Tetsuhiko Taira

BACKGROUND: In CAPItello-291, capivasertib-fulvestrant significantly improved progression-free survival (PFS) versus placebo-fulvestrant in the overall and PIK3CA/AKT1/PTEN-altered population with hormone receptor-positive (HR-positive)/human epidermal growth factor receptor 2-negative (HER2-negative) advanced breast cancer. Capivasertib-fulvestrant is approved in Japan for the treatment of patients with one or more tumor biomarker alterations (PIK3CA, AKT1 or PTEN). Here, we report outcomes in the CAPItello-291 subgroup of patients from Japan. METHODS: Adults with HR-positive/HER2-negative advanced breast cancer whose disease had relapsed or progressed during or after treatment with an aromatase inhibitor, with or without previous cyclin-dependent kinase 4/6 (CDK4/6) inhibitor therapy, were randomly assigned (1:1 ratio) to receive capivasertib or placebo, plus fulvestrant. The dual primary endpoint was investigator-assessed PFS in the overall and PIK3CA/AKT1/PTEN-altered population. Safety was a secondary endpoint. RESULTS: Of 708 patients randomized in CAPItello-291, 78 were from Japan (37 randomized to capivasertib-fulvestrant and 41 to placebo-fulvestrant). In the Japan subgroup, PFS numerically favored the capivasertib-fulvestrant arm (hazard ratio 0.73; 95% CI 0.40-1.28), consistent with the analysis of PFS in the global population. Similarly, in the Japan subgroup of patients with PIK3CA/AKT1/PTEN-altered tumors, PFS favored the capivasertib-fulvestrant arm (hazard ratio 0.65; 95% CI 0.29-1.39), consistent with the global population. The adverse event profile of capivasertib-fulvestrant in the Japan subgroup was broadly similar to that in the global population; no new safety concerns were identified. CONCLUSION: Outcomes in the Japan subgroup were broadly similar to those of the global population, supporting the clinical benefit of capivasertib-fulvestrant in treating HR-positive/HER2-negative advanced breast cancer that has progressed on, or after, an endocrine-based regimen.

BACKGROUND: Talazoparib, a poly(ADP-ribose) polymerase enzyme inhibitor, is approved for the treatment of patients with germline BRCA1/2 (gBRCA1/2)-mutated HER2-negative advanced breast cancer. This two-part study, a recently published dose-escalation part followed by the dose-expansion part reported here, evaluated the efficacy and safety of talazoparib in Japanese patients with gBRCA1/2-mutated advanced breast cancer. METHODS: In this open-label, multicenter phase 1 study (NCT03343054), the primary endpoint of the dose-expansion part was confirmed objective response rate (ORR), determined by investigator assessment (RECIST 1.1). Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and pharmacokinetics. Patients received the recommended phase 2 dose (1 mg/day; 0.75 mg/day moderate renal impairment). RESULTS: Nineteen Japanese patients with gBRCA1/2-mutated locally advanced or metastatic breast cancer were enrolled. Confirmed ORR was 57.9% (11/19; 90% confidence interval [CI] 36.8-77.0). Stable disease was observed in 36.8% (7/19) of patients. Per investigator assessment, median PFS was 7.2 months (95% CI 4.1-not estimable) and 12-month OS rate was 84.7% (90% CI 57.5-95.1). Median OS was not reached; 17/19 patients were alive and censored at 12 months. All patients experienced treatment-related adverse events (AEs); the majority were hematologic. The most common treatment-related AE was anemia (68.4%; [13/19]). Grade 3/4 treatment-related AEs were observed in 52.6% (10/19) of patients. During the safety period, there were no grade 5 treatment-emergent AEs, treatment-related serious AEs, or deaths. CONCLUSIONS: In Japanese patients with gBRCA mutations and locally advanced or metastatic breast cancer, talazoparib monotherapy was generally well tolerated and resulted in clinically meaningful ORRs. GOV IDENTIFIER: NCT03343054.