Summary of main results

We identified a total of 49 articles describing six eligible studies for qualitative analysis. Five studies comprising a total of 1474 participants were included in the meta‐analyses. Three studies were large phase 3 randomised controlled trials (BROCADE 3; EMBRACA; OLYMPIAD) and two were phase 2 trials (BROCADE 2; Kummar 2016). Trial design differed in that two of the phase 3 studies compared single agent PARP inhibitors to physician’s choice of chemotherapy (EMBRACA; OLYMPIAD) and the other three studies compared PARP inhibitors plus chemotherapy to placebo plus chemotherapy (BROCADE 2; BROCADE 3; Kummar 2016. Three studies used veliparib (BROCADE 2; BROCADE 3; Kummar 2016) and the others used olaparib (OLYMPIAD) and talazoparib (EMBRACA) in their PARP inhibitor intervention arms. Four of the five studies (BROCADE 2; BROCADE 3; EMBRACA; OLYMPIAD) were powered to assess progression‐free survival, with overall survival being a secondary outcome and one phase 2 study, the smallest, (Kummar 2016) assessed tumour response rate as the primary outcome and progression‐free survival as a secondary outcome.

The primary objective of this review was to assess the effects of PARP inhibitors for patients with locally advanced or metastatic breast cancer. Four out of five studies (1435/1474 patients) included only women with a germline BRCA mutation and similarly most participants were HER2‐negative (only 10 patients in BROCADE 2 were HER2‐positive) so our results pertain to these groups predominantly.

Our systematic review indicates that PARP inhibitors offer a PFS benefit in advanced/metastatic HER2‐negative, BRCA germline mutated breast cancer patients. Importantly, to the authors' knowledge, our systematic review provides the first evidence that PARP inhibitors may also offer a small advantage in overall survival. Pooled analysis also showed a likely improved response rate with PARP inhibitors. There was little to no heterogeneity in the overall analyses and most of the subgroup analyses, consistent with the observation that included studies were largely designed in a similar fashion. This provides evidence that the use of PARP inhibitors can form part of the therapeutic strategy for this subgroup of breast cancer patients. The risk of death at two years is 55% for patients not treated with PARPi, and 49.7% for patients treated with PARPi (equivalent to a number needed to treat for an additional beneficial outcome of 18.9). The risk of progression or death at one year was 62.5% for patients not treated with PARPi, and 46.1% for patients treated with PARPi (equivalent to a number needed to treat for an additional beneficial outcome of 6.1) (See summary of findings Table 1).

These positive overall findings are supported by the subgroup analyses all showing consistent findings of a persistent PFS benefit. We showed that PARP inhibitors confer a PFS benefit in advanced HER2‐negative, BRCA germline mutated breast cancer regardless of whether the patient carries a BRCA 1 or 2 mutation, whether the tumour is triple‐negative or not and regardless of whether chemotherapy was previously given in the metastatic setting.

Several studies have evaluated the use of platinum agents in patients with germline BRCA mutations. In particular, the TNT trial (Tutt 2018) showed an objective response rate of 68% with carboplatin versus 33% with docetaxel among 43 patients with metastatic triple‐negative breast cancer and a known BRCA mutation. That is, platinum chemotherapy is also an effective treatment for our patient population. Platinum‐based agents were not included as an option in the standard‐therapy groups of OLYMPIAD or EMBRACA so, given the results of the TNT study, the trials realistically only compared PARP inhibitors against second‐line therapies which is a limitation. It is unknown how PARP inhibitors would compare with first‐line drugs. In our systematic review, four out of the five studies (Kummar 2016 did not specify) excluded patients who failed prior treatment with platinum chemotherapy but patients were allowed prior platinum exposure in EMBRACA, OLYMPIAD and BROCADE 3. In this admittedly small subgroup of patients who had prior exposure to platinum‐based agents (205 patients), there was no significant PFS benefit demonstrated with PARP inhibitors, however, a 29% risk reduction was shown. As mentioned, these results need to be interpreted with caution and, given the small numbers, benefit from a PARP inhibitor in this particular subgroup should be confirmed in future studies. BROCADE 2 and BROCADE 3 assessed the efficacy of the combination of a PARP inhibitor and platinum chemotherapy acknowledging shared mechanisms of resistance and showed superiority with the combination compared to platinum chemotherapy alone. Head‐to‐head studies to compare platinum‐based agents with PARP inhibitors and to compare the response rates after progression among classes of inhibitors are lacking. A further limitation is the lack of taxane in the comparator arms of trials comparing PARP inhibitors to physicians' choice, such that it is unclear whether a patient should have a taxane or PARP inhibitor if taxane is being considered either first‐line (e.g. when platinum was given adjuvantly) or after platinum. This research is necessary to provide important insight into efficacy and sequencing.

