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Treatment resistant mCRPC

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https://www.readbyqxmd.com/read/28321130/effective-combinatorial-immunotherapy-for-castration-resistant-prostate-cancer
#1
Xin Lu, James W Horner, Erin Paul, Xiaoying Shang, Patricia Troncoso, Pingna Deng, Shan Jiang, Qing Chang, Denise J Spring, Padmanee Sharma, John A Zebala, Dean Y Maeda, Y Alan Wang, Ronald A DePinho
A significant fraction of patients with advanced prostate cancer treated with androgen deprivation therapy experience relapse with relentless progression to lethal metastatic castration-resistant prostate cancer (mCRPC). Immune checkpoint blockade using antibodies against cytotoxic-T-lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1/programmed cell death 1 ligand 1 (PD1/PD-L1) generates durable therapeutic responses in a significant subset of patients across a variety of cancer types. However, mCRPC showed overwhelming de novo resistance to immune checkpoint blockade, motivating a search for targeted therapies that overcome this resistance...
March 20, 2017: Nature
https://www.readbyqxmd.com/read/28319807/targeting-nf-kappa-b-signaling-by-artesunate-restores-sensitivity-of-castrate-resistant-prostate-cancer-cells-to-antiandrogens
#2
Jessica J Nunes, Swaroop K Pandey, Anjali Yadav, Sakshi Goel, Bushra Ateeq
Androgen deprivation therapy (ADT) is the most preferred treatment for men with metastatic prostate cancer (PCa). However, the disease eventually progresses and develops resistance to ADT in majority of the patients, leading to the emergence of metastatic castration-resistant prostate cancer (mCRPC). Here, we assessed artesunate (AS), an artemisinin derivative, for its anticancer properties and ability to alleviate resistance to androgen receptor (AR) antagonists. We have shown AS in combination with bicalutamide (Bic) attenuates the oncogenic properties of the castrate-resistant (PC3, 22RV1) and androgen-responsive (LNCaP) PCa cells...
March 16, 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/28318331/docetaxel-chemotherapy-in-metastatic-castration-resistant-prostate-cancer-cost-of-care-in-medicare-and-commercial-populations
#3
A Armstrong, C Bui, K Fitch, T Goss Sawhney, B Brown, S Flanders, M Balk, J Deangelis, J Chambers
OBJECTIVE: To estimate the healthcare costs and characteristics of docetaxel chemotherapy episodes of care for men with metastatic castration-resistant prostate cancer (mCRPC). METHODS: We used Medicare 5% sample and MarketScan® Commercial (2010 - 2013) claims data sets to identify men with mCRPC and initial episodes of docetaxel treatment. Docetaxel episodes included docetaxel claim costs from the first claim until 30 days after the last claim, with earlier termination for death, insurance disenrollment, or the end of a 24-month look-forward period from initial docetaxel index date...
March 20, 2017: Current Medical Research and Opinion
https://www.readbyqxmd.com/read/28314838/a-phase-i-study-of-abiraterone-acetate-combined-with-bez235-a-dual-pi3k-mtor-inhibitor-in-metastatic-castration-resistant-prostate-cancer
#4
Xiao X Wei, Andrew C Hsieh, Won Kim, Terence Friedlander, Amy M Lin, Mirela Louttit, Charles J Ryan
LESSONS LEARNED: The combination of standard dose abiraterone acetate and BEZ235, a pan-class I PI3K and mTORC1/2 inhibitor, was poorly tolerated in men with progressive mCRPC.Although the clinical development of BEZ235 has been discontinued in prostate cancer, agents that more selectively target PI3K-AKT-mTOR signaling may have a more favorable therapeutic index and should continue to be explored. BACKGROUND: Androgen receptor (AR) and phosphatidylinositol-3 kinase (PI3K) signaling are two commonly perturbed pathways in prostate cancer...
