Fulvestrant Plus Ipatasertib Fails to Demonstrate an Overall Survival Benefit in ER+/HER2− Metastatic Breast Cancer: Final Results From the FINER Study
The CCTG/BCT MA.40/FINER study (NCT04650581) is a randomized, double-blind, placebo-controlled Phase III trial evaluating ipatasertib plus fulvestrant versus placebo plus fulvestrant in pre-, peri-, and postmenopausal women and men with ER+/HER2− advanced or metastatic breast cancer following disease progression on first-line CDK4/6 inhibitor plus aromatase inhibitor therapy. A total of 250 patients were randomized in a 1:1 ratio to receive ipatasertib (400 mg orally once daily on days 1–21 of each 28-day cycle) plus fulvestrant or placebo plus fulvestrant. Randomization was stratified according to AKT pathway alteration status, including PIK3CA, AKT1, and/or PTEN genomic alterations assessed through circulating tumor DNA (ctDNA), and the duration of prior CDK4/6 inhibitor treatment, reflecting primary versus secondary endocrine resistance. The primary endpoint was investigator-assessed PFS in the intention-to-treat (ITT) population, while OS was evaluated as a secondary endpoint. The earlier analysis, presented at ASCO 2025, demonstrated a significant PFS improvement with ipatasertib. The ESMO 2026 presentation reported the OS analysis after a median follow-up of 35.0 months, providing further insight into the long-term clinical benefit of the combination.
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Key Efficacy and Safety Highlights | |||
|
Category |
Parameter |
Ipatasertib + Fulvestrant (n=125) |
Placebo + Fulvestrant (n=125) |
|
Efficacy |
Median follow-up (OS analysis) |
35 months |
35 months |
|
Patients remaining on protocol treatment |
3.2% |
2.4% | |
|
Median PFS in ITT population |
5.32 months |
1.94 months | |
|
PFS hazard ratio (95% CI) |
0.61 |
Reference | |
|
PFS statistical significance |
p=0.0007 |
Reference | |
|
Median PFS in AKT pathway altered subgroup |
5.45 months |
1.91 months | |
|
PFS hazard ratio in AKT pathway-altered subgroup |
0.47 |
Reference | |
|
Median OS in ITT population |
26.68 months |
25.76 months | |
|
OS hazard ratio (95% CI) |
0.97 (0.70–1.33) |
Reference | |
|
OS statistical significance |
p=0.83; not significant |
Reference | |
|
Median OS in AKT pathway-altered subgroup |
23.66 months |
25.23 months | |
|
OS hazard ratio in AKT pathway-altered subgroup |
1.14 (0.72–1.80) |
Reference | |
|
OS statistical significance in AKT pathway-altered subgroup |
p=0.58; not significant |
Reference | |
|
Safety |
Grade ≥3 adverse events |
37.1% |
27.4% |
|
Grade ≥3 treatment-related diarrhea |
16% |
0% | |
|
Treatment discontinuation due to adverse events |
6.5% |
0.8% | |
Conclusion-
The Phase III CCTG/BCT MA.40/FINER study demonstrated that although ipatasertib plus fulvestrant significantly improved PFS in patients with ER+/HER2− metastatic breast cancer following progression on first-line CDK4/6 inhibitor plus aromatase inhibitor therapy, this benefit did not translate into improved OS. The median OS remained comparable between treatment arms, with no statistically significant survival advantage in either the overall population or the exploratory AKT pathway-altered subgroup. Furthermore, the higher incidence of grade ≥3 adverse events observed in the ipatasertib arm in the earlier analysis adds to the considerations surrounding its benefit–risk profile. These findings underscore the importance of distinguishing improvements in disease control from meaningful long-term survival benefits. Overall, despite demonstrating promising PFS activity, ipatasertib plus fulvestrant has not established an OS advantage, potentially limiting its ability to secure a differentiated position in the post-CDK4/6 treatment landscape.