Capivasertib/Fulvestrant Wins Approval in Japan for Advanced HR+/HER2– Breast Cancer With PIK3CA, AKT1, or PTEN Alterations


Capivasertib plus fulvestrant has been approved in Japan for pretreated, PIK3CA-, AKT1-, or PTEN-altered, HR-positive, HER2-negative breast cancer.

Masakazu Toi, MD, PhD

Masakazu Toi, MD, PhD

Japan’s Ministry of Health, Labour and Welfare (MHLW) has approved capivasertib (Truqap) in combination with fulvestrant (Faslodex) for the treatment of adult patients with unresectable or recurrent hormone receptor (HR)–positive, HER2-negative breast cancer harboring PIK3CA, AKT1, or PTEN alterations following progression after treatment with endocrine therapy.1

The approval was supported by findings from the phase 3 CAPItello-291 trial (NCT04305496), in which the risk of disease progression or death was reduced by 50% with the investigative combination compared with fulvestrant alone in patients with tumors harboring PIK3CA/AKT1/PTEN alterations (HR, 0.50; 95% CI, 0.38-0.65; P < .001). In turn, this met 1 of the trial’s dual primary end points. Moreover, the median progression-free survival (PFS) in this patient population was 7.3 months (95% CI, 5.5-9.0) with the combination (n = 155) and 3.1 months (95% CI, 2.0-3.7) with fulvestrant plus placebo (n = 134).2

“The approval of capivasertib and fulvestrant signifies a new era of care in advanced hormone receptor–positive breast cancer in Japan, providing a much-needed new treatment option for approximately half of patients in this setting who have tumors harboring mutations in PIK3CA, AKT1, or alterations in PTEN,” Masakazu Toi, MD, PhD, director of Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Japan, stated in a news release.1 “It is important for us to detect these specific tumor biomarker alterations in each patient we see, so that they are potentially able to benefit from this important combination to extend the effectiveness of endocrine-based treatment and delay disease progression.”

In November 2023, the FDA approved capivasertib plus fulvestrant for the treatment of adult patients with HR–positive, HER2-negative, locally advanced or metastatic breast cancer harboring 1 or more PIK3CA, AKT1, or PTEN alterations, as detected by an FDA-approved test, following progression on at least 1 endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy. That regulatory decision was also supported by data from CAPItello-291.3

The randomized, double-blind, placebo-controlled study enrolled patients at least 18 years of age (at least 20 years of age in Japan) with locally advanced or metastatic, HR–positive, HER2-negative breast cancer who experienced disease progression while receiving treatment with an aromatase inhibitor with or without a CDK4/6 inhibitor. Disease progression was defined as progression during previous therapy with an aromatase inhibitor in the context of metastatic disease or as progression during treatment or within 12 months following treatment with a neoadjuvant or adjuvant aromatase inhibitor.2

Up to 2 previous lines of endocrine therapy and 1 previous line of chemotherapy in the advanced disease setting were allowed. Other key inclusion criteria consisted of measurable disease per RECIST v1.1 criteria and an ECOG performance status of 0 or 1.

Activating PIK3CA and AKT1 mutations, as well as inactivating PTEN alterations, were identified through central laboratory testing via next-generation sequencing. Those harboring at least 1 of these alterations were included in the ATK pathway–altered group, and those without any of these alterations were included in the AKT pathway–non-altered population.

Prior treatment with fulvestrant or another selective estrogen-receptor degrader, or AKT, PI3K, or mTOR inhibitors, was not allowed.

Patients were randomly assigned 1:1 to receive oral capivasertib at 400 mg twice daily on a 4- days-on/3-days-off schedule plus intramuscular fulvestrant at 500 mg once every 14 days for the first 3 injections and once every 28 days thereafter; or matching placebo plus fulvestrant.

Investigator-assessed PFS per RECIST v1.1 criteria in the overall population and in the population of patients harboring PIK3CA/AKT1/PTEN alterations served as the trial’s dual primary end points. Secondary end points included overall survival (OS), objective response rate, and safety.

Additional data showed that in the overall population, patients treated with the combination (n = 355) experienced a median PFS of 7.2 months (95% CI, 5.5-7.4) compared with 3.6 months (95% CI, 2.8-3.7) for those given fulvestrant plus placebo (n = 353; HR, 0.60; 95% CI, 0.51-0.71; P < .001).

The estimated 18-month OS rate in the overall population was 73.9% (95% CI, 68.3%-78.7%) in the capivasertib group vs 65.0% (95% CI, 58.7%-70.6%) in the placebo group (HR, 0.74; 95% CI, 0.56-0.98). In the ATK pathway-altered population, the estimated 18-month OS rate was 73.2% (95% CI, 64.8%-80.0%) in the experimental arm and 62.9% (95% CI, 53.1%-71.2%) in the placebo arm (HR, 0.69; 95% CI, 0.45-1.05).

Regarding safety, the most common grade 3 or higher adverse effects (AEs) included rash (capivasertib/fulvestrant, 12.1%; fulvestrant/placebo, 0.3%) and diarrhea (9.3%; 0.3%).

AEs leading to treatment discontinuation occurred in 13.0% of the patients in the experimental arm and 2.3% of patients in the placebo arm. The rates of AEs leading to dose reductions and dose interruptions in the experimental arm were 19.7% and 34.9%, respectively. In the control arm, those rates were 1.7% and 10.3%, respectively.


  1. Truqap plus Faslodex approved in Japan for patients with advanced HR-positive breast cancer. News release. AstraZeneca. March 27, 2024. Accessed March 27, 2024.
  2. Turner NC, Oliveira M, Howell SJ, et al. Capivasertib in hormone receptor–positive advanced breast cancer. N Engl J Med. 2023;388(22):2058-2070. doi:10.1056/NEJMoa2214131
  3. FDA approves capivasertib with fulvestrant for breast cancer. FDA. November 16, 2023. Accessed March 27, 2024.
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