March 17, 2017: Oncologist
https://www.readbyqxmd.com/read/28314611/clinical-outcomes-from-androgen-signaling-directed-therapy-after-treatment-with-abiraterone-acetate-and-prednisone-in-patients-with-metastatic-castration-resistant-prostate-cancer-post-hoc-analysis-of-cou-aa-302
#5
Matthew R Smith, Fred Saad, Dana E Rathkopf, Peter F A Mulders, Johann S de Bono, Eric J Small, Neal D Shore, Karim Fizazi, Thian Kheoh, Jinhui Li, Peter De Porre, Mary B Todd, Margaret K Yu, Charles J Ryan
In the COU-AA-302 trial, abiraterone acetate plus prednisone significantly increased overall survival for patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC). Limited information exists regarding response to subsequent androgen signaling-directed therapies following abiraterone acetate plus prednisone in patients with mCRPC. We investigated clinical outcomes associated with subsequent abiraterone acetate plus prednisone (55 patients) and enzalutamide (33 patients) in a post hoc analysis of COU-AA-302...
March 14, 2017: European Urology
https://www.readbyqxmd.com/read/28302580/the-role-of-therapeutic-layering-in-optimizing-treatment-for-patients-with-castration-resistant-prostate-cancer-radar-ii
#6
E David Crawford, Daniel P Petrylak, Neal Shore, Fred Saad, Susan F Slovin, Nicholas J Vogelzang, Thomas E Keane, Phillip J Koo, Leonard G Gomella, Joe M O'Sullivan, Bertrand Tombal, Raoul S Concepcion, Paul Sieber, Nelson N Stone, Steven E Finkelstein, Evan Y Yu
OBJECTIVE: To offer recommendations on identification of disease progression, treatment management strategies, and suggestions on timing of initiating and discontinuing specific CRPC treatments. MATERIALS AND METHODS: The RADAR II [Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence] Working Group convened to provide guidance on sequencing, combination, or layering of approved treatments for mCRPC based on available data and clinical experience...
March 13, 2017: Urology
https://www.readbyqxmd.com/read/28278075/piecing-the-puzzle-together-docetaxel-cycles-and-current-considerations-in-the-treatment-of-metastatic-castration-resistant-prostate-cancer
#7
Hannah E Feinman, Douglas K Price, William D Figg
Docetaxel is the current first line therapy for metastatic castration-resistant prostate cancer (mCRPC), but there is no standard number of docetaxel cycles given to patients. In their post hoc analysis of the Mainsail study, de Morrée et al. show that the number of docetaxel cycles administered to a patient is a significant factor contributing to overall survival. These findings warrant further investigation into the standardization of the number of docetaxel cycles administered.
February 25, 2017: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/28277852/the-treatment-patterns-of-castration-resistant-prostate-cancer-in-japan-including-symptomatic-skeletal-events-and-associated-treatment-and-healthcare-resource-use
#8
Hiroji Uemura, Marco DiBonaventura, Ed Wang, Dianne Athene Ledesma, Kristen Concialdi, Yasuko Aitoku
BACKGROUND: Real-world treatment patterns of bone metastatic castration-resistant prostate cancer (mCRPC) in Japan were examined, focusing on treatment patterns and resource use differences attributed to symptomatic skeletal events (SSEs). METHODS: Urologists (N=176) provided retrospective chart data for patients with mCRPC (N=445) via online surveys. Descriptive analyses and chi-square tests evaluated treatment patterns and their differences by SSE presence; generalized linear mixed models examined healthcare resource utilization differences as a function of SSEs...
