SAN ANTONIO – For patients with hormone receptor-positive/HER2-negative (HR+/HER2–) breast cancers resistant to aromatase inhibitors, the combination of the investigational AKT inhibitor capivasertib with the selective estrogen receptor degrader fulvestrant (Faslodex) was associated with significant improvement in progression-free survival compared with fulvestrant alone in the CAPItelllo-291 study recently presented at the San Antonio Breast Cancer Symposium.
, reported Nicholas Turner, MD, PhD, of the Institute of Cancer Research and Royal Marsden NHS Foundation Trust in London.
“Capivasertib plus fulvestrant has the potential to be a future treatment option for patients with hormone receptor–positive advanced breast cancer who have progressed on an endocrine-based regimen,” he said.
AKT alterations
Many HR+/HER2– advanced breast cancers have activation of the AKT pathway through alteration in PIK3CA, AKT1, and PTEN, but this activation can also occur in the absence of genetic alterations. AKT signaling is also a mechanism of resistance to endocrine therapy, Dr. Turner said.
Capivasertib, a select inhibitor of the AKT isoforms 1, 2, and 3, was combined with fulvestrant in the phase 2 FAKTION trial. The combination was associated with significant improvements in both progression-free survival (PFS) and overall survival (OS) compared with fulvestrant plus placebo in CDK4/6-naive postmenopausal women with aromatase inhibitor–resistant HR+/HER2– advanced breast cancer. The clinical benefit in this trial was more pronounced among patients with tumors bearing AKT pathway alterations, he said.
In the phase 3 CAPItello study, Dr. Turner and colleagues enrolled men and both pre- and postmenopausal women with HR+/HER2– advanced breast cancer who experienced recurrence either during therapy with adjuvant aromatase inhibitor or within 12 months of the end of therapy, or who had disease progression while on prior aromatase inhibitor therapy for advanced breast cancer.
The patients could have no more than two prior lines of endocrine therapy and no more than one prior line of chemotherapy for advanced breast cancer, and no prior selective estrogen receptor degrader (SERD), mTOR inhibitor, PI3K inhibitor, or AKT inhibitor. Patients with hemoglobin A1c below 8% and with diabetes not requiring insulin were eligible for the study. After stratification for liver metastases, prior CDK4/6 inhibitor therapy, and geographic region, 708 patients were randomized to either capivasertib 400 mg twice daily 4 days on and 3 days off plus fulvestrant 500 mg on days 1 and 15 of cycle 1 and then every 4 weeks, or to fulvestrant in the same dose and schedule plus placebo.
Results
The dual primary endpoint was investigator assessed PFS in both the overall population and in those with AKT pathway alterations. The median PFS in the overall population was 7.2 months with the combination, compared with 3.6 months for fulvestrant alone, translating into an adjusted hazard ratio for progression of 0.60 (P < .001).
In the pathway-altered population, the median PFS was 7.3 months with capivasertib/fulvestrant vs. 3.1 months with fulvestrant placebo, which translated into an adjusted hazard ratio for progression on the combination of 0.50 (P < .001).
An exploratory analysis of PFS among patients either without pathway alterations or unknown AKT status showed median PFS of 7.2 months and 3.7 months, respectively, with a hazard ratio of 0.70.
An analysis of benefit by subgroups in the overall population showed that the balance tipped in favor of the combination in nearly all categories, including among patients with or without liver metastases and with or without prior CDK4/6 inhibitor use.
Among patients with measurable disease at baseline the combination was associated with objective response rates (ORR) of 22.9% in the overall population and 28.8% in the pathway-altered population. The respective ORR for fulvestrant/placebo were 12.2% and 9.7%.
Overall survival data were not mature at the time of data cutoff, but showed trends favoring capivasertib plus fulvestrant in both the overall and AKT-pathway-altered population.
There were four fatal adverse events in the combination arm (acute myocardial infarction, cerebral hemorrhage, pneumonia aspiration, and sepsis), and one in the fulvestrant alone arm (COVID-19).
The most common grade 3 or greater adverse events among patients treated with the combination were rash (12.1%), diarrhea (9.3 %), and hyperglycemia (2.3%). In all, 13% of patients randomized to capivasertib/fulvestrant discontinued therapy due to adverse events, compared with 2.3% of patients assigned to fulvestrant/placebo.
Dr. Turner said that the overall adverse event profile with the combination was manageable and consistent with data from previous studies.