Dr Brufsky on the FDA Approval of Capivasertib Plus Fulvestrant in PIK3CA/AKT1/PTEN-Altered HR+/HER2– Breast Cancer

Adam M. Brufsky, MD, PhD, FACP, professor, medicine, associate division chief, Division of Hematology/Oncology, Department of Medicine, the University of Pittsburgh School of Medicine; medical director, the Magee-Women's Cancer Program, associate director, clinical investigation, codirector, the Comprehensive Breast Cancer Center, UPMC Hillman Cancer Center, discusses the significance of the FDA approval of capivasertib (Truqap) in combination with fulvestrant (Faslodex) for patients with hormone receptor (HR)–positive, HER2-negative, locally advanced or metastatic breast cancer harboring 1 or more PIK3CA, AKT1, or PTEN alterations.

On November 16, 2023, the FDA approved this combination in this population based on data from the phase 3 CAPItello-291 trial (NCT04305496). Findings derived from the randomized, double-blind, placebo-controlled, multicenter trial demonstrated that among 289 patients with PIK3CA/AKT1/PTEN-altered tumors, treatment with capivasertib and fulvestrant (n = 155) elicited a median progression-free survival (PFS) of 7.3 months (95% CI, 5.5-9.0) vs 3.1 months (95% CI, 2.0-3.7) with placebo and fulvestrant (n = 134; HR 0.50; 95% CI, 0.38, 0.65; P < .0001).

Patients with HR-positive, HER2-negative, locally advanced or metastatic breast cancer with PIK3CA/AKT1/PTEN alterations currently require alternative treatment agents to those presently available, and capivasertib, an AKT inhibitor, has emerged as a promising candidate, Brufsky begins. The CAPItello-291 trial revealed a significant PFS improvement with capivasertib plus fulvestrant vs placebo plus fulvestrant, he explains, adding that this positive outcome extended to various patient populations, including those with PIK3CAmutations, those without PI3K results for unspecified reasons, and those without PIK3CA mutations.

Notably, benefits with capivasertib plus fulvestrant were observed in patients with PIK3CA mutations in the PI3K pathway and those with less common PTEN and AKT1 mutations within the same pathway. Although the FDA approved this combination exclusively for patients with alterations in the PI3K pathway, based on findings from a post hoc analysis that excluded patients with confirmed PIK3CA wild-type disease, the trial's primary end point success across all prespecified patient subgroups suggests broader efficacy, he continues. Despite concerns about potential adverse effects (AEs), such as diarrhea and rash, the latter requiring proactive management with Cetirizine and other H1 blockers, capivasertib's lower toxicity, as indicated in clinical trial results, offers a valuable addition to the breast cancer treatment paradigm, he emphasizes.

Preliminary observations with this combination hint at potential overall survival benefits vs fulvestrant alone, with ongoing patient monitoring expected to provide further insights, Brufsky expands. With its unique 4-days-on, 3-days-off dosing schedule and manageable grade 3 rash occurrences, capivasertib stands as a welcome addition to address unmet needs for patients with HR-positive, HER2-negative metastatic breast cancer, and may be widely adopted among oncologists, Brufsky concludes.