Yu Evan Y, Piulats Josep M, Gravis Gwenaelle, Fong Peter C C, Todenhöfer Tilman, Laguerre Brigitte, Arranz Jose A, Oudard Stephane, Massard Christophe, Heinzelbecker Julia, Nordquist Luke T, Carles Joan, Kolinsky Michael P, Augustin Marinela, Gurney Howard, Tafreshi Ali, Li Xin Tong, Qiu Ping, Poehlein Christian H, Schloss Charles, de Bono Johann S
University of Washington and Fred Hutchinson Cancer Center, Seattle, WA, USA.
Catalan Institute of Oncology, Barcelona, Spain.
Eur Urol. 2023 Jan;83(1):15-26. doi: 10.1016/j.eururo.2022.08.005. Epub 2022 Aug 30.
Pembrolizumab and olaparib have shown single-agent activity in patients with previously treated metastatic castration-resistant prostate cancer (mCRPC).
To evaluate the efficacy and safety of pembrolizumab plus olaparib in mCRPC.
DESIGN, SETTING, AND PARTICIPANTS: Cohort A of the phase 1b/2 KEYNOTE-365 study enrolled patients with molecularly unselected, docetaxel-pretreated mCRPC whose disease progressed within 6 mo of screening.
Pembrolizumab 200 mg intravenously every 3 wk plus olaparib 400-mg capsule or 300-mg tablet orally twice daily.
The primary endpoints were safety, confirmed prostate-specific antigen (PSA) response rate, and objective response rate (ORR) as per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, by blinded independent central review. The secondary endpoints included radiographic progression-free survival (rPFS) and overall survival (OS).
Of 104 enrolled patients, 102 were treated. The median age was 70 yr (interquartile range [IQR], 65-76), and 59 patients (58%) had measurable disease as per RECIST v1.1. The median time from the first dose to database cutoff was 24 mo (IQR, 22-47). The confirmed PSA response rate was 15%. The confirmed ORR was 8.5% (five partial responses) for patients with measurable disease. The median rPFS was 4.5 mo (95% confidence interval [CI], 4.0-6.5) and median OS was 14 mo (95% CI, 10.4-18.2). Clinical activity was consistent across the programmed death ligand 1 (PD-L1)-positive and homologous recombination repair mutation subgroups. Treatment-related adverse events (TRAEs) occurred in 93 patients (91%). Grade 3-5 TRAEs occurred in 49 patients (48%). Six deaths (5.9%) were due to adverse events; two (myocardial infarction and unknown cause) were attributed to treatment. Limitations of the study include the single-arm design.
Pembrolizumab plus olaparib had a safety profile consistent with the profiles of the individual agents and demonstrated antitumor activity in previously treated patients with molecularly unselected, docetaxel-pretreated mCRPC.
Pembrolizumab plus olaparib showed antitumor activity and expected safety in patients with metastatic castration-resistant prostate cancer.
帕博利珠单抗和奥拉帕利已在既往接受过治疗的转移性去势抵抗性前列腺癌（mCRPC）患者中显示出单药活性。
评估帕博利珠单抗联合奥拉帕利治疗mCRPC的疗效和安全性。
设计、设置和参与者：1b/2期KEYNOTE-365研究的A队列纳入了分子特征未筛选、接受过多西他赛治疗且在筛查后6个月内疾病进展的mCRPC患者。
帕博利珠单抗200mg静脉注射，每3周一次，联合奥拉帕利400mg胶囊或300mg片剂，口服，每日两次。
主要终点为安全性、根据实体瘤疗效评价标准（RECIST）1.1版经盲法独立中央审查确定的前列腺特异性抗原（PSA）缓解率和客观缓解率（ORR）。次要终点包括影像学无进展生存期（rPFS）和总生存期（OS）。
104例入组患者中，102例接受了治疗。中位年龄为70岁（四分位间距[IQR]，65 - 76岁），59例患者（58%）根据RECIST v1.1有可测量病灶。从首次给药到数据库截止的中位时间为24个月（IQR，22 - 47个月）。确定的PSA缓解率为15%。有可测量病灶患者的确定ORR为8.5%（5例部分缓解）。中位rPFS为4.5个月（95%置信区间[CI]，4.0 - 6.5），中位OS为14个月（95%CI，10.4 - 18.2）。程序性死亡配体1（PD-L1）阳性和同源重组修复突变亚组的临床活性一致。93例患者（91%）发生了治疗相关不良事件（TRAEs）。49例患者（48%）发生3 - 5级TRAEs。6例死亡（5.9%）归因于不良事件；2例（心肌梗死和不明原因）归因于治疗。本研究的局限性包括单臂设计。
帕博利珠单抗联合奥拉帕利具有与各单药相符的安全性，并在既往接受过治疗、分子特征未筛选、接受过多西他赛治疗的mCRPC患者中显示出抗肿瘤活性。
帕博利珠单抗联合奥拉帕利在转移性去势抵抗性前列腺癌患者中显示出抗肿瘤活性及预期的安全性。
