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Treatment resistant mCRPC

Giorgio Ivan Russo, Simone Bier, Jörg Hennenlotter, Gunthild Beger, Lucretia Pavlenco, Jens van de Flierdt, Siegfried Hauch, Moritz Maas, Simon Walz, Steffen Rausch, Jens Bedke, Giuseppe Morgia, Arnulf Stenzl, Tilman Todenhöfer
OBJECTIVE: To evaluate the presence of circulating tumour cells (CTC) at different stages of prostate cancer (PC) using the ProstateCancerDetect kit. Moreover, we aimed to assess the expression of transcripts that are specific for cancer stem cells (AdnaTest StemCell) and epithelial mesenchymal transition (EMT) in CTC (AdnaTest EMT) as well as additional genes that are known to promote PC progression. PATIENTS AND METHODS: In this prospective study, we included 81 patients who underwent treatment for PC between 07/2014 and 02/2015, including A) 18 patients (22...
March 15, 2018: BJU International
Rachana Patel, Janis Fleming, Ernest Mui, Carolyn Loveridge, Peter Repiscak, Arnaud Blomme, Victoria Harle, Mark Salji, Imran Ahmad, Katy Teo, Freddie C Hamdy, Ann Hedley, Niels van den Broek, Gillian Mackay, Joanne Edwards, Owen J Sansom, Hing Y Leung
Metastatic castration-resistant prostate cancer (mCRPC) is a lethal form of treatment-resistant prostate cancer and poses significant therapeutic challenges. Deregulated receptor tyrosine kinase (RTK) signalling mediated by loss of tumour suppressor Sprouty2 (SPRY2) is associated with treatment resistance. Using pre-clinical human and murine mCRPC models, we show that SPRY2 deficiency leads to an androgen self-sufficient form of CRPC Mechanistically, HER2-IL6 signalling axis enhances the expression of androgen biosynthetic enzyme HSD3B1 and increases SRB1-mediated cholesterol uptake in SPRY2-deficient tumours...
March 14, 2018: EMBO Molecular Medicine
Ellen Wargowski, Laura E Johnson, Jens C Eickhoff, Lauren Delmastro, Mary Jane Staab, Glenn Liu, Douglas G McNeel
BACKGROUND: Prostatic acid phosphatase (PAP) is a prostate tumor antigen, and the target of the only FDA-approved anti-tumor vaccine, sipuleucel-T. We have previously reported in two clinical trials that a DNA vaccine encoding PAP (pTVG-HP) could elicit PAP-specific, Th1-biased T cells in patients with PSA-recurrent prostate cancer. In the current pilot trial we sought to evaluate whether this vaccine could augment PAP-specific immunity when used as a booster to immunization with sipuleucel-T in patients with metastatic, castration-resistant prostate cancer (mCRPC)...
March 13, 2018: Journal for Immunotherapy of Cancer
Adriana C Vidal, Lauren E Howard, Amanda de Hoedt, Christopher J Kane, Martha K Terris, William J Aronson, Matthew R Cooperberg, Christopher L Amling, Stephen J Freedland
OBJECTIVE: At the population level, obesity is associated with prostate cancer (PC) mortality; however, some studies found higher body mass index (BMI) is associated with better long-term PC outcomes among men with metastatic castration-resistant PC (mCRPC). PATIENTS AND METHODS: We tested whether obesity was associated with progression to metastasis, PC-specific mortality (PCSM), and all-cause mortality (ACM) among 1192 non-metastatic CRPC patients from the SEARCH Database...
March 9, 2018: BJU International
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
Niven Mehra, David Dolling, Semini Sumanasuriya, Rossitza Christova, Lorna Pope, Suzanne Carreira, George Seed, Wei Yuan, Jane Goodall, Emma Hall, Penny Flohr, Gunther Boysen, Diletta Bianchini, Oliver Sartor, Mario A Eisenberger, Karim Fizazi, Stephane Oudard, Mustapha Chadjaa, Sandrine Macé, Johann S de Bono
BACKGROUND: Noninvasive biomarkers are needed to guide metastatic castration-resistant prostate cancer (mCRPC) treatment. OBJECTIVE: To clinically qualify baseline and on-treatment cell-free DNA (cfDNA) concentrations as biomarkers of patient outcome following taxane chemotherapy. DESIGN, SETTING, AND PARTICIPANTS: Blood for cfDNA analyses was prospectively collected from 571 mCRPC patients participating in two phase III clinical trials, FIRSTANA (NCT01308567) and PROSELICA (NCT01308580)...
February 27, 2018: European Urology
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
Takeo Kosaka, Toshiaki Shinojima, Shinya Morita, Mototsugu Oya
The present study aimed to evaluate the efficacy of cabazitaxel in Japanese patients affected by metastatic castration resistant prostate cancer (mCRPC) previously treated with a docetaxel-containing regimen.In this retrospective study, 41 patients with mCRPC treated with cabazitaxel at Keio University Hospital were retrospectively reviewed. Cabazitaxel at a dose of 20-25 mg/m² was administered every three or four weeks. Clinicopathological factors and laboratory data were collected to assess the prognostic factors for overall survival (OS) and progression-free survival (PFS)...
