背景：在 PALOMA-3 這項隨機、雙盲、安慰劑對照的 3 期研究中，PAL+FUL 與安慰劑（PBO）+FUL 相比顯著延長無進展生存期（PFS）（單側 P＜0.0001）。最終方案指定的 OS 分析，中位隨訪 44.8 個月（mo），顯示 PAL+FUL 比 PBO+FUL 有 OS 的提高（中位 OS，34.9 比 28.0 個月；危險比，0.814[95%CI，0.644-1.029]；單側 P=0.0429）。在這裏，我們報告了更長的平均隨訪時間 73.3 個月的 OS 分析結果。

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 例接受過內分泌治療進展的 HR+/HER2- ABC患者按 2：1 的比例隨機分為 PAL （125mg/d 口服，3/1 周方案）+FUL（500mg 肌肉注射）或 PBO+FUL。研究者評估 PFS 為主要終點；OS 是一個關鍵的次要終點。當觀察到 393 個事件（占總人數的 75%）時，進行特定的 OS 分析。循環腫瘤DNA（ctDNA）分析在同意本研究的患者中進行。

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.

結果：隨著隨訪時間的延長，OS 持續改善，危險比為 0.806（95%CI，0.654-0.994；1 側標稱P=0.0221）。5 年生存率在 PAL+FUL 組為 23.3%（95%CI，18.7-28.2），PBO+FUL 組為 16.8%（95%CI，11.2-23.3）。除內分泌抵抗或曾接受化療的 ABC 患者外，在大多數亞組中觀察到PAL+FUL 組比 PBO+FUL 的生存優勢。沒有發現新的安全性信號。18 名患者仍在接受研究治療，其中 15 名患者（4.3%）接受 PAL+FUL 治療，3 名患者（1.7%）接受 PBO+FUL 治療。PAL+FUL組 20 例（7.5%）患者和 PBO+FUL 組 32 例（22.2%）患者接受研究後的細胞周期蛋白依賴性激酶 4/6 抑製劑。治療結束時會對腫瘤突變形式（如 ESR1、PIK3CA、RB1）的 ctDNA 進行分析以及及其對 OS 的影響會發布。

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.

Updated OS in the ITT population and by subgroup.
Subgroup	n (%)	Hazard Ratio (95% CI)	PAL+FUL median OS (95% CI)	PBO+FUL median OS (95% CI)	1-sided P value
ITT population	521 (100)	0.81 (0.65–0.99)	34.8 (28.8–39.9)	28.0 (23.5–33.8)	0.0221
Sensitivity to prior endocrine therapy
Yes	410 (78.7)	0.76 (0.60–0.96)	39.7 (34.4–45.7)	29.5 (23.5–36.3)	0.011
No	111 (21.3)	0.97 (0.62–1.5)	19.9 (17.4–26.4)	26.2 (17.5–31.8)	0.440
Prior chemotherapy in ABC
Yes	177 (34.0)	0.97 (0.69-1.4)	24.6 (21.3-30.0)	24.3 (18.9-36.3)	0.432
No	344 (66.0)	0.72 (0.55-0.94)	39.3 (34.5-44.4)	29.7 (23.8-35.5)	0.008

結論：在 HR+/HER2-既往內分泌治療進展的 ABC 患者中，中位隨訪時間超過 6 年後，PAL+FUL組 OS 臨床獲益仍得以維持。

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.