March 6, 2017: Expert Review of Pharmacoeconomics & Outcomes Research
https://www.readbyqxmd.com/read/28263212/a-phase-1-trial-of-cabazitaxel-combined-with-188-re-hydroxyethylidene-diphosphonate-in-patients-with-metastatic-castration-resistant-prostate-cancer-who-progressed-on-or-after-a-docetaxel-containing-treatment-the-recab-trial
#9
Joyce M van Dodewaard-de Jong, Esther W Bouman-Wammes, Haiko J Bloemendal, Henk M W Verheul, John M H de Klerk, Alfons J M van den Eertwegh
PURPOSE: In patients with metastatic castration-resistant prostate cancer (mCRPC), bone-seeking radiopharmaceuticals, such as Re-hydroxyethylidene diphosphonate (HEDP), are effective for pain palliation and have a marked antitumor effect. Cabazitaxel is the standard second-line chemotherapy for mCRPC patients. We performed a phase 1 study investigating the safety and feasibility of the combined treatment with Re-HEDP and cabazitaxel in mCRPC patients. METHODS: Patients with mCRPC and documented disease progression on or after docetaxel were eligible for inclusion...
March 3, 2017: Clinical Nuclear Medicine
https://www.readbyqxmd.com/read/28259476/treatment-outcomes-and-tumor-loss-of-heterozygosity-in-germline-dna-repair-deficient-prostate-cancer
#10
Matti Annala, Werner J Struss, Evan W Warner, Kevin Beja, Gillian Vandekerkhove, Amanda Wong, Daniel Khalaf, Irma-Liisa Seppälä, Alan So, Gregory Lo, Rahul Aggarwal, Eric J Small, Matti Nykter, Martin E Gleave, Kim N Chi, Alexander W Wyatt
BACKGROUND: Germline mutations in DNA repair genes were recently reported in 8-12% of patients with metastatic castration-resistant prostate cancer (mCRPC). It is unknown whether these mutations associate with differential response to androgen receptor (AR)-directed therapy. OBJECTIVE: To determine the clinical response of mCRPC patients with germline DNA repair defects to AR-directed therapies and to establish whether biallelic DNA repair gene loss is detectable in matched circulating tumor DNA (ctDNA)...
March 1, 2017: European Urology
https://www.readbyqxmd.com/read/28239558/role-of-androgen-receptor-splice-variants-in-prostate-cancer-metastasis
#11
Jin Xu, Yun Qiu
Prostate cancer (PCa) is one of the most lethal cancers in western countries. Androgen receptor (AR) signaling pathway plays a key role in PCa progression. Despite the initial effectiveness of androgen deprivation therapy (ADT) for treatment of patients with advanced PCa, most of them will develop resistance to ADT and progress to metastatic castration resistant prostate cancer (mCRPC). Constitutively transcriptional activated AR splice variants (AR-Vs) have emerged as critical players in the development and progression of mCRPC...
October 2016: Asian J Urol
https://www.readbyqxmd.com/read/28213364/safety-and-antitumor-activity-of-apalutamide-arn-509-in-metastatic-castration-resistant-prostate-cancer-with-and-without-prior-abiraterone-acetate-and-prednisone
#12
Dana E Rathkopf, Emmanuel S Antonarakis, Neal D Shore, Ronald F Tutrone, Joshi J Alumkal, Charles J Ryan, Mansoor Saleh, Ralph J Hauke, Rajesh Bandekar, Edna Chow Maneval, Carla J de Boer, Margaret K Yu, Howard I Scher
PURPOSE: To evaluate the efficacy of apalutamide before or after treatment with abiraterone acetate and prednisone (AAP) in patients with progressive metastatic castration-resistant prostate cancer (mCRPC). EXPERIMENTAL DESIGN: Two cohorts were studied: AAP-naïve and post-AAP patients who had received ≥6 months of AAP. Patients had progressive mCRPC per rising prostate-specific antigen (PSA) and/or imaging, without prior chemotherapy exposure. All received apalutamide 240 mg/day...
