Platinum Priority – Brief Correspondence Editorial by Manfred P. Wirth and Michael Froehner on pp. 991–992 of this issue Combination AZD5363 with Enzalutamide Significantly Delays Enzalutamide-resistant Prostate Cancer in Preclinical Models Paul Toren a , Soojin Kim a , Thomas Cordonnier a , Claire Crafter b , Barry R. Davies b , Ladan Fazli a , Martin E. Gleave a , Amina Zoubeidi a, * a The Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada; b AstraZeneca, Alderley Park, Macclesfield, UK While new androgen receptor (AR)-targeting therapies such as abiraterone and enzalutamide (ENZ) highlight the success of targeting the AR axis in castrate-resistant prostate cancer (CRPC), these therapies are not curative and resistance inevitably develops. Therefore, there remains a need for rationale therapeutic strategies to delay the development of resistance. The Akt pathway is upregulated in CRPC and predicts a poorer prognosis [1]. Akt signalling is involved in many oncogenic cellular processes, including cell growth and EUROPEAN UROLOGY 67 (2015) 986–990 available at www.sciencedirect.com journal homepage: www.europeanurology.com Article info Article history: Accepted August 1, 2014 Keywords: Akt inhibitor Apoptosis Enzalutamide Prostate cancer Abstract The phosphatidylinositol-4,5-bisphosphate 3-kinase/Akt (PI3K/Akt) pathway is a key pathway activated in castrate-resistant prostate cancer (CRPC). This preclinical study evaluates targeting of Akt with AZD5363 alone and in combination with enzalutamide (ENZ) to prevent and delay resistance. Our results demonstrate AZD5363 has significant proapoptotic, antiproliferative activity as monotherapy in ENZ-resistant cell lines in vitro and significantly decreased tumour growth in ENZ-resistant xenograft. The com- bination of AZD5363 and ENZ showed synergistic decreases in cell proliferation and induced cell-cycle arrest and apoptosis in prostate cancer cell lines LNCaP and C4-2. Notably, the combination of AZD5363 and ENZ resulted in an impressive regression of castrate-resistant LNCaP xenograft tumours without any recurrence demonstrated, whereas progression occurred with both monotherapies. Serum prostate-specific anti- gen (PSA) levels were also continuously suppressed, and nadir PSA levels were lower in the combination arm compared to ENZ alone. Combination AZD5363 and ENZ at time of castration similarly resulted in significant regression of tumours, with greater relative suppression of PSA compared to when administered to castrate-resistant xenografts. In summary, combination AZD5363 and ENZ significantly delays the development of ENZ resistance in preclinical models through synergistic increases in apoptosis and cell cycle arrest. Our results also suggest greater efficacy may be seen with earlier combination treatment. This study provides preclinical data to support evaluation of combination targeting of the PI3K/Akt pathway and the androgen-receptor axis in the clinic using AZD5363 and ENZ, respectively. Patient summary: Targeting of the Akt and androgen receptor pathways with AZD5363 and enzalutamide, respectively, significantly delayed the development of enzalutamide- resistant prostate cancer through increased apoptosis and cell cycle arrest. This preclin- ical synergy provides a strong rationale for clinical evaluation of this combination. # 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. The Vancouver Prostate Centre, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada. E-mail address: azoubeidi@prostatecentre.com (A. Zoubeidi). http://dx.doi.org/10.1016/j.eururo.2014.08.006 0302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.