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. 2018 Jun 20;3(4):e000361.
doi: 10.1136/esmoopen-2018-000361. eCollection 2018.

Single-agent PARP inhibitors for the treatment of patients with BRCA-mutated HER2-negative metastatic breast cancer: a systematic review and meta-analysis

Francesca Poggio  1   2 , Marco Bruzzone  3 , Marcello Ceppi  3 , Benedetta Conte  2 , Samuel Martel  4 , Christian Maurer  5 , Marco Tagliamento  2 , Giulia Viglietti  6 , Lucia Del Mastro  7 , Evandro de Azambuja  1 , Matteo Lambertini  1   6
Affiliations

Single-agent PARP inhibitors for the treatment of patients with BRCA-mutated HER2-negative metastatic breast cancer: a systematic review and meta-analysis

Francesca Poggio et al. ESMO Open. .

Abstract

Single-agent poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have been approved as the first targeted therapy available for patients with BRCA-mutated HER2-negative metastatic breast cancer. This meta-analysis aimed to better evaluate activity, efficacy and safety of single-agent PARPi in this population. A systematic search of Medline, Embase and conference proceedings up to 31 January 2018 was conducted to identify randomised controlled trials (RCTs) investigating single-agent PARPi versus monochemotherapy in patients with BRCA-mutated HER2-negative metastatic breast cancer. Using the random-effect model, we calculated summary risk estimates (pooled HR and OR with 95% CI) for progression-free survival (PFS), overall survival (OS), objective response rate (ORR), any grade and grade 3-4 adverse events (AEs), treatment discontinuation rate and time to deterioration in quality of life (QoL). Two RCTs (n=733) were included. As compared with monochemotherapy, single-agent PARPi significantly improved PFS (HR 0.56(95% CI 0.45 to 0.70)) and ORR (OR 4.15 (95% CI 2.82 to 6.10)), with no difference in OS (HR 0.82 (95% CI 0.64 to 1.05)). Single-agent PARPi significantly increased risk of anaemia and any grade headache, but reduced risk of neutropenia and any grade palmar-plantar erythrodysesthesia syndrome as compared with monochemotherapy. No significant differences in other AEs and treatment discontinuation rate were observed. Patients treated with PARPi experienced a significant delayed time to QoL deterioration (HR 0.40 (95% CI 0.29 to 0.54)). Single-agent PARPi showed to be an effective, well tolerated and useful treatment in maintaining QoL of patients with BRCA-mutated HER2-negative metastatic breast cancer.

Keywords: BRCA mutation; PARP inhibitors; chemotherapy; metastatic breast cancer.

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Conflict of interest statement

Competing interests: LDM received personal fees from Novartis Pharma AG, Roche-Genentech, Ipsen, Astrazeneca, Takeda, Eli Lilly outside the submitted work. EdA received honoraria from Roche-Genentech, research grant from Roche-Genentech (to the institution) and travel grants from Roche-Genentech and GlaxoSmithKline outside the submitted work. ML served as a consultant for Teva outside the submitted work.

Figures

Figure 1
Figure 1
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart summarising the process for the identification of eligible studies. ASCO, American Society of Clinical Oncology; ESMO, European Society for Medical Oncology; SABCS, San Antonio Breast Cancer Symposium; PARPi, PARP inhibitor; RCT, randomised controlled trial.
Figure 2
Figure 2
(A) Progression-free survival in patients with BRCA-mutated HER2-negative breast cancer treated with PARPi versus those treated with monochemotherapy (controls). The size of the squares is proportional to the weight of each study. (B) Overall survival in patients with BRCA-mutated HER2-negative breast cancer treated with PARPi versu s those treated with monochemotherapy (controls).1 The size of the squares is proportional to the weight of each study. PARPi, PARP inhibitor.
Figure 3
Figure 3
(A) Progression-free survival in the hormone receptor-negative cohort patients treated with PARPi versus those treated with mono chemotherapy (controls). The size of the squares is proportional to the weight of each study. (B) Progression-free survival in the hormone receptor-positive cohort of patients treated with PARPi versus those treated with mono chemotherapy (controls). The size of the squares is proportional to the weight of each study. (C) Progression-free survival in the no prior platinum cohort of patients treated with PARPi versus those treated with mono chemotherapy (controls). The size of the squares is proportional to the weight of each study. (D) Progression-free survival in the prior platinum cohort of patients treated with PARPi versus those treated with mono chemotherapy (controls). The size of the squares is proportional to the weight of each study. PARPi, PARP inhibitor.
Figure 4
Figure 4
Objective response rate in patients with BRCA-mutated HER2-negative breast cancer treated with PARPi versus those treated with monochemotherapy (controls). The size of the squares is proportional to the weight of each study. PARPi, PARP inhibitor.
Figure 5
Figure 5
(A) Safety profile overview. Any grade neutropenia, any grade anaemia, any grade fatigue, any grade nausea, any grade vomiting, any grade decreased appetite, any grade headache, any grade diarrhoea and any grade palmar-plantar erythrodysesthesia in patients with BRCA-mutated HER2-negative breast cancer treated with PARPi versus those treated with monochemotherapy (controls). (B) Safety profile overview. Grade 3–4 neutropenia and grade 3–4 anaemia in BRCA-mutated HER2-negative patients treated with PARPi versus those treated with monochemotherapy (controls). (C) Treatment discontinuation rate in BRCA-mutated HER2-negative patients treated with PARPi versus those treated with monochemotherapy (controls). The size of the squares is proportional to the weight of each study. (D) Time to clinically meaningful deterioration in quality of life in patients with BRCA-mutated HER2-negative metastatic breast cancer treated with PARPi versus those treated with monochemotherapy (controls). The size of the squares is proportional to the weight of each study. PARPi, PARP inhibitors.
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