The Open Nursing Journal




ISSN: 1874-4346 ― Volume 13, 2019
SYSTEMATIC REVIEW

What is the Current Effectiveness of Olaparib for Breast Cancer Patients with a BRCA Mutation? A Systematic Review



Polly Marsh, Graham R Williamson*
School of Nursing and Midwifery, The Exeter School of Nursing, University of Plymouth, Topsham RD, Exeter, Devon. EX2 6HA, UK

Abstract

Background:

The Poly (ADP-ribose) polymerase inhibitor olaparib, acts against cancer cells in people with breast cancer pre-disposition gene mutations (BRCAm). Despite US and EU approval as a therapy for ovarian cancer patients with BRCAm, but research into olaparib therapy for breast cancer patients with BRCAm is in its infancy.

Objective:

As no systematic review has yet been undertaken to synthesise clinical trials looking at olaparib as a therapy for breast cancer patients with BRCAm, this systematic review aims to establish the current effectiveness of olaparib as a treatment for these patients.

Methods:

CINAHL, MEDLINE, Royal College of Nursing, Cochrane Library, Joanna Briggs Institute, Centre for Reviews and Dissemination, Internurse, Embase, Google Scholar and PubMed databases were searched, supplemented by a grey literature search, hand searching and cross-referencing. Authors independently reviewed and graded the studies also using Kmet et al. scoring system.

Results:

One long-term case study and six clinical trials were included. Heterogeneity prevented statistical meta-analysis, meaning only narrative synthesis was possible. The overall clinical benefit of olaparib appears to be greater and longer lived in BRCAm carriers compared to BRCAwt, and also when compared to standard chemotherapy treatments.

Conclusion:

Implications for nursing: nurses working in this field should be aware that the most compelling results were found in the subset of patients who harbour a BRCA mutation, meaning that olaparib should be regarded as a clinically effective potential therapy for these patients. Larger, longer-term trials including comparator arms are required to demonstrate benefits including overall survival, adverse effects and quality of life.

Keywords: Olaparib, BRCA, BRCAm, Systematic review, Narrative synthesis, Ovarian Cancers, TNBC, Ovarian cancers, TNBC.


Article Information


Identifiers and Pagination:

Year: 2019
Volume: 13
First Page: 39
Last Page: 59
Publisher Id: TONURSJ-13-39
DOI: 10.2174/1874434601913010039

Article History:

Received Date: 12/11/2018
Revision Received Date: 21/12/2018
Acceptance Date: 28/12/2018
Electronic publication date: 25/02/2019
Collection year: 2019

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© 2019 Marsh and Williamson.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: (https://creativecommons.org/licenses/by/4.0/legalcode). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the School of Nursing and Midwifery, The Exeter School of Nursing, University of Plymouth, Topsham RD, Exeter, Devon. EX2 6HA, UK; Tel: 07976761858; E-mail: gwilliamson@plymouth.ac.uk




1. INTRODUCTION

Alterations in the breast cancer (BC) genes, BRCA1 and BRCA2, can lead to autosomal dominant, highly penetrant, predisposition to breast and ovarian cancers, with lifetime risks as high as 84% [1King MC, Marks JH, Mandell JB. New York Breast Cancer Study Group. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 2003; 302(5645): 643-6.[http://dx.doi.org/10.1126/science.1088759] [PMID: 14576434] ].

BRCA-mutant (BRCAm) breast cancers are more often high-grade Triple Negative Breast Cancer (TNBC) which means they are negative for oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor2 (HER2), making them much harder to target therapeutically [2Lee A, Djamgoz MBA. Triple negative breast cancer: Emerging therapeutic modalities and novel combination therapies. Cancer Treat Rev 2018; 62: 110-22.[http://dx.doi.org/10.1016/j.ctrv.2017.11.003] [PMID: 29202431] ]. TNBC has the poorest overall survival of all breast cancer subtypes with the highest rates of metastatic disease [2Lee A, Djamgoz MBA. Triple negative breast cancer: Emerging therapeutic modalities and novel combination therapies. Cancer Treat Rev 2018; 62: 110-22.[http://dx.doi.org/10.1016/j.ctrv.2017.11.003] [PMID: 29202431] ]. Recent studies have revealed an emerging therapy using Poly (ADP-ribose) polymerase inhibitors (PARPi), which has had great success when treating BRCAm ovarian cancers. Olaparib is one of several known PARPis and has been in trials as a monotherapy, and in combination other standard therapies, and as maintenance therapy [3William AM. Oral PARPi olaparib in patients with BRCA1 or BRCA2 and recurrent OC: A proof of concept trial. Lancet 2010; 376(9737): 245-51.[http://dx.doi.org/10.1016/S0140-6736(10)60893-8] [PMID: 206094 68] -6Lee J-M, Hays JL, Annunziata CM, et al. Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses. J Natl Cancer Inst 2014; 106(6): dju089.[http://dx.doi.org/10.1093/jnci/dju089] [PMID: 24842883] ]

Olaparib has been granted approval in the USA, and in the EU to be used as a therapy for Ovarian Cancer (OC) patients with BRCAm, but as yet the research into olaparib therapy for BC patients with BRCAm is in its infancy.

No Systematic Review (SR) has been undertaken to synthesisethe clinical trials looking at olaparib as a therapy for BC patients with BRCAm. Given olaparib’s success with BRCAm OC, there is a clear need for an SR and synthesis of the trials investigating olaparib as a therapy in BRCAm BC patients. This paper is the first to conduct such an SR and draw tentative conclusions and recommendations based on a narrative review of the evidence.

In addition to germline BRCA tumours, BRCA deficiency is observed in somatic BRCAm tumours [7Lord CJ, Ashworth A. BRCAness revisited. Nat Rev Cancer 2016; 16(2): 110-20.[http://dx.doi.org/10.1038/nrc.2015.21] [PMID: 26775620] ], so this SR will look at all BRCAm patients regardless of whether the BRCAm was germline or somatic.

Firstly, we will outline the basic science and clinical applications of BRCAm BC, PARPi, and olaparib.

1.1. Aetiology of BRCAm Breast Cancer

Mistakes (mutations) in DNA replication and failures of DNA repair pathways are central to the development of cancer [8Alberts B, John HW, Hunt T. Molecular Biology of the Cell 6. 2015.6.]. Cancer cells are cells that have acquired malignant properties such as proliferation, invasion, and metastasis. These malignant cells can evade apoptosis (controlled cell death). Many chemotherapies and some targeted agents work by creating catastrophic damage to DNA in malignant cells, as to make the cell non viable [8Alberts B, John HW, Hunt T. Molecular Biology of the Cell 6. 2015.6.].

BRCA1 and BRCA2 are genes involved in DNA repair - they are broadly categorised as tumour suppressors [9Helleday T. The underlying mechanism for the PARP and BRCA synthetic lethality: Clearing up the misunderstandings. Mol Oncol 2011; 5(4): 387-93.[http://dx.doi.org/10.1016/j.molonc.2011.07.001] [PMID: 21821475] ]. So if this repair pathway is impaired (e.g. by BRCAm), then these patients are at increased risk of developing BC, OC and other cancers [10Ledermann JA. PARP inhibitors in ovarian cancer. Ann Oncol 2016; 27(Suppl. 1): i40-4.[http://dx.doi.org/10.1093/annonc/mdw094] [PMID: 27141070] ].

1.2. Synthetic Lethality

DNA continually sustains damaging mutations under a barrage of environmental and lifestyle assaults like UV light, tobacco, toxic products of metabolism, all promoting faulty DNA replication [8Alberts B, John HW, Hunt T. Molecular Biology of the Cell 6. 2015.6.]. Various DNA repair mechanisms have evolved to repair these mutations to maintain genomic integrity. A predominant repair pathway utilises Poly (ADP-ribose) polymerase (PARP) enzymes [9Helleday T. The underlying mechanism for the PARP and BRCA synthetic lethality: Clearing up the misunderstandings. Mol Oncol 2011; 5(4): 387-93.[http://dx.doi.org/10.1016/j.molonc.2011.07.001] [PMID: 21821475] ].

BRCAm cancer cells have lost both copies of their normal BRCA gene, so they lose normal BRCA repair activity, whereas non-tumour cells maintain one functional copy of the BRCA gene [8Alberts B, John HW, Hunt T. Molecular Biology of the Cell 6. 2015.6.].

This deficiency in repair makes BRCAm cancers hypersensitive to DNA damaging treatments such as platinum chemotherapy [9Helleday T. The underlying mechanism for the PARP and BRCA synthetic lethality: Clearing up the misunderstandings. Mol Oncol 2011; 5(4): 387-93.[http://dx.doi.org/10.1016/j.molonc.2011.07.001] [PMID: 21821475] ] and Poly (ADP-ribose) polymerase inhibitors [PARPi] [11Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005; 434(7035): 917-21.[http://dx.doi.org/10.1038/nature03445] [PMID: 15829967] , 12Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 2005; 434(7035): 913-7.[http://dx.doi.org/10.1038/nature03443] [PMID: 15829966] ]. With PARP inhibition (PARPi), DNA cannot be repaired in BRCAm cancer cells [13McLornan DP, List A, Mufti GJ. Applying synthetic lethality for the selective targeting of cancer. N Engl J Med 2014; 371(18): 1725-35.[http://dx.doi.org/10.1056/NEJMra1407390] [PMID: 25354106] ].

Cells with a working BRCA gene can repair any damage to the double helix. Cells without a functioning BRCA gene rely on PARP to repair the damage, so a deficiency of one repair pathway alone (PARP or BRCA) has no impact on cell viability. However, if PARP is inhibited in addition to BRCA being mutated, then the loss of both BRCA and PARP repair pathways results in cell death. This is a concept called synthetic lethality and leads to cell cycle arrest and apoptosis (controlled cell death) in these cancer cells, i.e. PARPi induces synthetic lethality in BRCAm tissues [9Helleday T. The underlying mechanism for the PARP and BRCA synthetic lethality: Clearing up the misunderstandings. Mol Oncol 2011; 5(4): 387-93.[http://dx.doi.org/10.1016/j.molonc.2011.07.001] [PMID: 21821475] , 13McLornan DP, List A, Mufti GJ. Applying synthetic lethality for the selective targeting of cancer. N Engl J Med 2014; 371(18): 1725-35.[http://dx.doi.org/10.1056/NEJMra1407390] [PMID: 25354106] ]. Olaparib is one of the first known PARPi to exploit this synthetic lethality.

1.3. Current Status of Parp Inhibitors

PARP inhibitors (PARPi) have been the centre of a great deal of new research into potential new anti-tumour agents since the concept of synthetic lethality was introduced, when BRCAm tumour cells showed over 1000 fold greater sensitivity to PARPi in preclinical models [11Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005; 434(7035): 917-21.[http://dx.doi.org/10.1038/nature03445] [PMID: 15829967] , 12Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 2005; 434(7035): 913-7.[http://dx.doi.org/10.1038/nature03443] [PMID: 15829966] ]. Since then, a great deal of research has been done looking at olaparib as a therapy for OC patients with BRCAm [3William AM. Oral PARPi olaparib in patients with BRCA1 or BRCA2 and recurrent OC: A proof of concept trial. Lancet 2010; 376(9737): 245-51.[http://dx.doi.org/10.1016/S0140-6736(10)60893-8] [PMID: 206094 68] , 4Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med 2012; 366(15): 1382-92.[http://dx.doi.org/10.1056/NEJMoa1105535] [PMID: 22452 356] , and 5Jonathan L, Philipp H, Charlie G, et al. Olaparib maintenance therapy in patients with platinum sensitive relapsed OC - A planned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 2014; 15(8): 852-61.[http://dx.doi.org/10.1016/S1470-2045(14)70228-1] [PMID: 248824 34] ]. Clinical studies have verified anti-tumour activities of PARPi in BRCA mutant OC tumours [3William AM. Oral PARPi olaparib in patients with BRCA1 or BRCA2 and recurrent OC: A proof of concept trial. Lancet 2010; 376(9737): 245-51.[http://dx.doi.org/10.1016/S0140-6736(10)60893-8] [PMID: 206094 68] ] and in contrast to the limited efficacy of PARPi alone, the combination of PARPi with DNA repair defects is often lethal to tumour cells. The clinical efficacy of PARPi as single agents has shown only moderate efficacy, except for in BRCAm or BRCA-like tumours [14Ratnma K, Low JA. Current development of clinical inhibitors of PARP in oncology. Clin Cancer Res 2007; 13(5): 1383-8.[http://dx.doi.org/10.1158/1078-0432.CCR-06-2260] [PMID: 17332 279] ].

In December 2014, twenty years after the discovery of the BRCA genes, olaparib (the first in human PARPi) was approved for treatment of patients with germline BRCA associated OC with three or more prior lines of chemotherapy [15 AstraZeneca Global. Lynparza TM. Approved in the European Union as first-in-class treatment for advanced BRCA-mutated ovarian cancer. Available at: http://astrazeneca. com]. This approval represents the first ‘personalised’ therapy for OC. As well as the approval of olaparib was the approval of the Myriad Genetics BRCAnalysis CDz TM test as the BRCAm diagnostic test to identify patients eligible for olparib treatment.

Comparatively, olaparib as a therapy for BC patients with the same BRCA deficiency is lagging behind with only one phase 3 trial completed to date, and another ongoing.

1.4. Olaparib/Lynparza

Although olaparib therapy has been approved for OC in the USA and the EU, the optimal application of olaparib in the treatment of BRCAm BC has not yet been determined.

In 2012, Ledermann et al. [5Jonathan L, Philipp H, Charlie G, et al. Olaparib maintenance therapy in patients with platinum sensitive relapsed OC - A planned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 2014; 15(8): 852-61.[http://dx.doi.org/10.1016/S1470-2045(14)70228-1] [PMID: 248824 34] ] published the results of his phase 2 trial on olaparib as maintenance therapy for platinum-sensitive OC patients. They reported that maintenance olaparib significantly improved progression-free survival (PFS) in a randomized, double-blind, placebo-controlled trial. Of note - there was a subset of patients (11%) in Ledermann et al. study [5Jonathan L, Philipp H, Charlie G, et al. Olaparib maintenance therapy in patients with platinum sensitive relapsed OC - A planned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 2014; 15(8): 852-61.[http://dx.doi.org/10.1016/S1470-2045(14)70228-1] [PMID: 248824 34] ], including patients with BRCAm and BRCAwt whose results showed long-term disease control on maintenance olaparib, and progression-free survival (PFS) of over 5 years.

Despite this, the drug failed to induce prolonged overall survival (OS) - 34.9 months versus 31.9 months. As a result of the benefit of PFS not translating into an improvement in OS, the sponsor announced it would abandon plans into phase 3 trials of olaparib therapy, so further development was put on hold.

A year later, the results from Ledermann et al. [5Jonathan L, Philipp H, Charlie G, et al. Olaparib maintenance therapy in patients with platinum sensitive relapsed OC - A planned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 2014; 15(8): 852-61.[http://dx.doi.org/10.1016/S1470-2045(14)70228-1] [PMID: 248824 34] ] pre-planned analysis of the data based on BRCAm status was presented at the 2013 ACSO annual meeting. Out of 131 patients receiving olaparib (plus 123 patients receiving placebo), 56% and 50% of patients had BRCAm or suspected BRCAm. The pre-planned retrospective analysis (done after patients were reassigned by BRCA status after confirmed Myriad testing), revealed that PFS was significantly longer in BRCAm patients than BRCA wild-type (wt) patients (11.2 months versus 4.3 months). These results demonstrated that OC patients with BRCAm might benefit from olaparib therapy - and also indicated that olaparib monotherapy was effective against platinum-sensitive recurrent OC with BRCAm [5Jonathan L, Philipp H, Charlie G, et al. Olaparib maintenance therapy in patients with platinum sensitive relapsed OC - A planned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 2014; 15(8): 852-61.[http://dx.doi.org/10.1016/S1470-2045(14)70228-1] [PMID: 248824 34] ]

This positive result led by Astra Zeneca (AZ) to reverse their decision in 2013 and restart the phase 3 clinical trials of olaparib. Additionally, in response to these results, the European Medicines Agency (EMA) also approved olaparib as a maintenance therapy on 18th December 2014 for platinum-sensitive OC in patients with BRCAm. The clinical data from these trials led to olaparib receiving approval by the US food and drug administration (FDA) in 2014 for the fourth line or maintenance treatment of BRCAm OC [15 AstraZeneca Global. Lynparza TM. Approved in the European Union as first-in-class treatment for advanced BRCA-mutated ovarian cancer. Available at: http://astrazeneca. com].

