Data from Phase I Trial of the PARP Inhibitor Olaparib and AKT Inhibitor Capivasertib in Patients with &lt;i&gt;BRCA1/2&lt;/i&gt;- and Non–&lt;i&gt;BRCA1/2&lt;/i&gt;-Mutant Cancers

Emma Hall,Nicholas C Turner,Johann S De Bono,Paul Rugman,Daniel Nava Rodrigues,Vasiliki Michalarea,Heidrun Gevensleben,Ruth Matthews,Ruth Riisnaes,Shaun Decordova,Stephen J Pettitt,Sarah Ward,Udai Banerji,Desamparados Roda,Florence I Raynaud,Mona Parmar,Christopher J Lord,Laura Finneran,Rebecca Kristeleit,Ines Figueiredo,Justin P.O Lindemann,Suzanne Carreira,Timothy A Yap,Alison Turner,Rowan Miller,Ruth Plummer,Yvette Drew,Andrew Foxley,Ruth Ruddle,Nina Tunariu,Neha Chopra,Bristi Basu,Joline S.J Lim,Susana Miranda,Juanita Lopez ,Karen E Swales

doi:10.1158/2159-8290.c.6547955.v1

Abstract

<div>AbstractPreclinical 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</div>

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