前列腺癌是男性第二大常見癌癥，也是全球男性癌癥死亡第五大原因，2020 年發(fā)病人數(shù) 140 萬，死亡人數(shù)375,000。轉(zhuǎn)移性前列腺癌與顯著的死亡率相關(guān) 。前列腺癌的發(fā)展通常由稱為雄激素的男性性激素驅(qū)動(dòng)，包括睪丸激素。在美國，2022年估計(jì)有 268,490 例新發(fā)患者和  34,500人死亡。mCRPC患者的總生存期在臨床研究中約為三年，在真實(shí)世界中甚至更短。 大約一半的 mCRPC 患者可能只接受過一線有效治療，后續(xù)治療效果會(huì)越來越差。

在 mCRPC 患者中，盡管使用雄激素剝奪療法來阻斷雄性激素的作用，但前列腺癌仍會(huì)進(jìn)展并擴(kuò)散到身體其他部位。大約 10-20% 的晚期前列腺癌患者會(huì)在五年內(nèi)進(jìn)展為去勢抵抗性前列腺癌 (CRPC)，其中至少 84% 的男性在確診 CRPC 時(shí)已經(jīng)發(fā)生了轉(zhuǎn)移。在診斷為CRPC時(shí)沒有轉(zhuǎn)移的患者中，33% 可能在兩年內(nèi)發(fā)生轉(zhuǎn)移。盡管過去十多年 mCRPC 治療因?yàn)槭褂米仙纪楹托滦蛢?nèi)分泌類藥物（NHA）取得了進(jìn)展，但該人群的醫(yī)療需求未能得到滿足。

PROpel III 期轉(zhuǎn)移性去勢抵抗性前列腺癌(mCRPC)的最終預(yù)設(shè)總生存期 (OS) 分析結(jié)果顯示阿斯利康和默沙東聯(lián)合開發(fā)的奧拉帕利聯(lián)合阿比特龍和潑尼松/潑尼松龍顯示的中位OS為 42.1 個(gè)月，而阿比特龍聯(lián)合安慰劑組為 34.7 個(gè)月。顯示聯(lián)合治療對比標(biāo)準(zhǔn)治療取得7.4個(gè)月的中位OS絕對差異（ 成熟度47.9%， HR 0.81；95% CI 0.67-1.00；p=0.0544）。

雖然中位OS未達(dá)到統(tǒng)計(jì)學(xué)差異，但這一臨床活動(dòng)建立在對照組為患者接受當(dāng)前的標(biāo)準(zhǔn)治療阿比特龍之上。研究結(jié)果將于今天在 2023 年美國臨床腫瘤學(xué)會(huì) (ASCO) 泌尿生殖系統(tǒng) (GU) 癌癥研討會(huì) (#LBA16) 上以口頭報(bào)告的形式公布。

在ASCO GU 2022上報(bào)道的研究主要終點(diǎn)結(jié)果顯示，PROpel 研究達(dá)到了主要終點(diǎn)影像學(xué)無進(jìn)展生存 (rPFS) ，并已發(fā)表在《新英格蘭醫(yī)學(xué)證據(jù)雜志》。結(jié)果顯示，奧拉帕利聯(lián)合阿比特龍與阿比特龍單藥治療相比，影像學(xué)進(jìn)展或死亡的風(fēng)險(xiǎn)顯著降低了 34%（HR 0.66；95% CI 0.54-0.81；p< 0.0001）。

曼徹斯特克里斯蒂/索爾福德皇家醫(yī)院和曼徹斯特大學(xué)泌尿外科醫(yī)生兼泌尿腫瘤學(xué)教授、PROpel 研究高級研究員 Noel Clarke 表示：“從去年在 ASCO GU 上展示的主要影像學(xué)無進(jìn)展生存期分析到今天展示的更新后總生存期數(shù)據(jù)，進(jìn)一步顯示了奧拉帕利聯(lián)合阿比特龍和潑尼松對轉(zhuǎn)移性去勢抵抗性前列腺癌患者在整個(gè)研究人群和各亞組的治療潛力。PROpel 研究結(jié)果對患者和腫瘤學(xué)界都非常重要，為這種聯(lián)合治療方案提供了支持依據(jù)，可作為轉(zhuǎn)移性去勢抵抗性前列腺癌潛在且急需的新治療選擇?！?/p>

阿斯利康全球執(zhí)行副總裁，腫瘤治療領(lǐng)域研發(fā)負(fù)責(zé)人Susan Galbraith表示：“奧拉帕利的PARP靶點(diǎn)和雄激素受體對于前列腺癌中DNA修復(fù)都很重要。PROpel總體研究人群結(jié)果表明，奧拉帕利和阿比特龍聯(lián)合治療可以發(fā)揮雄激素受體在DNA修復(fù)中對PARP的依賴性，提供比阿比特龍單藥更大的抗癌活性。值得注意的是，基于整體數(shù)據(jù)，在這種情況下聯(lián)合治療能為廣大患者帶來治療收益，而近期該適應(yīng)癥在歐盟獲批則進(jìn)一步強(qiáng)調(diào)了這一點(diǎn)。"

默沙東實(shí)驗(yàn)室全球臨床研究高級副總裁、首席醫(yī)學(xué)官Eliav Barr博士表示：“前列腺癌是男性患者中第二大最常診斷的癌癥，預(yù)計(jì)未來20年內(nèi)死亡率將幾乎翻倍。由于這些患者治療選擇有限，我們迫切需要能夠延遲疾病進(jìn)展的治療方案。我們?yōu)榕c阿斯利康的合作感到自豪，因?yàn)槲覀児餐铝τ谕七M(jìn)有待審批通過的監(jiān)管審查，并為前列腺癌群體帶來一種新的治療選擇。”

各亞組關(guān)鍵次要總生存期終點(diǎn)的結(jié)果摘要

*18 名 HRRm 狀態(tài)未知的患者被排除在亞組分析之外。 NR，未達(dá)到

奧拉帕利聯(lián)合阿比特龍的安全性和耐受性與之前臨床研究中觀察到的結(jié)果以及單藥治療的已知特征一致。 在這次更新分析時(shí)，沒有發(fā)現(xiàn)新的長期安全問題。

奧拉帕利聯(lián)合阿比特龍最常見的不良事件 (AEs)（大于或等于 20% 的患者）是貧血 (49.7%)、疲勞 (38.7%)、惡心 (30.7%)、背痛 (21.6%) 和腹瀉 (20.6%)。 在數(shù)據(jù)截止時(shí)，約83%接受奧拉帕利聯(lián)合阿比特龍治療并出現(xiàn)不良事件的患者中仍在接受治療。

2022年12月，歐盟委員會(huì)批準(zhǔn)奧拉帕利聯(lián)合阿比特龍用于治療臨床上未接受過化療的mCRPC成人男性患者，目前正在接受其他國家法規(guī)評審。

注：本文涉及研究中的藥品用法尚未在中國獲批適應(yīng)癥，阿斯利康不推薦任何未被批準(zhǔn)的藥品使用。

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