Capivasertib for locally advanced or metastatic breast cancer

Background:
Breast cancer that is hormone receptor (HR) positive and human epidermal growth factor receptor 2 (HER2) negative is the most common subtype of breast cancer. Patients who present with locally advanced or metastatic disease have a poorer prognosis and often require endocrine therapy in combination with targeted therapy. Current drug therapies approved in Australia for this indication include cyclin-dependent kinase (CDK) 4 and 6 inhibitors (e.g. palbociclib, ribociclib, abemaciclib) in combination with endocrine therapy using an aromatase inhibitor (e.g. anastrozole) or fulvestrant (an estrogen receptor antagonist), as well as the PI3K inhibitor alpelisib for men and postmenopausal women with a PIK3CA mutation.¹ Despite these treatments, many patients develop drug resistance and experience disease progression.

Mechanism of action:
Capivasertib inhibits AKT, which is a key protein in the PI3K–AKT–PTEN signalling pathway that regulates cell proliferation and survival. In some cancers, including HR-positive breast cancer, mutations in this pathway lead to overactivation of AKT, promoting increased cell proliferation and resistance to cell death. AKT activation is also implicated in resistance to endocrine therapy.² By inhibiting AKT and thereby blocking this pathway, capivasertib may reduce tumour cell proliferation and survival.^1,3

Clinical trials:
The efficacy of capivasertib was assessed in a phase 3 double-blind, placebo-controlled trial (CAPItello-291) in adults with HR-positive, HER2-negative advanced breast cancer that had progressed during or after aromatase inhibitor therapy, with or without prior CDK4 or 6 inhibitor treatment or chemotherapy (n=708, median age 58 years, 77.3% postmenopausal).² Patients were randomised to receive either oral capivasertib or placebo, plus intramuscular fulvestrant. Pre- and peri-menopausal women also received a luteinising hormone–releasing hormone agonist (e.g. goserelin). Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent or death. Mutations in PIK3CA, AKT1 and PTEN genes were identified in 40.8% of patients. Key exclusion criteria included prior treatment with fulvestrant or an AKT, PI3K or mTOR inhibitor, diabetes requiring insulin, and a baseline glycated haemoglobin (HbA1c) of at least 8%.

The median treatment duration was 5.4 months with capivasertib and 3.6 months with placebo. Treatment was discontinued in 82.3% of patients receiving capivasertib and 87.7% receiving placebo, most commonly due to disease progression. Progression-free survival and overall survival outcomes are summarised in Table 1.²

Table 1 Progression-free survival and overall survival outcomes from a phase 3 trial (CAPItello-291) in patients with HR-positive and HER2-negative advanced breast cancer receiving either capivasertib or placebo, in combination with fulvestrant²

Outcome	Overall study population		AKT pathway–altered population (PIK3CA, AKT1 or PTEN alteration in tumour)
	Capivasertib plus fulvestrant (n=355)	Placebo plus fulvestrant (n=353)	Capivasertib plus fulvestrant (n=155)	Placebo plus fulvestrant (n=134)
Median progression-free survival	7.2 months	3.6 months	7.3 months	3.1 months
Estimated overall survival at 18 months	73.9%	65.0%	73.2%	62.9%
AKT1 = AKT serine/threonine kinase 1; HER2 = human epidermal growth factor receptor 2; HR = hormone receptor; PIK3CA = phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PTEN = phosphatase and tensin homolog

For most of the study period, patient-reported global health status and quality of life scores were similar between the treatment groups, except at the beginning of treatment, when lower scores in the capivasertib group were likely due to a higher incidence of diarrhoea.⁴

Adverse effects:
The most frequently reported adverse effects were diarrhoea (72.4% in the capivasertib–fulvestrant group versus 20.0% in the placebo–fulvestrant group), rash (38.0% versus 7.1%), nausea (34.6% versus 15.4%), fatigue (20.8% versus 12.9%) and vomiting (20.6% versus 4.9%). Hyperglycaemia occurred in 16.3% of patients treated with capivasertib.² The most common serious adverse reactions were diarrhoea, rash and vomiting.⁵

Dosage and administration:
The dose of capivasertib is 400 mg (two 200 mg tablets) orally twice daily, approximately 12 hours apart (total daily dose of 800 mg), for 4 days followed by 3 days off treatment. It should be taken with fulvestrant 500 mg on days 1, 15 and 29, and once monthly thereafter.⁵

Treatment with capivasertib may be paused or the dose reduced to manage adverse reactions; suggested dose reductions are provided in the Product Information.

