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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.
LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].
Show detailsOVERVIEW
Introduction
Capivasertib is a small molecule inhibitor of serine/threonine kinase 1, 2 and 3 and is used in combination with other antineoplastic agents to treat selected adults with locally advanced or metastatic breast cancer. Capivasertib is associated with transient elevations in serum aminotransferase levels during therapy but has not been linked to episodes of clinically apparent liver injury with jaundice.
Background
Capivasertib (kap eye” va ser’ tib) is an orally available, specific inhibitor of all three isoforms of serine/threonine kinase (AKT1, AKT2, and AKT3) that is used in combination with fulvestrant in the therapy of advanced or metastatic breast cancer with one or more mutations or alterations in AKT, the phosphatidylinositol 3 kinase catalytic alpha subunit p110α (PIK3-CA), or the phosphatase and tensin homolog (PTEN) and is positive for hormone receptor (HR) and negative for human epidermal growth factor receptor 2 (HER2). At least one of these three mutated genes is found in a large proportion of cases of refractory, advanced or metastatic HR-positive breast cancer. PIK3 and PTEN are downstream signaling pathways of AKT and thus are inhibited if AKT isomers are blocked. In cell lines, capivasertib induced apoptosis in PIK3-CA, AKT, and PTEN mutated breast cancer cell lines and demonstrated antitumor activity in animal xenograft models of these mutated breast cancers. In a large, controlled trial, patients with HR-positive and HER2-negative advanced or metastatic breast cancer harboring one or more of these mutations were treated with fulvestrant combined with either capivasertib or placebo in 28 day cycles. The median progression-free survival was superior with capivasertib [7.2 months] compared to placebo [3.6 months]. Capivasertib was approved in 2023 in the United States as treatment for patients with locally advanced or metastatic HR-positive, HER2-negative breast cancer with mutations in PIK3-CA, AKT or PTEN. Capivasertib is available in tablets of 160 and 200 mg under the brand name Truqap. The recommended dose is 400 mg twice daily for 4 days followed by 3 days off, continuing until unacceptable toxicity or disease progression. Side effects are common and include mild-to-moderate diarrhea, fatigue, nausea, vomiting, stomatitis, and rash. Laboratory abnormalities can include increases in fasting and random glucose levels, creatinine, and triglycerides, as well as decreases in neutrophils, lymphocytes, and hemoglobin. Less frequent but potentially severe adverse events include severe hyperglycemia, rash, diarrhea, and embryo-fetal toxicity.
Hepatotoxicity
In the prelicensure trials of capivasertib in combination with fulvestrant as therapy of advanced or metastatic breast cancer, liver test abnormalities were frequent, with elevations in ALT levels in 23% compared to 13% of those on placebo and fulvestrant. However, the enzyme elevations were usually transient, mild-to-moderate in severity and not associated with symptoms or jaundice. ALT elevations above 5 times the upper limit of normal (ULN) arose in 3% of patients on capivasertib vs 0% with placebo. Because capivasertib was always given in combination with a hormonal agent, it was not always possible to attribute the liver test abnormalities to capivasertib alone. There were no discontinuations of capivasertib because of liver test abnormalities and no episodes of clinically apparent liver injury or deaths from liver failure. Since approval and clinical availability of capivasertib, there have been no published case reports of clinically apparent liver injury with jaundice, but clinical experience with its use has been limited.
Likelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury).
Mechanism of Injury
The causes of serum enzyme elevations or liver injury from capivasertib therapy are possibly due to direct toxicity of the multi-kinase inhibitor. Capivasertib is primarily metabolized in the liver by the hepatic microsomal enzyme CYP3A4. For this reason, inhibitors of CYP3A can increase capivasertib exposure, possibly increasing its toxicity, and inducers of CYP3A can decrease capivasertib exposure, possibly decreasing efficacy. For these reasons, use of concomitant CYP3A inhibitors or inducers while using capivasertib should be avoided, and dose adjustments may be needed if they are considered necessary.
Outcome and Management
The product label for capivasertib does not recommend monitoring of liver tests during therapy. If serum aminotransferase elevations above 5 times the upper limit of normal are identified or if any elevations are accompanied by jaundice or symptoms, therapy should be at least temporarily discontinued until the cause is apparent. There is no evidence to suggest a cross reactivity in risk for adverse events, hypersensitivity, or hepatic injury between capivasertib and other kinase inhibitors used to treat breast cancer, such as palbociclib, ribociclib, alpelisib, and inavolisib.
