A phase I dose-escalation study of enzalutamide in combination with the AKT inhibitor AZD5363 (capivasertib) in patients with metastatic castration-resistant prostate cancer

M. P. Kolinsky, P. Rescigno, D. Bianchini, Z. Zafeiriou, N. Mehra, J. Mateo, V. Michalarea, R. Riisnaes, M. Crespo, I. Figueiredo, S. Miranda, D. Nava Rodrigues, P. Flohr, N. Tunariu, U. Banerji, R. Ruddle, A. Sharp, J. Welti, M. Lambros, S. CarreiraF. I. Raynaud, K. E. Swales, S. Plymate, J. Luo, H. Tovey, N. Porta, R. Slade, L. Leonard, E. Hall, J. S. de Bono

Research output: Contribution to journalArticle

Abstract

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. Clinical Trial Number: NCT02525068

Original languageEnglish (US)
Pages (from-to)619-625
Number of pages7
JournalAnnals of Oncology
Volume31
Issue number5
DOIs
StatePublished - May 2020

Keywords

  • AKT inhibitor
  • AZD5363
  • biomarkers
  • capivasertib
  • enzalutamide
  • prostate cancer

ASJC Scopus subject areas

  • Hematology
  • Oncology

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    Kolinsky, M. P., Rescigno, P., Bianchini, D., Zafeiriou, Z., Mehra, N., Mateo, J., Michalarea, V., Riisnaes, R., Crespo, M., Figueiredo, I., Miranda, S., Nava Rodrigues, D., Flohr, P., Tunariu, N., Banerji, U., Ruddle, R., Sharp, A., Welti, J., Lambros, M., ... de Bono, J. S. (2020). A phase I dose-escalation study of enzalutamide in combination with the AKT inhibitor AZD5363 (capivasertib) in patients with metastatic castration-resistant prostate cancer. Annals of Oncology, 31(5), 619-625. https://doi.org/10.1016/j.annonc.2020.01.074