scholarly journals Antitumor activity and safety of the PARP inhibitor rucaparib in patients with high-grade ovarian carcinoma and a germline or somatic BRCA1 or BRCA2 mutation: Integrated analysis of data from Study 10 and ARIEL2

2017 ◽  
Vol 147 (2) ◽  
pp. 267-275 ◽  
Author(s):  
Amit M. Oza ◽  
Anna V. Tinker ◽  
Ana Oaknin ◽  
Ronnie Shapira-Frommer ◽  
Iain A. McNeish ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Ovarian Carcinoma ◽  
Parp Inhibitor ◽  
Brca2 Mutation ◽  
Integrated Analysis ◽  
High Grade

ARIEL4: An international, multicenter randomized phase 3 study of the PARP inhibitor rucaparib vs chemotherapy in germline or somatic BRCA1- or BRCA2-mutated, relapsed, high-grade ovarian carcinoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS5603-TPS5603 ◽  
Author(s):  
Amit M. Oza ◽  
Domenica Lorusso ◽  
Ana Oaknin ◽  
Tamar Safra ◽  
Elizabeth Swisher ◽  
...  
Keyword(s):  
Ovarian Carcinoma ◽  
Parp Inhibitor ◽  
Brca2 Mutation ◽  
Single Agent ◽  
Objective Response ◽  
The United States ◽  
Parp Inhibitors ◽  
Ca 125 ◽  
High Grade ◽  
Platinum Sensitive

TPS5603 Background: In high-grade epithelial ovarian carcinoma (OC), ≈18% of patients (pts) have tumors with a germline BRCA1 or BRCA2 mutation; ≈7% have tumors with a somatic BRCA1 or BRCA2 mutation (Pennington et al. Clin Cancer Res. 2014;20:764-75). The poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib is approved in the United States for treatment of pts with OC associated with a deleterious BRCA1 or BRCA2 mutation (germline and/or somatic) who have received ≥2 chemotherapies. Although PARP inhibitors have demonstrated clinical activity in OC in both treatment and maintenance settings, comparison to standard of care (SOC) has only been evaluated in the maintenance setting. Randomized studies are needed to assess the benefit-risk profile of PARP inhibitors vs current SOC as treatment for BRCA1- or BRCA2-mutated, relapsed, high-grade OC. Methods: ARIEL4 (NCT02855944) is evaluating rucaparib vs chemotherapy as treatment for pts with germline or somatic BRCA1- or BRCA2-mutated, relapsed, high-grade OC (regardless of histology) who have received ≥2 prior chemotherapy regimens. Approximately 345 pts will be randomized 2:1 to receive rucaparib (600 mg BID) (n = 230) or chemotherapy (n = 115) and stratified by progression-free interval after their most recent platinum regimen. Pts with platinum-resistant (progressive disease [PD] 1– < 6 mo after last platinum) or partially platinum-sensitive disease (PD 6– < 12 mo after last platinum) will be randomized to rucaparib or weekly paclitaxel; pts with platinum-sensitive disease (PD ≥12 mo after last platinum) will be randomized to rucaparib or platinum-based therapy (single-agent or doublet at the discretion of the investigator). Pts receiving chemotherapy have the option to cross over to rucaparib upon radiographic disease progression. The primary endpoint is progression-free survival. Secondary endpoints include investigator-assessed objective response rate (ORR) (RECIST version 1.1), ORR/CA-125 response, duration of response, overall survival, and pt-reported outcomes. Safety will be summarized descriptively using standard adverse event reporting. Clinical trial information: NCT02855944.

BRCA Reversion Mutations in Circulating Tumor DNA Predict Primary and Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma

2018 ◽  
Vol 9 (2) ◽  
pp. 210-219 ◽  
Author(s):  
Kevin K. Lin ◽  
Maria I. Harrell ◽  
Amit M. Oza ◽  
Ana Oaknin ◽  
Isabelle Ray-Coquard ◽  
...  
Keyword(s):  
Ovarian Carcinoma ◽  
Parp Inhibitor ◽  
Acquired Resistance ◽  
Circulating Tumor Dna ◽  
High Grade ◽  
Tumor Dna

Maintenance olaparib plus bevacizumab (bev) after platinum-based chemotherapy plus bev in patients (pts) with newly diagnosed advanced high-grade ovarian cancer (HGOC): Efficacy by BRCA1 or BRCA2 mutation in the phase III PAOLA-1 trial.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6039-6039
Author(s):  
Domenica Lorusso ◽  
Jean-Pierre Lotz ◽  
Philipp Harter ◽  
Claire Cropet ◽  
Maria Jesus Rubio Pérez ◽  
...  
Keyword(s):  
Brca Mutation ◽  
Brca1 Mutation ◽  
Parp Inhibitor ◽  
Brca2 Mutation ◽  
Phase Iii ◽  
Primary Data ◽  
High Grade ◽  
Newly Diagnosed ◽  
First Line ◽  
Platinum Based Chemotherapy

