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Lookup NU author(s): Dr Yvette DrewORCiD
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Preclinical studies have demonstrated synergy between PARP and PI3K/AKT path- way inhibitors in BRCA1 and BRCA2 (BRCA1/2)–de cient and BRCA1/2-pro cient 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 inhibi- tor) 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 con rmed phosphorylated (p) GSK3β suppression, increased pERK, and decreased BRCA1 expression. Twenty- ve (44.6%) of 56 evaluable patients achieved clinical bene t (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 withoutDDR and PI3K–AKT pathway alterations.SIGNIfICANCE: In the rst trial to combine PARP and AKT inhibitors, a prospective intrapatient dose- escalation design demonstrated safety, tolerability, and pharmacokinetic–pharmacodynamic activ- ity 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.
Author(s): 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
Publication type: Article
Publication status: Published
Journal: Cancer Discovery
Year: 2020
Volume: 10
Issue: 10
Pages: 1528-1543
Print publication date: 01/10/2020
Online publication date: 12/06/2020
Acceptance date: 09/06/2020
ISSN (print): 2159-8274
ISSN (electronic): 2159-8290
Publisher: American Association for Cancer Research
URL: https://doi.org/10.1158/2159-8290.CD-20-0163
DOI: 10.1158/2159-8290.CD-20-0163
Notes: key publication Yvette Drew senior author Newcastle
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