Capivasertib inhibits a key pathway in metastatic breast cancer
Authors: Azadeh Nasrazadani, Adam M Brufsky
Journal: The Lancet Oncology (2020)

In the pursuit of improved therapies for metastatic breast cancer, a succession of drugs have been approved that target a range of mechanisms. However, resistance to these therapies is inevitably encountered. This resistance underscores the emergence and perhaps persistence of compensatory pathways that allow cancer cells to survive. Hormone-directed strategies are integral in the management of hormone receptor-positive breast cancer, because they effectively target the oestrogen receptor signalling pathway. Ongoing research aims to explore the synergistic effects of additive therapies in this space. Notable examples include the CDK4/6 inhibitors, such as palbociclib, abemaciclib, and ribociclib, several of which have been reported to confer a survival advantage upon addition to the selective oestrogen receptor degrader fulvestrant.1Sledge Jr, GW Toi M Neven P et al.The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor-positive, ERBB2-negative breast cancer that progressed on endocrine therapy—MONARCH 2: a randomized clinical trial.JAMA Oncol. 2020; 6: 116-124Crossref Scopus (223) Google Scholar, 2Slamon D Neven P Chia S et al.Overall survival with ribociclib plus fulvestrant in advanced breast cancer.N Engl J Med. 2019; (published online Dec 22.)DOI:10.1056/NEJMoa1911149Crossref Scopus (167) Google Scholar Capivasertib is a potent pan-AKT inhibitor with notable anti-proliferative activity in preclinical models.3Davies 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: 873-887Crossref PubMed Scopus (225) Google Scholar The PI3K/AKT/mTOR axis specifically has a central position in several pathways with key functions in promoting cell survival, growth, and proliferation. Substantial cross-talk between these pathways and mediators of oestrogen receptor signalling are well appreciated, and thus these mediators are logical targets in hormone-sensitive disease.4Ciruelos Gil EM Targeting the PI3K/AKT/mTOR pathway in estrogen receptor-positive breast cancer.Cancer Treat Rev. 2014; 40: 862-871Summary Full Text Full Text PDF PubMed Scopus (193) Google Scholar Previous attempts at inhibition of these downstream kinases are highlighted by the BOLERO-2 trial,5Baselga J Campone M Piccart M et al.Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer.N Engl J Med. 2012; 366: 520-529Crossref PubMed Scopus (2002) Google Scholar which evaluated the addition of everolimus, a selective mTOR inhibitor, to the aromatase inhibitor exemestane, and reported an improvement in progression-free survival but not in overall survival. Inhibition of PI3K, although particularly effective in patients with tumours with PIK3CA mutations, has proved challenging owing to the toxicity profile of PI3K inhibitors.6André F Ciruelos E Rubovszky G et al.Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer.N Engl J Med. 2019; 380: 1929-1940Crossref PubMed Scopus (615) Google Scholar In The Lancet Oncology, Robert Jones and colleagues7Jones 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. 2019; (published online Feb 5.)https://doi.org/10.1016/S1470-2045(19)30817-4Google Scholar report a doubling of progression-free survival from 4·8 months (95% CI 3·1–7·7) to 10·3 months (5·0–13·2; hazard ratio 0·58, 95% CI 0·39–0·84, p=0·0044) with the addition of capivasertib to fulvestrant in oestrogen receptor-positive, HER2-negative, advanced breast cancer that had progressed or relapsed after treatment with an aromatase inhibitor. The addition of capivasertib to fulvestrant also increased the proportion of patients achieving an objective response by more than three times, to 29% (compared with 8% with fulvestrant plus placebo). This benefit of the combination therapy was independent of PIK3CA or PTEN alteration status, further highlighting the essential role of Akt at the root of major intersecting signalling cascades. A combinatorial approach with agents targeting multiple converging sites along upregulated signalling pathways could potentially curb the development of resistance mechanisms. Duration of response to therapy might be longer, although additive toxicities do remain a concern given the fundamental role that these kinases play in normal, non-cancerous cells. Clinicians therefore continue to aim to identify treatment regimens that can achieve maximal suppression of activating pathways with minimal adverse effects. The scope of use for capivasertib might be wider than initially surmised. AKT lies downstream of several notable targets, including ERBB2 (HER2) and ERBB3 (HER3). Strategies with combinations of HER2-directed therapy might reveal a role for AKT inhibition in the management of HER2-positive disease and triple-negative breast cancer, in which mutations in the PIK3CA/AKT/PTEN pathway occur in 10–23% of tumours.8Mosele F Lusque A Tran Dien et al.Outcome and mutational landscape of patients with PIK3CA-mutated metastatic breast cancer (mBC).Ann Oncol. 2019; 30 (abstr).: iii47-iii64Summary Full Text Full Text PDF Google Scholar, 9Cossu-Rocca P Orru S Muroni M et al.Analysis of PIK3CA mutations and activation pathways in triple negative breast cancer.PLoS One. 2015; 10e0141763Crossref PubMed Scopus (51) Google Scholar Two obvious questions that remain to be evaluated at this juncture are the possible first-line selection of capivasterib versus a CDK4/6 inhibitor and the ever-present question of drug sequencing. Whether or not therapy-specific resistance patterns would confer an advantage of one drug over another upfront is unclear. Although the overall survival data for capivasertib are not yet mature, the magnitude of improvement in outcomes between agents might shift current treatment standards. AMB reports personal fees from Eisai, Myriad, Merck, Puma, Genomic Health, Nanostring, Biotheranostics, Lilly, Novartis, Pfizer, Celgene, Agendia, Bayer, Genentech-Roche, and Astrazeneca, outside the submitted work. AN declares no competing interests. 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 trialProgression-free survival was significantly longer in participants who received capivasertib than in those who received placebo. The combination of capivasertib and fulvestrant warrants further investigation in phase 3 trials. 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