6039 Background: In PAOLA-1/ENGOT-ov25 (NCT02477644), adding the PARP inhibitor olaparib to maintenance bev after first-line platinum-based chemotherapy plus bev led to a statistically significant progression-free survival (PFS) benefit in pts with advanced HGOC (HR 0.59; 95% CI 0.49–0.72) (Ray-Coquard et al. 2019). Retrospective subgroup analysis in GOG-0218 (Norquist et al. 2018) suggested BRCA mutation (BRCAm) status did not significantly impact the PFS benefit provided by bev. We explored the efficacy of olaparib plus bev by BRCA1 mutation ( BRCA1m) or BRCA2 mutation ( BRCA2m) in PAOLA-1. Methods: PAOLA-1 is a randomized, double-blind, Phase III trial in pts with newly diagnosed, FIGO stage III–IV, high-grade serous or endometrioid OC, fallopian tube or primary peritoneal cancer receiving platinum-based chemotherapy plus bev then maintenance bev. Pts unrestricted by surgical outcome or BRCAm status and in response to first-line therapy were randomized to maintenance olaparib tablets (300 mg bid for up to 24 months) plus bev (15 mg/kg q3w for up to 15 months in total) or placebo plus bev, stratified by first-line treatment outcome and tumor BRCAm status. Investigator-assessed PFS (modified RECIST v1.1) by BRCAm was a predefined analysis. Results: Of 806 randomized pts, 160 (20%) had tumor BRCA1m, 76 (9%) had tumor BRCA2m and 1 (<1%) had both. Median PFS follow-up was 24.1 and 27.4 months in BRCA1m and BRCA2m pts, respectively. At primary data cutoff, PFS was prolonged with olaparib plus bev versus placebo plus bev in BRCA1m pts and BRCA2m pts (Table). The percentage of BRCA1m pts who received olaparib plus bev and were progression-free at 1 and 2 years was 95% and 73% (vs. 70% and 29% for placebo plus bev) and for BRCA2m pts was 89% and 84% (vs. 84% and 53%) (Kaplan-Meier estimates). Conclusions: In PAOLA-1, maintenance olaparib plus bev provided a significant PFS benefit versus placebo plus bev in all pts analysed, regardless of whether they had BRCA1m or BRCA2m. The median PFS in the control arm suggests a role for bev in this subgroup and the hazard ratio versus an active control arm shows the value of adding maintenance olaparib to bev. Clinical trial information: NCT02477644. [Table: see text]

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

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.

Handle with care – effektives Toxizitätsmanagement während Chemotherapie eines serösen high-grade Ovarialkarzinoms

2021 ◽  
Vol 53 (04) ◽  
pp. 179-182
Author(s):  
Peter Holzhauer
Keyword(s):  
Parp Inhibitor ◽  
Brca2 Mutation ◽  
High Grade ◽  
Genetische Testung ◽  
Maligne Erkrankung ◽  
Carboplatin Auc

ZusammenfassungHier wird der komplikationsreiche Behandlungsverlauf einer heute 50-jährigen Patientin dargestellt. Operativ konnte bei schon weit fortgeschrittener Peritonealkarzinose keine Tumorfreiheit erreicht werden. Wegen des sehr reduzierten Allgemeinzustands war initial nur eine Monochemotherapie mit Carboplatin AUC 5 möglich. Unter dieser deeskalierten Monotherapie kam es schon nach dem ersten Zyklus zu einer ausgeprägten Hämatotoxizität mit behandlungsbedürftiger Anämie, Thrombopenie sowie Leukopenie, sodass mehrmalige Transfusionen von Erythrozyten- und Thrombozytenkonzentraten und G-CSF-Gaben notwendig wurden. Die weiteren Zyklen mussten mit erheblich reduzierter Dosierung angepasst werden. Unter dieser suboptimalen Dosierung war die maligne Erkrankung progredient, die Patientin musste einen Sigmastent bei symptomatischer Sigmastenose erhalten.Ab diesem Zeitpunkt wurde die weitere Behandlung der Patientin in einem intensiven komplementär/supportiven Konzept und mit einer individualisierten Chemotherapiekombination fortgeführt. Darunter kam es zu einer rückläufigen Hämatotoxizität, die Chemotherapie konnte nach 6 Zyklen mit einer weitgehenden Remission aller Tumormanifestationen beendet werden. Die genetische Testung ergab eine BRCA2-Mutation. Daraufhin erhielt die Patientin eine orale Erhaltungstherapie mit dem PARP-Inhibitor Niraparib 4.

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