The approval of olaparib marked PARPi as a success and reactivated research into PARPi inhibitors as a therapeutic strategy for all cancers, especially those with BRCAm. Since that time, there have been two key lines of investigation into the concept of PARPi as a treatment - PARPi monotherapy and PARPi combined with DNA-damaging chemotherapy.

The USA granted approval for olaparib monotherapy to be used in patients with germline (g) BRCAm or suspected gBRCAm (as detected by Myriad’s FDA-approved test) advanced OC treated with three or more prior lines of chemotherapy [16 US FDA. FDA approves Lynparza to treat advanced ovarian cancer. Available at: http:// www.fda.gov/ newsevents/ newsroom/ pressannouncements/ ucm427554.htm]. At the 2017 American Society of Clinical Oncology (ASCO) annual meeting, in discussion regarding metastatic BC patients harbouring BRCAm, olaparib was shown to be superior to conventional chemotherapy - defining a potential novel treatment standard in this high-risk population.

1.5. Rationale for this Systematic Review

Olaparib is an emerging treatment with some questions about its efficacy as a treatment for BRCAm used singly or in combination. A Systematic Review (SR) is necessary to evaluate, compare and contrast scientific studies which examine combinations of therapies, dosage regimes, and outcomes including survival, remission or otherwise in the existing primary studies.

1.6. Aims and Objectives

This systematic review aims to investigate the current effectiveness of olaparib in patients with BC and a BRCA mutation, and to produce and present this information in such a way as to reduce bias or inaccuracies. This is fundamental to the principle of SR synthesis. This review also aims to make clear links between the studies and the conclusions and identify any controversies, weaknesses and gaps in the field.

2. METHODS

The methods for this SR were made explicit in a protocol (written in accordance with PRISMA-P guidelines), and published on PROSPERO (CRD42018087832), which is an international database of prospective SRs recording the key features from a review protocol.

PRISMA focuses on the reporting of reviews evaluating RCTs and other types of research [particularly evaluations of interventions] [17Parahoo K. Nursing research -principles, process and issues 3rd ed. 3rd ed.2014.]. The Preferred Reporting Items for Systematic reviews and Meta-Analyses for Protocols 2015 [18 PRISMA-P (Preferred Reporting Items for Systematic review and Meta-Analysis Protocols). 2015 checklist: Recommended items to address in a systematic review protocol. Available at: http:// prismastatement.org/ documents/ PRISMA-Pchecklist.pdf] is a reporting guideline for protocols, consisting of a 17-item checklist intended to facilitate the preparation and reporting of a robust protocol for the SR [19Moher D, Shamseer L, Clarke M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 2015; 4(1): 1.[http://dx.doi.org/10.1186/2046-4053-4-1] [PMID: 25554246] ].

2.1. Review Question

Key questions are commonly formulated according to the ‘PICO’ method, which defines the population (P), the intervention (I), the control/comparator (C), and the outcome (O) [20Counsell C. Formulating questions and locating primary studies for inclusion in systematic reviews. Ann Intern Med 1997; 127(5): 380-7.[http://dx.doi.org/10.7326/0003-4819-127-5-199709010-00008] [PMID: 9273830] ]. Describing the criteria for each of the PICO elements enables the researcher to understand what is relevant, and what is not relevant, to the specific question being asked [21Williamson GR, Whittaker A. Succeeding in literature Reviews and Research Project Plans for Nursing Students 3rd ed. 3rd ed.2017.]. The population for studies in this review is patients over the age of 18 with BC and BRCAm. Gender is not a variable in this study, although it is a fact that BC typically affects more women than men. The intervention is olaparib, in any dosage, either as a monotherapy or in combination with other therapies. The best trials will be phase 3 double-blind randomised clinical trials and have a placebo arm, or comparator intervention(s). However given the infancy of the research into olaparib in BC patients, most studies will be phase 1 or 2, and some studies will be a single arm. Overall Survival (OS) and longevity of Progression-Free Survival (PFS) are the ideal endpoints for patients. However, RCTs measure how the intervention works, so the Objective Response Rate (ORR) - Complete Response (CR), Partial Response (PR) or no response - will be the primary endpoint. Adverse Events (AE) are also measured and discussed. Analysis of the pharmacokinetic responses or any other focus isbeyond the scope of this SR.

Based on this PICO, the literature search question is ‘What is the Current Effectiveness of Olaparib for Patients with Breast Cancer and a BRCA Mutation?’

2.2. Search Strategy

Fig. (1) shows the methodical approach based on PRISMA guidelines for undertaking reviews using electronic databases to search the literature (supplemented by hand searching and cross-referencing). A literature search of databases was completed in January 2018. First, there is an initial database search using keywords - and identification of potentially relevant literature from all databases, as well as from grey literature. After that, the literature is screened using the inclusion and exclusion criteria, followed by a decision about its quality, followed by a final decision to include that literature or not, with reasons why. The resulting evidence should meet all the criteria to be included in the synthesis of the literature [21Williamson GR, Whittaker A. Succeeding in literature Reviews and Research Project Plans for Nursing Students 3rd ed. 3rd ed.2017.].

Fig. (1)
PRISMA flow diagram (2009).


Initial searches on PRIMO were based on a predetermined series of keywords as follows: Olaparib/ Lynparza, Breast Cancer, and BRCA mutation (including all permutations). PRIMO database searches 179 databases including 43 databases under Nursing and Medicine which include Core databases such as CINAHL, MEDLINE, Royal College of Nursing (RCN), Cochrane Library, Joanna Briggs Institute (JBI), CRD, Internurse, Embase, Google Scholar, PubMed. Searches of specialist databases (Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane library, Joanna Briggs Institute (JBI), National Health Service (NHS) website, and Clinical trials UK). Hand-searching and cross-referencing werealso undertaken. The first author contacted authors of several unpublished studies, as well as the UK’s leading expert on olaparib in BC patients with BRCAm (Professor James Tutt), and also the pharmaceutical company that manufactures olaparib to discuss trials they are involved in, their transparency biomedical policy and ethical code of conduct. The date for inclusion of papers in this systematic review is 2009, which is when Fong et al. (2009) key paper on maximum tolerated dose (MTD) of olaparib was published [22Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009; 361(2): 123-34.[http://dx.doi.org/10.1056/NEJMoa0900212] [PMID: 19553641] ].

After the literature search was undertaken, preliminary scanned or material to get a general sense of their contents and abstracts, next, inclusion and exclusion criteria were applied, these were: English language papers on BRCAm BC treated with olaparib, in scientific professional peer reviewed journals and conference proceedings, focussing on clinical effect were included. Studies not focussed on breast cancer data, or BRCAm data, or PARPi other than olaparib were excluded. Pre-clinical studies were not included. Studies whose focus lies outside of clinical effectiveness were also not included.

2.3. Quality Assessment and Eligibility for Inclusion

Kmet et al. [23Leanne M, Kmet MSc, Robert C, Lee MSc, Linda S. Standard quality assessment criteria for evaluating primary research papers from a variety of fields 2004.] was used for quality assessment, carried out independently by two independent assessors (the two authors) and the papers graded. Kmet et al. [23Leanne M, Kmet MSc, Robert C, Lee MSc, Linda S. Standard quality assessment criteria for evaluating primary research papers from a variety of fields 2004.] contains a 14-point checklist for assessing the quality of quantitative studies with a scoring system for each category and whether the study meets that criteria or not (2 points for yes, 1 point for partial, and 0 points for no) [23Leanne M, Kmet MSc, Robert C, Lee MSc, Linda S. Standard quality assessment criteria for evaluating primary research papers from a variety of fields 2004.]. For this SR, the authors agreed ona cut-off score for inclusion of atleast 0,75 or 75%. All the studies eventually included in the review scored over 75%.

2.4. Ethical Issues

As this is secondary research there is no need for ethical approval, however, the primary research should all be approved by review boards and ethics committees for each trial centre.

3. RESULTS

3.1. Meta-Analysis and Heterogeneity

The quantitative synthesis of results obtained from different studies is termed meta-analysis [24Lau J, Ioannidis JP, Schmid CH. Quantitative synthesis in systematic reviews. Ann Intern Med 1997; 127(9): 820-6.[http://dx.doi.org/10.7326/0003-4819-127-9-199711010-00008] [PMID: 9382404] ]. Meta-analysis can facilitate the synthesis of a large number of studies, and allow interpretation of studies with different sizes and estimates. As meta-analysis considers more than a single study, there is less uncertainty and results can facilitate evidence-based decision making in health care [17Parahoo K. Nursing research -principles, process and issues 3rd ed. 3rd ed.2014.]. By collating information from different studies, meta-analysis can detect associations that a single study may not be able to provide.

The aim of meta-analysis is to estimate an overall effect and whether the effect is similar or dissimilar. If studies are relatively homogeneous they can be combined statistically and outcomes can be analysed and pooled. Meta analysis is usually presented as the extent to which a change based on an intervention was affected and then presented in a forest plot [21Williamson GR, Whittaker A. Succeeding in literature Reviews and Research Project Plans for Nursing Students 3rd ed. 3rd ed.2017.]. Meta analysis is a mathematical synthesis of the results of two or more primary studies that addressed a similar hypothesis [25Greenhalgh T. How to read a paper. Papers that report drug trials. BMJ 1997; 315(7106): 480-3.[http://dx.doi.org/10.1136/bmj.315.7106.480] [PMID: 9284672] ].

Deciding when a meta-analysis is appropriate can be difficult because there are several sources of heterogeneity to be considered. If the designs, methods, quality, and results of the studies are deemed very heterogeneous, then statistically combining them can result in misleading conclusions. So a meta-analysis, in this case, would be inappropriate as it would be like attempting to ‘combine apples and pears’ [17Parahoo K. Nursing research -principles, process and issues 3rd ed. 3rd ed.2014.].

It is important to consider the key clinical and methodological differences between the qualifying studies in order to assess their heterogeneity. Clinical differences include population - geography (UK, EU or global) and intervention (dosages) [17Parahoo K. Nursing research -principles, process and issues 3rd ed. 3rd ed.2014.]. Methodological differences would include study design (cohort, case study, experimental design), reported outcomes (endpoints such as ORR, OS, PFS), and timing of outcomes [17Parahoo K. Nursing research -principles, process and issues 3rd ed. 3rd ed.2014.].

As none of the studies in this SR address the same hypothesis in the same way, and have both clinical and methodological differences, a meta-analysis would not be appropriate, in which case, CRD [26 CRD’s guidance for undertaking Reviews in healthcare. Centre for reviews and dissemination ( 2009). Pg 48. 2009. Published by CRD, University of York January 2009.] suggests that a narrative synthesis of studies, rather than statistical analysis, may be undertaken where studies are too heterogeneous (either clinically or methodologically) to combine. This approach clarified the similarities and differences among studies that appear to address the same or similar research questions [26 CRD’s guidance for undertaking Reviews in healthcare. Centre for reviews and dissemination ( 2009). Pg 48. 2009. Published by CRD, University of York January 2009.].

Fig. (2) details the results of the search strategy in a PRISMA diagram and shows that 1157 records were found on PRIMO and ordered by relevance. The top 100 records were screened. Ninety studies were rejected and ten full texts were retrieved and read. Three records were rejected. All articles passed the quality assessment for inclusion. Seven studies met and passed all the criteria for inclusion in quantitative synthesis. All seven met the minimum Kmet et al. threshold score of 75%.

Table 1 shows the papers that were included in the review.

In addition to searching on PRIMO, separate searches were conducted on Cumulative Index to Nursing and Allied Health Literature (CINAHL) (23 records found but none additional), and Cochrane Library (2 records found (not additional) plus several abstracts), Centre for Reviews and Dissemination (CRD) (no records found) and Joanna Briggs Institute (JBI) (no records found), National Health Service (NHS) Evidence (23 records found but none additional), and National Institute for Health and Care Excellence (NICE) (2 records found, but none additional).

Hand searching and cross-referencing found no additional studies, while agrey literature search found no studies, but it did provide some current information from Professor James Tutt, one of the leading researchers in this field.

Fig. (2)
PRISMA diagram completed.


Table 1
Papers included in the review.


Table 2
Methodologies of included studies.


To elaborate on grey literature: an hour-long conversation was held with the Medical Officer at AZ (who manufacture olaparib), who confirmed that, in his opinion, all the existing studies are included in this SR. He also confirmed that in OlympiA (NCT02032823), which is an ongoing phase 3 RCT sponsored by AZ, results were not available yet (originally due out in summer 2018 and now not expected until summer 2020) due to patient survival. The end point was a set number of AEs, which has not been reached at this time of writing. Neo-Olympia is another phase 3 trial looking at olaparib monotherapy in patients pre and post surgery, but the trial is ongoing and there are no results available yet. OlympiA, neo Olympia and OlympiAD are the only phase 3 trials to date looking at the effectiveness of olaparib in BC patients with BRCAm.

Professor Balmana was also contacted to ask about her recent research ‘Phase I, Open-Label, 2 Part Multicentre Study to Assess the Safety and Efficacy of Olaparib in Combination With Carboplatin in Patients With Advanced HER-2 Negative Breast Cancer’ (NCT02561832) and she replied to say that the trial stopped recruitment early and there is no efficacy data. The authors did not receive a reply about another ongoing trial by Abraham et al., although it appearslikely that this study is only just be starting. This is a randomised phase 2/3 trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCAm breast cancer patients [27Abraham J, Vallier A-L, Qian W, et al. PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients. NCT03150576. J Clin Oncol 2018; 36: 1.[http://dx.doi.org/10.1200/JCO.2018.36.15_suppl.TPS605] [PMID: 29087770] ].

3.1.1. Detailed Narrative Review and Critical Appraisal

Six of the trials in this review are experimental, while one [28van der Noll R, Marchetti S, Steeghs N, et al. Long-term safety and anti-tumour activity of olaparib monotherapy after combination with carboplatin and paclitaxel in patients with advanced breast, ovarian or fallopian tube cancer. Br J Cancer 2015; 113(3): 396-402.[http://dx.doi.org/10.1038/bjc.2015.256] [PMID: 26180927] ] is a long-term case study. All seven clinical trials in this SR vary in methods used. As shown in Table 1, all but Tutt et al. [29Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: A proof-of-concept trial. Lancet 2010; 376(9737): 235-44.[http://dx.doi.org/10.1016/S0140-6736(10)60892-6] [PMID: 20609 467] ] and Robson et al. [30Robson M, Im S-A, Senkus E, Xu B, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. The New England Journal of Medicine 2017; 377(6): 523-33.] are single arm studies. The interventions are different Fong et al. [22Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009; 361(2): 123-34.[http://dx.doi.org/10.1056/NEJMoa0900212] [PMID: 19553641] ] and Balmana et al. [31Balmaña J, Tung NM, Isakoff SJ, et al. Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors. Ann Oncol 2014; 25(8): 1656-63.[http://dx.doi.org/10.1093/annonc/mdu187] [PMID: 24827126] ] are dose-finding trials with increasing doses of olaparib. Fong et al. [22Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009; 361(2): 123-34.[http://dx.doi.org/10.1056/NEJMoa0900212] [PMID: 19553641] ], Tutt et al. [29Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: A proof-of-concept trial. Lancet 2010; 376(9737): 235-44.[http://dx.doi.org/10.1016/S0140-6736(10)60892-6] [PMID: 20609 467] ], Gelmon et al. [32Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: A phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 2011; 12(9): 852-61.[http://dx.doi.org/10.1016/S1470-2045(11)70214-5] [PMID: 218624 07] ], Kaufmann et al. [33Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015; 33(3): 244-50.[http://dx.doi.org/10.1200/JCO.2014.56.2728] [PMID: 25366685] ], Van der Noll et al. [28van der Noll R, Marchetti S, Steeghs N, et al. Long-term safety and anti-tumour activity of olaparib monotherapy after combination with carboplatin and paclitaxel in patients with advanced breast, ovarian or fallopian tube cancer. Br J Cancer 2015; 113(3): 396-402.[http://dx.doi.org/10.1038/bjc.2015.256] [PMID: 26180927] ] and Robson et al. [30Robson M, Im S-A, Senkus E, Xu B, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. The New England Journal of Medicine 2017; 377(6): 523-33.] study olaparib monotherapy at MTD while Balmana et al. [31Balmaña J, Tung NM, Isakoff SJ, et al. Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors. Ann Oncol 2014; 25(8): 1656-63.[http://dx.doi.org/10.1093/annonc/mdu187] [PMID: 24827126] ] investigate a combination therapy of olaparib with platinum treatment. None of the trials are randomised except Robson et al. [30Robson M, Im S-A, Senkus E, Xu B, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. The New England Journal of Medicine 2017; 377(6): 523-33.] where patients were randomised to olaparib therapy or one of three therapies of physician’s choice. Table 2 shows the methodologies of the included studies.

