What is the recommended dosing, monitoring, and contraindications for capivasertib (AKT inhibitor) combined with fulvestrant in adults with advanced hormone‑receptor‑positive, HER2‑negative breast cancer?

Capivasertib Dosing, Monitoring, and Contraindications

Capivasertib (TRUQAP) is dosed at 400 mg orally twice daily (approximately 12 hours apart) for 4 consecutive days followed by 3 days off each week, combined with fulvestrant 500 mg intramuscularly, and is FDA-approved specifically for HR-positive, HER2-negative advanced breast cancer with PIK3CA/AKT1/PTEN alterations after progression on at least one endocrine-based regimen. 11

Patient Selection Requirements

Before initiating capivasertib, you must:

• Confirm PIK3CA/AKT1/PTEN alterations in tumor tissue using an FDA-approved test 1
• Verify progression on at least one endocrine-based regimen in the metastatic setting OR recurrence within 12 months of completing adjuvant therapy 1
• Exclude patients with severe hypersensitivity to capivasertib 1

Dosing Schedule

The weekly dosing pattern is straightforward 1:

• Days 1-4: 400 mg (two 200 mg tablets) twice daily, morning and evening
• Days 5-7: No capivasertib dosing
• Repeat this 7-day cycle continuously

Fulvestrant dosing 1:

• 500 mg intramuscularly on days 1,15, and 29, then every 28 days thereafter
• Add LHRH agonist for premenopausal/perimenopausal women (required) and consider for men

Administration details 1:

• Take with or without food
• Swallow tablets whole—do not chew, crush, or split
• If dose missed within 4 hours: take the missed dose
• If dose missed >4 hours: skip and take next scheduled dose
• If vomiting occurs: do not take additional dose; continue with next scheduled dose

Required Monitoring

Before starting treatment 1:

• Fasting blood glucose (FG)
• Hemoglobin A1C (HbA1C)

During treatment 1:

• Regular monitoring of FG and HbA1C at each visit
• Watch for hyperglycemia, diarrhea, and cutaneous reactions

Dose Modifications for Adverse Reactions

Hyperglycemia management 1:

Fasting Glucose Level	Action
>ULN to 160 mg/dL (>ULN to 8.9 mmol/L) or HbA1C >7%	Consider initiating/intensifying oral antidiabetic treatment
161-250 mg/dL (9-13.9 mmol/L)	Withhold until FG ≤160 mg/dL; resume at same or reduced dose
>250 mg/dL (>13.9 mmol/L)	Withhold; manage aggressively; resume at reduced dose when FG ≤160 mg/dL

Dose reduction schedule 1:

• First reduction: 320 mg twice daily (4 days on, 3 days off)
• Second reduction: 200 mg twice daily (4 days on, 3 days off)
• Permanently discontinue if unable to tolerate second dose reduction

Other toxicities requiring dose modification 11:

• Diarrhea: Most common adverse event (72% all-grade, 9% grade ≥3) 2. Start antidiarrheal treatment immediately, increase oral fluids. Withhold, reduce dose, or discontinue based on severity
• Cutaneous reactions: Occur in 58% (17% grade ≥3) 2. Monitor closely and adjust dose based on severity

Contraindications

Absolute contraindication 1:

• Severe hypersensitivity to capivasertib or any component

Drug Interactions

Avoid or adjust 1:

• Strong CYP3A inhibitors: Avoid concomitant use; if unavoidable, reduce capivasertib dose
• Moderate CYP3A inhibitors: Reduce capivasertib dose
• Strong and moderate CYP3A inducers: Avoid concomitant use

Clinical Context and Evidence

The FDA approval was based on the CAPItello-291 trial, which demonstrated significant progression-free survival benefit in patients with PIK3CA/AKT1/PTEN alterations (HR 0.5,95% CI 0.37-0.68) 2. Critically, the benefit was uncertain in biomarker-negative patients (HR 0.78,95% CI 0.60-1.01), which is why FDA approval is restricted to the biomarker-positive population 2.

Patient-reported outcomes showed maintained quality of life with delayed time to deterioration (24.9 vs 12.0 months) compared to placebo-fulvestrant, though diarrhea was notably worse in the capivasertib group 3.

Common Pitfalls to Avoid

1. Do not use without confirmed PIK3CA/AKT1/PTEN alterations—the benefit-risk is unfavorable in biomarker-negative patients 2
2. Do not delay antidiabetic treatment—hyperglycemia occurs in 18% of patients and requires proactive management 2
3. Do not underestimate diarrhea—occurs in 72% of patients; counsel patients to start antidiarrheals early and maintain hydration 32
4. Do not forget LHRH agonist in premenopausal/perimenopausal women 1

Special Populations

Pregnancy and lactation 1:

• Can cause fetal harm
• Advise effective contraception during treatment
• Do not breastfeed during treatment and for duration specified in fulvestrant labeling