Alpelisib Plus Fulvestrant for PIK3CA-Mutated, Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor-2-Negative Advanced Breast Cancer: Final Overall Survival Results From SOLAR-1.

ABSTRACT Background Activation of the phosphatidylinositol-3-kinase (PI3K) pathway via PIK3CA mutations occurs in 28%-46% of hormone receptor-positive (HR+), human epidermal growth factor receptor-2–negative (HER2–) advanced breast cancers (ABC) and is associated with poor prognosis. The SOLAR-1 trial showed that the addition of alpelisib to fulvestrant treatment provided statistically significant and clinically meaningful progression-free survival (PFS) benefit in PIK3CA-mutated, HR+, HER2– ABC. Patients and Methods Men and postmenopausal women with HR+, HER2– ABC whose disease progressed on or after aromatase inhibitor (AI) were randomized 1:1 to receive alpelisib (300 mg/day) plus fulvestrant (500 mg every 28 days and once on Day 15) or placebo plus fulvestrant. Overall survival (OS) in the PIK3CA-mutant cohort was evaluated by Kaplan-Meier methodology and a 1-sided stratified log-rank test was performed with an O’Brien-Fleming efficacy boundary of P≤0.0161. Results In the PIK3CA-mutated cohort (n=341), median OS (95% confidence interval [CI]) was 39.3 months (34.1-44.9) for alpelisib-fulvestrant and 31.4 months (26.8-41.3) for placebo-fulvestrant (hazard ratio [HR] = 0.86 [95% CI, 0.64-1.15; P=0.15]). Overall survival results did not cross the prespecified efficacy boundary. Median OS (95% CI) in patients with lung and/or liver metastases was 37.2 months (28.7-43.6) and 22.8 months (19.0-26.8) in the alpelisib-fulvestrant and placebo-fulvestrant arms, respectively (HR=0.68 [0.46-1.00]). Median times to chemotherapy (95% CI) for the alpelisib-fulvestrant and placebo-fulvestrant arms were 23.3 months (15.2-28.4) and 14.8 months (10.5-22.6), respectively (HR=0.72 [0.54-0.95]). No new safety signals were observed with longer follow-up. Conclusions Although the analysis did not cross the prespecified boundary for statistical significance, there was a 7.9-month numeric improvement in median OS when alpelisib was added to fulvestrant treatment for patients with PIK3CA-mutated, HR+, HER2– ABC. Overall, these results further support the statistically significant prolongation of PFS observed with alpelisib plus fulvestrant in this population, which has a poor prognosis due to a PIK3CA mutation.