Alpelisib (ALP) + fulvestrant (FUL) for advanced breast cancer (ABC): Results of the phase III SOLAR-1 trial

Abstract

Background: Hyperactivation of the phosphatidylinositol-3-kinase (PI3K) pathway can occur due to PIK3CA mutations, present in 40% of patients (pts) with hormone receptor-positive (HRþ), human epidermal growth factor receptor 2-negative (HER2-) ABC. The Phase 3 randomized, double-blind SOLAR1 trial (NCT02437318) investigated the efficacy and safety of ALP (a-specific PI3K inhibitor) þ FUL in pts with HRþ, HER2-ABC. Methods: Men/postmenopausal women with HRþ, HER2-ABC and 1 prior line of endocrine therapy were randomized (1:1) to ALP (300 mg/day) þ FUL (500 mg every 28 days þ Cycle 1 Day 15) or placebo (PBO) þ FUL. Primary endpoint was locally assessed progression-free survival (PFS) in the PIK3CA-mutant (mut) cohort; PFS was analyzed in the non-mut cohort as a proof of concept (PoC). Safety was assessed in the total population. Other analyses were tumor response and PFS by important prognostic subgroups, including PIK3CA mutation exon/domain and subtype. Results: 572 pts enrolled; 341 had PIK3CA-mut ABC by tissue. Primary endpoint was met; PFS in the mut cohort was significantly longer with ALPþFUL vs PBOþFUL (HR 0.65; 95% CI 0.50-0.85; P ¼ 0.00065; median 11.0 vs 5.7 months [mo]); median follow-up was 20.0 mo. Secondary endpoint of locally assessed PFS in the non-mut cohort did not meet predefined PoC criteria (HR 0.85; 95% CI 0.58-1.25; median 7.4 vs 5.6 mo). In pts with measurable, PIK3CA-mut ABC (n ¼ 262), overall response rate was 36% for ALPþFUL vs 16% for PBOþFUL (p ¼ 0.0002). Overall, most frequent all-grade (G) adverse events (AEs; single preferred term; ALPþFUL vs PBOþFUL) were hyperglyce-mia (64% vs 10%), diarrhea (58% vs 16%), nausea (45% vs 22%), decreased appetite (36% vs 10%) and rash (36% vs 6%). G 3/4 hyperglycemia (fasting plasma glucose >250 mg/dL) was observed in 37% of patients for ALPþFUL vs < 1% for PBOþFUL; G 3/4 rash in 10% vs < 1%. Discontinuations of ALPþFUL/PBOþFUL due to AEs were 5% vs 1%. Conclusions: ALPþFUL met the primary endpoint by significantly extending PFS vs PBOþFUL and demonstrated a manageable tolerability profile. This is the first study to show statistically significant, clinically meaningful PFS treatment improvement with an a-specific PI3K inhibitor in PIK3CA-mut HRþ, HER2-ABC.