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.

Figures

Figure 1
Figure 1
Percent change in prostate-specific antigen (PSA) at 12 weeks relative to baseline PSA. Each bar represents an individual patient. Light colour indicates the patient previously received treatment with both abiraterone and enzalutamide; dark colour indicates prior treatment with only abiraterone and not enzalutamide. Patients indicated with × discontinued before 12 weeks but safety follow-up results are available; in these patients, the percent change of PSA at discontinuation relative to baseline is presented. The patient indicated with + also met response criteria for RECIST and circulating tumour cell (CTC) conversion. Patients indicated with a dot discontinued treatment before 12 weeks with no post-treatment PSA values obtained. Dose level refers to the dosage of capivasertib the patient received in mg. Phosphate and tensin homolog (PTEN) status refers to immunohistochemistry (IHC) expression with N representing normal and L representing loss. ARV7 status refers to pre-treatment tumour biopsy baseline AR-V7 expression by IHC with + indicating an H-score of >10 and − indicating ≤10. Phosphorylated extracellular signal-related kinases (pERK) refers to increased expression by IHC on post-treatment tumour biopsy samples relative to baseline indicated by +, whereas − indicates no increase. NGS refers to next-generation sequencing with + representing known or likely deleterious mutations in PI3K/AKT/mTOR pathway genes and − representing an absence of such mutations. NA indicates not available. Patients meeting response criteria assessed by PSA, soft tissue objective response by RECIST, CTC conversions, and overall [indicated by (-r) respectively] are indicated by (Yes), with non-responders indicated by (No), and (N/E) indicating non-evaluable. † indicates non-confirmed CTC conversions. Reasons for discontinuation included progressive disease (PD), patient choice (PC), and AE.
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