Capivasertib in combination with fulvestrant: New treatment options for HR⁺/HER2⁻ metastatic breast cancer

The identification and understanding of various signaling pathways involved in the pathogenesis of malignant neoplasms, particularly breast cancer (BC), have significantly transformed the therapeutic landscape of this disease. Hormone receptor-positive (HR⁺) HER2-negative (HER2⁻) metastatic BC (mBC) is the most common but biologically heterogeneous subtype, which largely accounts for the variability in response to endocrine therapy. In patients without visceral crisis, endocrine therapy remains the preferred treatment option due to its higher efficacy and better tolerability compared with chemotherapy. Activation of the AKT signaling pathway promotes tumor cell growth, proliferation, and survival, leading to the development of endocrine resistance. PIK3CA and AKT mutations, as well as PTEN loss, are among the most frequent alterations, occurring in approximately 20–40% of patients with early-stage BC and in up to 40% of those with metastatic disease. As an AKT inhibitor, capivasertib has shown promising results in both preclinical studies and clinical trials, either as monotherapy or in combination with fulvestrant. The FAKTION trial demonstrated the efficacy and safety of capivasertib combined with fulvestrant, particularly in patients with alterations in the PI3K/AKT/PTEN signaling pathway. The CAPItello-291 study confirmed these findings, leading to the approval of this combination for the treatment of HR⁺/HER2⁻ breast cancer harboring PI3K/AKT/PTEN pathway alterations. Several clinical trials are currently underway to evaluate the efficacy of capivasertib, including that in the first-line treatment of patients with HR⁺/HER2⁻ mBC harboring PI3K/AKT/PTEN pathway alterations.

1. Howlader N, Altekruse SF, Li CI, Chen VW, Clarke CA, Ries LA, Cronin KA. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst. 2014;106(5):dju055. https://doi.org/10.1093/jnci/dju055.

2. Gennari A, André F, Barrios CH, Cortés J, de Azambuja E, DeMichele A et al. ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. Ann Oncol. 2021;32(12):1475–1495. https://doi.org/10.1016/j.annonc.2021.09.019.

3. Huang J, Zheng L, Sun Z, Li J. CDK4/6 inhibitor resistance mechanisms and treatment strategies (Review). Int J Mol Med. 2022;50(4):128. https://doi.org/10.3892/ijmm.2022.5184.

4. Millis SZ, Ikeda S, Reddy S, Gatalica Z, Kurzrock R. Landscape of phosphatidylinositol-3-kinase pathway alterations across 19784 diverse solid tumors. JAMA Oncol. 2016;2(12):1565–1573. https://doi.org/10.1001/jamaoncol.2016.0891.

5. Pereira B, Chin SF, Rueda OM, Vollan HK, Provenzano E, Bardwell HA et al. The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes. Nat Commun. 2016;7:11479. https://doi.org/10.1038/ncomms11479.

6. Koboldt DC, Fulton RS, McLellan MD, Schmidt H, Kalicki-Veizer J, McMichael JF et al. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61–70. https://doi.org/10.1038/nature11412.

7. Razavi P, Chang MT, Xu G, Bandlamudi C, Ross DS, Vasan N et al. The genomic landscape of endocrine-resistant advanced breast cancers. Cancer Cell. 2018;34(3):427–438.e6. https://doi.org/10.1016/j.ccell.2018.08.008.

8. Tao Z, Li T, Feng Z, Liu C, Shao Y, Zhu M et al. Characterizations of Cancer Gene Mutations in Chinese Metastatic Breast Cancer Patients. Front Oncol. 2020;10:1023. https://doi.org/10.3389/fonc.2020.01023.

9. Jin J, Li B, Cao J, Li T, Zhang J, Cao J et al. Analysis of clinical features, genomic landscapes and survival outcomes in HER2-low breast cancer. J Transl Med. 2023;21(1):360. https://doi.org/10.1186/s12967-023-04076-9.

10. Lang GT, Jiang YZ, Shi JX, Yang F, Li XG, Pei YC et al. Characterization of the genomic landscape and actionable mutations in Chinese breast cancers by clinical sequencing. Nat Commun. 2020;11(1):5679. https://doi.org/10.1038/s41467-020-19342-3.

