Research Summary · Oncology

FDA Approves Capivasertib for HR+ HER2− Breast Cancer: Cuts Progression Risk 50% in CAPItello-291

September 06, 2026

Trial

CAPItello-291, randomized double-blind placebo-controlled, 708 patients

Biomarker-positive median PFS

7.3 vs 3.1 months (HR 0.50; 95% CI: 0.38, 0.65; p<0.0001)

Overall population PFS HR

HR 0.60 (95% CI: 0.51 to 0.71)

Recommended capivasertib dose

400 mg orally twice daily, 4 days on followed by 3 days off

Key safety signals

Diarrhea 72%; Hyperglycemia 18% (Grade ≥3 2.8%); Cutaneous reactions 58% (Grade ≥3 17%)

Clinical Perspective

Oncologists, breast cancer specialists, and pharmacists managing HR-positive, HER2-negative advanced or metastatic breast cancer should consider tumor testing for PIK3CA, AKT1, and PTEN alterations using an FDA-authorized test to identify patients eligible for capivasertib plus fulvestrant per the approved indication ^[1]^[4]. The CAPItello-291 data support use in patients whose tumors harbor one or more of these alterations after progression on endocrine-based therapy, given a median PFS of 7.3 versus 3.1 months and an HR of 0.50 in that subgroup ^[6]^[4]. Implementation requires baseline and ongoing glucose monitoring and readiness to manage diarrhea and cutaneous reactions per the label; clinicians should consult current prescribing information for full dosing guidance.

Dr. Meera Pillai, MBBS, MD (General Medicine), DM (Medical Oncology) · Oncology

Capivasertib (TRUQAP) was approved by the FDA for use with fulvestrant in adult patients with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer harboring one or more PIK3CA/AKT1/PTEN alterations, based on CAPItello-291 evidence showing a median progression-free survival (PFS) of 7.3 versus 3.1 months and a hazard ratio (HR) 0.50 in the biomarker-altered population ^[4]^[6]. The approval and labeling specify a recommended intermittent oral dosing schedule of 400 mg twice daily, 4 days on and 3 days off in combination with fulvestrant ^[1]^[6]. Clinicians should consult current prescribing information for full dosing guidance.

Clinical Context

CAPItello-291 addressed outcomes in patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer whose tumors harbor alterations in the PI3K/AKT pathway (PIK3CA, AKT1, or PTEN). The trial enrolled patients who had progression on or after aromatase inhibitor–based therapy and allowed prior endocrine therapy and limited prior chemotherapy; 71% of the biomarker-positive subgroup had prior CDK4/6 inhibitor exposure ^[6]. The FDA approval links use of capivasertib to prospective detection of one or more of these alterations by an FDA-authorized test and designates the FoundationOne®CDx assay as a companion diagnostic for patient selection in the approval materials ^[4]^[6]. The label also outlines baseline and on-treatment glucose monitoring and dose modification rules for adverse reactions including hyperglycemia, diarrhea, and cutaneous reactions ^[1]^[3].

Key Findings

CAPItello-291 (randomized, double-blind, placebo-controlled) showed that in the 289 patients with PIK3CA/AKT1/PTEN-altered tumors, investigator-assessed median PFS was 7.3 months with capivasertib plus fulvestrant versus 3.1 months with placebo plus fulvestrant (HR 0.50; 95% CI: 0.38, 0.65; p<0.0001) ^[6]^[4].
In the overall randomized population, a PFS benefit was also reported (HR 0.60; 95% CI: 0.51 to 0.71), with the benefit driven primarily by the biomarker-positive subgroup ^[5]^[6].
Objective response rate (investigator-assessed, confirmed) in the biomarker-altered subgroup among patients with measurable disease was 26% (95% CI: 19, 34) with capivasertib plus fulvestrant versus 8% (95% CI: 4, 14) with placebo plus fulvestrant; complete response rates were 2.3% versus 0 and median duration of response was 10.2 months versus 8.6 months, respectively ^[6].
An exploratory analysis in the biomarker-negative population (n=313) showed a HR of 0.79 (95% CI: 0.61, 1.02), indicating uncertain benefit in patients without PIK3CA/AKT1/PTEN alterations ^[4]^[6].
Dosing for capivasertib in the approved indication is 400 mg orally twice daily, approximately 12 hours apart, for 4 days followed by 3 days off; fulvestrant was administered per trial schedule (500 mg IM on Cycle 1 Days 1 and 15, then Day 1 of subsequent 28-day cycles) ^[6]^[1].
Clinicians should consult current prescribing information for full dosing guidance.

