背景：在 PALOMA-3 这项随机、双盲、安慰剂对照的 3 期研究中，PAL+FUL 与安慰剂（PBO）+FUL 相比显著延长无进展生存期（PFS）（单侧 P＜0.0001）。最终方案指定的 OS 分析，中位随访 44.8 个月（mo），显示 PAL+FUL 比 PBO+FUL 有 OS 的提高（中位 OS，34.9 比 28.0 个月；危险比，0.814[95%CI，0.644-1.029]；单侧 P=0.0429）。在这里，我们报告了更长的平均随访时间 73.3 个月的 OS 分析结果。

Background: In PALOMA-3, a randomized, double-blind, placebo-controlled, phase 3 study, PAL+FUL significantly prolonged progression-free survival (PFS) compared with placebo (PBO) + FUL (1-sided P<0.0001). The final protocol-specified OS analysis, which was conducted with a median follow-up of 44.8 months (mo), showed improved OS with PAL+FUL vs PBO+FUL (median OS, 34.9 vs 28.0 mo; hazard ratio, 0.814 [95% CI, 0.644–1.029]; 1-sided P=0.0429). Here, we report the results from an OS analysis with a longer median follow-up of 73.3 mo.

方法：共有 521 例接受过内分泌治疗进展的 HR+/HER2- ABC患者按 2：1 的比例随机分为 PAL （125mg/d 口服，3/1 周方案）+FUL（500mg 肌肉注射）或 PBO+FUL。研究者评估 PFS 为主要终点；OS 是一个关键的次要终点。当观察到 393 个事件（占总人数的 75%）时，进行特定的 OS 分析。循环肿瘤DNA（ctDNA）分析在同意本研究的患者中进行。

Methods: A total of 521 patients (pts) with HR+/HER2– ABC who had progressed on prior endocrine therapy were randomized 2:1 to PAL (125 mg/d orally, 3/1 week schedule) + FUL (500 mg intramuscular injection) or PBO+FUL. Investigator-assessed PFS was the primary endpoint; OS was a key secondary endpoint. An ad hoc OS analysis was performed when 393 events (75% of the total population) were observed. Circulating tumor DNA (ctDNA) analysis was conducted among pts who consented for this study.

结果：随着随访时间的延长，OS 持续改善，危险比为 0.806（95%CI，0.654-0.994；1 侧标称P=0.0221）。5 年生存率在 PAL+FUL 组为 23.3%（95%CI，18.7-28.2），PBO+FUL 组为 16.8%（95%CI，11.2-23.3）。除内分泌抵抗或曾接受化疗的 ABC 患者外，在大多数亚组中观察到PAL+FUL 组比 PBO+FUL 的生存优势。没有发现新的安全性信号。18 名患者仍在接受研究治疗，其中 15 名患者（4.3%）接受 PAL+FUL 治疗，3 名患者（1.7%）接受 PBO+FUL 治疗。PAL+FUL组 20 例（7.5%）患者和 PBO+FUL 组 32 例（22.2%）患者接受研究后的细胞周期蛋白依赖性激酶 4/6 抑制剂。治疗结束时会对肿瘤突变形式（如 ESR1、PIK3CA、RB1）的 ctDNA 进行分析以及及其对 OS 的影响会发布。

Results: Improvement in OS continues to be observed with longer follow-up, with a hazard ratio of 0.806 (95% CI, 0.654–0.994; 1-sided nominal P=0.0221). The 5-year OS rate was 23.3% (95% CI, 18.7–28.2) with PAL+FUL and 16.8% (95% CI, 11.2–23.3) with PBO+FUL. Favorable OS with PAL+FUL vs PBO+FUL was observed in most subgroups except among pts who were endocrine resistant or had prior chemotherapy for ABC. No new safety signals were identified. Eighteen pts remain on study treatment, including 15 (4.3%) on PAL+FUL and 3 (1.7%) on PBO+FUL. A post-study cyclin-dependent kinase 4/6 inhibitor was received by 20 pts (7.5%) in the PAL+FUL arm and 32 pts (22.2%) in the PBO+FUL arm. ctDNA analyses of tumor mutation profiles (ie, ESR1, PIK3CA, RB1) at the end of treatment and their effect on OS will also be presented.

结论：在 HR+/HER2-既往内分泌治疗进展的 ABC 患者中，中位随访时间超过 6 年后，PAL+FUL组 OS 临床获益仍得以维持。

Conclusions: The clinically meaningful improvement in OS with PAL+FUL was maintained with >6 years of median follow-up in pts with HR+/HER2– ABC who had progressed on prior endocrine treatment.