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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.

Purpose: Papillary renal cell carcinoma (PRCC) is the second most common cancer of the kidney and carries a poor prognosis for patients with nonlocalized disease. The HGF receptor MET plays a central role in PRCC and aberrations, either through mutation, copy number gain, or trisomy of chromosome 7 occurring in the majority of cases. The development of effective therapies in PRCC has been hampered in part by a lack of available preclinical models. We determined the pharmacodynamic and antitumor response of the selective MET inhibitor AZD6094 in two PRCC patient-derived xenograft (PDX) models.Experimental Design: Two PRCC PDX models were identified and MET mutation status and copy number determined. Pharmacodynamic and antitumor activity of AZD6094 was tested using a dose response up to 25 mg/kg daily, representing clinically achievable exposures, and compared with the activity of the RCC standard-of-care sunitinib (in RCC43b) or the multikinase inhibitor crizotinib (in RCC47).Results: AZD6094 treatment resulted in tumor regressions, whereas sunitinib or crizotinib resulted in unsustained growth inhibition. Pharmacodynamic analysis of tumors revealed that AZD6094 could robustly suppress pMET and the duration of target inhibition was dose related. AZD6094 inhibited multiple signaling nodes, including MAPK, PI3K, and EGFR. Finally, at doses that induced tumor regression, AZD6094 resulted in a doseand time-dependent induction of cleaved PARP, a marker of cell death.Conclusions: Data presented provide the first report testing therapeutics in preclinical in vivo models of PRCC and support the clinical development of AZD6094 in this indication.

Quantitative systems pharmacology (QSP) approaches have been increasingly applied in the pharmaceutical since the landmark white paper published in 2011 by a National Institutes of Health working group brought attention to the discipline. In this perspective, we discuss QSP in the context of other modeling approaches and highlight the impact of QSP across various stages of drug development and therapeutic areas. We discuss challenges to the field as well as future opportunities.

Background: DMPK data and knowledge are critical in maximising the probability of developing successful drugs via the application of in silico, in vitro and in vivo approaches in drug discovery. Methods: The evaluation, optimisation and prediction of human pharmacokinetics is now a mainstay within drug discovery. These elements are at the heart of the ‘right tissue’ component of AstraZeneca’s ‘5Rs framework’ which, since its adoption, has resulted in increased success of Phase III clinical trials. With the plethora of DMPK related assays and models available, there is a need to continually refine and improve the effectiveness and efficiency of approaches best to facilitate the progression of quality compounds for human clinical testing. Results: This article builds on previously published strategies from our laboratories, highlighting recent discoveries and successes, that brings our AstraZeneca Oncology DMPK strategy up to date. We review the core aspects of DMPK in Oncology drug discovery and highlight data recently generated in our laboratories that have influenced our screening cascade and experimental design. We present data and our experiences of employing cassette animal PK, as well as re-evaluating in vitro assay design for metabolic stability assessments and expanding our use of freshly excised animal and human tissue to best inform first time in human dosing and dose escalation studies. Conclusion: Application of our updated drug-drug interaction and central nervous system drug exposure strategies are exemplified, as is the impact of physiologically based pharmacokinetic and pharmacokinetic-pharmacodynamic modelling for human predictions.

Osimertinib is a third-generation, irreversible, oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), recommended as first-line treatment for patients with locally advanced/metastatic EGFR-mutation positive (EGFRm) non-small cell lung cancer (NSCLC). However, MET-amplification/overexpression is a common acquired osimertinib resistance mechanism. Savolitinib is an oral, potent, and highly selective MET-TKI; preliminary data suggest that combining osimertinib with savolitinib may overcome MET-driven resistance. A patient-derived xenograft (PDX) mouse model with EGFRm, MET-amplified NSCLC was tested with a fixed osimertinib dose (10 mg/kg, for exposures equivalent to [≈] 80 mg), combined with doses of savolitinib (0–15 mg/kg, ≈0–600 mg once-daily), both with 1-aminobenzotriazole (to better match clinical half-life). After 20 days of oral dosing, samples were taken at various timepoints to follow the time-course of drug exposure in addition to phosphorylated MET and EGFR (pMET; pEGFR) change. Population pharmacokinetics, savolitinib concentration versus percentage inhibition from baseline in pMET, and the relationship between pMET and tumor growth inhibition (TGI) were also modeled. As single agents, savolitinib (15 mg/kg) showed significant anti-tumor activity, reaching ~84% TGI and osimertinib (10 mg/kg) showed no significant anti-tumor activity (34% TGI, P>0.05 vs. vehicle). Upon combination, at a fixed dose of osimertinib, significant savolitinib dose-related anti-tumor activity was shown, ranging from 81% TGI (0.3 mg/kg) to 84% tumor regression (15 mg/kg). Pharmacokinetic-pharmacodynamic modeling showed that the maximum inhibition of both pEGFR and pMET increased with increasing savolitinib doses. Savolitinib demonstrated exposure-related combination anti-tumor activity when combined with osimertinib in the EGFRm MET-amplified NSCLC PDX model.

<div>AbstractPurpose:<p>The emergence of secondary mutations is a cause of resistance to current KIT inhibitors used in the treatment of patients with gastrointestinal stromal tumors (GIST). AZD3229 is a selective inhibitor of wild-type KIT and a wide spectrum of primary and secondary mutations seen in patients with GIST. The objective of this analysis is to establish the pharmacokinetic–pharmacodynamic (PKPD) relationship of AZD3229 in a range of mouse GIST tumor models harboring primary and secondary KIT mutations, and to benchmark AZD3229 against other KIT inhibitors.</p>Experimental Design:<p>A PKPD model was developed for AZD3229 linking plasma concentrations to inhibition of phosphorylated KIT using data generated from several <i>in vivo</i> preclinical tumor models, and <i>in vitro</i> data generated in a panel of Ba/F3 cell lines.</p>Results:<p>AZD3229 drives inhibition of phosphorylated KIT in an exposure-dependent manner, and optimal efficacy is observed when >90% inhibition of KIT phosphorylation is sustained over the dosing interval. Integrating the predicted human pharmacokinetics into the mouse PKPD model predicts that an oral twice daily human dose greater than 34 mg is required to ensure adequate coverage across the mutations investigated. Benchmarking shows that compared with standard-of-care KIT inhibitors, AZD3229 has the potential to deliver the required target coverage across a wider spectrum of primary or secondary mutations.</p>Conclusions:<p>We demonstrate that AZD3229 warrants clinical investigation as a new treatment for patients with GIST based on its ability to inhibit both ATP-binding and A-loop mutations of KIT at clinically relevant exposures.</p></div>

<p>PDF - 464KB, Supplementary Figure 1: Inhibition of AR transcripts with AZD3514 treated LNCaPs in steroid free media and the timecourse of AZD3514 effects in the presence and absence of DHT. Supplementary Figure 2: Effect of AZD3514 on growth of AR negative cells. Supplementary Figure 3: AR and PSA expression in LAPC4 cells treated with AZD3514. Supplementary Figure 4: AR degradation and synthesis rates of a C-terminal AR peptide, as measured by Mass Spectrometry. Supplementary Figure 5: Comparison of ARD1 & AZD3514 effects on seminal vesicle weight in rats, and pharmacokinetic effects in mice and rats Supplementary Figure 6: Effect of ARD1 on growth and AR in the HID28 model. Supplementary Figure 7: Dose response effects of AZD3514 on AR nuclear translocation and foci formation.</p>