Background
Phase III, double-blind, placebo-controlled RCT. N=708 HR+ HER2- advanced breast cancer progressing on/after aromatase inhibitor ± CDK4/6 inhibitor. Two co-primary populations: overall and the PIK3CA/AKT1/PTEN-altered subset (~40%). Capivasertib is a pan-AKT inhibitor targeting the PI3K/AKT/PTEN pathway regardless of specific mutation.
Interventions and follow up
Arm A: Capivasertib 400mg BID days 1–4 of 7-day cycle (4 on/3 off) + fulvestrant 500mg IM q28d
Arm B: Placebo + fulvestrant 500mg IM q28d
Primary endpoint: PFS in overall population and AKT pathway-altered subgroup
mFollow up: 24.8 months
Arm B: Placebo + fulvestrant 500mg IM q28d
Primary endpoint: PFS in overall population and AKT pathway-altered subgroup
mFollow up: 24.8 months
Results
PFS (overall): 7.2 vs 3.6mo, HR 0.60, 95% CI 0.51–0.71, P<.001
PFS (AKT pathway-altered): 7.3 vs 3.1mo, HR 0.50, 95% CI 0.38–0.65, P<.001
ORR (overall): 22.9% vs 12.2%
PFS (AKT pathway-altered): 7.3 vs 3.1mo, HR 0.50, 95% CI 0.38–0.65, P<.001
ORR (overall): 22.9% vs 12.2%
Adverse events
Dermatologic: Grade ≥3 rash 12.1% vs 0.3%
GI: Grade ≥3 diarrhea 9.3% vs 0.3%
Metabolic: Grade ≥3 hyperglycemia 3.8% vs 0.1%
Tolerability: Dose reduction 53.5%; discontinuation 13.0%
GI: Grade ≥3 diarrhea 9.3% vs 0.3%
Metabolic: Grade ≥3 hyperglycemia 3.8% vs 0.1%
Tolerability: Dose reduction 53.5%; discontinuation 13.0%
Conclusions
Capivasertib + fulvestrant significantly improved PFS vs fulvestrant alone after prior AI/CDK4/6i, with greater benefit in the AKT pathway-altered subgroup. Established AKT inhibition as a viable post-CDK4/6i strategy with broader biomarker scope than PI3Kα-only inhibition.
Key Limitations
Modest absolute PFS gains (~3.6mo overall, ~4.2mo AKT-altered). Rash and diarrhea require active management. Intermittent 4-on/3-off dosing reduces AE burden but adds scheduling complexity. OS data immature at primary analysis. Numerically positive benefit in pathway-unaltered patients may reflect off-target effects or panel detection limits.
Clinical Context
Capivasertib (Truqap) + fulvestrant: FDA approved 2023 for HR+ HER2- advanced/mBC with PIK3CA/AKT1/PTEN alteration after endocrine therapy progression. Unlike alpelisib (PI3Kα-selective), pan-AKT inhibition captures a broader population including PTEN-loss tumors, with better rash/hyperglycemia profile. Molecular testing required per label.
References