The Consolidated Standards of Reporting Trials (CONSORT) is a checklist and flow diagram that was developed to improve the transparency and quality of reporting of RCTs, and to improve reliability and validity of trial findings [19Moher D, Shamseer L, Clarke M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 2015; 4(1): 1.[http://dx.doi.org/10.1186/2046-4053-4-1] [PMID: 25554246] ]. All trials in this SR were found to abide by the CONSORT checklist [34 CONSORT 2010 checklist of information to include when reporting a randomised trial. http:// www.consortstatement.org /Media/ Default/ Downloads/ CONSORT%20 2010%20 Checklist.pdf]. However, none of the trials (except Robson et al. [30Robson M, Im S-A, Senkus E, Xu B, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. The New England Journal of Medicine 2017; 377(6): 523-33.]) in this SR used randomisation or blinding so those sections of the CONSORT checklist and diagram were not reported (except Robson et al. [30Robson M, Im S-A, Senkus E, Xu B, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. The New England Journal of Medicine 2017; 377(6): 523-33.]). The CONSORT 2010 Statement and website (www.consort-statement.org) also helps authors to critically appraise and interpret RCTs, and extract information for SRs, and the CONSORT checklist 2010 was used for this purpose

RCTs or true experiments are the most robust design for testing cause and effect relationships (e.g., whether a treatment or intervention affects outcomes) [35Melnyk BM, Fineout-Overholt E. Rapid critical appraisal of randomized controlled trials (RCTs): An essential skill for evidence-based practice (EBP) Pediatric Nursing.2005; 31(1)]. An RCT is an experiment with a random allocation of participants between experimental and control groups. The outcomes of the groups can then be compared [36Sibbald B, Roland M. Understanding controlled trials. Why are randomised controlled trials important? BMJ 1998; 316(7126): 201.[http://dx.doi.org/10.1136/bmj.316.7126.201] [PMID: 9468688] ]. For an RCT to be a true experiment, the following features apply: comparison and placebo arms, sampling and demographic equality at baseline, sample size estimation and power calculation, blinding and randomisation, consideration of drop-out rates and patient loss, and ethics and consent [21Williamson GR, Whittaker A. Succeeding in literature Reviews and Research Project Plans for Nursing Students 3rd ed. 3rd ed.2017.]. How these features appear in the studies within this SR is discussed below. RCTs in this SR were also examined for variation in study endpoints and data collection and analysis methods in order to collect all the evidence [37Grove SK, Burns N, Gray JR. The practice of nursing research: Appraisal, synthesis, and generation of evidence 7th ed. 7th ed.2012.].

3.1.2. Comparison and Placebo Arms

Comparator arms are important in order to be sure that the effects noted are due to the actions of the intervention, and not due to anything else [17Parahoo K. Nursing research -principles, process and issues 3rd ed. 3rd ed.2014., 38Aveyard H. Doing a literature review in health and social care – A practical guide (2014), third edition Published January 1st 2014 by Open University Press.]. Variables are manipulated and outcomes assessed between the experimental and control groups, so bias and other confounders can be controlled and factored out, and external influences removed, so that researchers can be sure effects noted are due to actions of the intervention and nothing else [17Parahoo K. Nursing research -principles, process and issues 3rd ed. 3rd ed.2014.]. However only Robson et al. [30Robson M, Im S-A, Senkus E, Xu B, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. The New England Journal of Medicine 2017; 377(6): 523-33.] study had true comparator arms with patients taking different interventions (although Van der Noll et al. [28van der Noll R, Marchetti S, Steeghs N, et al. Long-term safety and anti-tumour activity of olaparib monotherapy after combination with carboplatin and paclitaxel in patients with advanced breast, ovarian or fallopian tube cancer. Br J Cancer 2015; 113(3): 396-402.[http://dx.doi.org/10.1038/bjc.2015.256] [PMID: 26180927] ] and Kaufman et al. [33Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015; 33(3): 244-50.[http://dx.doi.org/10.1200/JCO.2014.56.2728] [PMID: 25366685] ] could compare results between different cancers, while Tutt et al. [29Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: A proof-of-concept trial. Lancet 2010; 376(9737): 235-44.[http://dx.doi.org/10.1016/S0140-6736(10)60892-6] [PMID: 20609 467] ] could compare different dosages and Gelmon et al. [32Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: A phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 2011; 12(9): 852-61.[http://dx.doi.org/10.1016/S1470-2045(11)70214-5] [PMID: 218624 07] ] could compare BRCAm with BRCAwt results.

For trials like the ones in this SR that are not placebo-controlled, there is no comparator so results may be misleading or biased, especially when it comes to reporting the efficacy of treatments [39Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ 2010; 340: c869.[http://dx.doi.org/10.1136/bmj.c869] [PMID: 20332511] ]. Placebo arms are required to test a hypothesis, but being as there were no placebo arms in any RCTs, this reduces the external validity of results of all the studies and is a serious limitation to this SR. Additional weaknesses to Robson et al. [30Robson M, Im S-A, Senkus E, Xu B, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. The New England Journal of Medicine 2017; 377(6): 523-33.] trial are highlighted by a lack of a platinum-based chemotherapy comparator arm, which seems strange given the evidence of platinum sensitivity correlating to olaparib sensitivity noted in previous studies [3William AM. Oral PARPi olaparib in patients with BRCA1 or BRCA2 and recurrent OC: A proof of concept trial. Lancet 2010; 376(9737): 245-51.[http://dx.doi.org/10.1016/S0140-6736(10)60893-8] [PMID: 206094 68] -5Jonathan L, Philipp H, Charlie G, et al. Olaparib maintenance therapy in patients with platinum sensitive relapsed OC - A planned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 2014; 15(8): 852-61.[http://dx.doi.org/10.1016/S1470-2045(14)70228-1] [PMID: 248824 34] ]. RCTs with comparator arms and large sample sizes provide the most reliable evidence regarding the efficacy of healthcare interventions [36Sibbald B, Roland M. Understanding controlled trials. Why are randomised controlled trials important? BMJ 1998; 316(7126): 201.[http://dx.doi.org/10.1136/bmj.316.7126.201] [PMID: 9468688] ], however, this is not the case with the seven studies considered as part of this SR.

3.1.3. Sampling and Demographic Equality of Groups at Baseline

It is not possible to include all potentially eligible subjects of a population so samples are taken and these should be random [21Williamson GR, Whittaker A. Succeeding in literature Reviews and Research Project Plans for Nursing Students 3rd ed. 3rd ed.2017.]. Data from randomly selected samples are generalisable to the target population and sometimes beyond (too similar populations and settings) [17Parahoo K. Nursing research -principles, process and issues 3rd ed. 3rd ed.2014.]. However sampling for the trials within this SR has been dictated by a specific characteristic in a population (BC with BRCAm), so sample sizes are often small, not randomly selected and results are relevant only for this subset of patients. Sacket et al. [40Sackett DL, Rosenberg WMC, Gray JA, Haynes RB, Richardson WS. Evidence based medicine: What it is and what it isn’t. BMJ 1996; 312(7023): 71-2. [Clin Res Ed].[http://dx.doi.org/10.1136/bmj.312.7023.71] [PMID: 8555924] ] remind us however that evidence-based medicine is not restricted to randomised RCTs and that to find out about a specific therapy for a specific group of patients, then we need studies using those patients who harbour the relevant disorder (in this case BC with BRCAm). Selection bias in these RCTs is not a factor, as selection bias only occurs when the participants are not a true representative sample of the target population about whom the conclusions will be drawn [41Ahmed I, Sutton AJ, Riley RD. Assessment of publication bias, selection bias, and unavailable data in meta-analyses using individual participant data: A database survey. BMJ 2012; 344: d7762.[http://dx.doi.org/10.1136/bmj.d7762] ].

Baseline demographic characteristics of patients were all similar in these studies, and are balanced between the treatment groups (age, gender, nationality, geography) [17Parahoo K. Nursing research -principles, process and issues 3rd ed. 3rd ed.2014.]. Baseline information is most efficiently presented in a table [39Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ 2010; 340: c869.[http://dx.doi.org/10.1136/bmj.c869] [PMID: 20332511] ] which was the case in all studies in this SR. All studies measured the same patient baseline characteristics (sex, age, tumour type and size, Eastern Cooperative Oncology Group (ECOG) performance status, and number of prior treatments) thus ensuring patient characteristics were as similar as they could be at baseline.

All trials assessed patients over 18 years of age with an overall average of 44 years. The vast majority of patients were female although gender was not an inclusion/exclusion criteria in any study. Fong et al. [22Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009; 361(2): 123-34.[http://dx.doi.org/10.1056/NEJMoa0900212] [PMID: 19553641] ], Tutt et al. [29Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: A proof-of-concept trial. Lancet 2010; 376(9737): 235-44.[http://dx.doi.org/10.1016/S0140-6736(10)60892-6] [PMID: 20609 467] ], Kaufmann et al. [33Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015; 33(3): 244-50.[http://dx.doi.org/10.1200/JCO.2014.56.2728] [PMID: 25366685] ] and Robson et al. [30Robson M, Im S-A, Senkus E, Xu B, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. The New England Journal of Medicine 2017; 377(6): 523-33.] studies are multi-national while Balmana et al. [31Balmaña J, Tung NM, Isakoff SJ, et al. Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors. Ann Oncol 2014; 25(8): 1656-63.[http://dx.doi.org/10.1093/annonc/mdu187] [PMID: 24827126] ] and Gelmon et al. [32Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: A phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 2011; 12(9): 852-61.[http://dx.doi.org/10.1016/S1470-2045(11)70214-5] [PMID: 218624 07] ] are multi-center studies so patients were assessed from all over the world (EU, Australia, Israel, Canada and USA). It is beyond the scope of this review to assess the benefits or downfalls of a multi-center or multi-national collaboration on clinical trials, but there is the question of confounding factors such as differences in equipment, methods, and personal opinions of different researchers between such diverse locations, compared to a study conducted in one central laboratory. However, multi-center studies are considered excellent sources of evidence for evaluating healthcare interventions [17Parahoo K. Nursing research -principles, process and issues 3rd ed. 3rd ed.2014., 42Evans D. Hierarchy of evidence: A framework for ranking evidence evaluating healthcare interventions. J Clin Nurs 2003; 12(1): 77-84.[http://dx.doi.org/10.1046/j.1365-2702.2003.00662.x] [PMID: 1251 9253] ].

3.1.4. Sample Size

Large-scale, multi-site RCTs are often required to establish the superiority of one treatment over another [17Parahoo K. Nursing research -principles, process and issues 3rd ed. 3rd ed.2014.]. However, very few of the trials in this SR had large sample sizes, which is understandable because the condition under investigation (BC patients with BRCAm) is not usual to the general population [38Aveyard H. Doing a literature review in health and social care – A practical guide (2014), third edition Published January 1st 2014 by Open University Press.]. All studies except Tutt et al. [29Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: A proof-of-concept trial. Lancet 2010; 376(9737): 235-44.[http://dx.doi.org/10.1016/S0140-6736(10)60892-6] [PMID: 20609 467] ], Kaufman et al. [33Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015; 33(3): 244-50.[http://dx.doi.org/10.1200/JCO.2014.56.2728] [PMID: 25366685] ] and Robson et al. [30Robson M, Im S-A, Senkus E, Xu B, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. The New England Journal of Medicine 2017; 377(6): 523-33.] have a very small sample size of patients (3-17 individuals), leading to the potential that some results from small cohorts could be due to chance. Fong et al. (2009) had only nine BC patients and of those, only three had BRCAm, so these are very small numbers indeed. Small sample sizes are a potential limitation of the papers included in this SR because large samples are necessary to detect small differences in effect size [39Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ 2010; 340: c869.[http://dx.doi.org/10.1136/bmj.c869] [PMID: 20332511] ]. Future large-scale trials are required to provide more externally valid results, because trials with inadequate samples sizes (like most in this SR) are associated with bias, as having too few patients runs the risk of missing statistically significant findings [21Williamson GR, Whittaker A. Succeeding in literature Reviews and Research Project Plans for Nursing Students 3rd ed. 3rd ed.2017.] due to type II errors.

3.1.5. Blinding and Randomisation

Being aware of which interventions the control and experimental groups are receiving may introduce bias on the part of the subjects and researchers [17Parahoo K. Nursing research -principles, process and issues 3rd ed. 3rd ed.2014.]. Blinding the groups of individuals (participants, researchers, or data collectors) who can introduce bias into a trial is crucial for successful randomisation [39Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ 2010; 340: c869.[http://dx.doi.org/10.1136/bmj.c869] [PMID: 20332511] ].

Robson et al. [30Robson M, Im S-A, Senkus E, Xu B, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. The New England Journal of Medicine 2017; 377(6): 523-33.] OlympiAD trial is the first and only trial in this SR to be randomised. However, this trial was also open label (unblinded) which may influence participants' compliance with the intervention, or risk participants dropping out of the trial. Participants may respond differently if they know which treatment group they are assigned to (e.g. by responding more positively when know they are receiving the new treatment) [17Parahoo K. Nursing research -principles, process and issues 3rd ed. 3rd ed.2014.].

Unfortunately, all studies in this SR are open-label, so participants could introduce biases as above, and researchers may also introduce different biases. Moher et al. [39Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ 2010; 340: c869.[http://dx.doi.org/10.1136/bmj.c869] [PMID: 20332511] ] suggest that unblinded researchers may assess subjective outcomes differently. Unblinded data analysts might introduce prejudice through a biased selection of positive results, or by making decisions to remove patients with unfavourable results from the analyses. Random assignment is the preferred method to assign interventions to trial participants, and when properly implemented, it eliminates bias in the assignment of treatments [39Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ 2010; 340: c869.[http://dx.doi.org/10.1136/bmj.c869] [PMID: 20332511] ]. Without randomisation, treatment comparisons and results can be biased, even subconsciously [17Parahoo K. Nursing research -principles, process and issues 3rd ed. 3rd ed.2014.]. This lack of randomisation and blinding in all the trials in this SR imposes a limitation of this SR because randomisation is such as this is a crucial component of high-quality RCTs [39Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ 2010; 340: c869.[http://dx.doi.org/10.1136/bmj.c869] [PMID: 20332511] ].

3.1.6. Dropout Rate and Patient Losses

If patients do not complete the study then data is lost and outcomes not fully assessed [21Williamson GR, Whittaker A. Succeeding in literature Reviews and Research Project Plans for Nursing Students 3rd ed. 3rd ed.2017.]. This may be because of AEs, voluntary withdrawal, secondary disease or death. The rate of retention of patients is very important in any study. If a large percentage of participants withdraw from the study or choose to drop out for any reason, the results are likely to be different than if all of the participants had remained in the study, since patients with specific characteristics may be more likely to drop out or be forced to discontinue [35Melnyk BM, Fineout-Overholt E. Rapid critical appraisal of randomized controlled trials (RCTs): An essential skill for evidence-based practice (EBP) Pediatric Nursing.2005; 31(1)]. ‘Intention to treat’ analysis was used in all studies, which means patients were analysed in the group to which they were originally assigned.

