by Hope Rugo, MD – UCSF
Dr. Hope S. Rugo is a highly respected oncologist and professor of medicine specializing in breast oncology at the University of California San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, where she serves as the Director of Breast Oncology and Clinical Trials Education.
The phase 3 CAPItello-291 trial evaluated the combination of Capivasertib (C) and Fulvestrant (F) in patients with aromatase inhibitor (AI)-resistant HR+/HER2- advanced breast cancer (ABC), focusing on the characterization and management of common adverse events (AEs). The trial demonstrated that adding C, a potent pan-AKT inhibitor, to F resulted in a significant improvement in progression-free survival (PFS) compared to placebo (P) in both the overall population and the population with AKT pathway alterations. The PFS hazard ratios were 0.60 (95% CI 0.51-0.71; p<0.001) and 0.50 (95% CI 0.38-0.65; p<0.001), respectively. The study conducted a comprehensive analysis of the AEs associated with the treatment regimen. Patients were randomly assigned to receive F (500 mg intramuscularly on days 1 and 15 of cycle 1, and day 1 of each subsequent 28-day cycle) along with either P or C (400 mg twice daily; 4 days on, 3 days off). Eligible patients had HbA1c <8.0% and non-insulin-requiring diabetes. The incidence, management, and time to onset of common AEs (>10% any grade and >2.0% grade ≥3; CTCAE v5.0) were summarized. In total, 708 patients were randomized to receive C+F (n=355) or P+F (n=353) in the safety population (C+F n=355; P+F n=350). Baseline risk factors potentially linked to hyperglycemia included a history of diabetes in 34 patients (10%) in the C+F arm compared to 20 patients (6%) in the P+F arm. The median baseline HbA1c levels were 5.4% (range: 4.0-8.3) and 5.4% (range: 3.9-7.7) for C+F and P+F arms, respectively, while median weight was 65.0 kg (range: 34-150) and 66.5 kg (range: 37-147). Approximately 54% of patients in the C+F arm and 53% in the P+F arm were classified as overweight or obese. Common AEs observed in the study were diarrhea, rash, and hyperglycemia, with most AEs being grade 1/2 and resulting in low discontinuation rates. The management of these AEs involved the use of specific medications. For instance, diarrhea was managed with medications in 59% of patients (151/257), mainly with loperamide (135 patients). Rash was managed in 81% of patients (109/135) with antihistamines (75 patients) and topical corticosteroids (64 patients). Hyperglycemia, observed in 47% of patients (28/60), was managed primarily with metformin (18 patients). In conclusion, the most commonly reported AEs associated with AKT pathway inhibition, such as diarrhea, rash, and hyperglycemia, occur early during treatment with C+F, are typically of low grade, manageable, and do not necessitate frequent dose modifications or discontinuations.