背景：Wee1 磷酸化並抑製細胞周期蛋白依賴性激酶 1 和 2，參與有絲分裂前 DNA 修複中 S 和 G2/M細胞周期檢查點阻滯的調控。Wee1 抑製劑 adavosertib 單獨或與其他藥物聯合使用都具有活性 PARP 抑製劑（PARPi）耐藥的臨床前模型。我們試圖評估療效阿達沃斯替布（A）聯合或不聯合奧拉帕利（O）治療複發性肝癌的Ⅱ期非對照研究抗 PARPi 卵巢癌。

Background: Wee1 phosphorylates and inhibits cyclin-dependent kinases 1 and 2 and is involved in regulation of the intra-S and G2/M cell cycle checkpoint arrest for premitotic DNA repair. The Wee1 inhibitor, adavosertib, has demonstrated activity alone and in combination with olaparib in PARP inhibitor (PARPi)-resistant preclinical models. We sought to evaluate efficacy of adavosertib (A) with or without olaparib (O) in a phase II noncomparative study of recurrent PARPi-resistant ovarian cancer.

方法：研究納入在 PARPi 治療後有進展性疾病的複發性卵巢癌、輸卵管癌或原發性腹膜癌的患者。所有患者都有可測量的疾病和足夠的終末器官功能。在阿達伐昔布組上(A)，患者在 21 天周期的第 1-5 天和第 8-12 天每天接受 300mg PO。在阿達伐昔布聯合奧拉帕利組(A/0)，患者在第 1-3 天和第 8-10 天接受阿達伐昔布 150mg，在第 21 天的第 1-21 天接受奧拉帕利 200mg。主要終點設定為客觀緩解率，按照 RECIST 1.1評價標準，每 2 周期評估一次，臨床受益率（CBR）定義為有客觀反應或有不良反應的患者病情穩定>16周的比例，。采用 Kaplan-Meier 方法評估無進展生存率（PFS），計算從治療開始到最早進展，死亡，或最後一次探視的時間。

Methods: Women with recurrent ovarian, fallopian tube or primary peritoneal cancer with documented progressive disease on a PARPi were eligible. All patients (pts) had measurable disease and adequate end organ function. On the A arm, pts received A 300mg PO daily on days 1-5 and 8-12 of a 21-day cycle. On the A/O arm, pts received A 150mg PO BID on days 1-3 and 8-10 and O 200mg PO BID on days 1-21 of a 21-day cycle. Primary endpoint was objective response per RECIST 1.1 and was assessed every 2 cycles. Clinical benefit rate (CBR) was defined as proportion of pts with objective response or stable disease > 16 weeks. Progression free survival (PFS) was assessed using the Kaplan Meier method and calculated from date of treatment initiation to earliest date of progression, death, or last visit.

結果：共篩選 116 例患者，80 例患者入選並隨機化（A：n=39，A/O:n=41）。中位年齡為 60 歲（36-76歲），大多數患者有鉑耐藥（64%）和高等級漿膜組織學（98%）。患者既往平均接受 4 次化療（範圍 1-11），48%有生殖係或體細胞 BRCA 突變。每組至少有 35 例可評價病例。下表顯示了療效數據。在 A 組上，3/4級毒性發生在 51%的患者中，最常見的是中性粒細胞減少（13%）、血小板減少（10%）和腹瀉（8%）。28（72%）例患者需要至少一次劑量中斷，20（51%）需要減少劑量。在 A/O 組上，76%的患者出現 3/4 級毒性，最常見的是血小板減少（20%）、中性粒細胞減少（15%）、腹瀉（12%）、疲勞（12%），貧血（10%）。36（88%）的患者至少需要中斷一次劑量，29（71%）的患者需要中斷一次劑量劑量減少，4 例（10%）因毒性未再啟動。

Results: 116 pts were screened with 80 pts enrolled and randomized (A: n=39, A/O: n=41). Median age was 60 years (range 36-76) and the majority of pts had platinum resistant disease (64%) and high grade serous histology (98%). Pts received a median of 4 prior therapies (range 1-11) and 48% had germline or somatic BRCA mutations. There were 35 pts evaluable for response in each arm. Table demonstrates efficacy data. On the A arm, Grade 3/4 toxicities occurred in 51% of pts, most commonly neutropenia (13%), thrombocytopenia (10%), and diarrhea (8%). 28 (72%) pts required at least one dose interruption and 20 (51%) required dose reduction. On the A/O arm, Grade 3/4 toxicities occurred in 76% of pts, most commonly thrombocytopenia (20%), neutropenia (15%), diarrhea (12%), fatigue (12%), and anemia (10%). 36 (88%) of pts required at least one dose interruption, 29 (71%) required dose reduction, and 4 (10%) did not restart due to toxicity.

Endpoint	A arm n=35	A/O arm n=35
ORR (90%CI)	23% (12–38)	29% (16–44)
Duration of response, months (95%CI)	5.5 (2.8–NE)	6.4 (2.8–14.6)
CBR (90%CI)	63% (48–76)	89% (76–96)
Median PFS, months (90%CI)	5.5 (3.9–6.9)	6.8 (4.3–8.3)

結論：單獨和單獨給予聯合化療對 PARPi 耐藥的卵巢癌患者有明顯療效。盡管在兩組中觀察到3級和4級毒性，這些通常是可以控製的支持性護理，必要時中斷和減少劑量。附加平移目前正在進行分析，以弄清楚哪些患者獲得了臨床益處。

Conclusions: A given alone and in combination with O demonstrated efficacy in pts with PARPi-resistant ovarian cancer. Although grade 3 and 4 toxicities were observed on both arms, these were generally manageable with supportive care, dose interruptions and dose reductions as needed. Additional translational analyses are ongoing to clarify which pts received clinical benefit.