Journal ArticleDOI
Resistance to second-generation androgen receptor antagonists in prostate cancer.
TLDR
The use of second-generation androgen receptor antagonists (SG-ARAs) has greatly impacted the treatment of metastatic prostate cancer, providing tolerable and efficacious alternatives to chemotherapy as mentioned in this paper.Abstract:
The introduction of second-generation androgen receptor antagonists (SG-ARAs) has greatly impacted the treatment of metastatic prostate cancer, providing tolerable and efficacious alternatives to chemotherapy. SG-ARAs provide similar therapeutic benefit to abiraterone, a potent CYP17 inhibitor, and do not require the co-administration of prednisone. Despite considerable improvements in clinical outcomes in the settings of both castration sensitivity and castration resistance, the durability of clinical response to the SG-ARAs enzalutamide, apalutamide and darolutamide, similar to abiraterone, is limited by inevitable acquired resistance. Genomic aberrations that confer resistance to SG-ARAs or provide potential alternative treatment modalities have been identified in numerous studies, including alterations of the androgen receptor, DNA repair, cell cycle, PI3K-AKT-mTOR and Wnt-β-catenin pathways. To combat resistance, researchers have explored approaches to optimizing the utility of available treatments, as well as the use of alternative agents with a variety of targets, including AR-V7, AKT, EZH2 and HIF1α. Ongoing research to establish predictive biomarkers for the treatment of tumours with resistance to SG-ARAs led to the approval of the PARP inhibitors olaparib and rucaparib in pre-treated metastatic castration-resistant prostate cancer. The results of ongoing studies will help to shape precision medicine in prostate cancer and further optimize treatment paradigms to maximize clinical outcomes.read more
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Tumor microenvironment heterogeneity an important mediator of prostate cancer progression and therapeutic resistance
TL;DR: In this article , the authors discuss how nongenetic factors contribute to heterogeneity of prostate cancer and summarize the challenges targeting the tumor environments, and emphasize that continued exploration of tumor heterogeneity is needed in order to offer a personalized therapy for advanced prostate cancer patients.
Journal ArticleDOI
Second generation androgen receptor antagonists and challenges in prostate cancer treatment
TL;DR: In this paper , the authors summarize the current state of AR antagonist development and highlight the emerging challenges of their clinical application and the potential resistance mechanisms, which might be addressed by combination therapies or the development of novel AR-targeted therapies.
Journal ArticleDOI
Immune system and intestinal microbiota determine efficacy of androgen deprivation therapy against prostate cancer
Safae Terrisse,Anne-Gaëlle Goubet,Kousuke Ueda,Andrew Maltez Thomas,Valentin Quiniou,Cassandra Thelemaque,Garett Dunsmore,Emmanuel Clave,Melissa Gamat-Huber,Satoru Yonekura,Gladys Ferrere,Conrad Rauber,Hang-Phuong Pham,Jean-Eudes Fahrner,Eugenie Pizzato,Pierre Ly,Marine Fidelle,Marine Mazzenga,Carolina Alves Costa Silva,Federica Armanini,Federica Pinto,Francesco Asnicar,Romain Daillère,Lisa Derosa,Corentin Richard,Pierre Blanchard,Bertrand Routy,Stéphane Culine,Paule Opolon,Aymeric Silvin,Florent Ginhoux,Antoine Toubert,Nicola Segata,Douglas G. McNeel,Karim Fizazi,Guido Kroemer,Laurence Zitvogel +36 more
TL;DR: The potential clinical utility of reversing intestinal dysbiosis and repairing acquired immune defects in PC patients is suggested, as compared with HSPC controls, CRPC patients demonstrated a shift in their intestinal microbiota that significantly correlated with sjTRECs.
Journal ArticleDOI
Unravelling the molecular mechanisms of prostate cancer evolution from genotype to phenotype.
TL;DR: The identification of canonical genetic alterations and signaling pathway activation in prostate cancer has shed more insight into genetic background, molecular subtype and disease landscape of PC evolution, resulting in a more flexible role of individual therapies targeting diverse genotype and phenotype presentation as discussed by the authors.
Journal ArticleDOI
Dissecting the Hormonal Signaling Landscape in Castration-Resistant Prostate Cancer.