It is not uncommon for participants not to complete a study-they may drop out for their own reasons or be withdrawn from active treatment due to adverse effects (related to the treatment or otherwise) - and therefore their outcomes are not assessed at the end of a trial [39Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ 2010; 340: c869.[http://dx.doi.org/10.1136/bmj.c869] [PMID: 20332511] ]. Despite reporting of several patients dropping out in the trials in this SR, all patients were accounted for, and their results were included in the analysis if they had had at least one dose of olaparib, given that ORR had to be confirmed at a second assessment four weeks later.

3.1.7. Publication Bias

Every researcher has an ethical obligation to publish complete and accurate research results of all trials with human participants [43 World Medical Association, Inc. Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects, last amended 64th WMA General Assembly, Fortaleza, Brazil, October 2013., 44Bassler D, Mueller KF, Briel M, et al. Bias in dissemination of clinical research findings: Structured OPEN framework of what, who and why, based on literature review and expert consensus. BMJ Open 2016; 6(1): e010024.[http://dx.doi.org/10.1136/bmjopen-2015-010024] [PMID: 26801469] ]. However, for many reasons, not all research results are published in an accurate way, and in some cases, they are not released at all [45Struver V. Current therapeutic research Development Agenda for WIPO http:// www.wipo.int/ ip-development/ Volume 78, Supplement, 2016; S7 ]. Publication bias may occur after manuscripts are submitted to a journal, as well as before. Publication bias creates a false impression on the reliability of these clinical trials and also affects the clinical conclusions about the best treatments, which is an issue for evidence-based practice [45Struver V. Current therapeutic research Development Agenda for WIPO http:// www.wipo.int/ ip-development/ Volume 78, Supplement, 2016; S7 ].

A clear finding from this SR, based on the results of all but one study [22Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009; 361(2): 123-34.[http://dx.doi.org/10.1056/NEJMoa0900212] [PMID: 19553641] ] (as this study was published prior to AZ acquisition of the company that made olaparib) is the risk of publication bias. Risk of publication bias is particularly highlighted in Robson et al. [30Robson M, Im S-A, Senkus E, Xu B, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. The New England Journal of Medicine 2017; 377(6): 523-33.] trial, as the 2.8 months, PFS benefit was measured by blinded independent central review. However, it is interesting to note that when the same data was assessed by the investigator, the PFS benefit of olaparib was 4 months (7.8 months PFS in olaparib versus 3.8 in a standard). The authors say their 4 months is similar to the blinded central review result of 2.8 months, but there is a 1.2-month gap which is certainly significant when the independent review result was only initially 2.8 months. Another potentially misleading statement by Robson et al [30Robson M, Im S-A, Senkus E, Xu B, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. The New England Journal of Medicine 2017; 377(6): 523-33.] is that the risk of disease progression or death was 42% lower - however, the results show patients have not actually lived for longer when taking olaparib versus TPC so this suggests there may be some bias reporting.

Almost all of the research into olaparib is funded by one pharmaceutical company (AZ) or undertaken in collaboration with them, or assistance given with writing up [31Balmaña J, Tung NM, Isakoff SJ, et al. Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors. Ann Oncol 2014; 25(8): 1656-63.[http://dx.doi.org/10.1093/annonc/mdu187] [PMID: 24827126] -33Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015; 33(3): 244-50.[http://dx.doi.org/10.1200/JCO.2014.56.2728] [PMID: 25366685] ], so there is a need to assess the level of bias in the reporting and publishing of these trials. In all of the trials in this SR, AZ was the major sponsor with researchers and authors having connections to AZ, or will benefit in other ways if olaparib proves to be a success. In Robson et al. [30Robson M, Im S-A, Senkus E, Xu B, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. The New England Journal of Medicine 2017; 377(6): 523-33.], AZ was responsible for overseeing the collection, analysis, and interpretation of the data. The manuscript was written with medical-writing support funded by AZ, with critical review and input from authors [30Robson M, Im S-A, Senkus E, Xu B, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. The New England Journal of Medicine 2017; 377(6): 523-33.]. Although in no way to question the integrity of AZ as a company, or of any of its employees or researchers, it may not be helpful in establishing the clinical efficacy of olaparib for one company to so completely dominate the research agenda. It is difficult to see how this may be ameliorated, however, given the huge expense involved in the development of new medicines. We note and commend the willingness of key personnel, mentioned above, to discuss their research with us in relation to this systematic review. Recent developments in clinical trials registration and in publishing, including transparent reporting of potential conflicts of interest, are also welcome in this regard.

3.1.8. Ethics and Consent

Beauchamp & Childress [46Beauchamp TL, Childress JF. Principles of biomedical ethics (principles of biomedical ethics (Beauchamp)) 7ed ed. 7ed ed.2013.] suggest that there are fundamental ethical principles that all researchers should abide by including: autonomy, beneficence, non malevolence (do no harm), and informed consent, as well as the right for participants to refuse to participate or change their mind without prejudice, the right to revoke their permission to use their data, and even how their data is anonymised and accessed [17Parahoo K. Nursing research -principles, process and issues 3rd ed. 3rd ed.2014.]. The World Health Organisation (WHO) advisesthat authors of SRs of primary research identify how these principles were put into practice in order to protect the participants [47 World Health Organisaiton. The World Health Report 2013: Research for Universal Health Coverage. ISBN: 978 92 4 156459 5 (Eng). ]. However, of the seven trials of this SR, major ethical weaknesses were found in three. There is no patient consent mentioned we in three studies [22Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009; 361(2): 123-34.[http://dx.doi.org/10.1056/NEJMoa0900212] [PMID: 19553641] , 28van der Noll R, Marchetti S, Steeghs N, et al. Long-term safety and anti-tumour activity of olaparib monotherapy after combination with carboplatin and paclitaxel in patients with advanced breast, ovarian or fallopian tube cancer. Br J Cancer 2015; 113(3): 396-402.[http://dx.doi.org/10.1038/bjc.2015.256] [PMID: 26180927] , 33Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015; 33(3): 244-50.[http://dx.doi.org/10.1200/JCO.2014.56.2728] [PMID: 25366685] ]. Informed consent by study participants is normally required in all intervention studies [39Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ 2010; 340: c869.[http://dx.doi.org/10.1136/bmj.c869] [PMID: 20332511] ], and without full documentation of ethical considerations, concerns are raised because without proof participants understood the nature and stage of the disease being studied, the study may include persons vulnerable to harm from the study intervention, and this raise issues as to whether these studies satisfy WHO as above, as well as other legal and ethical norms [39Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ 2010; 340: c869.[http://dx.doi.org/10.1136/bmj.c869] [PMID: 20332511] ].

3.2. Methods of Data Collection and Analysis

Critical appraisal of the quality of RCTs is possible only if the design and methods of data collection and analysis are thoroughly and accurately described in the published literature [39Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ 2010; 340: c869.[http://dx.doi.org/10.1136/bmj.c869] [PMID: 20332511] ]

Despite the heterogeneity of the studies in this review, all methods used in all trials were described thoroughly. Recognised standard methods of data collection and analysis were used, and in many cases the same methods were used in other trials, enabling valid and reliable comparisons to be drawn between the studies where it was possible [17Parahoo K. Nursing research -principles, process and issues 3rd ed. 3rd ed.2014.].

Both dose-finding trials [22Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009; 361(2): 123-34.[http://dx.doi.org/10.1056/NEJMoa0900212] [PMID: 19553641] , 31Balmaña J, Tung NM, Isakoff SJ, et al. Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors. Ann Oncol 2014; 25(8): 1656-63.[http://dx.doi.org/10.1093/annonc/mdu187] [PMID: 24827126] ] used a standard 3+3 dose finding method - this means treating at least three assessable patients per dose for one cycle, with a doubling of the dose in the absence of AE of grade 2 [22Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009; 361(2): 123-34.[http://dx.doi.org/10.1056/NEJMoa0900212] [PMID: 19553641] ] at that dosage or grade 3 [31Balmaña J, Tung NM, Isakoff SJ, et al. Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors. Ann Oncol 2014; 25(8): 1656-63.[http://dx.doi.org/10.1093/annonc/mdu187] [PMID: 24827126] ]. Each cohort was expanded to six or more when olaparib dose was increased or if one dose-limiting toxicity (DLT) was observed at a given dose. A dose was considered the MTD if two manifestations of DLT were observed at that dose during the first treatment cycle. A drug related AE of grade 3 or 4 occurring in the first cycle was considered a DLT.

Another finding of these studies was that they all measured Objective Response Rates (ORR) (CR or PR) using the recognised Response Evaluation Criteria in Solid Tumours (RECIST] [49Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92(3): 205-16.[http://dx.doi.org/10.1093/jnci/92.3.205] [PMID: 10655437] ], and all studies assessed radiological response by means of Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) which were carried out at least 28 days initially [22Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009; 361(2): 123-34.[http://dx.doi.org/10.1056/NEJMoa0900212] [PMID: 19553641] , 28van der Noll R, Marchetti S, Steeghs N, et al. Long-term safety and anti-tumour activity of olaparib monotherapy after combination with carboplatin and paclitaxel in patients with advanced breast, ovarian or fallopian tube cancer. Br J Cancer 2015; 113(3): 396-402.[http://dx.doi.org/10.1038/bjc.2015.256] [PMID: 26180927] , 29Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: A proof-of-concept trial. Lancet 2010; 376(9737): 235-44.[http://dx.doi.org/10.1016/S0140-6736(10)60892-6] [PMID: 20609 467] , 33Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015; 33(3): 244-50.[http://dx.doi.org/10.1200/JCO.2014.56.2728] [PMID: 25366685] ]. An additional strength of Robson et al. [30Robson M, Im S-A, Senkus E, Xu B, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. The New England Journal of Medicine 2017; 377(6): 523-33.] was that the authors also assessed overall survival (OS) although this was not the primary endpoint (PFS was primary endpoint), and assessed the time to second progression event or death after first progression event.

In every study, the analyses of measurable response weredone for all patients who had had at least one dose of olaparib. Importantly for the precision of results, all trials ensured 95% confidence intervals [34 CONSORT 2010 checklist of information to include when reporting a randomised trial. http:// www.consortstatement.org /Media/ Default/ Downloads/ CONSORT%20 2010%20 Checklist.pdf], which were measured using the recognised Wilson score method as recommended by Newcombe and Altman [50Altman Douglas G. Statistics with Confidence 2nd ed. 2nd ed.2000.]. Confidence intervals (CIs) are the best indicators of the precision of the result values [35Melnyk BM, Fineout-Overholt E. Rapid critical appraisal of randomized controlled trials (RCTs): An essential skill for evidence-based practice (EBP) Pediatric Nursing.2005; 31(1)], as a 95% CI is a range of values within which the reader can be 95% confident the true value lies for the study population.

The olaparib dose used in Robson et al. [30Robson M, Im S-A, Senkus E, Xu B, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. The New England Journal of Medicine 2017; 377(6): 523-33.] study is different from the FDA approved 400-mg twice daily dose in capsule formulation used in all the previous trials in this review. Tablets give a higher exposure while the adverse effects are not expected to be different [30Robson M, Im S-A, Senkus E, Xu B, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. The New England Journal of Medicine 2017; 377(6): 523-33.], however how much difference the dosage and delivery method of olaparib makes is outside the scope of this review but is something that should be determined by future investigations and analysis.

Where BRCAm analysis was done, the validated and approved external central reference laboratory Myriad Genetic Laboratories carried out the analysis (this is the laboratory that was granted the sole rights to perform these tests since 2014). A weakness of Balmana et al. (2014) trial is that they did not originally test for BRCAm. However due to a protocol amendment, BRCAm status was collected for patients who had previously been tested for gBRCAm but as these patients BRCAm status is not centrally validated by Myriad Genetic Laboratories results must be treated with some caution. The same caution applies to Kaufman et al. [33Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015; 33(3): 244-50.[http://dx.doi.org/10.1200/JCO.2014.56.2728] [PMID: 25366685] ] results as patients’ BRCA status was not centrally validated.

Data was collected and analysed wholly or in part by a third party in some of the trials [22Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009; 361(2): 123-34.[http://dx.doi.org/10.1056/NEJMoa0900212] [PMID: 19553641] , 29Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: A proof-of-concept trial. Lancet 2010; 376(9737): 235-44.[http://dx.doi.org/10.1016/S0140-6736(10)60892-6] [PMID: 20609 467] , 33Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015; 33(3): 244-50.[http://dx.doi.org/10.1200/JCO.2014.56.2728] [PMID: 25366685] ] which leads to a reduction of potential bias in these studies. In others, however, data collection and analysis was done by AZ themselves, with interpretation by the authors in collaboration with the sponsor. Gelmon et al. [32Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: A phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 2011; 12(9): 852-61.[http://dx.doi.org/10.1016/S1470-2045(11)70214-5] [PMID: 218624 07] ] admitted that there was no independent review of responses done in her trial, but where statistical analyses weredone [29Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: A proof-of-concept trial. Lancet 2010; 376(9737): 235-44.[http://dx.doi.org/10.1016/S0140-6736(10)60892-6] [PMID: 20609 467] , 31Balmaña J, Tung NM, Isakoff SJ, et al. Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors. Ann Oncol 2014; 25(8): 1656-63.[http://dx.doi.org/10.1093/annonc/mdu187] [PMID: 24827126] ] a recognised system using SAS software (version 8 or 9) was used.

PFS (assessed by RESIST) plots were created using the recognised Kaplan Meier method, and Robson et al [30Robson M, Im S-A, Senkus E, Xu B, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. The New England Journal of Medicine 2017; 377(6): 523-33.] also used Kaplan Meier method to generate time to event curves. Additional validity and reliability for adverse events (AE) data wereprovided by an independent data monitoring committee who reviewed Tutt et al.’s [29Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: A proof-of-concept trial. Lancet 2010; 376(9737): 235-44.[http://dx.doi.org/10.1016/S0140-6736(10)60892-6] [PMID: 20609 467] ] safety data, but this was not something mentioned for AE in any other trial. However, all AEs in all trials were graded according to the standard and recognised Common Terminology Criteria for Adverse Events (CTCAE), [51Common terminology criteria for adverse effects version 4.0 (Published May 28 2009) v4.03 June 2010. US Dept of Health and Human Service, National Institute of Health, National Cancer Institute. ].

Overall, the approved methods used for data collection and analyses in these studies abide by the CONSORT checklist, with results for all analyses performed, including subgroup analyses [39Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ 2010; 340: c869.[http://dx.doi.org/10.1136/bmj.c869] [PMID: 20332511] ].

3.3. Study End Points

In oncology trials, an increase in overall survival (OS) is the most convincing measure of drug efficacy and patient benefit [52Arkenau, Hendrik Tobias; Nordman, Ina; Dobbins, Timothy; Ward, Robyn. Reporting time -to -event endoints and response rates in 4 decades of randomised controlled trials in advanced colorectal cancer. Cancer 2011; 117(4): 832-40.[http://dx.doi.org/10.1002/cncr.25636] [PMID: 20886631] ]. Measuring OS requires extended follow-up with large numbers of participants, so OS results may be confounded by the use of rescue therapies during this time. To address this limitation, recent studies have introduced a range of intermediate endpoints such as Progression-Free Survival (PFS) and time to Progressive Disease (PD). Researchers in the RCTs in this SR subcategorise ORR in terms of Complete Response (CR), Partial Response (PR) or Stable Disease (SD) [52Arkenau, Hendrik Tobias; Nordman, Ina; Dobbins, Timothy; Ward, Robyn. Reporting time -to -event endoints and response rates in 4 decades of randomised controlled trials in advanced colorectal cancer. Cancer 2011; 117(4): 832-40.[http://dx.doi.org/10.1002/cncr.25636] [PMID: 20886631] ].

