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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

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Summary

Background AZD3514 is a first-in-class, orally bio-available, androgen-dependent and -independent androgen receptor inhibitor and selective androgen-receptor down-regulator (SARD). Methods 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. Results 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. Conclusion 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.

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Acknowledgments

Aurelius Omlin’s work is supported by a grant by the Swiss Cancer League (BIL KLS-02592-02-2010). Professor Johann de Bono is supported by The Prostate Cancer Foundation (Santa Monica); Prostate Cancer UK; Cancer Research UK and an Experimental Cancer Medical Centre Grant for Cancer Research UK and the UK Department of Health and a Biomedical Research Grant to the Royal Marsden NHS Foundation Trust. Robert Jones is supported by Cancer Research UK and an Experimental Cancer Medicine Centre Grant from Cancer Research UK and the Chief Scientist’s Office (Scotland). Malcolm Ranson was supported by Cancer Research UK and an Experimental Cancer Medical Centre Grant for Cancer Research UK and the UK Department of Health.

The authors thank the study participants, without whom this study would never have been accomplished, and Dr. Ken-ichi Tabata (Kitasato University School of Medicine) for participation in this study.

Conflict of interest

vdNR, JHMS, RR, N-R D, JJA, AZ, MC, MO, JG, CD, RS, DM, MN: no conflict of interest.

TE: Advisory role for Astellas, AstraZeneca, Janssen, Sanofi.

AO: Advisory role for Pfizer, Janssen, Bayer, Sanofi, Astellas, AstraZeneca.

RJJ: Consultancy for Janssen, Astellas, Sanofi, Dendreon; speaker honoraria for Astellas, Janssen, Sanofi, Ferring. Research funding from AstraZeneca, Janssen, Astellas, Medivation, Sanofi.

MR: Advisory role for AstraZeneca.

SAS, GC, PD, AD, MM, RDF: (1) AstraZeneca stock ownership; (2) AstraZeneca employee at the time of this study.

JDB: has received consulting fees and travel support from AstraZeneca, and grant support from AstraZeneca

TS: Speaking fees from Daiichi Sanko, AstraZeneca, Astellas, Janssen

None of the above mentioned conflicts of interest have affected the publication of this work.

Funding

This trial was sponsored by AstraZeneca.

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Authors and Affiliations

  1. Prostate Targeted Therapy Group and Drug Development Unit, The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Downs Road, Sutton, Surrey, UK

    A. Omlin, M. Ong, A. Zivi, M. Crespo, R. Riisnaes, D. Nava-Rodrigues & J. de Bono

  2. The Beatson West of Scotland Cancer Centre, Glasgow, UK

    R. J. Jones & J. Graham

  3. The Netherlands Cancer Institute, Amsterdam, The Netherlands

    R. van der Noll & J. H. M. Schellens

  4. Department of Urology, Kitasato University School of Medicine, Sagamihara, Japan

    T. Satoh

  5. Division of Urology, Shizuoka Cancer Center Hospital, Shizuoka, Japan

    M. Niwakawa

  6. AstraZeneca, Macclesfield, UK

    S. A. Smith, M. D. Malone, A. Dymond, P. A. Dickinson & G. Clack

  7. AstraZeneca, Wilmington, DE, USA

    R. D. Finkelman

  8. Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht, The Netherlands

    J. H. M. Schellens

  9. Knight Cancer Institute at Oregon Health & Science University, Oregon, USA

    J. J. Alumkal

  10. The Christie NHS Foundation Trust, Manchester, UK

    M. Ranson & T. Elliott

  11. Cancer Research UK Manchester Institute, Manchester, UK

    C. Dive, R. Sloane & D. Moore

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  1. A. Omlin
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Correspondence to T. Elliott.

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Omlin, A., Jones, R.J., van der Noll, R. et al. 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. Invest New Drugs 33, 679–690 (2015). https://doi.org/10.1007/s10637-015-0235-5

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