Integrated efficacy and safety analysis of the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib in patients (pts) with high-grade ovarian carcinoma (HGOC)

e17552 Background: In platinum-resistant ovarian cancer treatment, single-agent paclitaxel can be used alone or in combination with bevacizumab. We aimed to assess the efficacy and safety profile of a weekly paclitaxel (WP) scheme in heavily pretreated platinum-resistant high-grade serous ovarian carcinoma. Methods: We retrospectively analyzed 30 adult patients with platinum-resistant high-grade serous ovarian carcinoma treated with WP at our institution between 2015 and 2020. Patients with platinum-resistant ovarian, fallopian tube or primary carcinoma of the peritoneum who had received at least 3 doses of WP (80 mg/m2) alone or in combination with bevacizumab until disease progression or unacceptable toxicity were included in the analysis. Progression-free survival was assessed according to the Response Evaluation Criteria in Solid Tumors version 1.1. Information about toxicity was gathered from medical reports and lab tests. Kaplan-Meier curves and Log-rank test were performed for survival estimates. Results: In our sample, the median age was 68 years (IQR: 60-75) and the median number of previous lines of systemic treatment was 3 (range 1-5). 40% of patients received WP in combination with bevacizumab. The disease control rate was 60.7% (42.9% partial response and 17.8% stable disease). In the overall analysis, the median progression-free survival (mPFS) was 5.0 months (95% CI: 2.0-7.1 months). The presence of ascites significantly shortened the mPFS compared to patients without it (1.1 vs 5.1 months, p < 0.001). Even though the addition of bevacizumab to WP improved the mPFS, the difference was not statistically significant compared to WP alone (7.1 vs 4.06 months, p=0.30). Peripheral neuropathy was the most common adverse event (78% all grades, 18% grade 3). No grade 3 hematologic toxicity was registered. Treatment was discontinued in 6 patients (20%) – 4 due to peripheral neuropathy and two because of toxicoderma. Conclusions: In our sample, WP was an active and safe regimen in heavily pretreated platinum-resistant ovarian carcinoma. WP was well tolerated in elderly patients. The presence of ascites was associated to a shorter PFS in patients treated with WP compared to ascites-free patients.

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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).

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Abstract LB-A12: Results from the phase 3 study ARIEL3: mutations in non-BRCAhomologous recombination repair genes confer sensitivity to maintenance treatment with the PARP inhibitor rucaparib in patients with recurrent platinum-sensitive high-grade ovarian carcinoma

10.1158/1535-7163.targ-17-lb-a12 ◽

2018 ◽

Cited By ~ 2

Author(s):

David M. O'Malley ◽

Robert L. Coleman ◽

Amit M. Oza ◽

Domenica Lorusso ◽

Carol Aghajanian ◽

...

Keyword(s):

Ovarian Carcinoma ◽

Maintenance Treatment ◽

Parp Inhibitor ◽

High Grade ◽

Phase 3 ◽

Platinum Sensitive ◽

Recombination Repair ◽

Repair Genes

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Feasibility of monitoring response to the PARP inhibitor rucaparib with targeted deep sequencing of circulating tumor DNA (ctDNA) in women with high grade ovarian carcinoma on the ARIEL2 trial

European Journal of Cancer ◽

10.1016/s0959-8049(16)32966-5 ◽

2016 ◽

Vol 69 ◽

pp. S123

Author(s):

A.M. Piskorz ◽

K.K. Lin ◽

J. Morris ◽

E. Mann ◽

A. Oza ◽

...

Keyword(s):

Ovarian Carcinoma ◽

Deep Sequencing ◽

Parp Inhibitor ◽

Circulating Tumor Dna ◽

High Grade ◽

Targeted Deep Sequencing ◽

Tumor Dna ◽

Monitoring Response

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Acquired RAD51C promoter methylation loss causes PARP inhibitor resistance in high grade serous ovarian carcinoma

10.1101/2020.12.10.419176 ◽

2020 ◽

Author(s):

Ksenija Nesic ◽

Olga Kondrashova ◽

Rachel M. Hurley ◽

Cordelia McGehee ◽

Cassandra J Vandenberg ◽

...

Keyword(s):

Ovarian Carcinoma ◽

Promoter Methylation ◽

Single Gene ◽

Parp Inhibitor ◽

Predictive Biomarker ◽

Gene Copy ◽

High Grade ◽

Serous Ovarian Carcinoma ◽

Gene Copies ◽

Inhibitor Resistance

ABSTRACTWhile loss of BRCA1 promoter methylation has been shown to cause PARP inhibitor (PARPi) resistance in high-grade serous ovarian carcinoma (HGSC), the impacts of RAD51C methylation (meRAD51C) remain unresolved. In this study, three PARPi-responsive HGSC patient-derived xenografts (PDX) with RAD51C gene silencing and homologous recombination deficiency were found to have either homogeneous or heterogeneous patterns of meRAD51C. PDX could lose meRAD51C following PARPi treatment (rucaparib/niraparib), where a single unmethylated RAD51C copy was sufficient to drive PARPi-resistance. Genomic profiling revealed this resistance was acquired independently in two distinct PDX lineages. Furthermore, we describe a patient sample where 1/3 RAD51C gene copies lost methylation following neoadjuvant chemotherapy. We show meRAD51C is a positive predictive biomarker for PARPi response and should be screened for routinely in patients. However, methylation loss in a single gene copy is sufficient to cause PARPi resistance and should be carefully assessed in previously treated patients considering PARPi therapy.

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