February 17, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28212536/targeting-the-stress-oncoprotein-ledgf-p75-to-sensitize-chemoresistant-prostate-cancer-cells-to-taxanes
#13
Leslimar Ríos-Colón, Christina K Cajigas-Du Ross, Anamika Basu, Catherine Elix, Ivana Alicea-Polanco, Tino W Sanchez, Vinodh Radhakrishnan, Chien-Shing Chen, Carlos A Casiano
Prostate cancer (PCa) is associated with chronic prostate inflammation resulting in activation of stress and pro-survival pathways that contribute to disease progression and chemoresistance. The stress oncoprotein lens epithelium-derived growth factor p75 (LEDGF/p75), also known as DFS70 autoantigen, promotes cellular survival against environmental stressors, including oxidative stress, radiation, and cytotoxic drugs. Furthermore, LEDGF/p75 overexpression in PCa and other cancers has been associated with features of tumor aggressiveness, including resistance to cell death and chemotherapy...
February 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/28188090/independent-association-between-time-to-prostate-specific-antigen-psa-nadir-and-psa-progression-free-survival-in-patients-with-docetaxel-na%C3%A3-ve-metastatic-castration-resistant-prostate-cancer-receiving-abiraterone-acetate-but-not-enzalutamide
#14
Hideaki Miyake, Takuto Hara, Keita Tamura, Takayuki Sugiyama, Hiroshi Furuse, Seiichiro Ozono, Masato Fujisawa
PURPOSE: The objective of this study was to compare the prognostic effect of time to prostate-specific antigen (PSA) nadir (TTPN) after treatment with abiraterone acetate (AA) and enzalutamide (Enz) in patients with docetaxel-naïve, metastatic castration-resistant prostate cancer (mCRPC). METHODS: This study included a total of 297 consecutive patients with mCRPC, of whom 125 and 172 received AA and Enz, respectively, without previous treatment with docetaxel and subsequently achieved any degree of PSA reduction after the administration of either agent...
February 7, 2017: Urologic Oncology
https://www.readbyqxmd.com/read/28185462/-options-of-chemotherapy-in-the-treatment-of-prostate-cancer
#15
I Richter, J Dvořák, J Bartoš
BACKGROUND: Prostate cancer is one of the most common malignancies in men. Chemotherapy has an important role in the management of prostate cancer, especially for the treatment of castrate resistant prostate cancer (mCRPC). According to recently published studies, chemotherapy can also be used to treat advanced hormone sensitive disease. AIM: The aim of this report is to review the currently available options for chemotherapy of prostate cancer. RESULTS: Docetaxel is a chemotherapeutic agent used for standard treatment of mCRPC as 1st line therapy...
2017: Klinická Onkologie: Casopis Ceské a Slovenské Onkologické Spolecnosti
https://www.readbyqxmd.com/read/28171710/clinical-outcomes-and-survival-surrogacy-studies-of-prostate-specific-antigen-declines-following-enzalutamide-in-men-with-metastatic-castration-resistant-prostate-cancer-previously-treated-with-docetaxel
#16
Andrew J Armstrong, Fred Saad, De Phung, Carl Dmuchowski, Neal D Shore, Karim Fizazi, Mohammad Hirmand, David Forer, Howard I Scher, Johann De Bono
BACKGROUND: In the AFFIRM trial, enzalutamide significantly increased overall survival (OS) for men with metastatic castration-resistant prostate cancer (mCRPC) after chemotherapy versus placebo and significantly decreased prostate-specific antigen (PSA) levels. The goal of this post hoc analysis was to associate levels of PSA decline from baseline after enzalutamide with clinical outcomes in the postchemotherapy mCRPC setting. METHODS: Men in the AFFIRM trial (n = 1199) were grouped by maximal PSA decline in the first 90 days of treatment...
