The impact of second to sixth line therapy on survival of relapsed ovarian cancer after primary taxane/platinum-based therapy

Hanker, Lars; Loibl, Sibylle; Burchardi, Nicole; Pfisterer, Jacobus; Meier, W.; Pujade-Lauraine, Éric; Ray‐Coquard, Isabelle; Sehouli, Jalid; Harter, Philipp; Bois, Andreas du

doi:10.1093/annonc/mds203

Cited by 289 publications

(251 citation statements)

References 30 publications

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“…It is noteworthy that similar levels of ORRs were also observed with the use of taxanes and PLD as monotherapies (Tables 2 and 3). Although published data on ORRs are scarce in patients with EOC carrying germline BRCA1/2 mutations in the third-line (and later) settings, the ORRs observed in this study seem to be in keeping with other phase II data for the same regimens in the general EOC population (26). Overall, these data point to significant differences in the mechanisms of resistance between PARPi and chemotherapy including platinum-based agents.…”

Section: Discussionsupporting

confidence: 87%

Efficacy of Chemotherapy in BRCA1/2 Mutation Carrier Ovarian Cancer in the Setting of PARP Inhibitor Resistance: A Multi-Institutional Study

Ang

Gourley

Powell

et al. 2013

Clinical Cancer Research

132

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Purpose: Preclinical data suggest that exposure to PARP inhibitors (PARPi) may compromise benefit to subsequent chemotherapy, particularly platinum-based regimens, in patients with BRCA1/2 mutation carrier ovarian cancer (PBMCOC), possibly through the acquisition of secondary BRCA1/2 mutations. The efficacy of chemotherapy in the PARPi-resistant setting was therefore investigated.Experimental Design: We conducted a retrospective review of PBMCOC who received chemotherapy following disease progression on olaparib, administered at !200 mg twice daily for one month or more. Tumor samples were obtained in the post-olaparib setting where feasible and analyzed by massively parallel sequencing.Results: Data were collected from 89 patients who received a median of 3 (range 1-11) lines of preolaparib chemotherapy. The overall objective response rate (ORR) to post-olaparib chemotherapy was 36% (24 of 67 patients) by Response Evaluation Criteria in Solid Tumors (RECIST) and 45% (35 of 78) by RECIST and/or Gynecologic Cancer InterGroup (GCIG) CA125 criteria with median progression-free survival (PFS) and overall survival (OS) of 17 weeks [95% confidence interval (CI), 13-21] and 34 weeks (95% CI, 26-42), respectively. For patients receiving platinum-based chemotherapy, ORRs were 40% (19 of 48) and 49% (26/53), respectively, with a median PFS of 22 weeks (95% CI, 15-29) and OS of 45 weeks (95% CI, 15-75). An increased platinum-to-platinum interval was associated with an increased OS and likelihood of response following post-olaparib platinum. No evidence of secondary BRCA1/2 mutation was detected in tumor samples of six PARPi-resistant patients [estimated frequency of such mutations adjusted for sample size: 0.125 (95%-CI: 0-0.375)].Conclusions: Heavily pretreated PBMCOC who are PARPi-resistant retain the potential to respond to subsequent chemotherapy, including platinum-based agents. These data support the further development

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Section: Discussionsupporting

confidence: 87%

Efficacy of Chemotherapy in BRCA1/2 Mutation Carrier Ovarian Cancer in the Setting of PARP Inhibitor Resistance: A Multi-Institutional Study

Ang

Gourley

Powell

et al. 2013

Clinical Cancer Research

132

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“…3 Platinum retreatment is used in patients in whom there is an assumed platinum sensitivity, with diminishing effectiveness and a cumulative increase in toxicity. 3 Niraparib is a highly selective inhibitor of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) 1/2, 4 nuclear proteins that detect DNA damage and promote its repair. Clinical studies have evaluated PARP inhibitors in patients with recurrent ovarian cancer, including those with germline BRCA mutations, platinum-sensitive disease, or both.…”

