Triapine-olaparib combination therapy deters peritoneal progression of PARP inhibitor-resistant epithelial ovarian cancer

The PARP inhibitor olaparib has been approved in the maintenance setting of platinum-sensitive epithelial ovarian cancer patients with germline or somatic BRCA1/2 mutation. Therefore, the availability of a tumor BRCA test has become a clinical need. We report the results of the clinical implementation of a tumor BRCA test within the frame of an institutional workflow for the management of patients with nonmucinous and nonborderline epithelial ovarian cancer. In total, 223 patients with epithelial ovarian cancer were prospectively analyzed. BRCA1/2 status was evaluated on formalin-fixed, paraffin-embedded tumor specimens using next-generation sequencing technology. The tumor BRCA test had a success rate of 99.1% (221 of 223 successfully analyzed cases) and a median turnaround time of 17 calendar days. Among the 221 cases, BRCA1 or BRCA2 pathogenic/likely pathogenic mutations were found in 62 (28.1%) cases and variants of uncertain significance in 25 (11.3%) cases. The concordance rate between tumor BRCA test results and germline BRCA1/2 status was 87%, with five cases harboring pathogenic/likely pathogenic somatic-only mutations. The next-generation, sequencing-based tumor BRCA test showed a high success rate and a turnaround time compatible with clinical purposes. The tumor BRCA test could be implemented in a molecular diagnostic setting and it may guide the clinical management of patients with epithelial ovarian cancer.

Download Full-text

Tolerance and toxicity of the PARP inhibitor olaparib in older women with epithelial ovarian cancer

Gynecologic Oncology ◽

10.1016/j.ygyno.2017.10.007 ◽

2017 ◽

Vol 147 (3) ◽

pp. 509-513 ◽

Cited By ~ 9

Author(s):

Lauren E. Dockery ◽

William P. Tew ◽

Kai Ding ◽

Kathleen N. Moore

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Older Women ◽

Parp Inhibitor

Download Full-text

Rationale for combination PARP inhibitor and antiangiogenic treatment in advanced epithelial ovarian cancer: A review

Gynecologic Oncology ◽

10.1016/j.ygyno.2021.05.018 ◽

2021 ◽

Author(s):

Angeles Alvarez Secord ◽

David M. O'Malley ◽

Anil K. Sood ◽

Shannon N. Westin ◽

Joyce F. Liu

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Parp Inhibitor ◽

Antiangiogenic Treatment ◽

Advanced Epithelial Ovarian Cancer

Download Full-text

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

Gynecologic Oncology ◽

10.1016/j.ygyno.2021.08.024 ◽

2021 ◽

Author(s):

Payal D. Shah ◽

Stephanie L. Wethington ◽

Cheyenne Pagan ◽

Nawar Latif ◽

Janos Tanyi ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Parp Inhibitor ◽

Phase 2 ◽

Platinum Resistant ◽

Phase 2 Study

Download Full-text

Efficacy and Safety of PARP Inhibitor Combination Therapy in Recurrent Ovarian Cancer: A Systematic Review and Meta-Analysis

Frontiers in Oncology ◽

10.3389/fonc.2021.638295 ◽

2021 ◽

Vol 11 ◽

Author(s):

Ning Ren ◽

Leyin Zhang ◽

Jieru Yu ◽

Siqi Guan ◽

Xinyang Dai ◽

...

Keyword(s):

