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

Abstract

OBJECTIVE:

Platinum-resistant, high-grade serous ovarian cancer (HGSOC) has limited treatment options. Preclinical data suggest that poly(ADP-ribose) polymerase inhibitors (PARPi) and ataxia telangiectasia and Rad3-related 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-naïve 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 include alternate dosing strategies in genomically-selected populations.

• Authors: Payal D Shah, Stephanie L Wethington, Cheyenne Pagan, Nawar Latif, Janos Tanyi, Lainie P Martin, Mark Morgan, Robert A Burger, Ashley Haggerty, Haley Zarrin, Diego Rodriguez, Susan Domchek, Ronny Drapkin, Ie-Ming Shih, Simon A Smith, Emma Dean, Stéphanie Gaillard, Deborah Armstrong, Drew A Torigian, Wei-Ting Hwang, Robert Giuntoli, Fiona Simpkins
• Journal: Gynecologic oncology (Gynecol Oncol) Vol. 163 Issue 2 Pg. 246-253 (11 2021) ISSN: 1095-6859 [Electronic] United States
• PMID: 34620496 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• BRCA1 Protein
• BRCA1 protein, human
• Indoles
• Morpholines
• Phthalazines
• Piperazines
• Poly(ADP-ribose) Polymerase Inhibitors
• Protein Kinase Inhibitors
• Pyrimidines
• Sulfonamides
• ceralasertib
• ATR protein, human
• Ataxia Telangiectasia Mutated Proteins
• olaparib

Topics

• Administration, Oral
• Aged
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects)
• Ataxia Telangiectasia Mutated Proteins (antagonists & inhibitors)
• BRCA1 Protein (genetics)
• Drug Administration Schedule
• Drug Resistance, Neoplasm
• Female
• Humans
• Indoles (administration & dosage, adverse effects)
• Magnetic Resonance Imaging
• Middle Aged
• Morpholines (administration & dosage, adverse effects)
• Neoplasm Recurrence, Local (drug therapy, mortality, pathology)
• Ovarian Neoplasms (diagnosis, drug therapy, genetics, mortality)
• Ovary (diagnostic imaging, pathology)
• Phthalazines (administration & dosage, adverse effects)
• Piperazines (administration & dosage, adverse effects)
• Poly(ADP-ribose) Polymerase Inhibitors (administration & dosage, adverse effects)
• Progression-Free Survival
• Protein Kinase Inhibitors
• Pyrimidines (administration & dosage, adverse effects)
• Response Evaluation Criteria in Solid Tumors
• Sulfonamides (administration & dosage, adverse effects)
• Tomography, X-Ray Computed