Overall Survival (OS) is the gold standard for oncology trials, followed by PFS and then ORR [39Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ 2010; 340: c869.[http://dx.doi.org/10.1136/bmj.c869] [PMID: 20332511] ]. However, all studies in this SR assess PFS as a primary endpoint rather than OS. PFS seems acceptable when survival is good as it takes a long time to get the OS data, but for patients with BRCAm BC who have already progressed on two or more previous lines of therapy (which all these patients in these trials have), then the OS is short. It would have been far more reliable and more valid to have been able to assess the OS of BRCAm patients taking olaparib for BC. Although Robson et al. [3William AM. Oral PARPi olaparib in patients with BRCA1 or BRCA2 and recurrent OC: A proof of concept trial. Lancet 2010; 376(9737): 245-51.[http://dx.doi.org/10.1016/S0140-6736(10)60893-8] [PMID: 206094 68] ] did assess OS in their study, the primary endpoint was PFS so despite the OlympiAD trial meeting its primary endpoint, without the full data on OS the true clinical effectiveness of olaparib cannot be certain.

One weakness of RCTs is that they tell us nothing on their own about the patient’s experience [21Williamson GR, Whittaker A. Succeeding in literature Reviews and Research Project Plans for Nursing Students 3rd ed. 3rd ed.2017.]. There are also concerns regarding whether olaparib improves meaningful outcomes for these patients other than clinical effectiveness, such as appropriateness and feasibility [42Evans D. Hierarchy of evidence: A framework for ranking evidence evaluating healthcare interventions. J Clin Nurs 2003; 12(1): 77-84.[http://dx.doi.org/10.1046/j.1365-2702.2003.00662.x] [PMID: 1251 9253] ]. Evidence-based medicine requires any external evidence to be integrated with an individual patient’s clinical state and personal preferences [40Sackett DL, Rosenberg WMC, Gray JA, Haynes RB, Richardson WS. Evidence based medicine: What it is and what it isn’t. BMJ 1996; 312(7023): 71-2. [Clin Res Ed].[http://dx.doi.org/10.1136/bmj.312.7023.71] [PMID: 8555924] ] which was not the case for the trials in this SR (except 30, where Quality of Life was included as a secondary study endpoint). Therefore, future trials should go on for longer and include OS results, which would mean data for assessing the effectiveness of olaparib is more reliable and free of bias. However, as explained by AZ’s medical officer, trials could go on for a very long time, e.g. Olympia. Given the apparent benefit of olaparib for these patients, it could be argued that it is better to have more results sooner, rather than wait for confirmed OS data which may take years, as questions about some therapies cannot wait for large-scale, long term trials to be conducted [40Sackett DL, Rosenberg WMC, Gray JA, Haynes RB, Richardson WS. Evidence based medicine: What it is and what it isn’t. BMJ 1996; 312(7023): 71-2. [Clin Res Ed].[http://dx.doi.org/10.1136/bmj.312.7023.71] [PMID: 8555924] ].

3.4. Overall Synthesis

The major limitation of the studies included in this SR is their lack of randomisation and lack of proper control/placebo arms. Even in Robson et al. [30Robson M, Im S-A, Senkus E, Xu B, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. The New England Journal of Medicine 2017; 377(6): 523-33.] randomised phase 3 trial which did have comparator arms, neither the patients nor the researchers were blinded. Another major limitation of this SR is the small number of trials to date, and within those trials, the small sample sizes who fit the criteria of having BC and BRCAm - there are cohorts of 17 or less in over half of the trials [22Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009; 361(2): 123-34.[http://dx.doi.org/10.1056/NEJMoa0900212] [PMID: 19553641] , 28van der Noll R, Marchetti S, Steeghs N, et al. Long-term safety and anti-tumour activity of olaparib monotherapy after combination with carboplatin and paclitaxel in patients with advanced breast, ovarian or fallopian tube cancer. Br J Cancer 2015; 113(3): 396-402.[http://dx.doi.org/10.1038/bjc.2015.256] [PMID: 26180927] , 31Balmaña J, Tung NM, Isakoff SJ, et al. Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors. Ann Oncol 2014; 25(8): 1656-63.[http://dx.doi.org/10.1093/annonc/mdu187] [PMID: 24827126] , 32Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: A phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 2011; 12(9): 852-61.[http://dx.doi.org/10.1016/S1470-2045(11)70214-5] [PMID: 218624 07] ].

Despite patient demographics being consistent, and methods of data collection and analysis recognised, producing valid ORRs, the number of studies, the small sample sizes and heterogeneous nature of the trials in this SR prevented a statistical meta analysis being undertaken.

AZ did confirm that all studies they are aware of have been sourced for this SR, and despite a limited number of studies, it is clear from the studies included here that the evidence contains similar themes and overall there is a benefit of olaparib therapy (monotherapy or combination therapy) over standard therapy. Larger, longer term trials with more comparator arms should be undertaken if this hypothesis is to be substantiated.

The main ORRs are shown for comparison in Table 3 below.

The ORR was not measured in Van der Noll et al.’s [28van der Noll R, Marchetti S, Steeghs N, et al. Long-term safety and anti-tumour activity of olaparib monotherapy after combination with carboplatin and paclitaxel in patients with advanced breast, ovarian or fallopian tube cancer. Br J Cancer 2015; 113(3): 396-402.[http://dx.doi.org/10.1038/bjc.2015.256] [PMID: 26180927] ] long-term safety study, so no results are shown, however, results of Lee et al. [6Lee J-M, Hays JL, Annunziata CM, et al. Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses. J Natl Cancer Inst 2014; 106(6): dju089.[http://dx.doi.org/10.1093/jnci/dju089] [PMID: 24842883] ] combination study (did not meet all inclusion criteria for SR) are included for interest and comparison with Balmana et al. [31Balmaña J, Tung NM, Isakoff SJ, et al. Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors. Ann Oncol 2014; 25(8): 1656-63.[http://dx.doi.org/10.1093/annonc/mdu187] [PMID: 24827126] ] combination trial.

Clinical effectiveness has been measured in all the trials in this review as the Objective Response Rate (ORR). Despite ORRs varying wildly from zero response [32Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: A phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 2011; 12(9): 852-61.[http://dx.doi.org/10.1016/S1470-2045(11)70214-5] [PMID: 218624 07] ], to 71% [31Balmaña J, Tung NM, Isakoff SJ, et al. Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors. Ann Oncol 2014; 25(8): 1656-63.[http://dx.doi.org/10.1093/annonc/mdu187] [PMID: 24827126] ], the overall clinical benefit of olaparib appears to be greater and longer lived in BRCAm carriers compared to BRCAwt, and also when compared to standard chemotherapy treatments.

Table 3
Objective response results for all trials in this systematic review.


Tutt et al. [29Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: A proof-of-concept trial. Lancet 2010; 376(9737): 235-44.[http://dx.doi.org/10.1016/S0140-6736(10)60892-6] [PMID: 20609 467] ] reported 400mg BiD shows a near doubling of ORR when compared to patients on lower 100mg BiD (41% versus 22%), and median reduction in tumour size was of 30% compared to only 7% for the 100mg cohort suggesting the MTD is the most clinically effective. The presence of a dose-response result is recognised as an important criterionfor believing there to be a reputed cause and effect relationship.

Long-term monotherapy also reported good results, with Van der Noll et al. [28van der Noll R, Marchetti S, Steeghs N, et al. Long-term safety and anti-tumour activity of olaparib monotherapy after combination with carboplatin and paclitaxel in patients with advanced breast, ovarian or fallopian tube cancer. Br J Cancer 2015; 113(3): 396-402.[http://dx.doi.org/10.1038/bjc.2015.256] [PMID: 26180927] ] reporting 43% of all patients still on the study at the time of data cut off, including four patients who had been on the study for over 2 years - 43% with CR, 22% PR, and 29% SD. Only 5% of patients showed PD.

When compared to standard chemotherapy, olaparib showed improved clinical effectiveness. In Robson et al. [30Robson M, Im S-A, Senkus E, Xu B, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. The New England Journal of Medicine 2017; 377(6): 523-33.] trial comparing olaparib with standard chemotherapies, ORR in the olaparib cohort doubled (59·9% compared with 28·8%), and CR was seen in 9% of olaparib group versus just 1.5% in TPC group. Further encouraging results show that the tumour reduction of -45.1% for olaparib arm compared to 14.8% for TPC arm.

The studies that reported zero or low ORR are important to consider. Gelmon et al. [32Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: A phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 2011; 12(9): 852-61.[http://dx.doi.org/10.1016/S1470-2045(11)70214-5] [PMID: 218624 07] ] saw no ORR in BC cohorts at all, while Kaufman et al. [32Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: A phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 2011; 12(9): 852-61.[http://dx.doi.org/10.1016/S1470-2045(11)70214-5] [PMID: 218624 07] ] saw ORR of only 12.9%. Despite no ORR to olaparib monotherapy for any of the BC patients, it is important to note that there was a clinical benefit. SD was seen in 63% in BRCAm cohort compared to 13% in the BRCAwt cohort. PD in BRCAm cohort was less than half that seen in the BRCAwt cohort (38% versus 80%), and despite not being included in the final confirmed results, 50% of BRCAm patients saw tumours reduce in size by more than 30%, which definitely warrants further exploration. Clinical benefit was also derived in one trial [33Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015; 33(3): 244-50.[http://dx.doi.org/10.1200/JCO.2014.56.2728] [PMID: 25366685] ] as 47% of the BRCAm BC cohort maintained SD which was higher than any other cancer type in this trial.

Overall, whilst the number of trials to date is small, and the patient cohort size within those trials is often even smaller, the overall results suggest that olaparib does show clinical effectiveness for BC patients with BRCAm.

In Fong et al. [22Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009; 361(2): 123-34.[http://dx.doi.org/10.1056/NEJMoa0900212] [PMID: 19553641] ] study, the clinical benefit rates for patients with BC and BRCAm were 69% in platinum-sensitive patients, 45% in platinum-resistant patients, and 23% in platinum-refractory patients, suggesting a link between platinum resistance and olaparib response; that platinum-sensitive patients will benefit the most from olaparib therapy. In Gelmon et al. [32Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: A phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 2011; 12(9): 852-61.[http://dx.doi.org/10.1016/S1470-2045(11)70214-5] [PMID: 218624 07] ] study, trial responses were also consistent with prior platinum sensitivity as post hoc analysis showed activity mostly in patients with platinum-sensitive disease. This hypothesis gains strength as the studies continue with 62 platinum resistant BC patients [33Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015; 33(3): 244-50.[http://dx.doi.org/10.1200/JCO.2014.56.2728] [PMID: 25366685] ] with at least three lines of prior therapies (median of 4.6) resulting in ORR of 12.9%, compared to minimum of 1 treatment and median of three treatments in another [29Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: A proof-of-concept trial. Lancet 2010; 376(9737): 235-44.[http://dx.doi.org/10.1016/S0140-6736(10)60892-6] [PMID: 20609 467] ], which resulted in ORR of 41%. In addition, although the ECOG status was the same in both trials (ECOG range 0-2), Kaufman et al. [33Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015; 33(3): 244-50.[http://dx.doi.org/10.1200/JCO.2014.56.2728] [PMID: 25366685] ] had more patients with ECOG of 2 (which means they have longer cancer history which tallies with the higher pre-treatments) than Tutt et al. [29Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: A proof-of-concept trial. Lancet 2010; 376(9737): 235-44.[http://dx.doi.org/10.1016/S0140-6736(10)60892-6] [PMID: 20609 467] ]. Gelmon et al. [32Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: A phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 2011; 12(9): 852-61.[http://dx.doi.org/10.1016/S1470-2045(11)70214-5] [PMID: 218624 07] ] results showed zero response to olaparib but 70% of the BRCAm BC patients had had at least 3 prior lines of chemotherapy, so were also heavily pre-treated, while in Robson et al (30) trial, the superiority of olaparib was even more pronounced in patients without prior platinum exposure. Of particular note in Kaufman et al. [33Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015; 33(3): 244-50.[http://dx.doi.org/10.1200/JCO.2014.56.2728] [PMID: 25366685] ] trial, there was a doubling of response in BC patients (20% versus 9.5%) who had not had prior platinum treatment.

Consistent across all the trials in this review, the clinical benefit rates seem to correlate to platinum sensitivity, suggesting that platinum sensitivity may be a surrogate marker for sensitivity to olaparib treatment. Indeed looking at the results of all studies it appears that platinum sensitivity may be enough to predict response to olaparib. For all the trials that measured it, there was also a consistent association between clinical benefit and platinum-free interval (the period between last platinum therapy, and disease progression) which should be explored in longer term studies in the future.

Mechanisms of resistance are not measured in any of the trials and areoutside of the scope of this SR, but it is certainly something for future investigation in order to understand the relationship between prior platinum exposure and response to olaparib. Unfortunately, in Robinson et al. [30Robson M, Im S-A, Senkus E, Xu B, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. The New England Journal of Medicine 2017; 377(6): 523-33.] trial, there was no platinum-based chemotherapy to compare with olaparib. It is encouraging that efficacy was seen in patients with prior platinum exposure, however, it was outside the scope of the trial toassess the effectiveness of olaparib in patients with the platinum-resistant disease. Considering the high success rate seen by Lee et al. [6Lee J-M, Hays JL, Annunziata CM, et al. Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses. J Natl Cancer Inst 2014; 106(6): dju089.[http://dx.doi.org/10.1093/jnci/dju089] [PMID: 24842883] ], carboplatin as a control arm in Robson et al. [30Robson M, Im S-A, Senkus E, Xu B, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. The New England Journal of Medicine 2017; 377(6): 523-33.] trial would have been the ideal control to test the efficacy of olaparib compared to carboplatin. Although previous treatment with carboplatin was allowed in Robson et al. [30Robson M, Im S-A, Senkus E, Xu B, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. The New England Journal of Medicine 2017; 377(6): 523-33.] trial, only 14% of patients had received platinum previously and subgroup analysis shows that the superiority of olaparib was even more pronounced in patients without prior platinum exposure. Further research into the link between platinum sensitivity and response to olaparib is warranted.

A consistent theme throughout all the trials in this review is that despite the majority of patients being affected by AE’s grade 1-2,and 40-50% of all patients being affected by grade 3 AEs for all of the olaparib monotherapy trials in this review, the drug was generally well tolerated causing mainly mild toxicities such as nausea, vomiting, fatigue, headache, cough, and a low incidence of myelosuppression. No secondary malignancies were seen as a consequence of taking the drug in any trial. The toxicities did not differ based on germline BRCAm status of those patients except for in a long-term safety study [28van der Noll R, Marchetti S, Steeghs N, et al. Long-term safety and anti-tumour activity of olaparib monotherapy after combination with carboplatin and paclitaxel in patients with advanced breast, ovarian or fallopian tube cancer. Br J Cancer 2015; 113(3): 396-402.[http://dx.doi.org/10.1038/bjc.2015.256] [PMID: 26180927] ] where BRCA2m patients had 100% CR (but this is only three patients so could be due to chance).

In combination, olaparib seems to improve the therapeutic responses of patients with different cancers to platinum [6Lee J-M, Hays JL, Annunziata CM, et al. Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses. J Natl Cancer Inst 2014; 106(6): dju089.[http://dx.doi.org/10.1093/jnci/dju089] [PMID: 24842883] , 31Balmaña J, Tung NM, Isakoff SJ, et al. Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors. Ann Oncol 2014; 25(8): 1656-63.[http://dx.doi.org/10.1093/annonc/mdu187] [PMID: 24827126] ], although toxicities of these drugs were also increased. Olaparib seems to enhance the anti tumor activity of platinum chemotherapies. The combination of olaparib with platinum appears a promising approach to increase efficacy and warrants further investigation in the future.

4. DISCUSSION

This is the first systematic review looking at the effectiveness of olaparib in BC patients with BRCAm, and there are several themes arising from the research into these trials, as well as several limitations. All the studies in this SR used quantitative research designs, and all were examining olaparib’s effectiveness in patients with BRCAm and associated cancers, measured by objective response rates and adverse effects. This SR focusses on the results for patients with BC.

