The emerging role of capivasertib in breast cancer

• Published in: Breast (Edinburgh) 2022-06, Vol.63, p.157-167
• Main Authors: Andrikopoulou, Angeliki, Chatzinikolaou, Spyridoula, Panourgias, Evangelia, Kaparelou, Maria, Liontos, Michalis, Dimopoulos, Meletios-Athanasios, Zagouri, Flora
• Format: Article
• Language: English
• Subjects: AKT inhibitor; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Breast cancer; Breast Neoplasms - pathology; Capivasertib; Class I Phosphatidylinositol 3-Kinases - genetics; Female; Fulvestrant; Humans; Mutation; Paclitaxel; Phosphatidylinositol 3-Kinases; PI3K/AKT/mTOR pathway; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins c-akt - genetics; Pyrimidines; Pyrroles; Receptor, ErbB-2 - genetics; Review
• ISSN: 0960-9776; 1532-3080
• DOI: 10.1016/j.breast.2022.03.018

Over 50% of breast tumors harbor alterations in one or more genes of the phosphatidylinositol 3-kinase (PI3K) pathway including PIK3CA mutations (31%), PTEN loss (34%), PTEN mutations (5%) and AKT1 mutations (3%). While PI3K and mTOR inhibitors are already approved in advanced breast cancer, AKT inhibitors have been recently developed as a new therapeutic approach. Capivasertib (AZD5363) is a novel, selective ATP-competitive pan-AKT kinase inhibitor that exerts similar activity against the three AKT isoforms, AKT1, AKT2, and AKT3. Preclinical studies demonstrated efficacy of capivasertib in breast cancer cell lines as a single agent or in combination with anti-HER2 agents and endocrine treatment, especially in tumors with PIK3CA or MTOR alterations. Phase I/II studies demonstrated greater efficacy when capivasertib was co-administered with paclitaxel, fulvestrant in hormone receptor (HR)-positive, HER2-negative breast cancer or olaparib. The recommended phase II dose of capivasertib as monotherapy was 480 mg bid on a 4-days-on, 3-days-off dosing schedule. Toxicity profile proved to be manageable with hyperglycemia (20–24%), diarrhea (14–17%) and maculopapular rash (11–16%) being the most common grade ≥3 adverse events. Ongoing Phase III trials of capivasertib in combination with fulvestrant (CAPItello-291), CDK4/6 inhibitor palbociclib (CAPItello-292) and paclitaxel (CAPItello- 290) will better clarify the therapeutic role of capivasertib in breast cancer. •Phosphatidylinositol-3-kinase (PI3K)/Akt (PI3K/AKT) pathway is one of the most commonly altered pathways in breast cancer.•Capivasertib (AZD5363) is a highly potent Akt kinase inhibitor with activity against the three isoforms AKT1, AKT2, and AKT3.•Preclinical studies demonstrated efficacy of capivasertib either alone or in combination with anti-HER2 agents, chemotherapy and endocrine treatment.•Dose-limiting toxicities include hyperglycemia (20–24%), diarrhea (14–17%) and maculopapular rash (11–16%).•Capivasertib increased susceptibility to paclitaxel (PAKT, BEECH), fulvestrant (NCT01226316, FAKTION) or Olaparib (ComPAKT).