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Capivasertib: First Approval

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Abstract

Capivasertib (Truqap™) is an orally available, small-molecule pan-AKT inhibitor being developed by AstraZeneca for the treatment of various cancers, including breast and prostate cancers. Capivasertib received its first approval, in the USA, in November 2023 for use in combination with fulvestrant for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor 2 (HER2)-negative, locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN-alterations following progression on at least one endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy. Capivasertib is also under regulatory review for HR-positive, HER2-negative breast cancer in the EU and several other countries, and in phase III clinical development for use (in combination with other anti-cancer agents) in the treatment of triple-negative breast cancer, castration-resistant prostate cancer, and hormone-sensitive prostate cancer. This article summarizes the milestones in the development of capivasertib leading to this first approval for HR-positive, HER2-negative, locally advanced or metastatic breast cancer.

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References

  1. Millis SZ, Ikeda S, Reddy S, et al. Landscape of phosphatidylinositol-3-kinase pathway alterations across 19 784 diverse solid tumors. JAMA Oncol. 2016;2(12):1565–73.

    Article  PubMed  Google Scholar 

  2. Rascio F, Spadaccino F, Rocchetti MT, et al. The pathogenic role of PI3K/AKT pathway in cancer onset and drug resistance: an updated review. Cancers (Basel). 2021;13(16):1–15.

    Article  Google Scholar 

  3. AstraZeneca. AstraZeneca advances ambition to redefine care for blood cancer at ASH 2021 [media release]. 2021. https://www.astrazeneca.com/media-centre/press-releases/2021/astrazeneca-advances-ambition-to-redefine-care-for-blood-cancer-at-ash-2021.html#. Accessed 11 Jan 2024.

  4. AstraZeneca. Truqap (capivasertib) plus Faslodex approved in the US for patients with advanced HR-positive breast cancer [media release]. 2023. https://www.astrazeneca.com/media-centre/press-releases/2023/truqap-approved-in-us-for-hr-plus-breast-cancer.html. Accessed 11 Jan 2024.

  5. US FDA. TRUQAP™ (capivasertib) tablets, for oral use. 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/218197s000lbl.pdf. Accessed 11 Jan 2024.

  6. Davies BR, Greenwood H, Dudley P, et al. Preclinical pharmacology of AZD5363, an inhibitor of AKT: pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background. Mol Cancer Ther. 2012;11(4):873–87.

    Article  CAS  PubMed  Google Scholar 

  7. US FDA. FDA approves capivasertib with fulvestrant for breast cancer [media release]. 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-capivasertib-fulvestrant-breast-cancer. Accessed 11 Jan 2024.

  8. Astex Pharmaceuticals Inc. Clinical candidate from PKB/AKT collaboration with Astex selected by AstraZeneca [media release]. 2010. https://astx.com/wp-content/uploads/2016/11//ASTX_News_2010_1_7_General_Releases.pdf. Accessed 11 Jan 2024.

  9. John P, Waldt N, Liebich J, et al. AKT1E17K-mutated meningioma cell lines respond to treatment with the AKT inhibitor AZD5363. Neuropathol Appl Neurobiol. 2022;48(2): e12780.

    Article  CAS  PubMed  Google Scholar 

  10. Zhang Y, Zheng Y, Faheem A, et al. A novel AKT inhibitor, AZD5363, inhibits phosphorylation of AKT downstream molecules, and activates phosphorylation of mTOR and SMG-1 dependent on the liver cancer cell type. Oncol Lett. 2016;11(3):1685–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. De Velasco MA, Kura Y, Yoshikawa K, et al. Efficacy of targeted AKT inhibition in genetically engineered mouse models of PTEN-deficient prostate cancer. Oncotarget. 2016;7(13):15959–76.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Li J, Davies BR, Han S, et al. The AKT inhibitor AZD5363 is selectively active in PI3KCA mutant gastric cancer, and sensitizes a patient-derived gastric cancer xenograft model with PTEN loss to Taxotere. J Transl Med. 2013;11:241.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Crafter C, Vincent JP, Tang E, et al. Combining AZD8931, a novel EGFR/HER2/HER3 signalling inhibitor, with AZD5363 limits AKT inhibitor induced feedback and enhances antitumour efficacy in HER2-amplified breast cancer models. Int J Oncol. 2015;47(2):446–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Fox EM, Kuba MG, Miller TW, et al. Autocrine IGF-I/insulin receptor axis compensates for inhibition of AKT in ER-positive breast cancer cells with resistance to estrogen deprivation. Breast Cancer Res. 2013;15(4):R55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Toren P, Kim S, Cordonnier T, et al. Combination AZD5363 with enzalutamide significantly delays enzalutamide-resistant prostate cancer in preclinical models. Eur Urol. 2015;67(6):986–90.