4.1. Interpretation of Results and Limitations of this Review

Despite the author abiding by a strict standard process in order to write this SR as objectively as possible, there will always be a difference in interpretation between Kmet et al [23Leanne M, Kmet MSc, Robert C, Lee MSc, Linda S. Standard quality assessment criteria for evaluating primary research papers from a variety of fields 2004.], CASP and hierarchy of evidence. Of particular note for this SR, is that the Kmet et al. [23Leanne M, Kmet MSc, Robert C, Lee MSc, Linda S. Standard quality assessment criteria for evaluating primary research papers from a variety of fields 2004.] method may be flawed as all except one of the trials were non-randomised - so for most papers, there were irrelevant questions in the Kmet et al. [23Leanne M, Kmet MSc, Robert C, Lee MSc, Linda S. Standard quality assessment criteria for evaluating primary research papers from a variety of fields 2004.] score sheet.

5. If interventional and random allocation was possible, was it described? NA

6. If interventional and blinding of investigators was possible, was it reported? NA

7. If interventional and blinding of subjects werepossible, was it reported? NA

So quality guidelines such as Kmet et al. [23Leanne M, Kmet MSc, Robert C, Lee MSc, Linda S. Standard quality assessment criteria for evaluating primary research papers from a variety of fields 2004.] can be inconsistent in how they rate quality of evidence because scoring in this instance means that what are effectively poorer study designs of the RCTs in this review (non-randomised and open-label, small sample sizes) can score as highly as a large sample size fully blinded RCTs using Kmet et al. [23Leanne M, Kmet MSc, Robert C, Lee MSc, Linda S. Standard quality assessment criteria for evaluating primary research papers from a variety of fields 2004.] method.

Trial designs in the studies included here are very heterogeneous with all except one being phase 1 or 2, meaning current research in this area is still in its infancy and, although two other phase 3 trials are currently ongoing, no results are yet available. Treatment and dosages are not always the same in all studies, and even within the same study dosages can be suspended, reduced, increased, or given intermittently. In dose-finding trials, there were reports of fluctuation in dosage and duration of therapies, with patients switching between dosages.

Despite the heterogeneity of the study designs, the studies did use recognised and established methods for conducting the intervention, data collection and analysis, providing valid and reliable results, so although the numbers of patients in the studies are small, and there are only a few studies to date, these results can be compared and an overview of the body of evidence can be assessed [40Sackett DL, Rosenberg WMC, Gray JA, Haynes RB, Richardson WS. Evidence based medicine: What it is and what it isn’t. BMJ 1996; 312(7023): 71-2. [Clin Res Ed].[http://dx.doi.org/10.1136/bmj.312.7023.71] [PMID: 8555924] ].

Robson et al. [30Robson M, Im S-A, Senkus E, Xu B, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. The New England Journal of Medicine 2017; 377(6): 523-33.] OlympiAD Trial is the first and only trial in this SR to be randomised. This trial was designed to compare the efficacy and safety of olaparib with the efficacy and safety of standard Therapy of the Physicians’ Choice (TPC) among BC BRCAm patients. Randomisation was stratified according to previous use of chemotherapy, hormone receptor status, and previous use of platinum-based therapy. 302 patients were randomised 2:1 to olaparib (205 patients) or chemotherapy of the physician’s choice (97 patients), consisting of either capecitabine, vinorelbine or eribulin, although the ideal comparator would have been carboplatin. Future trials should have multiple arms, including platinum arms and placebo control. It is of interest to note that the ongoing OlympiA study has randomised patients with BRCAm to olaparib or placebo for 12 months, after completing surgery and chemotherapy (NCT02032823), but these patients are surviving for a long time so the endpoint for this study has not yet been reached, so we wait to see these results when they are available.

It is important that the demographics of patients at baseline is similar [53Steventon A, Grieve R, Bardsley M. An approach to assess Generalizability in comparative effectiveness research: A case study of the whole systems Demonstrator cluster Randomized trial comparing Telehealth with usual care for patients with chronic health conditions. Med Decis Making 2015; 35(8): 1023-36.[http://dx.doi.org/10.1177/0272989X15585131] [PMID: 25986472] ]. Patient demographics in all arms were similar in all trials, except for the unavoidable differences in individuals’ prior treatment regimes. Some patients were more than three times more heavily treated than others. All the studies except Robson et al. [30Robson M, Im S-A, Senkus E, Xu B, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. The New England Journal of Medicine 2017; 377(6): 523-33.] and Gelmon et al. [32Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: A phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 2011; 12(9): 852-61.[http://dx.doi.org/10.1016/S1470-2045(11)70214-5] [PMID: 218624 07] ] had patients with a median of 3 prior chemotherapies. Robson et al.’s (2017) patients had a maximum of two prior treatments and Gelmon et al. [32Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: A phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 2011; 12(9): 852-61.[http://dx.doi.org/10.1016/S1470-2045(11)70214-5] [PMID: 218624 07] ] patients were much more heavily pre-treated with a median of 4.6 chemotherapies.

In particular, when reading Van der Noll et al.’s [28van der Noll R, Marchetti S, Steeghs N, et al. Long-term safety and anti-tumour activity of olaparib monotherapy after combination with carboplatin and paclitaxel in patients with advanced breast, ovarian or fallopian tube cancer. Br J Cancer 2015; 113(3): 396-402.[http://dx.doi.org/10.1038/bjc.2015.256] [PMID: 26180927] ] data for this long-term safety study, it is important that baseline characteristics are taken into account as most patients had already shown anti-tumour response during previous combination study (19 out of 21 had to benefit, one had PD and one had a non-evaluable response). There is also potential selection bias over time, as only patients that tolerated the treatment actually remained on the study, however, none of the patients that went off study did so because of AEs. The Berger-Exner test detects selection bias but has not been widely utilized in practice [54Mickenautsch S, Fu B, Gudehithlu S, Berger VW. Accuracy of the Berger-Exner test for detecting third-order selection bias in randomised controlled trials: A simulation-based investigation. BMC Med Res Methodol 2014; 14(1): 114.[http://dx.doi.org/10.1186/1471-2288-14-114] [PMID: 25283963] ]. One reason for the non use of this test may be a lack of information regarding its accuracy but Michenautsch et al. [54Mickenautsch S, Fu B, Gudehithlu S, Berger VW. Accuracy of the Berger-Exner test for detecting third-order selection bias in randomised controlled trials: A simulation-based investigation. BMC Med Res Methodol 2014; 14(1): 114.[http://dx.doi.org/10.1186/1471-2288-14-114] [PMID: 25283963] ] concluded that the Berger-Exner test is generally accurate for identifying selection bias so this could be utilised to avoid the same potential bias in future long-term safety studies.

RCTs where baseline characteristics of patients in each are balanced (which all of these trials did achieve) can ensure high levels of internal validity [53Steventon A, Grieve R, Bardsley M. An approach to assess Generalizability in comparative effectiveness research: A case study of the whole systems Demonstrator cluster Randomized trial comparing Telehealth with usual care for patients with chronic health conditions. Med Decis Making 2015; 35(8): 1023-36.[http://dx.doi.org/10.1177/0272989X15585131] [PMID: 25986472] ]. However, despite establishing that everything that could be done to ensure baseline characteristics are as similar as they could be, it must be remembered that none of the studies in this SR used a randomised double-blinded method in their experimental design, so the risk of bias must always be considered, and this compromises their external validity.

Small sample sizes are also a limitation of the papers in this SR and all results from studies with small sample sizes should be considered with caution. One of the three patients with BRCAm BC in Fong et al. [22Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009; 361(2): 123-34.[http://dx.doi.org/10.1056/NEJMoa0900212] [PMID: 19553641] ] trial had a CR lasting more than 60 weeks on olaparib 200 mg twice daily, one had SD, but one left the trial. Of the 26 patients in Gelmon et al. [32Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: A phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 2011; 12(9): 852-61.[http://dx.doi.org/10.1016/S1470-2045(11)70214-5] [PMID: 218624 07] ] BC cohort, 11 had BRCAm (although this changed at interim analysis to 10 as a result of baseline BRCAm testing which found one BRCAm BC patient actually did not have BRCAm, and so switched cohort). The poor sensitivity of BC patients in Gelmon et al. [32Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: A phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 2011; 12(9): 852-61.[http://dx.doi.org/10.1016/S1470-2045(11)70214-5] [PMID: 218624 07] ] trial could simply be due to chance because of the very small sample size (10 patients) in this study. Consistent with many of the trials in this review, the cohort numbers in Van der Noll et al.s [28van der Noll R, Marchetti S, Steeghs N, et al. Long-term safety and anti-tumour activity of olaparib monotherapy after combination with carboplatin and paclitaxel in patients with advanced breast, ovarian or fallopian tube cancer. Br J Cancer 2015; 113(3): 396-402.[http://dx.doi.org/10.1038/bjc.2015.256] [PMID: 26180927] ] safety study are very small which can lead to bias [21Williamson GR, Whittaker A. Succeeding in literature Reviews and Research Project Plans for Nursing Students 3rd ed. 3rd ed.2017., 39Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ 2010; 340: c869.[http://dx.doi.org/10.1136/bmj.c869] [PMID: 20332511] , 40Sackett DL, Rosenberg WMC, Gray JA, Haynes RB, Richardson WS. Evidence based medicine: What it is and what it isn’t. BMJ 1996; 312(7023): 71-2. [Clin Res Ed].[http://dx.doi.org/10.1136/bmj.312.7023.71] [PMID: 8555924] ].

A much larger study, so potentially one with greater power [17Parahoo K. Nursing research -principles, process and issues 3rd ed. 3rd ed.2014., 38Aveyard H. Doing a literature review in health and social care – A practical guide (2014), third edition Published January 1st 2014 by Open University Press.] by Kaufman et al. [33Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015; 33(3): 244-50.[http://dx.doi.org/10.1200/JCO.2014.56.2728] [PMID: 25366685] ], published results of a single arm, non-randomised phase 2 trial with 298 patients with recurrent BRCAm cancers, to discover the efficacy and safety of olaparib as a monotherapy in platinum-resistant OC, heavily pre-treated BC, pancreatic cancer and prostate cancer. For all patients, ORR was 26.2%, but only 12.9% for BC patients, which is low when compared to Tutt et al. [29Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: A proof-of-concept trial. Lancet 2010; 376(9737): 235-44.[http://dx.doi.org/10.1016/S0140-6736(10)60892-6] [PMID: 20609 467] ] 41% for same BRCAm breast cancer patients. This inconsistency could be explained by the more heavily pre-treated nature of Kaufman et al. [33Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015; 33(3): 244-50.[http://dx.doi.org/10.1200/JCO.2014.56.2728] [PMID: 25366685] ] patients, but it could also be a more precise result due to the larger sample size.

It is important to consider timescale and dosing [17Parahoo K. Nursing research -principles, process and issues 3rd ed. 3rd ed.2014.] as well as patient drop out [21Williamson GR, Whittaker A. Succeeding in literature Reviews and Research Project Plans for Nursing Students 3rd ed. 3rd ed.2017.] in studies using experimental designs. All trials gave treatment cycles of three or four weeks initially and ran for at least six cycles (24 weeks). Not all patients finished six cycles (only 12% in Gelmon et al. [32Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: A phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 2011; 12(9): 852-61.[http://dx.doi.org/10.1016/S1470-2045(11)70214-5] [PMID: 218624 07] ] heavily pre-treated population), but in some cases, patients were still on trial at data cut off [32Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: A phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 2011; 12(9): 852-61.[http://dx.doi.org/10.1016/S1470-2045(11)70214-5] [PMID: 218624 07] , 33Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015; 33(3): 244-50.[http://dx.doi.org/10.1200/JCO.2014.56.2728] [PMID: 25366685] ] with some surviving over three years [28van der Noll R, Marchetti S, Steeghs N, et al. Long-term safety and anti-tumour activity of olaparib monotherapy after combination with carboplatin and paclitaxel in patients with advanced breast, ovarian or fallopian tube cancer. Br J Cancer 2015; 113(3): 396-402.[http://dx.doi.org/10.1038/bjc.2015.256] [PMID: 26180927] , 31Balmaña J, Tung NM, Isakoff SJ, et al. Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors. Ann Oncol 2014; 25(8): 1656-63.[http://dx.doi.org/10.1093/annonc/mdu187] [PMID: 24827126] ]. The median duration of treatment in BC patients ranged from 56 days [32Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: A phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 2011; 12(9): 852-61.[http://dx.doi.org/10.1016/S1470-2045(11)70214-5] [PMID: 218624 07] ] heavily pre-treated population) to [33Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015; 33(3): 244-50.[http://dx.doi.org/10.1200/JCO.2014.56.2728] [PMID: 25366685] ] days for combination with cisplatin [31Balmaña J, Tung NM, Isakoff SJ, et al. Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors. Ann Oncol 2014; 25(8): 1656-63.[http://dx.doi.org/10.1093/annonc/mdu187] [PMID: 24827126] ]. Additionally, it seems that the higher dose of olaparib is tolerable over a long time, as Tutt et al. [29Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: A proof-of-concept trial. Lancet 2010; 376(9737): 235-44.[http://dx.doi.org/10.1016/S0140-6736(10)60892-6] [PMID: 20609 467] ] patients, treatment exposure ranged from 11 weeks in cohort 2 (taking 100mg BiD) to 163 weeks in cohort 1 (taking 400mg BiD).

Although results are highly variable, it is interesting to note that those patients who survived the longest (over 3.5 years) were on maintenance therapy after receiving combination therapy. For those patients who continued on olaparib monotherapy after a combination therapy [28van der Noll R, Marchetti S, Steeghs N, et al. Long-term safety and anti-tumour activity of olaparib monotherapy after combination with carboplatin and paclitaxel in patients with advanced breast, ovarian or fallopian tube cancer. Br J Cancer 2015; 113(3): 396-402.[http://dx.doi.org/10.1038/bjc.2015.256] [PMID: 26180927] ] the median treatment time of olaparib monotherapy was 52 weeks, with a range of 7 weeks to 183 weeks. It is important for future studies to include long-term follow up assessments in order to realise the sustainability of olaparib so that both the short-term and the long-term outcomes of olaparib can be determined [35Melnyk BM, Fineout-Overholt E. Rapid critical appraisal of randomized controlled trials (RCTs): An essential skill for evidence-based practice (EBP) Pediatric Nursing.2005; 31(1)].

In Gelmon et al. [32Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: A phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 2011; 12(9): 852-61.[http://dx.doi.org/10.1016/S1470-2045(11)70214-5] [PMID: 218624 07] ] trial three participants results were not confirmed as OR because of the absence of confirmation at their next visit (three BC patients (two BRCAm and one wt). Given the small numbers in the BC BRCAm cohort in this trial (10 patients), had the results of these three BC patients been confirmed and included in the results, the data would have looked very different, and consistent with findings of other studies in this review. This study design is certainly something reexamined with larger sample sizes in order to provide more reliable results.

Fong et al. [22Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009; 361(2): 123-34.[http://dx.doi.org/10.1056/NEJMoa0900212] [PMID: 19553641] ] also had one BRCAm patient who dropped out with no given reason after one week so no ORR was recorded. Further details on this patient would have been useful as they may have experienced an acute exacerbation of their illness or AE to treatment. Due to the lack of information given [22Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009; 361(2): 123-34.[http://dx.doi.org/10.1056/NEJMoa0900212] [PMID: 19553641] ], it was not possible to ascertain why this participant dropped out. This information is crucial because this patient may have been different to the other BRCAm patients in the study [39Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ 2010; 340: c869.[http://dx.doi.org/10.1136/bmj.c869] [PMID: 20332511] ] but these were early days before BRCAm benefit in humans was only beginning to be noticed or acted upon [22Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009; 361(2): 123-34.[http://dx.doi.org/10.1056/NEJMoa0900212] [PMID: 19553641] ]. There will always be patient drop out in RCTs, especially in females diagnosed with aggressive cancer affected by strong emotional involvement [55Goldhirsch A, Gelber RD, Yothers G, et al. Adjuvant therapy for very young women with breast cancer: Need for tailored treatments. J Natl Cancer Inst Monogr 2001; 30(30): 44-51.[http://dx.doi.org/10.1093/oxfordjournals.jncimonographs.a003459] [PMID: 11773291] ], therefore measures should be taken (such as counselling and better communication between researchers and participants) to minimise drop out rates in future, and account for missing data, in order for the findings to be valid and generalisable.