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confidence: 99%

Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer

et al. 2016

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BACKGROUNDNiraparib is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) 1/2 inhibitor that has shown clinical activity in patients with ovarian cancer. We sought to evaluate the efficacy of niraparib versus placebo as maintenance treatment for patients with platinum-sensitive, recurrent ovarian cancer. METHODSIn this randomized, double-blind, phase 3 trial, patients were categorized according to the presence or absence of a germline BRCA mutation (gBRCA cohort and non-gBRCA cohort) and the type of non-gBRCA mutation and were randomly assigned in a 2:1 ratio to receive niraparib (300 mg) or placebo once daily. The primary end point was progression-free survival. RESULTSOf 553 enrolled patients, 203 were in the gBRCA cohort (with 138 assigned to niraparib and 65 to placebo), and 350 patients were in the non-gBRCA cohort (with 234 assigned to niraparib and 116 to placebo). Patients in the niraparib group had a significantly longer median duration of progression-free survival than did those in the placebo group, including 21.0 vs. 5.5 months in the gBRCA cohort (hazard ratio, 0.27; 95% confidence interval [CI], 0.17 to 0.41), as compared with 12.9 months vs. 3.8 months in the non-gBRCA cohort for patients who had tumors with homologous recombination deficiency (HRD) (hazard ratio, 0.38; 95% CI, 0.24 to 0.59) and 9.3 months vs. 3.9 months in the overall non-gBRCA cohort (hazard ratio, 0.45; 95% CI, 0.34 to 0.61; P<0.001 for all three comparisons). The most common grade 3 or 4 adverse events that were reported in the niraparib group were thrombocytopenia (in 33.8%), anemia (in 25.3%), and neutropenia (in 19.6%), which were managed with dose modifications. CONCLUSIONSAmong patients with platinum-sensitive, recurrent ovarian cancer, the median duration of progression-free survival was significantly longer among those receiving niraparib than among those receiving placebo, regardless of the presence or absence of gBRCA mutations or HRD status, with moderate bone marrow toxicity. (Funded by Tesaro; ClinicalTrials.gov number, NCT01847274.)

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“…In contrast, treatments beyond second-line therapy are rather heterogeneous, and data about response rate and survival are controversial and even disappointing. Recently, Hanker et al [18] in a retrospective multicenter analysis found that the application of 3 lines of relapse treatment seems to be the maximum acceptable therapy and that additional lines of subsequent treatment appear not to be beneficial for all ROC patients. On the other hand, it should also be considered that most patients prefer subsequent chemotherapy even with a small survival benefit [19] .…”

Section: Discussionmentioning

confidence: 99%

Short-Infusion Trabectedin in Heavily Pretreated Ovarian Cancer Patients: A Single-Institution Experience

Marchetti¹,

Musella²,

Romito³

et al. 2017

Oncology

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Objective: The aim of this study was to assess the efficacy and tolerability of trabectedin given every 10 days as a single agent in recurrent ovarian cancer after 3 prior regimens. Method: Trabectedin 0.6 mg/m² was administered as a 3-h infusion every 10 days on a 21-day cycle. The study population was compared to patients treated with weekly paclitaxel 80 mg/m² intravenously on days 1, 8, 15, and 22 every 4 weeks. Results: We identified 34 patients previously submitted to at least 3 lines of chemotherapy who received single-agent trabectedin between 2010 and 2015. They were matched with a historical series of 34 patients who received weekly paclitaxel. No significant differences in response rate were found. Median progression-free survival was 4 months; 5 months in the trabectedin group and 4 months in the paclitaxel group. Overall survival (OS) was 13 months for the trabectedin group and 7 months for the paclitaxel group (p = 0.015). Patients who received platinum after trabectedin had a significant OS increase compared to those who received platinum after paclitaxel (18 vs. 9 months, respectively; p = 0.009). The most frequent drug-related grade 3/4 toxicities were reversible hepatic toxicity, neutropenia, anemia, thrombocytopenia, and gastrointestinal toxicity. Conclusion: Single-agent trabectedin every 10 days is an active treatment with a manageable toxicity profile in heavily pretreated advanced relapsed ovarian cancer patients.

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The impact of second to sixth line therapy on survival of relapsed ovarian cancer after primary taxane/platinum-based therapy

Abstract: A maximum of three lines of subsequent relapse treatment seems to be beneficial for patients with recurrent ovarian cancer. Optimal primary tumor debulking and platinum sensitivity remain independent prognostic factors even after more frequent relapses.

Cited by 289 publications

References 30 publications

Efficacy of Chemotherapy in BRCA1/2 Mutation Carrier Ovarian Cancer in the Setting of PARP Inhibitor Resistance: A Multi-Institutional Study

Efficacy of Chemotherapy in BRCA1/2 Mutation Carrier Ovarian Cancer in the Setting of PARP Inhibitor Resistance: A Multi-Institutional Study

Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer

Short-Infusion Trabectedin in Heavily Pretreated Ovarian Cancer Patients: A Single-Institution Experience

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