Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study

By H. Scher, T. Beer, Celestia S. Higano, A. Anand, M. Taplin, E. Efstathiou, D. Rathkopf, J. Shelkey, E. Yu, J. Alumkal and 9 more. The Lancet, 2010

1,043 citations recorded by the source corpus.

Background MDV3100 is a rationally-designed androgen receptor antagonist that blocks androgen receptor (AR) binding, nuclear translocation, and co-activator recruitment more effectively than the androgen receptor antagonists currently in use. MDV3100 is also unique in that it prevents DNA binding, induces apoptosis, and has no agonist activity when AR is overexpressed. Because growth of castration-resistant prostate cancer (CRPC) appears to depend upon continued androgen receptor signaling, we hypothesized that MDV3100 could be effective therapy for men with CRPC. Antitumor activity and safety were assessed in a phase 1-2 trial. Methods Eligible patients with progressive metastatic CRPC were enrolled in cohorts of 3-6 patients. Once the safety of a dose was established, cohorts were expanded to include at least 12 chemotherapy-naïve and 12 post-chemotherapy treated patients. Findings 140 patients were treated with doses ranging from 30 to 600 mg daily. Positron emission tomography (PET) imaging to assess androgen receptor blockade showed decreased 18-fluorodihydrotestosterone binding at dosages of 60 mg/day and above. Antitumor effects were observed at all dosages including declines in serum PSA of 50% or more in 56% of patients, responses in soft tissue, stabilized bone disease, and conversion from unfavourable to favourable circulating tumour cell counts. The median time to progression was 47 weeks for radiological progression. The maximal tolerated dose for sustained treatment (>28 days) was 240 mg and the most common adverse event was dose-dependent fatigue, which generally resolved following dose reduction. Interpretation Encouraging antitumor activity on all outcomes assessed was observed for MDV3100 in both chemotherapy-naïve and post-chemotherapy patients with CRPC, establishing that patients with CRPC are not uniformly hormone-refractory. A phase 3 trial in patients with progressive disease after docetaxel treatment is underway.

Subfields: Pulmonary and Respiratory Medicine, Radiology, Nuclear Medicine and Imaging

View Paper: https://www.semanticscholar.org/paper/439781f27b35ea67a53384ec09b14062ced15e11

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In Pulmonary and Respiratory Medicine

Citations in the corpus

ARN-509: a novel anti-androgen for prostate cancer treatment (2012, neutral): “Abiraterone acetate targets 7-αhydroxylase/17,20-lyase (CYP17A), thereby inhibiting residual androgen biosynthesis (4, 5), while MDV3100 is an anti-androgen discovered by the Sawyers/Jung groups in a screen for potent anti-androgens lacking agonist activity in context of AR over-expression (6, 7).”
Resistance to CYP17A1 inhibition with abiraterone in castration resistant prostate cancer: Induction of steroidogenesis and androgen receptor splice variants (2011, neutral): “Incorporation of potent AR inhibitors, such as MDV3100, or agents targeting the AR Nterminal domain, such as EPI-001, could be utilized for tumors adapting to CYP17A1 inhibition via induction of full-length AR and/or AR splice variants lacking the ligand binding C-terminal domain (13, 34-36).”
Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor (2010, positive): “The antiandrogen MDV3100 has shown impressive clinical activity in end-stage, castrationresistant prostate cancer and is currently under evaluation in a phase III registration trial (18, 19).”
Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines (2012, background): “These studies are significant because resistance, either de novo or acquired during therapy, is a major clinical limitation for new AR-axis inhibitors (4, 20).”
Identification of Targetable FGFR Gene Fusions in Diverse Cancers (2013, neutral): “16 this patient should respond to second generation anti-androgens, such as MDV3100 (39), as well as FGFR inhibition.”
Enzalutamide in Metastatic Prostate Cancer before Chemotherapy (2014, neutral): “Decreased appetite 158 (18) 2 (<1) 136 (16) 6 (1)”
Molecular genetics of prostate cancer: new prospects for old challenges. (2010, background): “In this regard, a second-generation AR antagonist, MDV3100, which completely lacks agonist activity and binds AR with greater affinity than bicalutamide, has provided new insights into castration resistance, and has given promising results in mouse models and in a human phase 1–2 trial (Tran et al. ”