In Kaufman et al. study [33Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015; 33(3): 244-50.[http://dx.doi.org/10.1200/JCO.2014.56.2728] [PMID: 25366685] ], BC and OC patients were moved between cohorts after centrally validated BRCAm testing was performed. Like Balmana et al. [31Balmaña J, Tung NM, Isakoff SJ, et al. Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors. Ann Oncol 2014; 25(8): 1656-63.[http://dx.doi.org/10.1093/annonc/mdu187] [PMID: 24827126] ], Kaufman et al. [33Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015; 33(3): 244-50.[http://dx.doi.org/10.1200/JCO.2014.56.2728] [PMID: 25366685] ] trial has a weakness in that no central validation of mutation status was done before enrolment. The authors of that study believe that the chance of miss-classification was low, however several patients were moved from one cohort to the other in Gelmon et al. [32Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: A phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 2011; 12(9): 852-61.[http://dx.doi.org/10.1016/S1470-2045(11)70214-5] [PMID: 218624 07] ] trial after BRCA status was subsequently confirmed by Myriad central laboratory, meaning that this may be an optimistic view, and therefore further trials are warranted where patients BRCAm status is centrally validated prior to a study commencing.

A point of interest resulting from one trial [31Balmaña J, Tung NM, Isakoff SJ, et al. Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors. Ann Oncol 2014; 25(8): 1656-63.[http://dx.doi.org/10.1093/annonc/mdu187] [PMID: 24827126] ] of those patients who continued single agent olaparib monotherapy after the end of the combination trial - is that SD (>1 year) occurred in five breast cancer patients. Also, of all patients on the trial with various cancers, two had responses lasting for over three years, but Balmana et al. fail to disclose whether these were BC or OC patients.

Interestingly, Van der Noll et al. [28van der Noll R, Marchetti S, Steeghs N, et al. Long-term safety and anti-tumour activity of olaparib monotherapy after combination with carboplatin and paclitaxel in patients with advanced breast, ovarian or fallopian tube cancer. Br J Cancer 2015; 113(3): 396-402.[http://dx.doi.org/10.1038/bjc.2015.256] [PMID: 26180927] ] long term safety study showed reduction of severity and frequency of AEs over time. The most common AE was bone marrow suppression, highest at baseline, suggesting a possible carry over from the combination study with chemotherapy. The only haematological AE that persisted was anaemia, warranting further investigation of olaparib’s role in anaemia, but encouragingly for olaparib therapy, no patients had to omit or discontinue due to AEs. One specific weakness of Van der Noll et al. [28van der Noll R, Marchetti S, Steeghs N, et al. Long-term safety and anti-tumour activity of olaparib monotherapy after combination with carboplatin and paclitaxel in patients with advanced breast, ovarian or fallopian tube cancer. Br J Cancer 2015; 113(3): 396-402.[http://dx.doi.org/10.1038/bjc.2015.256] [PMID: 26180927] ] study is that there appears to be a discrepancy in the text versus the table. The authors say in the text that in total 8 out of 16 (50%) patients with known BRCA mutations had to come off study due to PD. Whereas in Table 4 (in the original text), it shows only one patient (8%) having PD. One patient would be more consistent with previous and subsequent data for olaparib monotherapy. There is also a subsequent error in the text, referring to the same 8 patients there were eight patients with BRCA mutation who did show disease progression. The authors have declined to comment despite contacting them several times

Table 4
GRADE quality of evidence and definitions


Robson et al. [30Robson M, Im S-A, Senkus E, Xu B, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. The New England Journal of Medicine 2017; 377(6): 523-33.] trial had comparator arms, which showed more serious AEs occurring more often in the TPC cohort. Grade ≥3 adverse events rate was 36.6% in the olaparib arm and 50.5% in the TPC arm. In addition, 4.9% in the olaparib arm discontinued the study because of AEs versus 7.7% in the TPC arm. The median treatment duration was more than double in the olaparib arm (8.2 months) than in the TPC arm (3.4 months). Interestingly, the most common grade 3 or worse AE’s were caused by anaemia (16·1% in the olaparib group vs 4·4% in the TPC group) again raising questions about olaparib’s role in anaemia (which is beyond the scope of this SR but worthy of future investigation).

Despite the apparent success of olaparib monotherapy, combination studies with cisplatin found hematologic toxicity too great, and the tolerable schemas required decreasing the standard doses of platinum and were limited by Dose-Limiting Toxicities (DLTs) [31Balmaña J, Tung NM, Isakoff SJ, et al. Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors. Ann Oncol 2014; 25(8): 1656-63.[http://dx.doi.org/10.1093/annonc/mdu187] [PMID: 24827126] ]. This increase in myelosuppression could be attributed to an increase in the sensitivity of rapidly dividing cells to the toxic effects of platinum by olaparib. A schema of intermittent olaparib (50mg BiD, days 1-5) with cisplatin 60mg/m2 was deemed tolerable for further development, and this should be explored in the future. Although not a trial appraised in this review due to its focus on biomarker analysis, it is noteworthy here to compare the results of Lee et al. [6Lee J-M, Hays JL, Annunziata CM, et al. Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses. J Natl Cancer Inst 2014; 106(6): dju089.[http://dx.doi.org/10.1093/jnci/dju089] [PMID: 24842883] ]carboplatin/olaparib combination therapy trial, which reported 87.5% ORR (Table 3). This is the most impressive ORR to olaparib in BRCAm cancers found during the research for this SR, and further investigation with different combinations of olaparib/ platinum is needed in order to achieve anti-tumor efficacy with well tolerable regimens, which could greatly improve prognosis and disease outcomes. Interestingly, Lee et al. study [6Lee J-M, Hays JL, Annunziata CM, et al. Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses. J Natl Cancer Inst 2014; 106(6): dju089.[http://dx.doi.org/10.1093/jnci/dju089] [PMID: 24842883] ] with carboplatin/olaparib combination therapy reported less frequent AEs, but this could be because a tolerable dose was found more quickly.

All studies except [22Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009; 361(2): 123-34.[http://dx.doi.org/10.1056/NEJMoa0900212] [PMID: 19553641] , 28van der Noll R, Marchetti S, Steeghs N, et al. Long-term safety and anti-tumour activity of olaparib monotherapy after combination with carboplatin and paclitaxel in patients with advanced breast, ovarian or fallopian tube cancer. Br J Cancer 2015; 113(3): 396-402.[http://dx.doi.org/10.1038/bjc.2015.256] [PMID: 26180927] , 33Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015; 33(3): 244-50.[http://dx.doi.org/10.1200/JCO.2014.56.2728] [PMID: 25366685] ] state that patients had provided written informed consent. Although there is no mention of ethical considerations in one study [28van der Noll R, Marchetti S, Steeghs N, et al. Long-term safety and anti-tumour activity of olaparib monotherapy after combination with carboplatin and paclitaxel in patients with advanced breast, ovarian or fallopian tube cancer. Br J Cancer 2015; 113(3): 396-402.[http://dx.doi.org/10.1038/bjc.2015.256] [PMID: 26180927] ], this is a long-term safety study following on from a phase 1 trial, so approval may have been sought previously for the phase 1 stage. All studies had been approved by review boards and ethics committees for each trial centre, and done in accordance with the recognised Good Clinical Practice guidelines and the declaration of Helsinki, which shows that each study has considered and addressed the wider ethical concerns. An additional strength of three studies [29Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: A proof-of-concept trial. Lancet 2010; 376(9737): 235-44.[http://dx.doi.org/10.1016/S0140-6736(10)60892-6] [PMID: 20609 467] -31Balmaña J, Tung NM, Isakoff SJ, et al. Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors. Ann Oncol 2014; 25(8): 1656-63.[http://dx.doi.org/10.1093/annonc/mdu187] [PMID: 24827126] ], is that they are the only papers to state that they abide by the sponsor's policy on bioethics [48Zeneca A. Astra Zeneca. Global Policy: Bioethics 2016. www. astrazeneca. com/ content/ dam/az/ PDF/2016/ Bioethics_ policy.pdf]. However, without written consent from each patient, there remainsconcerns about whether participant’s autonomy, confidentiality, anonymity and personal safety have been considered, and we cannot know if the authors have ensured their patients understood what the trial was, or agreed to take part [17Parahoo K. Nursing research -principles, process and issues 3rd ed. 3rd ed.2014., 21Williamson GR, Whittaker A. Succeeding in literature Reviews and Research Project Plans for Nursing Students 3rd ed. 3rd ed.2017., 38Aveyard H. Doing a literature review in health and social care – A practical guide (2014), third edition Published January 1st 2014 by Open University Press., 39Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ 2010; 340: c869.[http://dx.doi.org/10.1136/bmj.c869] [PMID: 20332511] ].

Another ethical consideration, given the apparent success of olaparib as a monotherapy, is a potential limitation for future RCTs. Giving olaparib to one cohort whilst giving standard (believed to be inferior) alternative therapy or placebo to another cohort can be thought unethical [56Sibbald B, Roland M. Understanding controlled trials. Why are randomised controlled trials important? BMJ 1998; 316(7126): 201.[http://dx.doi.org/10.1136/bmj.316.7126.201] [PMID: 9468688] ]. For example, a non-randomised study suggested that multivitamin supplementation (which included folic acid) during pregnancy could prevent neural tube defects in developing embryos [57Smithells RW, Sheppard S, Schorah CJ, et al. Apparent prevention of neural tube defects by periconceptional vitamin supplementation. Arch Dis Child 1981; 56(12): 911-8.[http://dx.doi.org/10.1136/adc.56.12.911] [PMID: 7332338] ]. Despite the study being deemed flawed [56Sibbald B, Roland M. Understanding controlled trials. Why are randomised controlled trials important? BMJ 1998; 316(7126): 201.[http://dx.doi.org/10.1136/bmj.316.7126.201] [PMID: 9468688] ], ethics committees believed it was unethical to deprive patients of this potentially beneficial treatment. It appears unlikely that this currently applies to olaparib, due to the heterogeneous nature of the results so far, but it gives another reason to look forward to the results of the randomised double blinded phase 3 RCT results due to be released later this year (OlympiA and neo-Olympia).

All RCTs in this SR reported a combination of multiple single endpoints (CR, PR, PFS, PD) and all endpoints, primary or secondary, should be identified and completely defined [39Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ 2010; 340: c869.[http://dx.doi.org/10.1136/bmj.c869] [PMID: 20332511] ], which they were. Robson et al. [30Robson M, Im S-A, Senkus E, Xu B, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. The New England Journal of Medicine 2017; 377(6): 523-33.] trial primary endpoint was PFS, but the authors did also report OS where possible. At data cut off (December 9, 2016) 36 patients were still receiving olaparib and three were still receiving standard therapy. It would be interesting to know whether these patients are still alive and if not, what the OS was. However, OS results could be unreliable because, after first disease progression, patients in TPC group received treatment with PARPi, platinum and other chemotherapy while still receiving the assigned treatment for this trial (supplementary appendix of Robson et al. 2017 (30]). Additionally, Robson et al.’s [30Robson M, Im S-A, Senkus E, Xu B, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. The New England Journal of Medicine 2017; 377(6): 523-33.] trial is the first trial to measure time to second progression and further analysis should be done in future for PFS2, and even PFS3, as it could be hypothesised that olaparib as a maintenance therapy extends the period of time in between chemotherapy treatments, which is better for patients from a toxicity point of view.

Endpoints are equally important to patients but no trials documented patient preference, or whether patients weigh the importance of each endpoint differently [58Yousif A, Sukhjinder N. A new method of applying RCT data to individual patients: A novel quantitative patient-centred approach to interpreting composite end points. Int J Cardiol 2015; 195: 216-24.[http://dx.doi.org/10.1016/j.ijcard.2015.05.109] [PMID: 26048380] ]. Measuring QoL is important because it improves understanding of a patient's problems by enabling communication between physician and patient [59Klinkhammer-Schalke M, Koller M, Steinger B, et al. Direct improvement of quality of life using a tailored quality of life diagnosis and therapy pathway: Randomised trial in 200 women with breast cancer. Br J Cancer 2012; 106(5): 826-38.[http://dx.doi.org/10.1038/bjc.2012.4] [PMID: 22315052] ]. Robson et al. [30Robson M, Im S-A, Senkus E, Xu B, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. The New England Journal of Medicine 2017; 377(6): 523-33.] OlympiAD trial did measure quality of life (QoL) alongside clinical effectiveness. Despite being outside the scope of this review, it is interesting to note that the QoL data showed a meaningful improvement in health-related quality of life measures in the olaparib arm. Briefly, the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire QLQ-C30 has 100 points, developed to assess the quality of life of cancer patients [60 http:// qol.eortc.org/ questionnaire/ eortc-qlq-c30/ European Organisation for Research and Treatment of Cancer (1995) Quality of Life Group. Version 3.0. ]. In the OlympiAD trial [30Robson M, Im S-A, Senkus E, Xu B, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. The New England Journal of Medicine 2017; 377(6): 523-33.] a drop of 10 points or more was considered a clinically meaningful decrease, which was not reached in the olaparib group and took 15.3 months in a standard therapy group. The onset of response was similar for both groups, which is important when deciding which therapy to give patients in future, especially given the higher ORs and lesion shrinkage rates with olaparib versus standard therapy [30Robson M, Im S-A, Senkus E, Xu B, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. The New England Journal of Medicine 2017; 377(6): 523-33.].

At the time of writing, the complete OS data is not available due to the authors report that it is not yet mature, but a pre-planned interim analysis revealed no difference between olaparib and TPC cohorts (19.3 vs 19.6 months, respectively), likely because of the high degree of cross-over during treatments for PD as mentioned previously. However, if olaparib does extend PFS, but does not extend OS, then it will become important in future trials to assess patients’ QoL during this time, in order to assess additional benefit of olaparib to patient’s lives, rather than just clinical effectiveness.

4.2. Implications Regarding Hierarchy of Evidence and Clinical Effectiveness

Most quantitative investigators argue that RCTs should be central to evidence-based decision making, since, in terms of clinical effectiveness, it is necessary to know the cause and effect relationship between and intervention and the results, based on valid and reliable outcomes [61Ryle G. The Concept of Mind 2000., 62Richards DA, Hamers JP. RCTs in complex nursing interventions and laboratory experimental studies. Int J Nurs Stud 2009; 46(4): 588-92.[http://dx.doi.org/10.1016/j.ijnurstu.2008.12.002] ]. RCTs are a way of assessing the effectiveness of different treatments to find out which one works best relative to others [39Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ 2010; 340: c869.[http://dx.doi.org/10.1136/bmj.c869] [PMID: 20332511] ] and are considered to be the ‘gold standard’ in this regard [63Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS. Evidence based medicine: What it is and what it isn’t. BMJ 1996; 312(7023): 71-2.[http://dx.doi.org/10.1136/bmj.312.7023.71] [PMID: 8555924] ].

However, as we have seen, the trials assessed here have several limitations: small sample sizes, single arm, non-randomised and unblinded designs, imprecision and possible reporting bias. Additionally, there is variation in some methods and results between studies, resulting in a lack of statistical analysis, all of which weakens the strength of the evidence contained within this SR. Guyatt et al. [64Guyatt GH, Oxman AD, Vist GE, et al. GRADE: An emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008; 336(7650): 924-6.[http://dx.doi.org/10.1136/bmj.39489.470347.AD] [PMID: 18436948] ], highlights that a high risk of bias can mean studies are rated down as a lesser robust quality evidence when compared to the gold standard RCT, which has been shown to be the case for the studies in this SR. From a post-positivist stance, Mantzoukas et al. [65Mantzoukas S. A review of evidence-based practice, nursing research and reflection: Levelling the hierarchy. J Clin Nurs 2008; 17(2): 214-23.[PMID: 17419779] ] discourage an acceptance of RCT as the ‘gold standard’ in some circumstances because they cannot accommodate the diversity of patients and real situations faced in daily practice, and therefore the trials included in this SR illustrate pragmatism in design and conduct which has allowed scientists to begin evaluating the effectiveness of olaparib, but has not yet delivered a conclusive result.

