azd3514 and Prostatic-Neoplasms--Castration-Resistant

The androgen receptor (AR) plays a key role in the maintenance of muscle and bone and the support of male sexual-related functions, as well as in the progression of prostate cancer. Accordingly, AR-targeted therapies have been developed for the treatment of related human diseases and conditions. AR agonists are an important class of drugs in the treatment of bone loss and muscle atrophy. AR antagonists have also been developed for the treatment of prostate cancer, including metastatic castration-resistant prostate cancer (mCRPC). Additionally, selective AR degraders (SARDs) have been reported. More recently, heterobifunctional degrader molecules of AR have been developed, and four such compounds are now in clinical development for the treatment of human prostate cancer. This review attempts to summarize the different types of compounds designed to target AR and the current frontiers of research on this important therapeutic target.

Topics: Androgen Antagonists; Androgen Receptor Antagonists; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen

AZD3514 is a first-in-class, orally bio-available, androgen-dependent and -independent androgen receptor inhibitor and selective androgen-receptor down-regulator (SARD).. In study 1 and 2, castration-resistant prostate cancer (CRPC) patients (pts) were initially recruited into a once daily (QD) oral schedule (A). In study 1, pharmacokinetic assessments led to twice daily (BID) dosing (schedule B) to increase exposure. Study 2 explored a once daily schedule.. In study 1, 49 pts were treated with escalating doses of AZD3514 (A 35 pts, B 14 pts). Starting doses were 100 mg (A) and 1000 mg (B). The AZD3514 formulation was switched from capsules to tablets at 1000 mg QD. 2000 mg BID was considered non-tolerable due to grade (G) 2 toxicities (nausea [N], vomiting [V]). No adverse events (AEs) met the dose-limiting toxicity (DLT) definition. Thirteen pts received AZD3514 in study 2, with starting doses of 250 mg QD. The most frequent drug-related AEs were N: G1/2 in 55/70 pts (79 %); G3 in 1 pt (1.4 %); & V: G1/2 in 34/70 pts (49 %) & G3 in 1 pt (1.4 %). PSA declines (≥50 %) were documented in 9/70 patients (13 %). Objective soft tissue responses per RECIST1.1 were observed in 4/24 (17 %) pts in study 1.. AZD3514 has moderate anti-tumour activity in pts with advanced CRPC but with significant levels of nausea and vomiting. However, anti-tumour activity as judged by significant PSA declines, objective responses and durable disease stabilisations, provides the rationale for future development of SARD compounds.

Topics: Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Agents; Dose-Response Relationship, Drug; Down-Regulation; Humans; Male; Middle Aged; Neoplastic Cells, Circulating; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Pyridazines; Radiography; Receptors, Androgen

First-in-human (FIH) studies with AZD3514, a selective androgen receptor (AR) down-regulator, showed decreases of >30% in the prostate-specific antigen (PSA) in some patients. A modeling approach was adopted to understand these observations and define the optimum clinical use hypothesis for AZD3514 for clinical testing. Initial empirical modeling showed that only baseline PSA correlated significantly with this biological response, whereas drug concentration did not. To identify the mechanistic cause of this observation, a mechanism-based model was first developed, which described the effects of AZD3514 on AR protein and PSA mRNA levels in LNCaP cells with and without dihydrotestosterone (DHT). Second, the mechanism-based model was linked to a population pharmacokinetic (PK) model; PSA effects of clinical doses were subsequently simulated under different clinical conditions. This model was used to adjust the design of the ongoing clinical FIH study and direct the backup program.

Topics: Androgen Receptor Antagonists; Down-Regulation; Humans; Male; Models, Biological; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Pyridazines; Receptors, Androgen; Systems Analysis; Treatment Outcome

The continual reassessment method (CRM) requires an underlying model of the dose-toxicity relationship ("prior skeleton") and there is limited guidance of what this should be when little is known about this association. In this manuscript the impact of applying the CRM with different prior skeleton approaches and the 3 + 3 method are compared in terms of ability to determine the true maximum tolerated dose (MTD) and number of patients allocated to sub-optimal and toxic doses.. Post-hoc dose-escalation analyses on real-life clinical trial data on an early oncology compound (AZD3514), using the 3 + 3 method and CRM using six different prior skeleton approaches.. All methods correctly identified the true MTD. The 3 + 3 method allocated six patients to both sub-optimal and toxic doses. All CRM approaches allocated four patients to sub-optimal doses. No patients were allocated to toxic doses from sigmoidal, two from conservative and five from other approaches.. Prior skeletons for the CRM for phase 1 clinical trials are proposed in this manuscript and applied to a real clinical trial dataset. Highly accurate initial skeleton estimates may not be essential to determine the true MTD, and, as expected, all CRM methods out-performed the 3 + 3 method. There were differences in performance between skeletons. The choice of skeleton should depend on whether minimizing the number of patients allocated to suboptimal or toxic doses is more important.. NCT01162395 , Trial date of first registration: July 13, 2010.

Topics: Algorithms; Androgen Antagonists; Antineoplastic Agents; Bayes Theorem; Clinical Trials, Phase I as Topic; Computer Simulation; Dose-Response Relationship, Drug; Humans; Male; Maximum Tolerated Dose; Models, Theoretical; Prostatic Neoplasms, Castration-Resistant; Pyridazines

Continued androgen receptor (AR) expression and signaling is a key driver in castration-resistant prostate cancer (CRPC) after classical androgen ablation therapies have failed, and therefore remains a target for the treatment of progressive disease. Here, we describe the biological characterization of AZD3514, an orally bioavailable drug that inhibits androgen-dependent and -independent AR signaling. AZD3514 modulates AR signaling through two distinct mechanisms, an inhibition of ligand-driven nuclear translocation of AR and a downregulation of receptor levels, both of which were observed in vitro and in vivo. AZD3514 inhibited testosterone-driven seminal vesicle development in juvenile male rats and the growth of androgen-dependent Dunning R3327H prostate tumors in adult rats. Furthermore, this class of compound showed antitumor activity in the HID28 mouse model of CRPC in vivo. AZD3514 is currently in phase I clinical evaluation.

Topics: Abiraterone Acetate; Androgen Receptor Antagonists; Androstadienes; Animals; Antineoplastic Agents; Benzamides; Cell Line, Tumor; Disease Models, Animal; Down-Regulation; Drug Screening Assays, Antitumor; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Male; Mice; Mice, Nude; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Pyridazines; Rats; Rats, Wistar; Receptors, Androgen; Seminal Vesicles; Signal Transduction; Xenograft Model Antitumor Assays