Combination ATR and PARP Inhibitor (CAPRI): A phase 2 study of ceralasertib plus olaparib in patients with recurrent, platinum-resistant epithelial ovarian cancer

被引：75

作者：

Shah, Payal D. ^{[1
,4
]}

Wethington, Stephanie L. ^{[2
]}

Pagan, Cheyenne ^{[3
]}

Latif, Nawar ^{[3
]}

Tanyi, Janos ^{[3
]}

Martin, Lainie P. ^{[4
]}

Morgan, Mark ^{[3
]}

Burger, Robert A. ^{[3
]}

Haggerty, Ashley ^{[3
]}

Zarrin, Haley ^{[3
]}

Rodriguez, Diego ^{[3
]}

Domchek, Susan ^{[1
,4
]}

Drapkin, Ronny ^{[1
,3
]}

Shih, Ie-Ming ^{[2
]}

Smith, Simon A. ^{[5
]}

Dean, Emma ^{[5
]}

Gaillard, Stephanie ^{[2
]}

Armstrong, Deborah ^{[2
]}

Torigian, Drew A. ^{[6
]}

Hwang, Wei-Ting ^{[7
]}

Giuntoli, Robert ^{[3
]}

Simpkins, Fiona ^{[3
]}

机构：

[1] Univ Penn, Basser Ctr BRCA, Perelman Sch Med, Philadelphia, PA 19104 USA

[2] Johns Hopkins Med, Kelly Gynecol Oncol Serv, Dept Gynecol & Obstet, Baltimore, MD USA

[3] Univ Penn, Dept Obstet & Gynecol, Div Gynecol Oncol, Perelman Sch Med, 3400 Civ Ctr Blvd,South Tower,Suite 10-176, Philadelphia, PA 19104 USA

[4] Univ Penn, Div Med Oncol, Perelman Sch Med, Philadelphia, PA 19104 USA

[5] AstraZeneca, R&D Oncol, Cambridge, England

[6] Univ Penn, Abramson Canc Ctr, Dept Radiol, Perelman Sch Med, Philadelphia, PA 19104 USA

[7] Univ Penn, Abramson Canc Ctr, Div Biostat, Perelman Sch Med, Philadelphia, PA 19104 USA

来源：

GYNECOLOGIC ONCOLOGY | 2021年 / 163卷 / 02期

关键词：

Ovarian cancer; Platinum-resistant; Ceralasertib; Olaparib; PARP; ATR; PEGYLATED LIPOSOMAL DOXORUBICIN; GERMLINE BRCA1/2 MUTATION; OPEN-LABEL; MAINTENANCE THERAPY; HOMOLOGOUS RECOMBINATION; DOUBLE-BLIND; III TRIAL; CARCINOMA; CHEMOTHERAPY; MULTICENTER;

D O I：

10.1016/j.ygyno.2021.08.024

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Objective: Platinum-resistant, high-grade serous ovarian cancer (HGSOC) has limited treatment options. Pre clinical data suggest that poly(ADP-ribose) polymerase inhibitors (PARPi) and ataxia telangiectasia and Rad3related kinase inhibitors (ATRi) are synergistic. CAPRI (NCT03462342) is an investigator-initiated study of olaparib plus ceralasertib in recurrent HGSOC. Herein, we present results from the platinum-resistant cohort. Methods: A Simon 2-stage design was utilized. Platinum-resistant HGSOC patients received ceralasertib 160 mg orally daily, days 1-7 and olaparib 300 mg orally twice daily, days 1-28 of a 28-day cycle until toxicity or progression. Primary endpoints were toxicity and efficacy including objective response rate (ORR) by RECIST. Secondary endpoint was progression-free survival (PFS). The null hypothesis (<= 5% ORR) would be rejected if there were >_ 1 responses in 12 patients. Results: Fourteen PARPi-naive patients were evaluable for toxicity; 12 were evaluable for response. Three had BRCA1 mutations (1 germline, 2 somatic). Adverse events possibly related to treatment were primarily grade (G) 1/2. G3 toxicities included nausea (14.3%), fatigue (7.1%), anorexia (7.1%), and anemia (7.1%). No objective responses occurred. Best response was stable disease in 9 patients and progressive disease in three. Five patients had a >_ 20% to <30% reduction in disease burden, including 3 with BRCA1 mutations. Three of 11 patients (27%; 2 with BRCA1 mutations) evaluable by Gynecologic Cancer Intergroup criteria had >50% CA-125 decline, including 2 with CA-125 normalization. Median PFS was 4.2 months overall (90% CI:3.5-8.2) and 8.2 months (3.6 months- not determined) for patients with BRCA1 mutations. Conclusions: Olaparib plus ceralasertib is well-tolerated. No objective responses occurred, though a signal of activity was seen particularly in disease associated with BRCA1. Further evaluation of this combination should in-clude alternate dosing strategies in genomically-selected populations. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

引用

页码：246 / 253

页数：8