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Gurulingappa Hallur, Buchi Reddy Purra, Suresh P Sulochana, Neeraj Kumar Saini, Prasanthi Daram, Mohd Zainuddin, Ramesh Mullangi
A sensitive, specific, selective and rapid LC-ESI-MS/MS method has been developed and validated for the quantification of apalutamide in mice plasma using apalutamide-d3 as an internal standard (I.S.). Sample preparation was accomplished through a simple protein precipitation process. Chromatography of apalutamide and the I.S. was achieved on an Atlantis dC18 column using an isocratic mobile phase comprising 0.2% formic acid in water and acetonitrile (20:80, v/v) delivered at a flow rate of 0.8 mL/min. LC-MS/MS was operated under the multiple reaction-monitoring mode (MRM) using the electrospray ionization technique in positive ion mode and the transitions of m/z 478 → 450 and m/z 481 → 453 were used to measure the derivative of apalutamide and the I...
February 27, 2018: Journal of Pharmaceutical and Biomedical Analysis
(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
Elizabeth Gourd
No abstract text is available yet for this article.
February 15, 2018: Lancet Oncology
Matthew R Smith, Fred Saad, Simon Chowdhury, Stéphane Oudard, Boris A Hadaschik, Julie N Graff, David Olmos, Paul N Mainwaring, Ji Youl Lee, Hiroji Uemura, Angela Lopez-Gitlitz, Géralyn C Trudel, Byron M Espina, Youyi Shu, Youn C Park, Wayne R Rackoff, Margaret K Yu, Eric J Small
Background Apalutamide, a competitive inhibitor of the androgen receptor, is under development for the treatment of prostate cancer. We evaluated the efficacy of apalutamide in men with nonmetastatic castration-resistant prostate cancer who were at high risk for the development of metastasis. Methods We conducted a double-blind, placebo-controlled, phase 3 trial involving men with nonmetastatic castration-resistant prostate cancer and a prostate-specific antigen doubling time of 10 months or less. Patients were randomly assigned, in a 2:1 ratio, to receive apalutamide (240 mg per day) or placebo...
February 8, 2018: New England Journal of Medicine
Michael I Koukourakis, Christos Kakouratos, Dimitra Kalamida, Achilleas Mitrakas, Stamatia Pouliliou, Erasmia Xanthopoulou, Evdokia Papadopoulou, Virginia Fasoulaki, Alexandra Giatromanolaki
Apalutamide (ARN-509) is an antiandrogen that binds selectively to androgen receptors (AR) and does not show antagonist-to-agonist switch like bicalutamide. We compared the activity of ARN versus bicalutamide on prostate cancer cell lines. The 22Rv1, PC3, and DU145 cell lines were used to study the effect of ARN and bicalutamide on the expression cytoplasmic/nuclear kinetics of AR, AR-V7 variant, phosphorylated AR, as well as the levels of the AR downstream proteins prostate-specific antigen and TMPRSS2, under exposure to testosterone and/or hypoxia...
January 29, 2018: Anti-cancer Drugs
P S Suresh, Nuggehally R Srinivas, Ramesh Mullangi
Prostate cancer is the most common cancer and one of the leading causes of cancer deaths in men. One of the commonly used approaches to treat metastatic prostate cancer was via first-generation nonsteroidal anti-androgens (NSAAs), namely flutamide, nilutamide, bicalutamide and topilutamide. Most prostate cancer patients who are initially responsive develop the most aggressive form of disease called castration-resistant prostate cancer. Second-generation NSAA receptor antagonists (enzalutamide, apalutamide and darolutamide) are emerging as additional new options to treat castration-resistant prostate cancer...