TL;DR: In this paper, the role of the androgen/androgen receptor (AR) axis in prostate cancer (PCa) progression towards its most aggressive, castration-resistant (CRPC) stage is analyzed.
References
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Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial.
Matthew R. Smith,Chris Parker,Fred Saad,Kurt Miller,Bertrand Tombal,Quan Sing Ng,Martin Boegemann,Vsevolod Matveev,Josep M. Piulats,Luis Eduardo Zucca,Oleg Karyakin,Go Kimura,Nobuaki Matsubara,William C. Nahas,Franco Nolè,Eli Rosenbaum,Axel Heidenreich,Yoshiyuki Kakehi,Amily Zhang,Heiko Krissel,Michael Teufel,Junwu Shen,Volker Wagner,Celestia S. Higano +23 more
TL;DR: Concurrent treatment with abiraterone acetate plus prednisone or prednisolone and radium-223 improves overall survival and delays the onset of symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases.
Journal ArticleDOI
Enzalutamide Versus Bicalutamide in Castration-Resistant Prostate Cancer: The STRIVE Trial
David F. Penson,Andrew J. Armstrong,Raoul S. Concepcion,Neeraj Agarwal,Carl A. Olsson,Lawrence Karsh,Curtis Dunshee,Fong Wang,Kenneth Wu,Andrew Krivoshik,De Phung,Celestia S. Higano +11 more
TL;DR: Enzalutamide significantly reduced risk of prostate cancer progression or death compared with bicalutamide in patients with nonmetastatic or metastatic CRPC in this randomized, double-blind, phase II study of men with CRPC.
Journal ArticleDOI
TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer
Geoffrey R. Oxnard,J.C.-H. Yang,Helena A. Yu,Sang We Kim,Hideo Saka,Leora Horn,Koichi Goto,Yuichiro Ohe,Helen Mann,Kenneth S. Thress,Melanie M. Frigault,Karthick Vishwanathan,Dana Ghiorghiu,Suresh S. Ramalingam,Myung-Ju Ahn +14 more
TL;DR: Results demonstrate the feasibility of combining osimertinib 80 mg with selumetinib or savolitinib at identified tolerable, active doses and represent a compelling approach now being further investigated.
Journal ArticleDOI
Prospective Multicenter Validation of Androgen Receptor Splice Variant 7 and Hormone Therapy Resistance in High-Risk Castration-Resistant Prostate Cancer: The PROPHECY Study
Andrew J. Armstrong,Susan Halabi,Jun Luo,David M. Nanus,Paraskevi Giannakakou,Russell Z. Szmulewitz,Daniel C. Danila,Daniel C. Danila,Patrick Healy,Monika Anand,Colin Rothwell,Julia Rasmussen,Blair Thornburg,William R. Berry,Rhonda Wilder,Changxue Lu,Yan Chen,John L. Silberstein,Gabor Kemeny,Giuseppe Galletti,Jason A. Somarelli,Santosh Gupta,Simon G. Gregory,Howard I. Scher,Howard I. Scher,Ryan Dittamore,Scott T. Tagawa,Emmanuel S. Antonarakis,Daniel J. George +28 more
TL;DR: In this article, the Androgen receptor splice variant 7 (AR-V7) results in a truncated receptor, which leads to ligand-independent constitutive activation that is not inhibited by anti-androgen therapies.
Journal ArticleDOI
Optimal sequencing of enzalutamide and abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase 2, crossover trial.
Daniel Khalaf,Matti Annala,Sinja Taavitsainen,Sinja Taavitsainen,Daygen Finch,Conrad D. Oja,Joanna Vergidis,Muhammad Zulfiqar,Katherine Sunderland,Arun Azad,Christian Kollmannsberger,Bernhard J. Eigl,Krista Noonan,Deepa Wadhwa,Andrew Attwell,Bruce Keith,Susan Ellard,Lyly H. Le,Martin E. Gleave,Alexander W. Wyatt,Kim N. Chi +20 more
TL;DR: The data suggest that using a sequencing strategy of abiraterone acetate followed by enzalutamide provides the greatest clinical benefit in this multicentre, randomised, open-label, phase 2, crossover trial of metastatic castration-resistant prostate cancer.