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Ref Type Journal Article
PMID (32532747)
Authors Yap TA, Kristeleit R, Michalarea V, Pettitt SJ, Lim JSJ, Carreira S, Roda D, Miller R, Riisnaes R, Miranda S, Figueiredo I, Nava Rodrigues D, Ward S, Matthews R, Parmar M, Turner A, Tunariu N, Chopra N, Gevensleben H, Turner NC, Ruddle R, Raynaud FI, Decordova SA, 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
Title Phase I trial of the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib and AKT inhibitor capivasertib in patients with BRCA1/2 and non-BRCA1/2 mutant cancers.
Journal Cancer discovery
Vol
Issue
Date 2020 Jun 12
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Capivasertib AZD5363 Akt Inhibitor (Pan) 19 Capivasertib (AZD5363) decreases PI3K/AKT/mTOR signaling by inhibition of AKT1, AKT2, and AKT3, resulting in decreased cell proliferation (PMID: 22294718, PMID: 32532747, PMID: 32312891).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown Advanced Solid Tumor not applicable Capivasertib + Olaparib Phase I Actionable In a Phase I trial, Capivasertib (AZD5363) and Lynparza (olaparib) combination therapy was well-tolerated, and resulted in a clinical benefit rate of 44.6% (25/56, 14 partial responses, 11 stable disease >= 4 months) in patients with advanced solid tumors (PMID: 32532747; NCT02338622). 32532747