Drug Class: Antineoplastic Agents, Protein Kinase Inhibitors
Other Kinase Inhibitors Used for Breast Cancer: Alpelisib, Inavolisib, Ribociclib, Talazoparib, Tucatinib
PRODUCT INFORMATION
REPRESENTATIVE TRADE NAMES
Capivasertib – Truqap®
DRUG CLASS
Antineoplastic Agents
Product labeling at DailyMed, National Library of Medicine, NIH
CHEMICAL FORMULA AND STRUCTURE
| DRUG | CAS REGISTRY NO. | MOLECULAR FORMULA | STRUCTURE |
|---|---|---|---|
| Capivasertib | 1143532-39-1 | C21-H25-ClN6-O2 |
|
ANNOTATED BIBLIOGRAPHY
References updated: 05 April 2025
Abbreviations: AKT, serine/threonine kinase; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; PIK3, phosphatidylinositol-3-kinase; PIK3-CA, PIK3 catalytic alpha subunit p110α; PTEN, phosphatase and tensin homolog; ULN, upper limit of the normal range.
- Zimmerman HJ. Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.(Review of hepatotoxicity published in 1999 before the availability of tyrosine kinase inhibitors such as capivasertib).
- DeLeve LD. Erlotinib. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 556.(Review of hepatotoxicity of cancer chemotherapeutic agents discusses several tyrosine kinase inhibitors including imatinib, gefitinib, erlotinib and crizotinib, but not capivasertib).
- Wellstein A, Giaccone G, Atkins MB, Sausville EA. Pathway-targeted therapies: monoclonal antibodies, protein kinase inhibitors, and various small molecules. In, Brunton LL, Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 1203-36.(Textbook of pharmacology and therapeutics).
- FDA. Multi-Discipline Review. 2023. https://www
.accessdata .fda.gov/drugsatfda_docs /nda/2023/218197Orig1s000MultidisciplineR.pdf (FDA review of the data on efficacy and safety of capivasertib in support of its approval for advanced or metastatic breast cancer in the US, mentions that liver test abnormalities were frequent in the patients who received capivasertib and fulvestrant vs placebo and fulvestrant, ALT elevations arising in 23% vs 13% which were above 5 times the upper limit of normal (ULN) in 3% vs 0%, but that there were no instances of clinically apparent liver injury with jaundice or life-threatening or fatal liver injury). - Spraggs CF, Xu CF, Hunt CM. Genetic characterization to improve interpretation and clinical management of hepatotoxicity caused by tyrosine kinase inhibitors. Pharmacogenomics 2013; 14: 541-54. [PubMed: 23556451](Review of genetic associations of serum ALT and bilirubin elevations during therapy with tyrosine kinase inhibitors focusing on lapatinib and pazopanib; capivasertib is not discussed).
- Shah RR, Morganroth J, Shah DR. Hepatotoxicity of tyrosine kinase inhibitors: clinical and regulatory perspectives. Drug Saf 2013; 36: 491-503. [PubMed: 23620168](Review of the hepatotoxicity of 18 tyrosine kinase inhibitors approved for use in cancer in the US as of 2013, before the availability of capivasertib which is not discussed).
- Schmid P, Abraham J, Chan S, Wheatley D, Brunt AM, Nemsadze G, Baird RD, Park YH, et al. Capivasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer: the PAKT trial. J Clin Oncol. 2020;38:423-433. [PubMed: 31841354](Among 140 women with triple negative, metastatic breast cancer treated with paclitaxel and either capivasertib or placebo, progression-free survival was 5.9 vs 4.2 months (but was 9.3 vs 3.7 months in the 28 patients with mutations in PIK3-CA, AKT, or PTEN); adverse events arose in 97% vs 91% and were severe in 54% vs 26% of participants, which were most frequently diarrhea, fatigue, rash, infection, and neutropenia; no mention of ALT elevations or hepatotoxicity).
