Reviews/Targeted Therapy Breast Cancer/Capivasertib (AKT inhibitor) in hormone receptor-positive metastatic breast cancer
Pi3k Akt · BC-PI3K-02 · v2
The question is whether adding capivasertib to fulvestrant slows cancer growth in advanced hormone-driven breast cancer that carries PIK3CA, AKT1 or PTEN changes and has already stopped responding to hormone therapy. A large, rigorously designed phase 3 trial tested exactly this and found that patients on the combination went longer before their disease worsened than those on fulvestrant alone [1]. An earlier, smaller independent trial pointed the same way once its patients were re-tested for these genetic changes [2][13]. Analyses of patients from China [5] and Japan [8], and a separate look at tumours low in the PTEN protein [17], all leaned in the same direction, though some of these groups were small. The main caution the panel noted is that most of the genetically-defined evidence comes from that one big trial, and the second trial only showed a biomarker-specific pattern after extra testing done later.
In the phase 3 CAPItello-291 trial of 708 patients, 289 (40.8%) with PIK3CA/AKT1/PTEN alterations had a median progression-free survival of 7.3 months on capivasertib-fulvestrant versus 3.1 months on placebo-fulvestrant (hazard ratio 0.50; 95% CI 0.38 to 0.65; P<0.001) [1]. The independent phase 2 FAKTION trial's expanded pathway-altered subgroup showed a consistent benefit (12.8 vs 4.6 months; HR 0.44; 95% CI 0.26 to 0.72) [2][7], against its original intention-to-treat result (HR 0.58; 95% CI 0.39 to 0.84) [13]. The same direction appears in the extended Chinese cohort (altered HR 0.41; 95% CI 0.19 to 0.85) [5], the Japan subgroup (altered HR 0.65; 95% CI 0.29 to 1.39) [8], and a PTEN-deficient-by-IHC subgroup (HR 0.52; 95% CI 0.28 to 0.90) [17]. All enrolled patients had relapsed or progressed on or after aromatase-inhibitor therapy, matching the claim's population [1][2][13]. The contested point: The division is over how much independent support the altered-population estimate truly has: the Chinese [5], Japan [8] and subgroup [6] analyses are additional looks at the same CAPItello-291 cohort rather than separate trials, leaving FAKTION [13][2] as the sole independent randomized confirmation. Compounding this, FAKTION's original report found benefit independent of pathway status [13], and the biomarker-specific effect emerged only on later, partly retrospective NGS re-testing [2][7], making it a post-hoc refinement.
All 17 papers behind this claim with their DOIs and what each does to it, the panel’s arbitration, the evidence gap map and the open research questions. Free, and sent to your inbox.
We’ll also send you other claims from Targeted Therapy Breast Cancer, one at a time, and tell you when a release or a pivotal trial changes a grade. Unsubscribe by replying.
One reviewer's only job is to attack the finding. The challenges below were weighed before the grade was set.
The decisive altered-population estimate rests on one trial (CAPItello-291); the Chinese [5], Japan [8], subgroup [6] and AE-paper [4][12] results are not independent replications but analyses of the same cohort, so apparent corroboration overstates independence.
FAKTION's original report [13] found PFS benefit independent of pathway status; the biomarker-specific effect emerged only on expanded, partly retrospective NGS re-testing [2][7], a post-hoc subgroup refinement carrying selection/definition bias.
Where it remains uncertain. Most altered-population data come from the single CAPItello-291 trial [1][5][8], and FAKTION's biomarker-specific effect was defined post hoc on expanded NGS re-testing [2][7] after its original report showed benefit regardless of pathway status [13].
Aleatory
The Japan altered subgroup rests on 78 randomized patients and yields a wide CI of 0.29 to 1.39 that crosses 1 [8]; the Chinese altered group (n=46) and PTEN-IHC group (n=70) are likewise small [5][17], so random variation plausibly drives part of the point estimates.
Epistemic
Most altered-population data derive from CAPItello-291; its Chinese [5] and Japan [8] subgroups and the AE papers [4][12] are analyses of the same cohort, leaving FAKTION [2][13] as the only independent randomized source.