June 21, 2017: Biomedical Chromatography: BMC
D E Rathkopf, M R Smith, C J Ryan, W R Berry, N D Shore, G Liu, C S Higano, J J Alumkal, R Hauke, R F Tutrone, M Saleh, E Chow Maneval, S Thomas, D S Ricci, M K Yu, C J de Boer, A Trinh, T Kheoh, R Bandekar, H I Scher, E S Antonarakis
Background: Mutations in the androgen receptor (AR) ligand-binding domain (LBD), such as F877L and T878A, have been associated with resistance to next-generation AR-directed therapies. ARN-509-001 was a phase I/II study that evaluated apalutamide activity in castration-resistant prostate cancer (CRPC). Here, we evaluated the type and frequency of 11 relevant AR-LBD mutations in apalutamide-treated CRPC patients. Patients and methods: Blood samples from men with nonmetastatic CRPC (nmCRPC) and metastatic CRPC (mCRPC) pre- or post-abiraterone acetate and prednisone (AAP) treatment (≥6 months' exposure) were evaluated at baseline and disease progression in trial ARN-509-001...
September 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Daniel J Crona, Young E Whang
Despite the initial efficacy of androgen deprivation in prostate cancer, virtually all patients progress to castration-resistant prostate cancer (CRPC). Androgen receptor (AR) signaling is critically required for CRPC. A new generation of medications targeting AR, such as abiraterone and enzalutamide, has improved survival of metastatic CRPC (mCRPC) patients. However, a significant proportion of patients presents with primary resistance to these agents, and in the remainder, secondary resistance will invariably develop, which makes mCRPC the lethal form of the disease...
June 12, 2017: Cancers
Xuehai Pang, Yingwei Wang, Yuanwei Chen
A series of deuterated apalutamide were designed and prepared. Compared to its prototype compound 18, deuterated analogues 19 and 21 showed obviously higher plasma concentrations and better PK parameters after oral administration in mice. In rats, N-trideuteromethyl compound 19 displayed 1.8-fold peak concentration (Cmax ), and nearly doubled its drug exposure in plasma (AUC0-∞ ) compared to compound 18. Unsurprisingly, compounds 18 and 19 had similar affinity for AR in vitro. In summary, the deuteration strategy could obviously improve PK parameters of apalutamide...
June 15, 2017: Bioorganic & Medicinal Chemistry Letters
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. Primary endpoint was ≥50% decline in 12-week PSA according to Prostate Cancer Working Group 2 criteria...
July 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Howard I Scher, Ryon P Graf, Nicole A Schreiber, Brigit McLaughlin, David Lu, Jessica Louw, Daniel C Danila, Lyndsey Dugan, Ann Johnson, Glenn Heller, Martin Fleisher, Ryan Dittamore
BACKGROUND: Circulating tumor cells (CTCs) expressing AR-V7 protein localized to the nucleus (nuclear-specific) identify metastatic castration-resistant prostate cancer (mCRPC) patients with improved overall survival (OS) on taxane therapy relative to the androgen receptor signaling inhibitors (ARSi) abiraterone acetate, enzalutamide, and apalutamide. OBJECTIVE: To evaluate if expanding the positivity criteria to include both nuclear and cytoplasmic AR-V7 localization ("nuclear-agnostic") identifies more patients who would benefit from a taxane over an ARSi...
June 2017: European Urology
Matthew R Smith, Emmanuel S Antonarakis, Charles J Ryan, William R Berry, Neal D Shore, Glenn Liu, Joshi J Alumkal, Celestia S Higano, Edna Chow Maneval, Rajesh Bandekar, Carla J de Boer, Margaret K Yu, Dana E Rathkopf
BACKGROUND: Apalutamide is a potent androgen receptor (AR) antagonist that targets the AR ligand-binding domain and prevents AR nuclear translocation, DNA binding, and transcription of AR gene targets. OBJECTIVE: To evaluate the activity and safety of apalutamide in patients with high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC). DESIGN, SETTING, AND PARTICIPANTS: We conducted a multicenter phase 2 study of nmCRPC patients with a high risk for progression (prostate-specific antigen [PSA] ≥8 ng/ml or PSA doubling time [PSA DT] ≤10 mo)...
December 2016: European Urology
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