Capivasertib

Drug Overview:

Capivasertib, marketed as Truqap, marks a milestone in targeted oncology as the first pan-AKT inhibitor approved for the precision treatment of advanced breast cancer. This oral “smart drug” targets the hyperactive PI3K/AKT/PTEN pathway prevalent in hormone receptor-positive tumors, offering new options for patients progressing on endocrine therapies in the US and European markets. Developed by AstraZeneca, it addresses a critical unmet need in approximately 40-50% of HR+/HER2- cases with pathway alterations, enhancing progression-free survival post-CDK4/6 inhibitor failure.​

• Generic name: Capivasertib​
• US Brand names: Truqap​
• Drug Class: Pan-AKT kinase inhibitor (targeted therapy)​
• Route of Administration: Oral (tablets)​
• FDA Approval Status: Approved November 16, 2023, in combination with fulvestrant for HR-positive, HER2-negative locally advanced or metastatic breast cancer with PIK3CA/AKT1/PTEN alterations following progression on endocrine-based therapy; EU approval followed in 2024​

What Is It and How Does It Work? (Mechanism of Action)

Capivasertib functions as a selective targeted therapy by inhibiting all three isoforms of AKT (AKT1, AKT2, AKT3), the central node in the PI3K/AKT/PTEN signaling cascade often dysregulated in cancers. This “smart drug” counters pathway hyperactivation from PIK3CA mutations, AKT1 alterations, or PTEN loss, restoring tumor suppression at the molecular level while sparing normal cells through isoform-specific potency.​

• Binds competitively to the ATP-binding site of AKT kinases, preventing phosphorylation at key activation sites (T308 by PDK1, S473 by mTORC2) and inhibiting kinase activity across all isoforms with high selectivity and potency​
• Blocks downstream signaling through inhibition of AKT substrates, disrupting PI3K-generated PIP3-mediated membrane recruitment and activation, halting proliferation via FOXO transcription factors and cell cycle regulators like p27​
• Suppresses mTORC1 activation by preventing TSC1/2 phosphorylation/inactivation, reducing protein synthesis, autophagy inhibition, and metabolic reprogramming critical for tumor survival, growth, and endocrine resistance​
• Induces apoptosis and cell cycle arrest by relieving AKT-mediated inhibition of pro-apoptotic proteins (BAD, BIM, FOXO) and GSK3β, with preclinical synergy in PIK3CA-mutant models, xenograft tumor regression, and reversal of endocrine resistance​

FDA Approved Clinical Indications

Capivasertib holds FDA approval exclusively for oncological use in biomarker-selected breast cancer patients post-endocrine therapy. Comprehensive genomic profiling identifies eligible cases, aligning with precision medicine standards and NCCN/ESMO guidelines for advanced HR+/HER2- disease.​

• Oncological uses: Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN-alterations, in combination with fulvestrant, following progression on at least one endocrine-based regimen (with or without CDK4/6 inhibitor) or recurrence within 12 months of adjuvant therapy​
• Non-oncological uses: None​

Dosage and Administration Protocols

Capivasertib dosing follows a 4-days-on/3-days-off schedule to mitigate toxicity while maintaining efficacy, taken orally with fulvestrant on a 28-day cycle. No infusion required; adjustments focus on hyperglycemia, rash, and diarrhea management for optimal tolerability.​

Clinical Efficacy and Research Results

The phase 3 CAPItello-291 trial (NCT04305496, data through 2025) demonstrated capivasertib plus fulvestrant’s superiority in biomarker-selected patients. Subgroup analyses confirmed consistent benefits across therapy lines, including post-CDK4/6i progression.​

• Progression-free survival (PFS) improvement: Median PFS 7.4 months vs 3.5 months placebo (HR 0.50, 95% CI 0.38-0.65, p<0.0001) in overall cohort; 7.2 vs 3.1 months in PIK3CA-mutated subgroup​
• Objective response rate (ORR): 22.9% capivasertib vs 12.3% placebo; clinical benefit rate 40.6% vs 26.9%​
• Ongoing overall survival (OS) data maturation favorable; CAPItello-101 trial explores combinations with CDK4/6i and immunotherapy​

Safety Profile and Side Effects

Capivasertib exhibits a profile dominated by on-target class effects like hyperglycemia and rash, manageable with proactive monitoring and supportive care. No black box warnings issued, with 13% discontinuation rate due to adverse events.​

Common Side Effects (>10%)

• Diarrhea (73%; manage with loperamide prophylaxis from day 1, dose interruption; ensure hydration)​
• Cutaneous reactions (rash/pruritus 70%; topical steroids like hydrocortisone 1%, emollients prophylactically from cycle 1)​
• Hyperglycemia (13% Grade 3/4; monitor fasting glucose weekly first 2 cycles, titrate metformin/insulin)​
• Fatigue/nausea/stomatitis (30-40%; supportive care, antiemetics, magic mouthwash rinses)​
• Anemia/lymphopenia (decreased hemoglobin 50%, lymphocytes 40%; monitor CBC monthly)​

Serious Adverse Events

• Severe hyperglycemia (Grade 3/4 in 13%; urgent glucose control, endocrinology consult, hospitalization if DKA)​
• Grade 3+ cutaneous reactions/Stevens-Johnson syndrome (<1%; immediate dermatology referral, permanent discontinuation if non-resolving)​
• Opportunistic infections (due to lymphopenia ~20%; PJP/HSV prophylaxis if CD4<200, fever/neutropenia workup)​

Patient Management and Practical Recommendations

Proactive toxicity management optimizes capivasertib adherence, with baseline metabolic screening and patient education essential. Multidisciplinary support including endocrinology, dermatology, and nutrition aids long-term use in metastatic settings.​

Pre-treatment Tests

• Confirm PIK3CA/AKT1/PTEN alterations via FDA-approved NGS test (e.g., FoundationOne Liquid CDx)​
• Fasting glucose/HbA1c (<8% ideal), LFTs, renal function (CrCl), CBC/differential, pregnancy test​
• Dermatologic baseline exam, ECG if QT history, diabetes screening​

Precautions During Treatment

• Weekly glucose/CBC/LFTs first 2 cycles, biweekly thereafter; pre-cycle antidiabetic adjustment​
• Skin surveillance every 2 weeks; strict sun protection SPF 50+, moisturize bid​
• Hold for Grade 3+ AEs; avoid strong CYP3A4 inhibitors (ketoconazole) or inducers (rifampin)​

Do’s and Don’ts

• Do take tablets whole with/without food at consistent daily time on days 1-4​
• Do apply emollients and report rash/hyperglycemia/diarrhea at first sign​
• Don’t consume grapefruit, St. John’s wort, or pomegranate; start loperamide early for diarrhea​
• Don’t breastfeed during treatment and for 1 week after last dose​

Legal Disclaimer

This guide provides general information about capivasertib and is not a substitute for professional medical advice, diagnosis, or treatment. Always consult a qualified healthcare provider for personalized recommendations. Treatment decisions should consider individual patient factors, and this content does not endorse any specific therapy.​