Comparison of PARPis with Angiogenesis Inhibitors and Chemotherapy for Maintenance in Ovarian Cancer: A Network Meta-Analysis
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Seventy-five percent of ovarian cancer would relapse within 18–28 months after platinum-base chemotherapy. Evidence suggests that maintenance chemotherapy is effective in prolonging remission. Recent target therapies such as poly(ADP-ribose) polymerase inhibitors (PARPis) and angiogenesis inhibitors (AIs) are known to ease burden and recurrence of ovarian cancer. There is limited data for head-to-head comparison of PARPis, AIs, and chemotherapeutic agents (CTAs) as maintenance treatment. This network meta-analysis thus assessed the effectiveness and toxicity of these three maintenance therapies in patients with ovarian cancer.
We searched relevant sources (PubMed, EMBASE) to identify randomized controlled trials assessing efficacy and safety of maintenance therapy in patients with ovarian cancer. Primary outcome was progression-free survival (PFS) as assessed by blinded review; safety and tolerability were secondary outcomes. A network meta-analysis to compare three drug classes was performed using statistical software R.
We included 24 trials (11,366 patients) assessing efficacy and safety of PARPis (n = 4), AIs (n = 12), and CTAs (n = 8). PARPis [hazard ratio (HR) 0.64; 95% credible intervals (CrI) 0.55–0.73] and AIs (HR 0.87; 95% CrI 0.81–0.93) showed significant improvement in PFS compared to placebo but not CTA (HR 1.00; 95% CrI 0.86–1.15). PARPis showed significant improvement in PFS compared to AIs (HR 0.73; 95% CrI 0.63–0.86) and CTA (HR 0.64; 95% CrI 0.52–0.78). Adverse events (AEs) leading to treatment discontinuation and dose reduction were lower in PARPis [incidence rate ratio (IRR) 0.60; CrI 0.31–1.18 and IRR 0.73, 95% CrI 0.50–1.06, respectively] compared to AIs, but the differences were not significant.
PARPi as maintenance treatment improved PFS in ovarian cancer and was relatively safer in terms of implications caused by AEs when compared to AIs. This network meta-analysis provides valuable evidence and significant insights into treatment of ovarian cancer.
KeywordsAngiogenesis inhibitors Chemotherapy Maintenance therapy Ovarian cancer PARP inhibitors
No funding or sponsorship was received for this study or publication of this article. The Rapid Service Fee was funded by the authors.
Medical Writing Assistance
Medical writing support was provided by Dr Anuradha Nalli and Dr Amit Bhat of Indegene and funded by AstraZeneca China Investment Co., Ltd.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Yanling Feng, He Huang, Ting Wan, Chuyao Zhang, Chongjie Tong, and Jihong Liu have nothing to disclose.
Compliance with Ethics Guidelines
This article is based on previously conducted studies and does not contain any experiments with human participants or animals performed by any of the authors.
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
- 2.Burges A, Schmalfeldt B. Ovarian Cancer. Dtsch Aerzteblatt Online. 2011. https://www.aerzteblatt.de/10.3238/arztebl.2011.0635. Accessed 25 Feb 2019.
- 3.The World Ovarian Cancer Coalation atlas: global trends in incidence, mortality, and survival. World Ovarian Cancer Coalition. 2018.https://worldovariancancercoalition.org/wp-content/uploads/2018/10/THE-WORLD-OVARIAN-CANCER-COALITION-ATLAS-2018.pdf. Accessed 25 Feb 2019.
- 8.Markman M, Liu PY, Wilczynski S, et al. Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: a Southwest Oncology Group and Gynecologic Oncology Group trial. J Clin Oncol. 2003;21:2460–5.PubMedGoogle Scholar
- 9.Markman M, Liu PY, Moon J, et al. Impact on survival of 12 versus 3 monthly cycles of paclitaxel (175 mg/m2) administered to patients with advanced ovarian cancer who attained a complete response to primary platinum-paclitaxel: follow-up of a Southwest Oncology Group and Gynecologic Oncology Group phase 3 trial. Gynecol Oncol. 2009;114:195–8.PubMedPubMedCentralGoogle Scholar
- 13.Lesueur P, Chevalier F, Austry J-B, et al. Poly-(ADP-ribose)-polymerase inhibitors as radiosensitizers: a systematic review of pre-clinical and clinical human studies. Oncotarget. 2017;8. http://www.oncotarget.com/fulltext/19079. Accessed 25 Feb 2019.
