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.
de Bono, JS
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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>.
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Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Medicine (de Bono Prostate)
Clinical PD Biomarker Group
Clinical Pharmacology – Adaptive Therapy
ICR-CTSU Urology and Head and Neck Trials Team
Prostate Cancer Targeted Therapy Group
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Cancer discovery, 2020, 10 (10), pp. 1528 - 1543