Nicholas C. Turner, MD, PhD, on New Data on Capivasertib and Fulvestrant for Advanced Breast Cancer
2022 San Antonio Breast Cancer Symposium
Nicholas C. Turner, MD, PhD, of London’s Institute of Cancer Research and The Royal Marsden, discusses phase III results from the CAPItello-291 clinical trial, which showed that in patients with hormone receptor–positive, HER2-negative tumors resistant to aromatase inhibitors, adding the investigational AKT inhibitor capivasertib to fulvestrant doubled the median progression-free survival compared with placebo plus fulvestrant (Abstract GS3-04).
Disclaimer: This video transcript has not been proofread or edited and may contain errors.
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.
Mariana Chavez-MacGregor, MD, MSc, of The University of Texas MD Anderson Cancer Center, discusses phase III results from the SWOG S1207 trial which was designed to evaluate the role of adjuvant everolimus in combination with adjuvant endocrine therapy among patients with high-risk, hormone receptor–positive, HER2-negative early-stage breast cancer. Adding everolimus did not improve invasive disease–free or overall survival and was associated with high rates of adverse events (Abstract GS1-07).
Lisa A. Carey, MD, and Joannie M. Ivory, MD, MSPH, both of the University of North Carolina at Chapel Hill, discuss the higher frequency and treatment implications of nonluminal A or high-risk tumors in Black and younger women. In this study, PAM50 and 21-gene assays revealed different demographic patterns by race and age (Abstract PD1-08).
Erica L. Mayer, MD, PhD, of Dana-Farber Cancer Institute, discusses findings from the PACE study of patients with endocrine- and CDK4/6 inhibitor–pretreated estrogen receptor–positive/HER2-negative metastatic breast cancer who were randomly assigned to fulvestrant alone; fulvestrant and palbociclib; or fulvestrant, palbociclib, and avelumab. Combining palbociclib with fulvestrant beyond disease progression on a prior CDK4/6 inhibitor regimen did not improve progression-free survival compared with fulvestrant alone. A longer progression-free survival when a PD-L1 inhibitor was added to fulvestrant and palbociclib deserves further study. A baseline circulating tumor DNA analysis suggests that the potential benefit of palbociclib after progression on a prior CDK4/6 inhibitor may be influenced by ESR1 or PIK3CA status (Abstract GS3-06).
Sara A. Hurvitz, MD, of the University of California, Los Angeles, Jonsson Comprehensive Cancer Center, discusses phase III findings from the DESTINY-Breast03 study, which showed that second-line treatment with fam-trastuzumab deruxtecan-nxki (T-DXd) led to longer overall survival compared with ado-trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer. Patients treated with T-DXd had a 36% lower risk of death than those treated with T-DM1 (Abstract GS2-02).
Ann H. Partridge, MD, MPH, of Dana-Farber Cancer Institute, discusses results from the POSITIVE trial, which showed that a temporary interruption of endocrine therapy in women with hormone-responsive breast cancer in order to attempt pregnancy, does not affect short-term disease outcomes. The study found that 74% of women had at least one pregnancy, most (70%) within 2 years. Birth defects were low (2%) and were not clearly associated with treatment exposure. Dr. Partridge explains that these data stress the need to incorporate patient-centered reproductive health care in the treatment and follow-up of young women with breast cancer (Abstract GS4-09).