| Title: |
Phase I Trial of the PARP Inhibitor Olaparib and AKT Inhibitor Capivasertib in Patients with BRCA1/2- and Non-BRCA1/2-Mutant Cancers. |
| Authors: |
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 |
| Contributors: |
Pettitt, Stephen; Carreira, Suzanne; Miranda, Susana; Figueiredo, Ines; Tunariu, Nina; Turner, Nicholas; Ruddle, Ruth; Raynaud, Florence; Swales, Karen; Finneran, Laura; Hall, Emma; Lord, Christopher; Banerji, Udai; Lopez, Juanita; De Bono, Johann |
| Publisher Information: |
AMER ASSOC CANCER RESEARCH |
| Publication Year: |
2020 |
| Collection: |
The Institute of Cancer Research (ICR): Publications Repository |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
Print-Electronic; 1543; application/pdf |
| Language: |
English |
| ISSN: |
2159-8290; 2159-8274 |
| Relation: |
Cancer discovery, 2020, 10 (10), pp. 1528 - 1543; https://repository.icr.ac.uk/handle/internal/3762 |
| Availability: |
https://repository.icr.ac.uk/handle/internal/3762 |
| Rights: |
https://creativecommons.org/licenses/by/4.0 |
| Accession Number: |
edsbas.E7B65843 |
| Database: |
BASE |