HR+/HER2– breast cancer is the most common subtype of breast cancer, accounting for about 211,600 cases in the US, in 2024. Although endocrine therapy combined with CDK4/6 inhibitors is a widely used first-line treatment, resistance frequently develops in the advanced setting, resulting in disease progression. The PI3K–AKT–mTOR signaling pathway, which regulates key cellular processes such as growth and survival, has been implicated in driving resistance to endocrine therapy in some ER-positive tumors. Ipatasertib, an oral AKT inhibitor, targets this pathway and may help overcome endocrine resistance by disrupting tumor cell proliferation and survival. The FINER trial is managed in Australia and New Zealand in partnership with the Canadian Cancer Trials Group (CCTG).

The Phase III MA.40 trial evaluated the AKT inhibitor ipatasertib plus fulvestrant versus placebo plus fulvestrant in patients with ER+/HER2-negative metastatic breast cancer who had progressed on first-line CDK4/6 inhibitor plus aromatase inhibitor. Patients—both women (pre-, peri-, and postmenopausal) and men—were randomized 1:1, with stratification based on AKT pathway status (PIK3CA, AKT1, and/or PTEN alterations vs wild-type/unknown) and type of endocrine resistance (primary vs secondary).

In the final progression-free survival (PFS) analysis, the combination treatment showed a median PFS of 5.32 months in the ITT population (n = 125) compared to 1.94 months in the placebo arm (Hazard Ratio 0.61; p = 0.0007). Per BICR, median PFS was 9.07 months in the investigational arm versus 3.71 months in the control (Hazard Ratio 0.65; p = 0.0177). At a median follow-up of 15.2 months, the median OS in the combination arm was 23.13 months, compared with 24.87 months in the placebo arm (Hazard Ratio 1.07; p = 0.75). In patients with AKT pathway alterations, median PFS was 12.88 months in the combination arm vs. 3.68 months in the placebo arm (Hazard Ratio 0.50; p = 0.011). In the ESR1 wild-type cohort, median PFS was 5.55 months in the combination arm vs. 2.00 months in the placebo arm (Hazard Ratio 0.54). In the ESR1-mutated cohort, median PFS was 3.71 months in the combination arm vs. 1.87 months in the placebo arm (Hazard Ratio 0.61). Ipatasertib was associated with higher rates of gastrointestinal and metabolic adverse events, though most were manageable; treatment discontinuation due to toxicity remained low.

KOL insights: 

“The ipatasertib and fulvestrant combination is generally tolerable and improved PFS in both the ITT and the AKT-altered cohort; both [findings] were statistically significant and clinically meaningful, this combination provides a potential treatment option immediately post CDK4/6 and aromatase inhibitor [disease] progression in [patients with] ER-positive, HER2-negative metastatic breast cancer.”– Expert Opinion.

Conclusion

The Phase III FINER trial (NCT04650581) demonstrated that the combination of ipatasertib and fulvestrant significantly improved PFS (statistically significant and clinically meaningful) in both the ITT and the AKT-altered cohort in patients with ER-positive, HER2-negative metastatic breast cancer . In addition to this, the combination was generally tolerable, with diarrhea, nausea, hyperglycemia, and fatigue as common adverse effects. Results support the potential of this regimen as a clinically meaningful second-line treatment strategy, with ongoing follow-up and additional analyses underway.