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 Carreira, F I Raynaud, K E Swales, S Plymate, J Luo, H Tovey, N Porta, R Slade, L Leonard, E Hall, J S de Bono, 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 Carreira, F I Raynaud, K E Swales, S Plymate, J Luo, H Tovey, N Porta, R Slade, L Leonard, E Hall, J S de Bono
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.
Keywords: AKT inhibitor; AZD5363; biomarkers; capivasertib; enzalutamide; prostate cancer.
Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.
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Source: PubMed