What considerations should be taken when starting capivasertib with fluvestrant in a postmenopausal woman with hormone receptor-positive breast cancer who is currently on letrozole?

Switching from Letrozole to Capivasertib Plus Fulvestrant

Stop letrozole immediately and initiate capivasertib 400 mg twice daily (4 days on, 3 days off) plus fulvestrant 500 mg intramuscularly (with loading doses on days 1,15, and 28 of cycle 1, then monthly). This transition is appropriate for postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer who have progressed on aromatase inhibitor therapy 1, 2.

Patient Eligibility and Biomarker Testing

Before starting capivasertib, you must confirm the presence of PIK3CA, AKT1, or PTEN alterations using an FDA-approved test. The FDA approval is restricted to patients with these biomarker alterations, as the benefit-risk profile is unfavorable in biomarker-negative patients 2. In the CAPItello-291 trial, patients with PIK3CA/AKT1/PTEN alterations achieved a median progression-free survival of 7.3 months versus 3.1 months with fulvestrant alone (HR 0.50, P<0.001) 1.

• The biomarker-negative population showed uncertain benefit with an HR of 0.78 (95% CI 0.60-1.01), which did not meet the threshold for approval in this subgroup 2
• This regimen is appropriate regardless of prior CDK4/6 inhibitor exposure, as 69.1% of patients in CAPItello-291 had received prior CDK4/6 inhibitors 1

Discontinuing Letrozole

Stop letrozole on the day you initiate capivasertib plus fulvestrant. There is no washout period required, and no data support continuing the aromatase inhibitor alongside this new regimen 3. The ASCO guidelines establish that sequential endocrine therapy is appropriate when disease progresses on prior treatment, and combination endocrine-chemotherapy is not recommended 3.

Dosing and Administration Protocol

Capivasertib dosing:

• 400 mg orally twice daily on an intermittent schedule: 4 consecutive days on, followed by 3 days off 4, 1
• Start capivasertib on day 15 of cycle 1 (after the first fulvestrant dose) 4

Fulvestrant dosing:

• 500 mg intramuscularly on day 1 of each 28-day cycle 3
• Loading schedule: additional 500 mg doses on day 15 and day 28 of cycle 1 3, 4

Mandatory Monitoring and Toxicity Management

Implement proactive monitoring from day 1 to catch adverse events early, as most toxicities occur within the first 2-3 weeks:

Early Monitoring (First 8 Weeks)

• Diarrhea monitoring: Occurs at median 8 days (IQR 2-22 days), affecting 72.4% of patients (9.3% grade ≥3) 5, 1
• Rash monitoring: Occurs at median 12 days (IQR 10-15 days), affecting 38.0% of patients (12.1% grade ≥3) 5, 1
• Hyperglycemia monitoring: Occurs at median 15 days (IQR 1-51 days), affecting 18% of patients (2.8% grade ≥3) 5, 2

Dose Modification Strategy

Up to two dose reductions are permitted for capivasertib (400 mg → 320 mg → 240 mg twice daily). 5 The low discontinuation rates (13.0% overall, 2.0% for diarrhea, 4.5% for rash, 0.3% for hyperglycemia) demonstrate that these toxicities are manageable with supportive care and dose adjustments 5.

Supportive Medications

• Initiate antidiarrheal prophylaxis (loperamide) at first sign of loose stools 5
• Prescribe topical corticosteroids for rash management 5
• Monitor fasting glucose and HbA1c; initiate metformin or other antihyperglycemic agents as needed 2

Critical Safety Considerations

Hypertension occurred in 32% of patients in the FAKTION trial (grade 3-4), requiring blood pressure monitoring and antihypertensive management. 4 This is distinct from the CAPItello-291 safety profile but represents an important class effect to monitor.

The most serious adverse event is infection risk. One death from atypical pulmonary infection was possibly related to capivasertib in the FAKTION trial 4. Educate patients on infection precautions and maintain a low threshold for antibiotic initiation.

Treatment Duration and Discontinuation Criteria

Continue capivasertib plus fulvestrant until disease progression, unacceptable toxicity, or patient withdrawal. 4, 1 The median progression-free survival of 7.2-7.3 months in biomarker-positive patients establishes the expected treatment duration, though individual responses vary 1.

Do not restart letrozole or another aromatase inhibitor after progression on capivasertib-fulvestrant. The ASCO guidelines state there are no data to support additional lines of therapy with the same class of targeted agent after progression 3. Consider chemotherapy or alternative endocrine strategies based on pace of progression and symptom burden 3.

Common Pitfalls to Avoid

• Do not delay biomarker testing: The FDA approval is biomarker-restricted, and treating biomarker-negative patients exposes them to toxicity without proven benefit 2
• Do not underdose fulvestrant: The 500 mg dose with loading schedule is superior to 250 mg and is the only approved regimen 3
• Do not wait for severe toxicity before dose reduction: Early intervention with supportive care and dose modification prevents treatment discontinuation 5
• Do not use capivasertib in premenopausal women without ovarian suppression: Although CAPItello-291 included premenopausal women, they must receive concurrent LHRH agonist therapy 1