Phase I Trial of the PARP Inhibitor Olaparib and AKT Inhibitor Capivasertib in Patients with BRCA1/2- and Non-BRCA1/2-Mutant Cancers.
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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DOI：
10.1158/2159-8290.cd-20-0163
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发表时间：
2020-10
期刊：
影响因子：
28.2
通讯作者：
de Bono JS
中科院分区：
文献类型：
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作者：
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
Preclinical studies have demonstrated synergy between poly(ADP-ribose) polymerase (PARP) and phosphatidylinositol-3-kinase (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-wildtype cancers harboring somatic DNA damage response (DDR) or PI3K/AKT pathway alterations. The combination was well-tolerated. Recommended phase 2 doses for the two schedules were: olaparib 300mg BID with either capivasertib 400mg BID 4- days-on, 3-days-off, or capivasertib 640mg BID 2-days-on, 5-days-off. Pharmacokinetics were dose-proportional. Pharmacodynamic studies confirmed pGSK3β suppression, increased pERK and decreased BRCA1 expression. 25 (44.6%) of 56 evaluable patients achieved clinical benefit (RECIST CR/PR or stable disease ≥4 months), including patients with tumors harboring germline BRCA1/2- mutations and BRCA1/2-wildtype cancers with or without DDR and PI3K/AKT pathway alterations.