March 1, 2018: Cancer Science
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
Ambreen Khawar, Elisabeth Eppard, Jean Phlippe Sinnes, Frank Roesch, Hojjat Ahmadzadehfar, Stefan Kürpig, Michael Meisenheimer, Florian C Gaertner, Markus Essler, Ralph A Bundschuh
AIM: [Sc]Sc-PSMA-617 with 3.9-hour half-life, in vitro and in vivo characteristics similar to [Lu]Lu-PSMA-617 and possibility of delayed imaging after 24 hours or later, implies it to be advantageous than [ Ga]Ga-PSMA-617 for pretherapeutic dosimetric assessment for [Lu]Lu-PSMA-617 in metastatic castration-resistant prostate carcinoma (mCRPC) patients. In this study, we investigated biodistribution and radiation exposure to normal organs with [Sc]Sc-PSMA-617 in mCRPC patients. METHODS: Five mCRPC patients (mean age, 69 years) enrolled for [Lu]Lu-PSMA-617 therapy were injected with 40-62 MBq [Sc]Sc-PSMA-617 intravenously; Siemens Biograph 2 PET/CT system was used to acquire dynamic PET data (30 minutes) in list mode over the abdomen, followed by the collection of static PET/CT images (skull to mid-thigh) at 45 minutes, 2 and approximately 20 hours postinjection...
February 27, 2018: Clinical Nuclear Medicine
Pedro Barata, Matthew Cooney, Allison Tyler, John Wright, Robert Dreicer, Jorge A Garcia
Background The inhibition of insulin-like growth factor receptor-1 (IGF-1R) induces cell cycle arrest and enhancing the effect of castration by delay of progression of human prostate cancer models. Linsitinib is a small molecule and potent dual inhibitor of IGF-1R and insulin receptor tyrosine kinase activity. We report results of a single-arm, phase II study evaluating the safety and efficacy of linsitinib in men with chemotherapy-naïve asymptomatic or mildly symptomatic metastatic castration resistant prostate cancer (mCRPC)...
February 23, 2018: Investigational New Drugs
Vanessa Basketter, Miranda Benney, Louise Causer, Louisa Fleure, David Hames, Sarah Jones, Kamlesh Patel, Lisa White
Several treatment options are now available to men with metastatic castration-resistant prostate cancer (mCRPC). While survival rates for mCRPC continue to improve, patients are faced with increasingly complex treatment pathways and decisions. The clinical nurse specialist (CNS) plays a crucial role in navigating patients with mCRPC through their treatment pathway and fulfils a number of key responsibilities, including providing holistic care and support to patients and their families, educating and communicating with them in a timely and effective manner, and liaising with other healthcare professionals to seamlessly coordinate patient treatment...
February 1, 2018: British Journal of Nursing: BJN
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
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
Vincenza Conteduca, Orazio Caffo, Luca Galli, Antonio Maugeri, Emanuela Scarpi, Francesca Maines, Vincenzo Emanuele Chiuri, Cristian Lolli, Stefania Kinspergher, Giuseppe Schepisi, Matteo Santoni, Daniele Santini, Lucia Fratino, Salvatore Luca Burgio, Samanta Salvi, Cecilia Menna, Ugo De Giorgi
BACKGROUND: Metabolic syndrome (MS) and inflammation (INF) alterations are among the factors involved in cancer progression. The study aimed to assess the relationship between MS and INF and its effect on progression-free/overall survival (PFS/OS) in metastatic castration-resistant prostate cancer (mCRPC) treaed with abiraterone or enzalutamide. METHODS: We, retrospectively, evaluated patients with mCRPC in 7 Italian Institutes between March 2011 and October 2016...
February 2, 2018: Urologic Oncology
Sarah Q To, Edmond M Kwan, Heidi C Fettke, Andrew Mant, Maria M Docanto, Luciano Martelotto, Patricia Bukczynska, Nicole Ng, Lisa-Jane K Graham, Phillip Parente, Carmel Pezaro, Kate Mahon, Lisa Horvath, Tilman Todenhöfer, Arun A Azad
In 2014, a landmark study was published demonstrating that the expression of androgen receptor splice variant (AR-V) 7 was a negative predictive biomarker for response to abiraterone acetate and enzalutamide in metastatic castration-resistant prostate cancer (mCRPC) patients. However, these results were not supported by the recently reported ARMOR3-SV phase III clinical trial, which employed an identical circulating tumour cell assay to assess AR-V7 expression. Therefore, the predictive utility of AR-V7 expression in mCRPC remains uncertain, as does any potential association between other AR-Vs and treatment response...
February 2, 2018: European Urology
Simone Albisinni, Fouad Aoun, Quentin Marcelis, Claude Jungels, Walid Al Hajj Obeid, Marc Zanaty, Andrea Tubaro, Thierry Roumeguere, Cosimo DE Nunzio
INTRODUCTION: The last decade has witnessed tremendous changes in the management of advanced and metastatic castration resistant prostate cancer (mCRPC). In the current systematic review, we analyze novel imaging techniques in the setting of recurrent and metastatic PCa, exploring available data and highlighting future exams which could enter clinical practice in the upcoming years. EVIDENCE ACQUISITION: The National Library of Medicine Database was searched for relevant articles published between January 2012 and August 2017...
January 31, 2018: Minerva Urologica e Nefrologica, the Italian Journal of Urology and Nephrology
Guru Sonpavde, Ahong Huang, Li Wang, Onur Baser, Raymond Miao
OBJECTIVES: To assess treatment patterns and outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) receiving first-line chemotherapy or anti-androgen therapy. PATIENTS AND METHODS: Patients initiating first-line anti-androgen therapy (abiraterone, enzalutamide) or chemotherapy (taxane) from Oct/2012-Sept/2014 were retrospectively identified in the US Veterans Health Administration (VHA) database. The impact of anti-androgen therapy versus chemotherapy on overall survival (OS) and time to discontinuation was assessed using Cox proportional hazard models, adjusting for prior androgen deprivation therapy (ADT) duration and available prognostic factors...
February 1, 2018: BJU International
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