However, CEBM says that not all SRs of heterogeneous RCTs need cause concern, and not all heterogeneity of results is statistically significant. Overall, despite RCTs currently being at the heart of evidence-based practice [66Higgins J, Green S. Cochrane handbook of systematic reviews Chicester 2008.], the conclusion of this SR suggests that RCTs being near the summit, and SRs of RCTs being the pinnacle of the ‘hierarchy of evidence’ remains a controversial issue. At the heart of this conclusion is the basis that the development of the RCT is to discover an intervention’s ‘effectiveness’. The function of the trials in this SR is to determine whether olaparib is clinically effective: does it ‘work’? What are the ORRs of olaparib as an autonomous treatment? These studies included in this SR have a clear concept of whether olaparib ‘works’, as the clinical effectiveness is measured, compared and analysed. There are further questions about whether olaparib ‘works’ for patients, and whether it ‘works’ for the healthcare service which isnot answered in six out of seven (all except 30) of the trials in this review.

CONCLUSION

The aim of a SR is to find, analyse, appraise, and summarise the best available evidence related to a specific research question, in order to provide evidence-based answers for practice [67Angela B, Gemma C, Rumona D. Doing a systematic review – A student’s guide 2nd ed. 2nd ed.2017.].

As this review is focussed on clinical effectiveness, results from studies used in this systematic review need the show clinical benefit (or not) to the patient and the response of a tumour/lesion to olaparib treatment. Results will ideally measure OS, PFS, and ORR, which include CR and PR and SD, and possibly the time until disease progression or other interventions (such as chemotherapy, surgery or death). Results also need to show AE resulting from the intervention.

Olaparib (made by Astra Zeneca), an oral PARP inhibitor, is tolerated as a single-agent in continuous doses up to 400 mg [22Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009; 361(2): 123-34.[http://dx.doi.org/10.1056/NEJMoa0900212] [PMID: 19553641] ]. Olaparib has been shown to have promising activity in patients with metastatic BC and BRCAm and has been active as monotherapy in tumours with defective HR repair, specifically with BRCAm [29Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: A proof-of-concept trial. Lancet 2010; 376(9737): 235-44.[http://dx.doi.org/10.1016/S0140-6736(10)60892-6] [PMID: 20609 467] , 33Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015; 33(3): 244-50.[http://dx.doi.org/10.1200/JCO.2014.56.2728] [PMID: 25366685] ]. Clinical activity with extended stable disease (SD) or tumour response (reduction) has been reported in BRCAm BC and OC [29Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: A proof-of-concept trial. Lancet 2010; 376(9737): 235-44.[http://dx.doi.org/10.1016/S0140-6736(10)60892-6] [PMID: 20609 467] , 32Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: A phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 2011; 12(9): 852-61.[http://dx.doi.org/10.1016/S1470-2045(11)70214-5] [PMID: 218624 07] ]. Phase 2 studies have confirmed the activity of olaparib monotherapy BRCAm patients with advanced BC [29Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: A proof-of-concept trial. Lancet 2010; 376(9737): 235-44.[http://dx.doi.org/10.1016/S0140-6736(10)60892-6] [PMID: 20609 467] ] and those with OC [22Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009; 361(2): 123-34.[http://dx.doi.org/10.1056/NEJMoa0900212] [PMID: 19553641] ]. Olaparib has been successful at inducing CR, PR and SD in BRCAm BC patients. Responses were often sustained, even in patients who were heavily pre-treated, making these results significant even in the absence of comparator arms in most studies.

In summary, olaparib as a targeted therapy for BC with BRCAm could potentially shift the paradigm of treating BRCAm BC away from chemotherapy towards targeting individual tumour biology. However, genetic complexity and ORR heterogeneity is currently a major limitation to the success of individually targeted therapy, and further research is needed.

Strength of Conclusion

The Grading of Recommendations Assessment, Development and Evaluation (GRADE) is an approach used to assist a transparent approach to gradequality of evidence, and in line with GRADE criteria (Table 4), the quality of evidence in all of these studies would be graded as low quality because further research is very likely to have an important impact on our confidence in the estimate of effect (Table 4 below). Only one [30Robson M, Im S-A, Senkus E, Xu B, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. The New England Journal of Medicine 2017; 377(6): 523-33.] had a comparatively large sample size (302 patients with BC and BRCAm) and used comparator arms with randomisation, so this trial could be graded as ‘moderate quality’ because further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate [68Guyatt GH, Oxman AD, Vist GE, et al. GRADE: An emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008; 336(7650): 924-6.[http://dx.doi.org/10.1136/bmj.39489.470347.AD] [PMID: 18436948] ]; (Table 4 below). Overall, the seven studies together as a body of evidence would be considered ‘low quality’ according to the GRADE criteria shown in Table 4.

Limitations

There is also the matter of subjectivity to consider. Despite this being a quantitative SR with quantitative methodology and methods, there is still room for personal subjectivity from the point of view of the reader. Are the papers in this review the ones someone else would rank as best answering the question: ‘What is the current effectiveness of olaparib for breast cancer patients with BRCAm?’ Are the methods and methodology used in this review ones that the reader agrees with or not. However, if GRADE is used consistently, then the advantages of simplicity and clarity outweigh these limitations.

Quality of evidence is subjective and judgments about evidence and recommendations in healthcare are complex, however despite the limitations regarding the quality of the evidence, the authors have been clear about how conclusions were drawn about the quality of evidence, and how it was synthesised in this review, explaining Kmet et al. [23Leanne M, Kmet MSc, Robert C, Lee MSc, Linda S. Standard quality assessment criteria for evaluating primary research papers from a variety of fields 2004.], GRADE measurement and scoring techniques, as well as using the CONSORT guidelines for reporting of clinical trials in order to assess the quality of the trials in this SR. Although poor quality studies may lead to biased outcomes [69Gray J A. Muir. Hallmarks for quality of information. British Medical Journal Nov 28, 1998; 317(7171): 1500(1).], and the conclusion of this review indicates the evidence to date is low quality, the researchers of the primary evidence included in this SR were rigorous in their methods and they reported their work in enough detail for others to assess its quality [70Altman DG. Better reporting of randomised controlled trials: The CONSORT statement. BMJ 1996; 313(7057): 570-1.[http://dx.doi.org/10.1136/bmj.313.7057.570] [PMID: 8806240] ]. Given the evidence to date, the outcome of the seven studies in this SR does suggest that the desirable effects of olaparib do outweigh the undesirable adverse effects.

Recommendations for Future Research

Questions remain about how best to use olaparib - either in combination with chemotherapy or as maintenance alone. Combination therapies with olaparib in this SR are extremely limited in number and the selection of the best therapeutic partner is as yet unknown. Such limitations increase the uncertainty of these combination therapies and more studies of combination therapy are needed. A randomised six arm study (including a placebo) could help to define whether an olaparib monotherapy, or olaparib/cisplatin combination therapy, or olaparib/carboplatin combination, improveclinical efficacy versus either platinum agent alone. Additionally, combination trials with other chemotherapy, radiation, immunotherapy and molecular targeted agents should also be explored.

It would also be very interesting to test whether a sequential treatment of olaparib monotherapy, after positive response with a platinum-based therapy, would improve the duration of response compared with olaparib/platinum combination therapy. Responses were observed with combination therapy, followed by durable responses to olaparib monotherapy in patients with BC. These findingssuggest that olaparib might be a promising maintenance treatment following monotherapy or combination chemotherapy, which is a strategy that should be tested in future studies.

Olaparib/chemotherapy combinations to date indicate platinum therapies might have overlapping mechanisms of actions to olaparib and might, therefore, be limited by the shared mechanism of resistance. This warrants further exploration, beyond our current knowledge that BRCAm tumours are sensitive to platinum for the same reason they are sensitive to olaparib. Not all BRCAm tumours in this SR responded to olaparib, and some non-BRCA tumours did respond to olaparib despite, in some cases, prior platinum treatment. This means there is a possibility that crossover of mechanism may not be as clear as we think, and is an area of research that needs further investigation.

Currently, BRCAm is the most reliable biomarker used to select patients for olaparib therapy, whether in combination or not, but as we have seen, not all BRCAm tumours responded to olaparib, and some non BRCA tumours did respond to olaparib, suggesting synthetic lethal interaction with olaparib may be exploited beyond BRCAm. New biomarkers to predict response to olaparib is an area requiring more research in order to identify all patients who might benefit from olaparib. It is clear that if olaparib is to expand into a BRCAwt population, a greater understanding of the mechanism of crossover of resistance is required and robust indicator tests outside of prior platinum response are needed.

While it is clear that olaparib has beneficial activity in BC, the timing of its use remains in question, whether as monotherapy, in combination therapy or as maintenance therapy. Given the success of olaparib in advanced metastatic BRCAm breast cancer, future trials are also needed to study the role of olaparib in early stage disease.

Quality of life (QoL) is something to consider for future trials. Olaparib did have lower toxicities and improved QoL compared to other therapies. Trials so far have not demonstrated increased OS, in spite of PFS benefit. However, the future gold standard for assessment of the efficacy of olaparib should be a clinically meaningful improvement in OS and quality of life (QOL), so future trials must include these in their measured outcomes.

The application of olaparib, (and other PARPi) is an ideal example of the concept of personalised cancer care: identifying molecular and or genetic differences and exploiting them to improve patient therapy and care. Studies in this SR looking at effectiveness show olaparib as an effective, tolerable therapy that could be expanded to other patients groups with further research. However, going forward, we have to further decide whether this is both feasible and appropriate with regard to patient care.

Firstly there is the matter of price. Olaparib is an expensive drug costing $12,155 per month [71 Memorial Sloan Kettering Cancer Centre 2018. Cancer drug costs for a month of treatment at initial Food and Drug Administration approval. https:// www.mskcc. org/sites/ default/ files/node /25097/ documents/ 111516-drug -coststable.pdf]. To put this into perspective, consider Robson et al. [30Robson M, Im S-A, Senkus E, Xu B, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. The New England Journal of Medicine 2017; 377(6): 523-33.] 2.8 month PFS benefit which amounts to $100,000 per patient. Despite the QoL results, we must consider whether the taxpayer is ready to spend this kind of money per person, for a relatively rare type of BC, when there are so many more people with other BCs, and other chronic diseases (diabetes and heart disease for example) that impact on our health as a society. This may not be such an acute consideration in insurance-based health care systems but will be central to decision making in the UK NHS. This will require evaluation by the National Institute for Health and Care Excellence (NICE).

Secondly, genetic testing comes with its own set of problems. Despite genetic testing becoming more affordable, clinical support services would need more funding to cover other services such as genetic counselling for patients and their relatives, and communication with patients and their families about results and what it means for everyone who could be affected. Further research to identify patients and tumour groups that may derive therapeutic benefit from olaparib is required, and research into predictive biomarkers will be crucial to help with that stratification in the future. These are important factors to consider in evidence-based practice and making the decision of whether to implement olaparib therapy in a clinical setting [35Melnyk BM, Fineout-Overholt E. Rapid critical appraisal of randomized controlled trials (RCTs): An essential skill for evidence-based practice (EBP) Pediatric Nursing.2005; 31(1)].

Bryant & Benton [72 Bryant Rosemary (president ICN) & Benton David (CEO ICN), Closing the Gap: From Evidence to Action. The International Council of Nurses. International Nurses Day, 12 May 2012. ISBN: 978-92-95094-75-8] suggest that in our quest for the very best healthcare, we must constantly strive to use evidence-based practice and healthcare practitioners should use the research to challenge, improve, or evaluate practice [73Oermann MH. Hit the web to help guide your practice. Nurs Manage 2007; 38(2): 20-1.[http://dx.doi.org/10.1097/00006247-200702000-00007] [PMID: 172 93769] ].

Overall, the purpose of this SR is to answer the question ‘What is the current effectiveness of olaparib for patients with breast cancer and a BRCA mutation?’ The answer is that olaparib is an active PARPi that has shown significant positive clinical effects in patients with recurrent BC and BRCAm, and compared with single-agent chemotherapy, olaparib monotherapy improves clinical benefit and reduces AE in patients with BC and BRCAm.

However, much larger, longer term studies to investigate the different treatment effects of olaparib among sub-groups are needed, particularly for patients with prior use of platinum therapy, as would a direct comparison study to determine the relative efficacy of olaparib versus platinum therapies. Development of combination regimes is also needed to find the most effective schema with lowest AEs. More long-term safety studies and follow-ups after RCTs are required to establish long-term toxicities and risk of secondary malignancies. Future trials must include OS and QoL in their measured outcomes. In addition, there are several further areas where more research is needed in order to realise the full potential effectiveness of olaparib.

However, since 2009, olaparib has been investigated in BC with the most compelling results found in the subset of patients who harbour BRCAm. Based upon this fact, olaparib should be regarded as a clinically effective potential addition in the fight against BC for patients with BRCAm.

LIST OF ABBREVIATIONS

AE = Adverse Event/Effect
ASCO = American Society of Clinical Oncology
AZ = Astra Zeneca
BiD = Twice a day
BRCA = Breast cancer gene
BRCAm = Mutant breast cancer gene
BRCAwt = Wild-type breast cancer gene
BC = Breast Cancer
CASP = Critical Appraisal Skills Programme
CEBM = The Oxford Centre for Evidence-based Medicine
CINAHL = Cumulative Index to Nursing and Allied Health Literature
COCHRANE = The Cochrane library
CR = Complete Response
CRD = Centre for Reviews and Dissemination
CTCAE = Common Terminology Criteria for Adverse Events
DLT = Dose limiting Toxicity
DNA = Deoxyribonucleic Acid
ECOG = Eastern Cooperative Oncology Group
EMA = European Medicines Agency
EORTC = European Organization for Research and Treatment of Cancer
FDA = Food and Drug Administration (USA government dept.)
GRADE = The Grading of Recommendations Assessment, Development and Evaluation
Grey material = Unpublished material or evidence
JBI = Joanna Briggs Institute
MTD = Maximum Tolerated Dose
NHS = National Health Service
NICE = National Institute for Health and Care Excellence
OC = Ovarian Cancer
OR(R) = Objective Response (Rate)
OS = Overall Survival
PR = Partial Response
PD = Progressive Disease
PFS = Progression Free Survival
PARPi = Poly (ADP-Ribose) Polymerase inhibitors
PICO = Population, Intervention, Comparative intervention, Outcome
PROSPERO = An international database of prospective SRs
PRIMO = University of Plymouth Online Library
PRISMA = Preferred Reporting items for Systematic Reviews and Meta-Analyses
PRISMA-P = Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols
QoL = Quality of Life
RCT = Randomised Clinical Trial
RECIST = Response Evaluation Criteria in Solid Tumours
SD = Stable Disease
SR = Systematic Review
TNBC = Triple Negative Breast Cancer
TPC = Therapy of Physician’s Choice
WHO = World Health Organisation

CONSENT FOR PUBLICATION

Not applicable.

CONFLICT OF INTEREST

This study is adapted from an unfunded MSc dissertation.

ACKNOWLEDGEMENTS

Declared none.

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Endorsements



"Open access will revolutionize 21st century knowledge work and accelerate the diffusion of ideas and evidence that support just in time learning and the evolution of thinking in a number of disciplines."


Daniel Pesut
(Indiana University School of Nursing, USA)

"It is important that students and researchers from all over the world can have easy access to relevant, high-standard and timely scientific information. This is exactly what Open Access Journals provide and this is the reason why I support this endeavor."


Jacques Descotes
(Centre Antipoison-Centre de Pharmacovigilance, France)

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."


Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


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