Precautions:
Avoid concurrent use with strong CYP3A4 inhibitors or inducers. Dose reduction of capivasertib may be required with moderate CYP3A4 inhibitors. No dose adjustment is needed for patients with mild or moderate renal impairment or mild hepatic impairment. Data are limited in severe renal impairment, moderate hepatic impairment, and in patients aged 75 years or above.⁵

Use in pregnancy and breastfeeding:
Reproductive toxicity has been shown in animal studies. Capivasertib is classified as Therapeutic Goods Administration pregnancy category D and should not be used in pregnancy or women of childbearing potential not using contraception. Capivasertib may be secreted into breastmilk so it should not be used during breastfeeding.⁵

Place in therapy:
The addition of capivasertib to fulvestrant therapy appears to improve progression-free survival in patients with HR-positive, HER2-negative advanced breast cancer who have experienced disease recurrence or progression with previous endocrine therapies.² Capivasertib can be used in adults with or without PIK3CA, AKT1 or PTEN alterations. CDK4 and 6 inhibitors (combined with endocrine therapy) remain the standard-of-care, first-line treatment for HR-positive, HER2-negative advanced breast cancer. No head-to-head trials between capivasertib and CDK4 and 6 inhibitors have been conducted to date. Other treatment combinations with capivasertib are under investigation.³

Another AKT inhibitor, ipatasertib, is undergoing clinical trials in Australia and overseas but is not currently an approved treatment in Australia.^6,7

Practice points:
Measure fasting blood glucose and HbA1c before and during treatment, as capivasertib can cause hyperglycaemia. In the presence of dehydration and sepsis, there is an increased risk of hyperglycaemia progressing to diabetic ketoacidosis. More frequent blood glucose and ketone monitoring, which may include self-monitoring, is recommended in patients who develop hyperglycaemia or have risk factors for diabetic ketoacidosis (e.g. diabetes mellitus, pre-diabetes, regular oral steroid use).⁵

Advise patients to start anti-diarrhoeal treatment at the first signs of diarrhoea and maintain adequate oral fluid intake. Monitor for signs of rash. Depending on the severity of the adverse reaction, capivasertib dosing may need to be adjusted or interrupted.

People of childbearing potential should be advised to use effective contraception during treatment and after stopping treatment – at least 4 weeks for females and 16 weeks for males.

This new drug comment was finalised on 20 April 2026. It was prepared by Sherilyn Wong, Clinical Editor, Australian Prescriber, and reviewed by Jeremy Dalziell, Pharmacist Team Leader of Cancer Services (Acting), Mater Hospital, South Brisbane.

At the time this new drug comment was prepared, the Australian Public Assessment Report was available from the Therapeutic Goods Administration. The sponsor did not provide the Clinical Evaluation Report.

This article is peer reviewed.

 

References

1. Therapeutic Goods Administration. Australian Public Assessment Report for Truqap. Department of Health, Disability and Ageing; 2025. [cited 2026 Mar 12]
2. 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;388:2058-70.
3. Luboff AJ, DeRemer DL. Capivasertib: A Novel AKT Inhibitor Approved for Hormone-Receptor-Positive, HER-2-Negative Metastatic Breast Cancer. Ann Pharmacother 2024;58:1229-37.
4. Oliveira M, Rugo HS, Howell SJ, Dalenc F, Cortes J, Gomez HL, et al. Capivasertib and fulvestrant for patients with hormone receptor-positive, HER2-negative advanced breast cancer (CAPItello-291): patient-reported outcomes from a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol 2024;25:1231-44.
5. Therapeutic Goods Administration. Australian Product Information – TRUQAP capivasertib. Department of Health, Disability and Ageing; 2025. [cited 2026 Mar 12]
6. Chia SKL, Redfern AD, Ayoub J-PM, Chalchal HI, Rayson D, Rushton M, et al. A double-blind placebo controlled randomized phase III trial of fulvestrant and ipatasertib as treatment for advanced HER2-negative and estrogen receptor positive (ER+) breast cancer following progression on first line CDK 4/6 inhibitor and aromatase inhibitor: The CCTG/BCT MA.40/FINER study (NCT04650581). Journal of Clinical Oncology 2025;43:LBA1005-LBA.
7. ClinicalTrials.gov. Double-Blind Placebo-Controlled Randomized Phase III Trial of Fulvestrant and Ipatasertib as Treatment for Advanced HER-2 Negative and Estrogen Receptor Positive (ER+) Breast Cancer Following Progression on First Line CDK 4/6 Inhibitor and Aromatase Inhibitor. Identifier NCTCanadian Cancer Trials Group; 2020. 2020. [cited 2025 Apr 28]

 

The new drug comments in Australian Prescriber are prepared by the editors and reviewed by subject matter experts. Some of the views expressed on newly approved products should be regarded as preliminary, as there may be limited published data at the time of publication, and little experience in Australia of their safety or efficacy. Before new drugs are prescribed, it is important that more detailed information is obtained from the approved product information, a medicines information centre or some other appropriate source.

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