A phase I dose-escalation study of enzalutamide in combination with the AKT inhibitor AZD5363 (capivasertib) in patients with metastatic castration-resistant prostate cancer.
Loading...
Embargo End Date
Authors
Kolinsky, MP
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
Carreira, S
Raynaud, FI
Swales, KE
Plymate, S
Luo, J
Tovey, H
Porta, N
Slade, R
Leonard, L
Hall, E
de Bono, JS
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
Carreira, S
Raynaud, FI
Swales, KE
Plymate, S
Luo, J
Tovey, H
Porta, N
Slade, R
Leonard, L
Hall, E
de Bono, JS
Document Type
Journal Article
Date
2020-02-21
Date Accepted
2020-01-29
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.
Citation
Annals of oncology : official journal of the European Society for Medical Oncology, 2020, 31 (5), pp. 619 - 625
Source Title
Publisher
ELSEVIER
ISSN
0923-7534
eISSN
1569-8041
Collections
Research Team
Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Cancer Biomarkers
Clinical PD Biomarker Group
Clinical Pharmacology – Adaptive Therapy
Clinical Trials & Statistics Unit
ICR-CTSU Urology and Head and Neck Trials Team
Prostate Cancer Targeted Therapy Group
Translational Therapeutics
Cancer Biomarkers
Clinical PD Biomarker Group
Clinical Pharmacology – Adaptive Therapy
Clinical Trials & Statistics Unit
ICR-CTSU Urology and Head and Neck Trials Team
Prostate Cancer Targeted Therapy Group
Translational Therapeutics