CAPTURE: A phase II trial evaluating alpelisib + fulvestrant vs capecitabine in advanced breast cancer patients with PIK3CA -mutant circulating DNA following CDK4/6 inhibition.

1064 Background: PIK3CA mutations are a key therapeutic target in ER+ advanced breast cancer (ABC) readily detectable through circulating tumor DNA (ctDNA). The PI3Kα inhibitor alpelisib is approved in ER+ HER2- ABC but it remains unclear when to incorporate it into the current treatment algorithm. To address this, we conducted a phase II study assessing superiority of alpelisib + fulvestrant vs capecitabine in ABC pts with detectable PIK3CA mutant ctDNA following CDK4/6i plus aromatase inhibition (AI). Methods: Eligible pts had ER+ HER2- ABC, prior progression on CDK4/6i+AI and PIK3CA mutations detected via ctDNA ddPCR. Pts were randomized 1:1 to receive alpelisib (300mg daily) + fulvestrant (Arm A), or capecitabine (1000-1250mg/m 2 BD D1-14 q21d) (Arm B); strata were prior chemo for ABC and visceral disease. Primary endpoint was progression free survival (PFS) defined from randomization until progressive disease per RECIST 1.1 or death. Secondary endpoints included objective response rate (ORR), clinical benefit rate (CBR) and adverse events (AE). Imaging was q8 weeks. Exploratory objectives included efficacy according to baseline ctDNA levels. Sample size was reduced from 140 to 66 pts randomized for 53 PFS events to detect median PFS of 9 vs 5 mo (HR=0.56;1-sided α=0.1,80% power). Interim inefficacy analysis (60% events) estimated HR>1.0 and IDMC recommended early termination. Follow-up continued until all pts completed alpelisib. Reported are stratified Cox model HR (2-sided 80% CI) and 2-sided log rank test. Results: From July 2020-Oct 2024, 396 pts were screened, 113 (29%) had PIK3CA mutant ctDNA, 58 were randomized and 55 initiated treatment (Arm A: 29/30; Arm B: 26/28). Median age was 56 (32-82 yrs), 75% had visceral disease; 87% had no prior chemo for ABC. At final analysis, 43 PFS events occurred. Median PFS was 7.4 mo for alpelisib + fulvestrant vs 9.4 mo for capecitabine (HR 1.28, 80% CI: 0.84-1.96, p=0.45). For pts with visceral disease, median PFS was 5.4 mo (80% CI:3.7-5.1) for alpelisib + fulvestrant and 12.1 mo (80% CI:5.4-15) for capecitabine. ORR was 24.1% vs 50.0% and CBR 55.2% vs 61.5% for alpelisib + fulvestrant vs capecitabine. Overall, 79.3% pts on alpelisib + fulvestrant had grade 3/4 AEs with 24% grade 3 hyperglycemia vs 46.2% on capecitabine with 12% grade 3 palmar-plantar erythrodysesthesia. Six of 30 pts discontinued alpelisib due to AEs; 5 of the 6 continued fulvestrant. There was no evidence of association between baseline ctDNA levels (PIK3CA mutant copies/ml; median 90; range 2-13678) and PFS (HR 1.03; 90%CI:0.90-1.19). Conclusions: In our trial of pts with PIK3CA mutant ABC after progression on CDK4/6i plus AI, targeted therapy with alpelisib + fulvestrant was not superior to standard chemotherapy with capecitabine. Compared with the targeted therapy, capecitabine was better tolerated and resulted in longer PFS. Clinical trial information: ACTRN12619001117101.