AZD3514, an oral selective androgen receptor down-regulator in patients with castration-resistant prostate cancer – results of two parallel first-in-human phase I studies

Omlin, Aurelius; Jones, Robert; Noll, Ruud van der; Satoh, Takefumi; Niwakawa, Masashi; Smith, Simon A.; Graham, John D.; Ong, Michael; Finkelman, Richard D.; Schellens, Jan H.M.; Zivi, Andrea; Crespo, Mateus; Riisnaes, Ruth; Nava-Rodrigues, Daniel; Malone, Michael J.; Dive, Caroline; Szczepaniak-Sloane, Robert; Moore, Donald C; Alumkal, Joshi J.; Dymond, Angela W.; Dickinson, Paul; Ranson, Malcolm R; Clack, Glen; Bono, Johann S. de; Elliott, Tony

doi:10.1007/s10637-015-0235-5

Cited by 44 publications

(37 citation statements)

References 29 publications

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“…Another strategy is to pharmacologically trigger AR degradation, given the analogous success with the estrogen receptor degrader fulvestrant, used for the treatment of metastatic breast cancer progressing after failure of first-line antiestrogen therapy 114 . AZD3514, a purported AR degrader, showed PSA declines in 13% of CRPC patients but clinical development was halted due to gastrointestinal toxicity 115 .…”

Section: Future Therapeutic Options For Crpcmentioning

confidence: 99%

Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer

2015

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Preface Over the past ten years, preclinical studies implicating sustained androgen receptor (AR) signaling as the primary driver of castration resistant prostate cancer (CRPC) led to the development of novel agents targeting the AR pathway that are now in widespread clinical use. These drugs prolong survival of patients with late stage prostate cancer but are not curative. In this review, we highlight emerging mechanisms of acquired resistance to these contemporary therapies, which fall into the three broad categories of restored AR signaling, AR bypass signaling and complete AR independence. This diverse spectrum of resistance mechanisms presents new challenges for long term disease control, which may be addressable through early use of combination therapies guided by recent insights from genomic landscape studies of CRPC.

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Section: Future Therapeutic Options For Crpcmentioning

confidence: 99%

Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer

2015

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“…At the end of that study, no patients below 2000 mg BID had met the pre-determined DLT criteria. However moderate or greater nausea and vomiting were significant tolerability concerns and caused higher doses to be considered non-tolerable [22]. Therefore, moderate or greater (CTCAE grade 2+) nausea and vomiting was retrospectively defined as a DLT.…”

Section: Methodsmentioning

confidence: 99%

Continual reassessment method for dose escalation clinical trials in oncology: a comparison of prior skeleton approaches using AZD3514 data

et al. 2016

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BackgroundThe 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.MethodsPost-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.ResultsAll 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.ConclusionsPrior 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.Trial registrationNCT01162395, Trial date of first registration: July 13, 2010.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2702-6) contains supplementary material, which is available to authorized users.

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“…AZD3514, which binds the AR LBD and prevents its ligand-driven nuclear translocation, promotes down-regulation of AR levels. It has been clinically evaluated, but disappointingly only moderate anti-tumour activity in patients with advanced CRPC was observed; it was also shown to be poorly tolerated, with nausea and vomiting being the main toxicities [148] . In the 2012, Yamashita et al [149] identified that ASC-J9 (73), also named as dimethylcurcumin, functioned as an AR degradation enhancer for full length AR and AR splicing variants.…”

Section: Seviteronel (5mentioning

confidence: 99%

Androgen-AR axis in primary and metastatic prostate cancer: chasing steroidogenic enzymes for therapeutic intervention

Pippione¹,

Boschi²,

Pors³

et al. 2017

JCMT

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Androgens play an important role in prostate cancer (PCa) development and progression. Although androgen deprivation therapy remains the front-line treatment for advanced prostate cancer, patients eventually relapse with the lethal form of the disease. The prostate tumor microenvironment is characterised by elevated tissue androgens that are capable of activating the androgen receptor (AR). Inhibiting the steroidogenic enzymes that play vital roles in the biosynthesis of testosterone (T) and dihydrotestosterone (DHT) seems to be an attractive strategy for PCa therapies. Emerging data suggest a role for the enzymes mediating pre-receptor control of T and DHT biosynthesis by alternative pathways in controlling intratumoral androgen levels, and thereby influencing PCa progression. This supports the idea for the development of multi-targeting strategies, involving both dual and multiple inhibitors of androgen-metabolising enzymes that are able to affect androgen synthesis and signalling at different points in the biosynthesis. In this review, we will focus on CYP17A1, AKR1C3, HSD17B3 and SRD5A, as these enzymes play essential roles in all the three androgenic pathways. We will review also the AR as an additional target for the design of bifunctional drugs. Targeting intracrine androgens and AKR1C3 have potential to overcome enzalutamide and abiraterone resistance and improve survival of advanced prostate cancer patients.

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AZD3514, an oral selective androgen receptor down-regulator in patients with castration-resistant prostate cancer – results of two parallel first-in-human phase I studies

Cited by 44 publications

References 29 publications

Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer

Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer

Continual reassessment method for dose escalation clinical trials in oncology: a comparison of prior skeleton approaches using AZD3514 data

Androgen-AR axis in primary and metastatic prostate cancer: chasing steroidogenic enzymes for therapeutic intervention

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