{"database":"biostudies-literature","file_versions":[],"scores":{"citationCount":0,"reanalysisCount":0,"viewCount":41,"searchCount":0},"additional":{"submitter":["Yap TA"],"funding":["NIHR","Cancer Research UK","National Institute for Health Research (NIHR)","NCI NIH HHS","AstraZeneca"],"pagination":["1528-1543"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC7611385"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["10(10)"],"pubmed_abstract":["Preclinical studies have demonstrated synergy between PARP and PI3K/AKT pathway inhibitors in <i>BRCA1</i> and <i>BRCA2</i> (<i>BRCA1/2)</i>-deficient and <i>BRCA1/2</i>-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 <i>BRCA1/2</i>-mutant tumors, or <i>BRCA1/2</i> 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 <i>BRCA1/2</i> mutations and <i>BRCA1/2</i> 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 <i>BRCA1/2</i> mutations and <i>BRCA1/2</i> wild-type cancers with or without somatic DDR and/or PI3K-AKT pathway alterations.<i>This article is highlighted in the In This Issue feature, p. 1426</i>."],"journal":["Cancer discovery"],"pubmed_title":["Phase I Trial of the PARP Inhibitor Olaparib and AKT Inhibitor Capivasertib in Patients with <i>BRCA1/2</i>- and Non-<i>BRCA1/2</i>-Mutant Cancers."],"pmcid":["PMC7611385"],"funding_grant_id":["24439","P30 CA016672","14276","AZD5363","RP-2016-07-028","NF-SI-0617-10099","25237","11566","22897"],"pubmed_authors":["Chopra N","Roda D","Gevensleben H","de Bono JS","Lindemann JPO","Turner A","Finneran L","Carreira S","Miller R","Ward S","Riisnaes R","Basu B","Pettitt SJ","Michalarea V","Kristeleit R","Rodrigues DN","Plummer R","Lopez JS","Turner NC","Hall E","Swales KE","Matthews R","Figueiredo I","Raynaud FI","Lord CJ","Banerji U","Drew Y","Lim JSJ","Miranda S","Yap TA","Rugman P","Tunariu N","Parmar M","Decordova S","Ruddle R","Foxley A"],"view_count":["41"],"additional_accession":[]},"is_claimable":false,"name":"Phase I Trial of the PARP Inhibitor Olaparib and AKT Inhibitor Capivasertib in Patients with <i>BRCA1/2</i>- and Non-<i>BRCA1/2</i>-Mutant Cancers.","description":"Preclinical studies have demonstrated synergy between PARP and PI3K/AKT pathway inhibitors in <i>BRCA1</i> and <i>BRCA2</i> (<i>BRCA1/2)</i>-deficient and <i>BRCA1/2</i>-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 <i>BRCA1/2</i>-mutant tumors, or <i>BRCA1/2</i> 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 <i>BRCA1/2</i> mutations and <i>BRCA1/2</i> 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 <i>BRCA1/2</i> mutations and <i>BRCA1/2</i> wild-type cancers with or without somatic DDR and/or PI3K-AKT pathway alterations.<i>This article is highlighted in the In This Issue feature, p. 1426</i>.","dates":{"release":"2020-01-01T00:00:00Z","publication":"2020 Oct","modification":"2024-11-20T19:12:23.17Z","creation":"2022-02-11T00:13:07.389Z"},"accession":"S-EPMC7611385","cross_references":{"pubmed":["32532747"],"doi":["10.1158/2159-8290.cd-20-0163","10.1158/2159-8290.CD-20-0163"]}}