February 7, 2017: Cancer
https://www.readbyqxmd.com/read/28161841/prognostic-factors-of-first-line-docetaxel-treatment-in-castration-resistant-prostate-cancer-roles-of-neutrophil-to-lymphocyte-ratio-in-patients-from-northwestern-china
#17
Xin-Qi Pei, Da-Lin He, Ge Tian, Wei Lv, Yu-Mei Jiang, Da-Peng Wu, Jin-Hai Fan, Kai-Jie Wu
OBJECTIVE: To evaluate the potential role of neutrophil-to-lymphocyte ratio (NLR) with therapeutic response in patients who were treated with docetaxel for mCRPC. MATERIALS AND METHODS: We retrospectively analyzed the clinical data from 111 consecutive patients who were treated with docetaxel for mCRPC from 2009 to 2016 in a single center from Northwestern China. Pretreatment baseline and follow-up data including age, PSA response, Gleason score, and cycle number were reviewed, and multivariable Cox regression models and Kaplan-Meier analysis were used to predict overall survival (OS) and progression-free survival (PFS)...
April 2017: International Urology and Nephrology
https://www.readbyqxmd.com/read/28161323/a-multicenter-phase-i-study-of-cabazitaxel-mitoxantrone-and-prednisone-for-chemotherapy-na%C3%A3-ve-patients-with-metastatic-castration-resistant-prostate-cancer-a-department-of-defense-prostate-cancer-clinical-trials-consortium-study
#18
Rahul Aggarwal, Alan Bryce, Charles J Ryan, Andrea Harzstark, Christina Derleth, Won Kim, Terence Friedlander, Amy M Lin, Tammy Rodvelt-Bagchi, Mallika Dhawan, Li Zhang, Mina Lee, Eric Siebeneck, Jeffrey Hough, Eric J Small
BACKGROUND: Cabazitaxel plus prednisone has significant activity in patients with chemotherapy-naïve and pretreated metastatic castration-resistant prostate cancer (mCRPC). Mitoxantrone has antitumor activity in mCRPC and nonoverlapping mechanism of action and toxicity profile. OBJECTIVE: To establish the maximally tolerated dose of the combination of cabazitaxel, mitoxantrone, and prednisone. METHODS AND MATERIALS: Patients with chemotherapy-naïve mCRPC were prospectively enrolled in a multicenter phase 1 trial...
February 1, 2017: Urologic Oncology
https://www.readbyqxmd.com/read/28151974/assessment-of-a-prognostic-model-psa-metrics-and-toxicities-in-metastatic-castrate-resistant-prostate-cancer-using-data-from-project-data-sphere-pds
#19
Bethany Pitcher, Leila Khoja, Robert J Hamilton, Kald Abdallah, Melania Pintilie, Anthony M Joshua
BACKGROUND: Prognostic models in metastatic castrate resistant prostate cancer (mCRPC) may have clinical utility. Using data from PDS, we aimed to 1) validate a contemporary prognostic model (Templeton et al., 2014) 2) evaluate prognostic impact of concomitant medications and PSA decrease 3) evaluate factors associated with docetaxel toxicity. METHODS: We accessed data on 2,449 mCRPC patients in PDS. The existing model was validated with a continuous risk score, time-dependent receiver operating characteristic (ROC) curves, and corresponding time-dependent Area under the Curve (tAUC)...
2017: PloS One
https://www.readbyqxmd.com/read/28144789/procaid-a-phase-i-clinical-trial-to-combine-the-akt-inhibitor-azd5363-with-docetaxel-and-prednisolone-chemotherapy-for-metastatic-castration-resistant-prostate-cancer
#20
Simon J Crabb, Alison J Birtle, Karen Martin, Nichola Downs, Ian Ratcliffe, Tom Maishman, Mary Ellis, Gareth Griffiths, Stuart Thompson, Lidia Ksiazek, Vincent Khoo, Robert J Jones
Background Docetaxel and prednisolone chemotherapy (DP) extends survival in metastatic castration resistant prostate cancer (mCRPC). However, emergent clinical resistance is almost inevitable. AKT pathway activation is highly prevalent in mCRPC contributing to disease progression and DP resistance. AZD5363 is a potent oral pan-AKT inhibitor with pre-clinical data indicating activity in mCRPC and synergy with docetaxel. Methods This phase I trial was to determine an AZD5363 recommended phase II dose (RP2D) for combination with DP...
February 1, 2017: Investigational New Drugs
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