Phase I Trial of the PARP Inhibitor Olaparib and AKT Inhibitor Capivasertib in Patients with BRCA1/2- and Non-BRCA1/2-Mutant Cancers.

Abstract

Preclinical 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.

• Authors: Timothy A Yap, Rebecca Kristeleit, Vasiliki Michalarea, Stephen J Pettitt, Joline S J Lim, Suzanne Carreira, Desamparados Roda, Rowan Miller, Ruth Riisnaes, Susana Miranda, Ines Figueiredo, Daniel Nava Rodrigues, Sarah Ward, Ruth Matthews, Mona Parmar, Alison Turner, Nina Tunariu, Neha Chopra, Heidrun Gevensleben, Nicholas C Turner, Ruth Ruddle, Florence I Raynaud, Shaun Decordova, Karen E Swales, Laura Finneran, Emma Hall, Paul Rugman, Justin P O Lindemann, Andrew Foxley, Christopher J Lord, Udai Banerji, Ruth Plummer, Bristi Basu, Juanita S Lopez, Yvette Drew, Johann S de Bono
• Journal: Cancer discovery (Cancer Discov) Vol. 10 Issue 10 Pg. 1528-1543 (10 2020) ISSN: 2159-8290 [Electronic] United States
• PMID: 32532747 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• BRCA1 Protein
• BRCA1 protein, human
• BRCA2 Protein
• BRCA2 protein, human
• Phthalazines
• Piperazines
• Poly(ADP-ribose) Polymerase Inhibitors
• Pyrimidines
• Pyrroles
• capivasertib
• olaparib

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• BRCA1 Protein (metabolism)
• BRCA2 Protein (metabolism)
• Female
• Humans
• Middle Aged
• Phthalazines (pharmacology, therapeutic use)
• Piperazines (pharmacology, therapeutic use)
• Poly(ADP-ribose) Polymerase Inhibitors (pharmacology, therapeutic use)
• Pyrimidines (pharmacology, therapeutic use)
• Pyrroles (pharmacology, therapeutic use)