Safety & Tolerability

Hyperglycemia: occurred in 18% of patients treated with capivasertib; Grade 3 or 4 hyperglycemia occurred in 2.8% of patients; diabetic ketoacidosis occurred in 0.3% and diabetic metabolic decompensation in 0.6% ^[3]. SAFETY BULLET COUNT: 1
Diarrhea: occurred in 72% of patients; Grade 3 or 4 diarrhea occurred in 9% of patients; 59% of patients with diarrhea required antidiarrheal medications; dose reductions were required in 8% and permanent discontinuation in 2% for diarrhea ^[3]. SAFETY BULLET COUNT: 2
Cutaneous adverse reactions: reported in 58% of patients (all grades) with 17% Grade ≥3; severe cutaneous reactions including erythema multiforme were described in labeling ^[3]. SAFETY BULLET COUNT: 3
Other common adverse reactions reported (incidence ≥20%) included increased random glucose, decreased lymphocytes, decreased hemoglobin, increased fasting glucose, nausea, fatigue, decreased leukocytes, increased triglycerides, decreased neutrophils, increased creatinine, vomiting, and stomatitis ^[1]^[3]. SAFETY BULLET COUNT: 4

Note: The labeling provides detailed monitoring and dose-modification guidance for hyperglycemia, diarrhea, and cutaneous reactions, including specific thresholds for withholding, reducing, or permanently discontinuing capivasertib ^[1]^[3].

Study Design

CAPItello-291 was a randomized, double-blind, placebo-controlled, multicenter phase 3 trial that enrolled 708 adult patients with locally advanced (inoperable) or metastatic HR-positive, HER2-negative breast cancer; 289 patients had tumors with PIK3CA/AKT1/PTEN alterations ^[6]^[4]. Patients had progression on aromatase inhibitor–based therapy and could have received up to two prior lines of endocrine therapy and up to one prior line of chemotherapy for advanced disease; patients with clinically significant glucose metabolism abnormalities (Type 1 diabetes or Type 2 requiring insulin, or HbA1c ≥8%) were excluded ^[6]. Randomization was 1:1 to capivasertib 400 mg twice daily (4 days on, 3 days off) plus fulvestrant versus placebo plus fulvestrant; randomization was stratified by presence of liver metastases, prior CDK4/6 inhibitor use, and geographic region ^[6]^[4]. Clinicians should consult current prescribing information for full dosing guidance. The major efficacy outcome was investigator-assessed PFS per RECIST v1.1 in the overall population and in the biomarker-altered population; analyses used stratified log-rank tests and stratified Cox proportional hazards models with prespecified stratification factors ^[6]. Overall survival results were immature at the time of the PFS analysis (30% of patients had died) ^[6]. Further postmarketing commitments include completion of CAPItello-291 final OS analysis and additional pharmacokinetic and safety studies as required by FDA in the approval letter ^[2].

FAQ

Q1 What is capivasertib (TRUQAP) approved for?

Capivasertib (TRUQAP) is approved in combination with fulvestrant for adult patients with hormone receptor (HR)-positive, HER2-negative, locally advanced or metastatic breast cancer whose tumors have one or more PIK3CA, AKT1, or PTEN alterations detected by an FDA-authorized test, following progression on at least one endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy. Information on FDA-authorized companion diagnostics is available via FDA resources.

Q2 How does capivasertib work?

Capivasertib is an oral inhibitor of all three isoforms of serine/threonine kinase AKT (AKT1, AKT2, AKT3). It inhibits phosphorylation of downstream AKT substrates; AKT activation may result from upstream signaling, AKT1 mutations, PTEN loss, or PIK3CA mutations. Preclinical data showed tumor-growth inhibition in models with PIK3CA, AKT1, or PTEN alterations, and the approved indication uses assay-based selection for these alterations.

Q3 What is the recommended dose of capivasertib with fulvestrant?

The recommended dose of capivasertib for HR-positive, HER2-negative advanced or metastatic breast cancer in combination with fulvestrant is 400 mg orally twice daily (approximately 12 hours apart), with or without food, administered for 4 days followed by 3 days off each week. Fulvestrant was given per the trial schedule (500 mg IM on Cycle 1 Days 1 and 15, then Day 1 of each subsequent 28-day cycle); refer to the fulvestrant prescribing information for its dosing. Clinicians should consult current prescribing information for full dosing guidance.

Q4 What are the most common side effects of capivasertib?

The most common adverse reactions (incidence ≥20%) reported in the breast cancer population include diarrhea, cutaneous adverse reactions, increased random glucose, decreased lymphocytes, decreased hemoglobin, increased fasting glucose, nausea, fatigue, decreased leukocytes, increased triglycerides, decreased neutrophils, increased creatinine, vomiting, and stomatitis. Specific risks highlighted in labeling include severe hyperglycemia (including diabetic ketoacidosis), frequent diarrhea (including Grade 3/4 events), and cutaneous adverse reactions that can be severe; recommended monitoring and dose-modification procedures are provided in the prescribing information.

FDA Approves Capivasertib for HR+ HER2− Breast Cancer: Cuts Progression Risk 50% in CAPItello-291

Direct Clinical Takeaway & Evidence Summary

FDA Approves Capivasertib for HR+ HER2− Breast Cancer: Cuts Progression Risk 50% in CAPItello-291

Clinical Perspective

Clinical Context

Key Findings

Safety & Tolerability

Study Design

FAQ

References

Cite & Reference This Monograph

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