期刊
ANNALS OF ONCOLOGY
卷 31, 期 5, 页码 619-625出版社
ELSEVIER
DOI: 10.1016/j.annonc.2020.01.074
关键词
prostate cancer; AZD5363; capivasertib; AKT inhibitor; enzalutamide; biomarkers
类别
资金
- AstraZeneca
- Cancer Research UK [CRUKE/12/050]
- Prostate Cancer Foundation Young Investigator Awards
- Movember
- Department of Defense US [W81XWH-15-2-0051]
- Prostate Cancer UK
- Cancer Research UK
- Experimental Cancer Medicine Centres (ECMC) grant
- Prostate Cancer Foundation
- National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden NHS Foundation Trust
- Institute of Cancer Research, London
- Novartis
- MRC [MR/M018318/1] Funding Source: UKRI
Background: Activation of the PI3K/AKT/mTOR pathway through loss of phosphatase and tensin homolog (PTEN) occurs in approximately 50% of patients with metastatic castration-resistant prostate cancer (mCRPC). Recent evidence suggests that combined inhibition of the androgen receptor (AR) and AKT may be beneficial in mCRPC with PTEN loss. Patients and methods: mCRPC patients who previously failed abiraterone and/or enzalutamide, received escalating doses of AZD5363 (capivasertib) starting at 320 mg twice daily (b.i.d.) given 4 days on and 3 days off, in combination with enzalutamide 160 mg daily. The co-primary endpoints were safety/tolerability and determining the maximum tolerated dose and recommended phase II dose; pharmacokinetics, antitumour activity, and exploratory biomarker analysis were also evaluated. Results: Sixteen patients were enrolled, 15 received study treatment and 13 were assessable for dose-limiting toxicities (DLTs). Patients were treated at 320, 400, and 480 mg b.i.d. dose levels of capivasertib. The recommended phase II dose identified for capivasertib was 400 mg b.i.d. with 1/6 patients experiencing a DLT (maculopapular rash) at this level. The most common grade >= 3 adverse events were hyperglycemia (26.7%) and rash (20%). Concomitant administration of enzalutamide significantly decreased plasma exposure of capivasertib, though this did not appear to impact pharmacodynamics. Three patients met the criteria for response (defined as prostate-specific antigen decline >= 50%, circulating tumour cell conversion, and/or radiological response). Responses were seen in patients with PTEN loss or activating mutations in AKT, low or absent AR-V7 expression, as well as those with an increase in phosphorylated extracellular signal-regulated kinase (pERK) in post-exposure samples. Conclusions: The combination of capivasertib and enzalutamide is tolerable and has antitumour activity, with all responding patients harbouring aberrations in the PI3K/AKT/mTOR pathway.
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