Nicholas C. Turner, MD, PhD, on New Data on Capivasertib and Fulvestrant for Advanced Breast Cancer

AKT inhibition is common in advanced hormone receptor positive HER2 negative breast cancers. The CAPitello 291 study investigated the AKT inhibitor, capivasertib. The study recruited patients with advanced hormone receptor positive HER2 negative breast cancer that had progressed on prior aromatase inhibitor. The study allowed up to two prior lines of endocrine therapy and one prior line of chemotherapy for advanced breast cancer, and also allowed prior CDK4/6 inhibitor, mandating 51% of patients to have had a prior CDK4/6 inhibitor at least. 708 patients were recruited, randomized one to one between fulvestrant and placebo and fulvestrant and capivasertib. There were two co-primary endpoints. Investigator assessed PPFs overall and in AKT pathway activated cancers. AKT pathway activated cancers were defined as the presence of PIC3CA, AKT1, or P10 mutations in the cancer, which was determined in tissue, which was submitted after randomization and analyzed with the FoundationOne assay. Overall, 41% of tumors had AKT pathway activating alterations. Overall, median PFS improved from 3.6 months on fulvestrant and placebo to 7.2 months on capivasertib and fulvestrant. A hazard ratio of 0.6, highly statistically significant. Then in the co-primary endpoint of AKT pathway activated cancers, PFS improved from 3.1 months on placebo to 7.2 months on capivasertib. A hazard ratio of 0.5. Again, highly statistically significant. If we come to adverse effects, overall capivasertib was well tolerated with a manageable safety profile. 13% of patients stopped due to adverse effects. The most prominent adverse effect was diarrhea, which occurred in 72% of patients, predominantly grade one diarrhea, although 9% of patients had grade three diarrhea. Rash also occurred in 38% of patients, 12% grade three, but prominently both hypoglycemia and stomatitis were relatively uncommon, grade three and only 2% of patients each. Overall the CAPitello 291 study showed a statistically significant and clinically meaningful improvement in progression-free survival, both overall and in AKT pathway activated cancers. The benefit was consistent across subgroups including in patients with prior CDK46 inhibitor use. Currently, overall survival data is immature and ongoing follow-up is going on for two further formal analyses of overall survival. In conclusion, it is hopeful that capivasertib will be a future treatment option for the population of patients who were recruited in the study.