- 15.Oza Amit M, Cibula D, Oaknin A, et al. Olaparib plus paclitaxel plus carboplatin (P/C) followed by olaparib maintenance treatment in patients (pts) with platinum-sensitive recurrent serous ovarian cancer (PSR SOC): a randomized, open-label phase II study. J Clin Oncol. 2012;30(15):Suppl 5001. https://doi.org/10.1200/jco.2012.30.15_suppl.5001.CrossRefGoogle Scholar
- 19.Swisher EM, McNeish IA, Coleman RL, et al. ARIEL 2/3: an integrated clinical trial program to assess activity of rucaparib in ovarian cancer and to identify tumor molecular characteristics predictive of response. J Clin Oncol. 2014;32(5):619.Google Scholar
- 21.Hirte HW, Vidal L, Fleming GF, et al. A phase II study of cediranib (AZD2171) in recurrent or persistent ovarian, peritoneal or fallopian tube cancer: final results of a PMH, Chicago and California consortia trial. J Clin Oncol. 2008;26:5521.Google Scholar
- 22.Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012;30:2039–45.PubMedPubMedCentralGoogle Scholar
- 25.Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1–12.Google Scholar
- 26.R package: Gemtc.. http://cran.r-project.org/web/packages/gemtc/index.html. Accessed 25 Feb 2019.
- 27.Comparing Frequencies Rate Ratios. http://sphweb.bumc.bu.edu/otlt/MPH-Modules/QuantCore/PH717_ComparingFrequencies/PH717_ComparingFrequencies9.html. Accessed 25 Feb 2019.
- 39.Mannel RS, Brady MF, Kohn EC, et al. A randomized phase III trial of IV carboplatin and paclitaxel × 3 courses followed by observation versus weekly maintenance low-dose paclitaxel in patients with early-stage ovarian carcinoma: a Gynecologic Oncology Group Study. Gynecol Oncol. 2011;122:89–94.PubMedPubMedCentralGoogle Scholar
- 41.Pecorelli S, Favalli G, Gadducci A, et al. Phase III trial of observation versus six courses of paclitaxel in patients with advanced epithelial ovarian cancer in complete response after six courses of paclitaxel/platinum-based chemotherapy: final results of the After-6 protocol 1. J Clin Oncol. 2009;27:4642–8.PubMedGoogle Scholar
- 43.Piccart MJ, Floquet A, Scarfone G, et al. Intraperitoneal cisplatin versus no further treatment: 8-year results of EORTC 55875, a randomized phase III study in ovarian cancer patients with a pathologically complete remission after platinum-based intravenous chemotherapy. Int J Gynecol Cancer. 2003;13(Suppl 2):196–203.PubMedGoogle Scholar
- 44.Sorbe B, Swedish-Norgewian Ovarian Cancer Study Group. Consolidation treatment of advanced (FIGO stage III) ovarian carcinoma in complete surgical remission after induction chemotherapy: a randomized, controlled, clinical trial comparing whole abdominal radiotherapy, chemotherapy, and no further treatment. Int J Gynecol Cancer. 2003;13:278–86.PubMedGoogle Scholar
- 47.Pujade-Lauraine E, Ledermann JA, Selle F, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18:1274–84.PubMedGoogle Scholar
- 48.Chen H, Fang F, Liu GJ, Xie HY, Zou J, Feng D. Maintenance chemotherapy for ovarian cancer. Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Group. Cochrane Database Syst Rev. 2013. https://doi.org/10.1002/14651858.CD007414.pub3. Accessed 11 Jun 2018.
- 49.Gaitskell K, Martinek I, Bryant A, Kehoe S, Nicum S, Morrison J. Angiogenesis inhibitors for the treatment of ovarian cancer. Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Group. Cochrane Database Syst Rev. 2011. https://doi.org/10.1002/14651858.CD007930.pub2. Accessed 12 Jun 2018.
- 50.Wiggans AJ, Cass GK, Bryant A, Lawrie TA, Morrison J. Poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of ovarian cancer. Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Group. Cochrane Database Syst Rev. 2015. https://doi.org/10.1002/14651858.CD007929.pub3. Accessed 12 Jun 2018.
- 54.Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005;434:913–7.Google Scholar