Inferential
The altered population is defined differently across sources (NGS panels [2][7], CAPItello-291 protocol alterations, and PTEN deficiency by IHC [17]), with imperfect concordance between tissue and liquid NGS [15] and between IHC and NGS (positive percent agreement 71.9%) [17], so the effect size is sensitive to how alteration status is ascertained.
The load-bearing papers from a corpus of 17, each classified by what it does to the claim. Every DOI is taken from the corpus the claim was graded on.
Prespecified dual primary endpoint met in a 708-patient phase 3 RCT; directly establishes the claim in the exact biomarker population.
“In the AKT pathway-altered population, the median progression-free survival was 7.3 months in the capivasertib-fulvestrant group, as compared with 3.1 months in the placebo-fulvestrant group (hazard ratio, 0.50; 95% CI, 0.38 to 0.65; P<0.001).”
Panel auditInternal validity: high · scope of inference: HR-positive, HER2-negative advanced breast cancer with PIK3CA/AKT1/PTEN alterations progressing on or after an aromatase inhibitor, with or without prior CDK4/6 inhibitor.Key limitations: industry funded · median PFS absolute gain modest (~4 months)
Independent phase 2 RCT replicating the PFS benefit in the PI3K/AKT/PTEN-altered subgroup.
“Median progression-free survival in the expanded pathway-altered subgroup for participants receiving capivasertib (n=39) was 12·8 months (95% CI 6·6-18·8) compared with 4·6 months (2·8-7·9) in the placebo group (n=37; adjusted HR 0·44 [95% CI 0·26-0·72]; two-sided p=0·0014).”
Panel auditInternal validity: medium · scope of inference: Postmenopausal women with ER-positive, HER2-negative advanced breast cancer, aromatase inhibitor-resistant, no prior CDK4/6 inhibitor; pathway-altered subgroup.Key limitations: phase 2, small n · post hoc biomarker reclassification · no prior CDK4/6 inhibitor exposure
Extended CAPItello-291 cohort reproducing a significant altered-population PFS benefit.
“patients with PIK3CA/AKT1/PTEN-altered tumors (n = 46; 5.7 versus 1.9 months; hazard ratio 0.41, 95% CI 0.19-0.85)”
Panel auditInternal validity: medium · scope of inference: Chinese patients with HR-positive, HER2-negative advanced breast cancer progressing during/after aromatase inhibitor; altered subgroup.Key limitations: exploratory regional subgroup · small n, wide CI · non-altered tumors also benefited
Only the overall-population PFS improvement is stated; no altered-population PFS contrast appears in this abstract.
Panel auditInternal validity: medium · scope of inference: Safety and tolerability of capivasertib-fulvestrant in HR-positive, HER2-negative advanced breast cancer after aromatase inhibitor therapy.Key limitations: safety-focused analysis · altered-subgroup PFS not reported
4 of 17 papers shown. The full review lists all of them, with the panel’s arbitration →
Claims are graded at each quarterly release, and re-graded between releases only when a pivotal trial lands. Every change is a new version of the claim.
A positive, prespecified, adequately powered phase 3 primary endpoint in the exact claimed population, independently corroborated by a second randomized trial, warrants the Established tier with a modest discount for single-trial dominance and post-hoc biomarker definition.
Release 2026-q4 re-graded every claim from its corpus under protocol v0.19. An earlier release's grade is shown for the record; it came from an earlier protocol and is not a movement.
Assumptions that carry weight but are not themselves established.
The panel records the gap that would most move the claim, and the study that would close it.
Independent phase 3 confirmation in the biomarker-defined population. Most altered-population evidence is from one trial [1][5][8]; a second independent randomized trial would resolve the single-trial-dominance discount. The panel rates this the highest-importance open gap for the claim, and names the study design that would close it: A separate adequately powered phase 3 RCT of capivasertib-fulvestrant versus fulvestrant enrolling prospectively identified PIK3CA/AKT1/PTEN-altered patients.
Open question: Is the altered-population PFS benefit reproducible in a second, independent, prospectively biomarker-selected phase 3 trial? Why it is still open: The decisive estimate rests on CAPItello-291 [1], with its Chinese [5] and Japan [8] data being subgroups of the same cohort and FAKTION [2][13] a phase 2 trial with a post-hoc panel.
Priors is a sceptical first reader, not peer review, and not medical advice.
Release 2026-q4 · graded 23 Oct 2026 · protocol v0.19