Phase I Trial of the PARP Inhibitor Olaparib and AKT Inhibitor Capivasertib in Patients with BRCA1/2- and Non-BRCA1/2-Mutant Cancers.
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Date
2020-10-01ICR Author
Author
Yap, TA
Kristeleit, R
Michalarea, V
Pettitt, SJ
Lim, JSJ
Carreira, S
Roda, D
Miller, R
Riisnaes, R
Miranda, S
Figueiredo, I
Rodrigues, DN
Ward, S
Matthews, R
Parmar, M
Turner, A
Tunariu, N
Chopra, N
Gevensleben, H
Turner, NC
Ruddle, R
Raynaud, FI
Decordova, S
Swales, KE
Finneran, L
Hall, E
Rugman, P
Lindemann, JPO
Foxley, A
Lord, CJ
Banerji, U
Plummer, R
Basu, B
Lopez, JS
Drew, Y
de Bono, JS
Type
Journal Article
Metadata
Show full item recordAbstract
Preclinical studies have demonstrated synergy between PARP and PI3K/AKT pathway inhibitors in BRCA1 and BRCA2 (BRCA1/2)-deficient and BRCA1/2-proficient tumors. We conducted an investigator-initiated phase I trial utilizing a prospective intrapatient dose- escalation design to assess two schedules of capivasertib (AKT inhibitor) with olaparib (PARP inhibitor) in 64 patients with advanced solid tumors. Dose expansions enrolled germline BRCA1/2-mutant tumors, or BRCA1/2 wild-type cancers harboring somatic DNA damage response (DDR) or PI3K-AKT pathway alterations. The combination was well tolerated. Recommended phase II doses for the two schedules were: olaparib 300 mg twice a day with either capivasertib 400 mg twice a day 4 days on, 3 days off, or capivasertib 640 mg twice a day 2 days on, 5 days off. Pharmacokinetics were dose proportional. Pharmacodynamic studies confirmed phosphorylated (p) GSK3β suppression, increased pERK, and decreased BRCA1 expression. Twenty-five (44.6%) of 56 evaluable patients achieved clinical benefit (RECIST complete response/partial response or stable disease ≥ 4 months), including patients with tumors harboring germline BRCA1/2 mutations and BRCA1/2 wild-type cancers with or without DDR and PI3K-AKT pathway alterations. SIGNIFICANCE: In the first trial to combine PARP and AKT inhibitors, a prospective intrapatient dose- escalation design demonstrated safety, tolerability, and pharmacokinetic-pharmacodynamic activity and assessed predictive biomarkers of response/resistance. Antitumor activity was observed in patients harboring tumors with germline BRCA1/2 mutations and BRCA1/2 wild-type cancers with or without somatic DDR and/or PI3K-AKT pathway alterations.This article is highlighted in the In This Issue feature, p. 1426.
Research team
Molecular Oncology
Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Medicine (de Bono Prostate)
Cancer Biomarkers
Clinical PD Biomarker Group
Clinical Pharmacology – Adaptive Therapy
ICR-CTSU Urology and Head and Neck Trials Team
Prostate Cancer Targeted Therapy Group
Gene Function
Language
eng
Date accepted
2020-06-09
License start date
2020-10
Citation
Cancer discovery, 2020, 10 (10), pp. 1528 - 1543
Publisher
AMER ASSOC CANCER RESEARCH