11. Chen C, Lin CJ, Pei YC, Ma D, Liao L, Li SY et al. Comprehensive genomic profiling of breast cancers characterizes germline-somatic mutation interactions mediating therapeutic vulnerabilities. Cell Discov. 2023;9(1):125. https://doi.org/10.1038/s41421-023-00614-3.

12. Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S, Nakshatri H. Phosphatidylinositol 3-kinase/akt-mediated activation of estrogen receptor α: A new model for anti-estrogen resistance. J Biol Chem. 2001;276(13):9817–9824. https://doi.org/10.1074/jbc.M010840200.

13. André F, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS et al. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med. 2019;380(20):1929–1940. https://doi.org/10.1056/NEJMoa1813904.

14. Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366(6):520–529. https://doi.org/10.1056/NEJMoa1109653.

15. Jerusalem G, de Boer RH, Hurvitz S, Yardley DA, Kovalenko E, Ejlertsen B et al. Everolimus plus Exemestane vs Everolimus or capecitabine monotherapy for estrogen receptor-positive, HER2-negative advanced breast cancer: the BOLERO-6 randomized clinical trial. JAMA Oncol. 2018;4(10):1367–1374. https://doi.org/10.1001/jamaoncol.2018.2262.

16. Wiechmann S, Ruprecht B, Siekmann T, Zheng R, Frejno M, Kunold E et al. Chemical Phosphoproteomics Sheds New Light on the Targets and Modes of Action of AKT Inhibitors. ACS Chem Biol. 2021;16(4):631–641. https://doi.org/10.1021/acschembio.0c00872.

17. Nitulescu GM, Van De Venter M, Nitulescu G, Ungurianu A, Juzenas P, Peng Q et al. The Akt pathway in oncology therapy and beyond (Review). Int J Oncol. 2018;53(6):2319–2331. https://doi.org/10.3892/ijo.2018.4597.

18. Manning BD, Toker A. AKT/PKB signaling: navigating the network. Cell. 2017;169(3):381–405. https://doi.org/10.1016/j.cell.2017.04.001.

19. Zhong Q, Xiao X, Qiu Y, Xu Z, Chen C, Chong B et al. Protein posttranslational modifications in health and diseases: functions, regulatory mechanisms, and therapeutic implications. MedComm. 2023;4(3):e261. https://doi.org/10.1002/mco2.261.

20. Ribas R, Pancholi S, Guest SK, Marangoni E, Gao Q, Thuleau A 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):2035–2048. https://doi.org/10.1158/1535-7163.MCT-15-0143.

21. Fox EM, Kuba MG, Miller TW, Davies BR, Arteaga CL. 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. https://doi.org/10.1186/bcr3449.

22. Jones RH, Casbard A, Carucci M, Cox C, Butler R, Alchami F 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):345–357. https://doi.org/10.1016/S1470-2045(19)30817-4.

23. Howell SJ, Casbard A, Carucci M, Ingarfield K, Butler R, Morgan S 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):851–864. https://doi.org/10.1016/S1470-2045(22)00284-4.

24. Turner NC, Oliveira M, Howell SJ, Dalenc F, Cortes J, Gomez Moreno HL et al. Capivasertib in Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2023;388(22):2058–2070. https://doi.org/10.1056/NEJMoa2214131.

25. Turner N, Oliveira M, Howell S, Dalenc F, Cortés J, Gomez H et al. Abstract GS3-04: GS3-04 Capivasertib and fulvestrant for patients with aromatase inhibitor-resistant hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: results from the Phase III CAPItello-291 trial. Cancer Res. 2023;83(5 Suppl.):GS3-04. https://doi.org/10.1158/1538-7445.SABCS22-GS3-04.

26. Rugo H, Pistilli B, Collins J, D’Cruz C, Gresty Ch, Sommavilla R et al. Abstract PO2-19-10: CAPItello-292 Phase 3: An open-label, randomized study of capivasertib, fulvestrant, and investigator’s choice of CDK4/6 inhibitor (palbociclib or ribociclib) in HR+/HER2– advanced breast cancer. Cancer Res. 2024;84(9 Suppl.):PO2-19-10. https://doi.org/10.1158/1538-7445.SABCS23-PO2-19-10.