- Turner NC, Oliveira M, Howell SJ, Dalenc F, Cortes J, Gomez Moreno HL, Hu X, et al.; CAPItello-291 Study Group. Capivasertib in hormone receptor-positive advanced breast cancer. N Engl J Med. 2023;388:2058-2070. [PMC free article: PMC11335038] [PubMed: 37256976](Among 708 adults with HR-positive, HER2-negative refractory, advanced or metastatic breast cancer treated with fulvestrant and either capivasertib or placebo, progression-free survival was 7.2 vs 3.6 months, and adverse events arose in most patients and were severe in 16% vs 8%, the most frequent adverse events being diarrhea [72% vs 20%], nausea [35% vs 15%], and severe rash [12% vs 13%]; adverse events leading to discontinuation in 13% vs 2.3%; no mention of ALT elevations or hepatotoxicity).
- Capivasertib (Truqap) for breast cancer. Med Lett Drugs Ther. 2024;66:e32-e33. [PubMed: 38412269](Concise review of the mechanism of action, clinical efficacy, safety, and costs of capivasertib shortly after its approval for use in breast cancer in the US mentions that diarrhea is the most frequent adverse event and that nausea, fatigue, vomiting, stomatitis, cutaneous adverse reactions, cytopenias, and hyperglycemia have been reported; no mention of ALT elevations or hepatotoxicity).
- Rugo HS, Oliveira M, Howell SJ, Dalenc F, Cortes J, Gomez HL, Hu X, et al. Capivasertib and fulvestrant for patients with hormone receptor-positive advanced breast cancer: characterization, time course, and management of frequent adverse events from the phase III CAPItello-291 study. ESMO Open. 2024;9:103697. [PMC free article: PMC11406080] [PubMed: 39241495](Review of the most frequent adverse events identified in the large, randomized, placebo-controlled trial of capivasertib given in combination with fulvestrant for patients with advanced breast cancer discusses diarrhea, rash, and hyperglycemia in detail; no mention of ALT elevations or hepatotoxicity).
- Dilawari A, Buturla J, Osgood C, Gao X, Chen W, Ricks TK, Schaefer T, et al. US Food and Drug Administration approval summary: capivasertib with fulvestrant for hormone receptor-positive, human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer with PIK3CA/AKT1/PTEN alterations. J Clin Oncol. 2024;42:4103-4113. [PMC free article: PMC11588547] [PubMed: 39159418](Summary of the data on efficacy and safety of capivasertib that supported its approval by the FDA as therapy of HR-positive, HER2 negative advanced breast cancer with alterations in PIK3CA, AKT1, or PTEN, discusses the major adverse events but does not mention ALT elevations or hepatotoxicity).
- PMCPubMed Central citations
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- Review Inavolisib.[LiverTox: Clinical and Researc...]Review Inavolisib.. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. 2012
- Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive breast cancer (FAKTION): a multicentre, randomised, controlled, phase 2 trial.[Lancet Oncol. 2020]Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive breast cancer (FAKTION): a multicentre, randomised, controlled, phase 2 trial.Jones RH, Casbard A, Carucci M, Cox C, Butler R, Alchami F, Madden TA, Bale C, Bezecny P, Joffe J, et al. Lancet Oncol. 2020 Mar; 21(3):345-357. Epub 2020 Feb 5.
- Review Lazertinib.[LiverTox: Clinical and Researc...]Review Lazertinib.. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. 2012
- Review Amivantamab.[LiverTox: Clinical and Researc...]Review Amivantamab.. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. 2012
- BEECH: a dose-finding run-in followed by a randomised phase II study assessing the efficacy of AKT inhibitor capivasertib (AZD5363) combined with paclitaxel in patients with estrogen receptor-positive advanced or metastatic breast cancer, and in a PIK3CA mutant sub-population.[Ann Oncol. 2019]BEECH: a dose-finding run-in followed by a randomised phase II study assessing the efficacy of AKT inhibitor capivasertib (AZD5363) combined with paclitaxel in patients with estrogen receptor-positive advanced or metastatic breast cancer, and in a PIK3CA mutant sub-population.Turner NC, Alarcón E, Armstrong AC, Philco M, López Chuken YA, Sablin MP, Tamura K, Gómez Villanueva A, Pérez-Fidalgo JA, Cheung SYA, et al. Ann Oncol. 2019 May 1; 30(5):774-780.
- Capivasertib - LiverToxCapivasertib - LiverTox
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