    Article  CAS  PubMed  Google Scholar 

  16. Ribas R, Pancholi S, Guest SK, et al. AKT antagonist AZD5363 influences estrogen receptor function in endocrine-resistant breast cancer and synergizes with fulvestrant (ICI182780) in vivo. Mol Cancer Ther. 2015;14(9):2035–48.

    Article  CAS  PubMed  Google Scholar 

  17. Miller C, Sommavilla R, Murphy D, et al. The effect of food and acid-reducing agents on the pharmacokinetic profile of capivasertib: results from a randomized, crossover study. Br J Clin Pharmacol. 2023;89(11):3330–9.

    Article  CAS  PubMed  Google Scholar 

  18. Miller C, Sommavilla R, Barry ST, et al. Pharmacokinetics of the Akt serine/threonine protein kinase inhibitor, capivasertib, administered to healthy volunteers in the presence and absence of the CYP3A4 inhibitor itraconazole. Clin Pharmacol Drug Dev. 2023;12(9):856–62.

    Article  CAS  PubMed  Google Scholar 

  19. Banerji U, Dean EJ, Pérez-Fidalgo JA, et al. A phase I open-label study to identify a dosing regimen of the pan-AKT inhibitor AZD5363 for evaluation in solid tumors and in PIK3CA-mutated breast and gynecologic cancers. Clin Cancer Res. 2018;24(9):2050–9.

    Article  CAS  PubMed  Google Scholar 

  20. Turner NC, Oliveira M, Howell SJ, et al. Capivasertib in hormone receptor-positive advanced breast cancer. N Engl J Med. 2023;388(22):2058–70.

    Article  CAS  PubMed  Google Scholar 

  21. Smyth LM, Tamura K, Oliveira M, et al. Capivasertib, an AKT kinase inhibitor, as monotherapy or in combination with fulvestrant in patients with AKT1E17K-mutant, ER-positive metastatic breast cancer. Clin Cancer Res. 2020;26(15):3947–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Smyth LM, Batist G, Meric-Bernstam F, et al. Selective AKT kinase inhibitor capivasertib in combination with fulvestrant in PTEN-mutant ER-positive metastatic breast cancer. NPJ Breast Cancer. 2021;7(1):44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Jones RH, Casbard A, Carucci M, et al. 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;21(3):345–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Howell SJ, Casbard A, Carucci M, et al. Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive, HER2-negative breast cancer (FAKTION): overall survival, updated progression-free survival, and expanded biomarker analysis from a randomised, phase 2 trial. Lancet Oncol. 2022;23(7):851–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Breast cancer - version 5.2023. 2023. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed 11 Jan 2024.

  26. Turner NC, Alarcón E, Armstrong AC, et al. 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;30(5):774–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Schmid P, Abraham J, Chan S, 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(5):423–33.

    Article  CAS  PubMed  Google Scholar 

  28. Schmid P, Abraham J, Chan S, et al. Mature survival update of the double-blind placebo-controlled randomised phase II PAKT trial of first-line capivasertib plus paclitaxel for metastatic triple-negative breast cancer [abstract PD1-11]. Cancer Res. 2021;81(4 Suppl):PD1-11.

    Google Scholar 

  29. Schmid P, Nowecki Z, Im SA, et al. BEGONIA: phase 1b/2 study of durvalumab (D) combinations in locally advanced/metastatic triple-negative breast cancer (TNBC): results from Arm 1 D + paclitaxel (P), Arm 2 D+P + capivasertib (C), and Arm 5 D+P + oleclumab (O) [abstract PD10-03]. Cancer Res. 2022;82(4 Suppl):PD10–3.

    Google Scholar 

  30. Crabb SJ, Griffiths G, Dunkley D, et al. Overall survival update for patients with metastatic castration-resistant prostate cancer treated with capivasertib and docetaxel in the phase 2 ProCAID clinical trial. Eur Urol. 2022;82(5):512–5.

    Article  CAS  PubMed  Google Scholar 

  31. Crabb SJ, Griffiths G, Marwood E, et al. Pan-AKT inhibitor capivasertib with docetaxel and prednisolone in metastatic castration-resistant prostate cancer: a randomized, placebo-controlled phase II trial (ProCAID). J Clin Oncol. 2021;39(3):190–201.