Systematic Review ◽

Ovarian Cancer ◽

Combination Therapy ◽

Data Extraction ◽

Meta Analysis ◽

Parp Inhibitor ◽

Recurrent Ovarian Cancer ◽

Parp Inhibitors ◽

High Grade ◽

Efficacy And Safety

ObjectivesThough it is known to all that PARP inhibitors (PARPis) are effective when used as maintenance alone for women with recurrent ovarian cancer (ROC), little is known about whether using them in combination with other drugs would contribute to a better efficacy. We performed a systematic review and meta-analysis to explore the efficacy and safety of PARPi combination therapy compared with monotherapy.Materials and MethodsWe searched for randomized controlled trials (RCTs) that offered the date we needed in PubMed, Embase, Cochrane, and major conference. Data extraction and processing were completed by three investigators to compare OS, PFS, and ORR both in intervention and in control subset. Then, we calculated the pooled RR and 95% CI of all-grade and high-grade adverse effects to study its safety. And we evaluated the within-study heterogeneity by using subgroup and sensitivity analysis.Results and ConclusionA total of three eligible RCTs covering 343 women were included. In PFS analysis, PARP inhibitor (PARPi) combination therapy can significantly improve PFS for women with ROC when compared with the controls (HR: 0.46, 95% CI: 0.35 to 0.59), especially for those with mutated BRCA (HR: 0.29, 95% CI: 0.19 to 0.45). And in OS analysis, combination therapy is not inferior to monotherapy (HR: 0.90, 95% CI: 0.50 to 1.61). As for ORR, the effectiveness of combination therapy and monotherapy was almost the same (RR: 1.04, 95% CI: 0.82 to 1.31). Additionally, combination therapy seldom causes more adverse events, both in all-grade and in high grade.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/, International Prospective Register of Systematic Reviews (PROSPERO) (identifier, CRD42018109933).

Download Full-text

Targeting the upregulation of the AKT pathway and homologous recombination repair as a therapeutic strategy for epithelial ovarian cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e13125 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e13125-e13125

Author(s):

Elena Ratner ◽

Z-Ping Lin ◽

Thomas J. Rutherford ◽

Masoud Azodi ◽

Alessandro Santin ◽

...

Keyword(s):

Ovarian Cancer ◽

Dna Damage ◽

Epithelial Ovarian Cancer ◽

Cell Lines ◽

Synthetic Lethality ◽

Parp Inhibitor ◽

Gynecologic Cancer ◽

The United States ◽

Platinum Drugs ◽

Wild Type

e13125 Background: Epithelial ovarian cancer (EOC) is the second most common gynecologic cancer in the United States, and carries the highest mortality in this category in the West. The progression free survival and overall survival depend greatly on tumor sensitivity to a platinum chemotherapy. Once platinum resistance is encountered, response rates of only 6–30% are achieved. A relatively new modality in EOC that would allow targeted treatments is a PARP inhibitor, a drug that inhibits the enzyme poly (ADP-ribose) polymerase (PARP), which is showing promise for the treatment of EOC with mutations in the BRCA1 or BRCA2 tumor suppressors. Triapine, a novel small-molecule drug developed in our laboratory, potently inhibits the activity of ribonucleotide reductase involved in the key step of DNA synthesis and replication. Methods: 1. Cell sensitivity to varying ratios of treating drug combinations (Triapine with cisplatin; PARP inhibitor, olaparib) was carried out by clonogenic survival assays using multiple EOC cell lines (A2780, Caov-3, EFO, IGROV-1, BG-1, PEO1, SKOV3). 2. AKT level was measured in the cell lines before and after treatment. 3. BRCA1 wild-type and BRCA1-knockdown EOC cells were treated with cisplatin or PARP alone and in combination with Triapine. Drug-induced DNA damage was assessed by the levels of g-H2AX, the marker of double stranded breaks (DSBs), and of Rad51 foci, a marker of HR repair of DSBs. Results: Treatment with Triapine leads to synergistic sensitization of BRCA1 wild-type EOC cells to platinum drugs and to olaparib. Both platinum drugs and olaparib induce DNA damage that is repaired by HR. This suggests that Triapine inhibits HR and sensitizes EOC cells to these drugs. Triapine attenuates olaparib-induced Rad51 foci in BRCA1-wild type cells, which resembles the impairment of such foci formation in BRCA1-knockdown cells. Triapine causes down-regulation of AKT activity in EOC cells. Conclusions: Triapine produces synthetic lethality by inhibiting both DNA repair and pro-survival pathways. Combination of Triapine and platinum drugs/PARP inhibitors represents a rational and innovative therapy that targets EOC with a high level of AKT activity.

Download Full-text