The VICTORIA-1 trial found that re-introducing palbociclib in a triplet with gedatolisib was effective, even in patients who had just progressed on palbociclib. This suggests that gedatolisib targets and overcomes the primary resistance mechanism to the CDK4/6 inhibitor, re-sensitizing the cancer to it.

Next-generation mutant-specific PI3K inhibitors could lead to complex biomarker requirements. A future drug label might require a PIK3CA mutation for eligibility but simultaneously exclude patients who also have downstream PTEN or AKT alterations, which can confer resistance.

Retrospective analysis of the BOLERO-2 trial revealed that the mTOR inhibitor everolimus benefits patients irrespective of their PI3K mutation status. This challenges the assumption that pathway-targeted therapies are only effective when a specific mutation is present, suggesting broader mechanisms of action.

The INOVO-123 trial strategically investigates a PI3K inhibitor-based triplet therapy for endocrine-sensitive, PIK3CA-mutated breast cancer. This moves beyond its current approval in the endocrine-resistant setting, aiming to establish its efficacy for patients with de novo metastatic disease or as a first-line treatment, thereby widening its use much earlier in the patient journey.

The VICTORIA-1 trial found that gedatolisib, a pan-PI3K/mTOR inhibitor, significantly improves progression-free survival in patients with PIK3CA *wild-type* tumors after CDK4/6 inhibitor progression. This is a crucial finding for a patient group lacking clear targeted options and broadens the utility of targeting the PI3K pathway beyond just mutated tumors.

For patients with a PIK3CA mutation who relapse on or shortly after adjuvant endocrine therapy, the INAVO120 trial established a new standard of care. Adding inavolisib to palbociclib and fulvestrant significantly improved overall survival by seven months, providing a potent option for this particularly high-risk, endocrine-resistant population.

Post-approval studies of the oral SERD elacestrant confirm its clinical benefit in ESR1-mutant breast cancer. However, this real-world evidence also reveals a new insight: patients who have both an ESR1 and a PIK3CA mutation tend to have a shorter time on treatment, suggesting that the PIK3CA mutation may drive resistance to this therapy.

Despite the presence of PIK3CA mutations in some triple-negative breast cancer (TNBC) tumors, Phase III trials with AKT inhibitors have been negative. Currently, there is insufficient evidence to support using PI3K/AKT pathway inhibitors for TNBC in clinical practice.

For patients with both ESR1 and PIK3CA mutations, emerging data suggests prioritizing an oral SERD-based combination. The EMBER-3 trial showed imlunestrant plus abemaciclib achieved a ~12-month PFS in this subgroup, starkly outperforming the ~5.6-month PFS seen with PI3K/AKT inhibitor combinations like capivasertib-fulvestrant in the CAPItello-291 trial.