    Article  CAS  PubMed  Google Scholar 

  32. Crabb SJ, Ye DW, Uemura H, et al. CAPItello-280: a phase III study of capivasertib and docetaxel versus placebo and docetaxel in metastatic castration-resistant prostate cancer [abstract TPS287]. J Clin Oncol. 2023;41(6_Suppl):TPS287.

    Article  Google Scholar 

  33. Hodson D, Shouse G, Shin HJ, et al. A phase II, open-label, multicenter study of capivasertib, a potent, oral pan-AKT inhibitor, in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (CAPITAL) [abstract P1098]. Hemasphere. 2023;7(Suppl 3):2111–2.

    Google Scholar 

  34. Hyman DM, Smyth LM, Donoghue MTA, et al. AKT inhibition in solid tumors with AKT1 mutations. J Clin Oncol. 2017;35(20):2251–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kalinsky K, Hong F, McCourt CK, et al. Effect of capivasertib in patients with an AKT1 E17K-mutated tumor: NCI-MATCH subprotocol EAY131-Y nonrandomized trial. JAMA Oncol. 2021;7(2):271–8.

    Article  PubMed  Google Scholar 

  36. Turner NC, Kingston B, Kilburn LS, et al. Circulating tumour DNA analysis to direct therapy in advanced breast cancer (plasmaMATCH): a multicentre, multicohort, phase 2a, platform trial. Lancet Oncol. 2020;21(10):1296–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Westin SN, Labrie M, Litton JK, et al. Phase Ib dose expansion and translational analyses of olaparib in combination with capivasertib in recurrent endometrial, triple-negative breast, and ovarian cancer. Clin Cancer Res. 2021;27(23):6354–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yap TA, Kristeleit R, Michalarea V, et al. Phase I trial of the PARP inhibitor olaparib and AKT inhibitor capivasertib in patients with BRCA1/2- and non-BRCA1/2-mutant cancers. Cancer Discov. 2020;10(10):1528–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Foundation Medicine. FoundationOne®CDx technical information. 2023. https://www.foundationmedicine.com/sites/default/files/media/documents/2023-11/RAL-0003-24%20F1CDx%20Technical%20Label%20%28P170019_S048%29_Clean.pdf. Accessed 11 Jan 2024.

  40. Neven P, Hamilton E, Pistilli B, et al. Capivasertib (C) + palbociclib (P) and fulvestrant (F) in patients (pts) with HR+/HER2- advanced breast cancer (ABC): phase Ib data from CAPItello-292 [abstract 206P plus poster]. ESMO Open. 2023;8(1 Suppl 4):17–8.

    Google Scholar 

  41. Schmid P, Cortes J, Robson ME, et al. A phase III trial of capivasertib and paclitaxel in first-line treatment of patients with metastatic triple-negative breast cancer (CAPItello290) [abstract TPS1109]. J Clin Oncol. 2020;38(15 Suppl):TPS1109.

    Article  Google Scholar 

  42. Fizazi K, George DJ, De Santis M, et al. A phase III trial of capivasertib and abiraterone versus placebo and abiraterone in patients with de novo metastatic hormonesensitive prostate cancer characterized by PTEN deficiency (CAPItello-281) [abstract TPS178]. J Clin Oncol. 2021;39(6 Suppl):TPS!78.

    Google Scholar 

  43. Lee J, Kim ST, Kim K, et al. Tumor genomic profiling guides patients with metastatic gastric cancer to targeted treatment: the VIKTORY umbrella trial. Cancer Discov. 2019;9(10):1388–405.

    Article  CAS  PubMed  Google Scholar 

  44. Middleton G, Fletcher P, Popat S, et al. The National Lung Matrix Trial of personalized therapy in lung cancer. Nature. 2020;583(7818):807–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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    Matt Shirley

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During the peer review process the manufacturer of the agent under review was offered an opportunity to comment on the article. Changes resulting from any comments received were made by the author on the basis of scientific completeness and accuracy. Matt Shirley is a salaried employee of Adis International Ltd/Springer Nature, and declares no relevant conflicts of interest. All authors contributed to this article and are responsible for its content.

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Shirley, M. Capivasertib: First Approval. Drugs 84, 337–346 (2024). https://doi.org/10.1007/s40265-024-01998-6

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