Qiang Lv, Ninghong Song, Lixin Hua, Min Gu, Jie Li, Zengjun Wang
Hormone therapy drugs, such as bicalutamide and enzalutamide, directed against prostate cancer focus on androgen receptor (AR) signaling and are initially effective, but the disease progresses to lethality as resistance to these drugs develops. A method to prolong the drug response time and improve the drug efficacy is still unavailable. TRIM36 was reported as a novel androgen signaling target gene and is upregulated in prostate cancer. In this study, we found that 63.4% (64/95) of PCa in TMA expressed the TRIM36 protein...
February 5, 2018: Cell Death & Disease
Emmanuel S Antonarakis, Changxue Lu, Brandon Luber, Chao Liang, Hao Wang, Yan Chen, John L Silberstein, Danilo Piana, Zhao Lai, Yidong Chen, William B Isaacs, Jun Luo
BACKGROUND: Inherited DNA-repair gene mutations are more prevalent in men with advanced prostate cancer than previously thought, but their clinical implications are not fully understood. OBJECTIVE: To investigate the clinical significance of germline DNA-repair gene alterations in men with metastatic castration-resistant prostate cancer (mCRPC) receiving next-generation hormonal therapy (NHT), with a particular emphasis on BRCA/ATM mutations. DESIGN, SETTING, AND PARTICIPANTS: We interrogated 50 genes for pathogenic or likely pathogenic germline mutations using leukocyte DNA from 172 mCRPC patients beginning treatment with first-line NHT with abiraterone or enzalutamide...
February 10, 2018: European Urology
Jibril O Bello
Purpose: Native sub-Saharan African black men (SSBM) are disproportionately impacted by higher stage and incurable forms of prostate cancer (PCa). This study evaluates the natural history and survival of a cohort of SSBM with castration-resistant prostate cancer (CRPC). Methods: A retrospective study of patients with CRPC as defined by the Prostate Cancer Working Group 2 managed at a centre in sub-Saharan Africa between January 2011 and December 2015 was conducted...
2018: Ecancermedicalscience
Jeong Hee Hong
Enzalutamide is the first approved second-generation androgen receptor (AR) antagonist in the treatment of metastatic castration-resistant prostate cancer (mCRPC) with or without docetaxel-based chemotherapy. Over the past 5 years, a number of attempts were made to determine the efficacy of enzalutamide in the different clinical settings. Areas covered: A literature search was performed at the PubMed, Embase, and Web of Science database to collect the most relevant and impactful studies, including basic science investigations, clinical trials, and reviews...
February 12, 2018: Expert Opinion on Drug Metabolism & Toxicology
Bram De Laere, Steffi Oeyen, Peter Van Oyen, Christophe Ghysel, Jozef Ampe, Piet Ost, Wim Demey, Lucien Hoekx, Dirk Schrijvers, Barbara Brouwers, Willem Lybaert, Els Everaert, Piet Van Kerckhove, Daan De Maeseneer, Michiel Strijbos, Alain Bols, Karen Fransis, Nick Beije, Inge de Kruijff, Valerie van Dam, Anja Brouwer, Pieter-Jan van Dam, Gert Van den Eynden, Annemie Rutten, Stefan Sleijfer, Jean Vandebroek, Steven Van Laere, Luc Dirix
BACKGROUND: The outcome to treatment administered to patients with metastatic castration-resistant prostate cancer (mCRPC) greatly differs between individuals, underlining the need for biomarkers guiding treatment decision making. OBJECTIVE: To investigate the prognostic value of circulating tumor cell (CTC) enumeration and dynamics, in the context of second-line endocrine therapies (ie, abiraterone acetate or enzalutamide), irrespective of prior systemic therapies...
February 12, 2018: Prostate
Joaquin Mateo, Heather H Cheng, Himisha Beltran, David Dolling, Wen Xu, Colin C Pritchard, Helen Mossop, Pasquale Rescigno, Raquel Perez-Lopez, Verena Sailer, Michael Kolinsky, Ada Balasopoulou, Claudia Bertan, David M Nanus, Scott T Tagawa, Heather Thorne, Bruce Montgomery, Suzanne Carreira, Shahneen Sandhu, Mark A Rubin, Peter S Nelson, Johann S de Bono
BACKGROUND: Germline DNA damage repair gene mutation (gDDRm) is found in >10% of metastatic prostate cancer (mPC). Their prognostic and predictive impact relating to standard therapies is unclear. OBJECTIVE: To determine whether gDDRm status impacts benefit from established therapies in mPC. DESIGN, SETTING, AND PARTICIPANTS: This is a retrospective, international, observational study. Medical records were reviewed for 390 mPC patients with known gDDRm status...
January 29, 2018: European Urology
WanYing Lin, Jie Luo, Yin Sun, ChangYi Lin, Gonghui Li, Yuanjie Niu, Chawnshang Chang
Unlike the androgen-deprivation therapy (ADT) to either reduce the androgen biosynthesis (for example, Abiraterone) or to prevent binding of androgen to the androgen receptor (AR) (for example, Casodex or Enzalutamide), that may result in the decreasing the prostate cancer (PCa) cell growth yet may also increasing the PCa cell invasion, the recently identified AR degradation enhancer ASC-J9® may function via degrading the AR protein to simultaneously suppress the PCa cell proliferation and invasion. The details of this unique mechanism, however, remain unclear...
February 6, 2018: Cancer Letters
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