Our systematic review indicates there is likely to be no increase in toxicity with PARP inhibitors when looking at overall grade 3 or above adverse events. Combining this with the added advantages of ease of administration and convenience of oral administration, PARP inhibitors are an appealing alternative to intravenous chemotherapy. It is important to note that our systematic review included studies using three different PARP inhibitors. Common toxicities for all PARP inhibitors included fatigue, gastrointestinal toxicities and cytopenias (Ho 2019, Murthy 2019). However, differences in toxicities between PARP inhibitors have emerged from the studies included in this review as well as other clinical trials (Murthy 2019). Olaparib’s most common grade 3 toxicity is anaemia (OLYMPIAD). The most frequent grade 3 or 4 toxicity for talazoparib was anaemia (EMBRACA). A phase 2 trial evaluating single agent veliparib in recurrent ovarian cancer patients showed the main grade 4 toxicity was thrombocytopenia (Coleman 2015). Our systematic review showed neutropenia was significantly less common and anaemia was significantly more common in patients receiving PARP inhibitors but there was not a meaningful difference in rates of other adverse events of any grade including thrombocytopaenia and fatigue. An upcoming systematic review and meta‐analysis may shed further light on the incidence of adverse events following use of different PARP inhibitors (Ho 2019).
Quality of life data were not easily available and were not amenable to quantitative analysis (only reported in two studies). This is obviously an important issue for both patients and clinicians, for objective quality of life indices help determine whether the adverse events from PARP inhibitors are outweighed by the known clinical benefit. This highlights the importance of collecting such data in future studies.

Overall completeness and applicability of evidence

The studies identified are relevant to the aims of this review and the clinical needs of the defined subgroup of patients with advanced breast cancer. This review allowed evaluation of all protocol‐defined endpoints, some fully and some partially. In terms of efficacy endpoints, OS, PFS, and response rates have been well reported with sufficient statistical information to allow meta‐analysis. On the other hand, documentation of quality of life outcomes was inadequate for meta‐analysis.

The overall survival results, our primary outcome, were limited by the lack of trials powered for overall survival as a primary endpoint. Also, only four out of five studies reported overall survival.

Our results were also limited by availability of only three phase 3 clinical trials, as well as the differing comparator arms of PARP inhibitor plus chemotherapy versus chemotherapy alone (BROCADE 2; BROCADE 3; Kummar 2016) compared to single agent PARP inhibitor versus physician’s choice of chemotherapy (EMBRACA; OLYMPIAD). Although there was minimal statistical heterogeneity, there is obvious clinical heterogeneity when combining outcomes from single‐agent PARP inhibitor studies and those from combination chemotherapy and PARP inhibitor studies. Potential ways to shed light on this heterogeneity would include between‐study analysis using individual patient data and/or a network meta‐analysis, however, data were not available to do this.

Our review identified studies that used three different PARP inhibitors. Given there were only five studies included, this means that there was a small number of studies for each PARP inhibitor. In pooling outcome data for the current study, we determined that there was an insufficient number of studies and no methodological grounds to perform analyses comparing the effects of individual PARP inhibitors. Therefore, investigation of which PARP inhibitor may be superior to another (and particularly in differing clinical settings) is outside the scope of the current study.

Baseline characteristics differed slightly in the trial populations. BROCADE 2; BROCADE 3 and EMBRACA included patients with locally advanced breast cancer whereas Kummar 2016 and OLYMPIAD only included metastatic patients. BROCADE 2 and BROCADE 3 had a higher proportion of patients without any prior chemotherapy treatment for metastatic disease compared to the other trials. BROCADE 2 is the only study to include HER2‐positive patients, albeit very small numbers (three in the PARP inhibitor arm and seven in the control arm).

In terms of applicability to current practice, our results support the use of PARP inhibitors in advanced/metastatic HER2‐negative, BRCA germline mutated breast cancer patients. This is in line with current FDA approvals. Olaparib was approved by the FDA in January 2018 for the treatment of patients with previously treated advanced or metastatic HER2‐negative, BRCA germline mutated breast cancer, on the basis of the progression‐free survival benefits published in the OlympiAD trial (OLYMPIAD). Talazoparib was approved for the same indication, based on the EMBRACA results, in October 2018. The third PARP inhibitor identified by our review, veliparib, has not yet been approved but the complete results of BROCADE 3 are yet to be formally published.

Quality of the evidence

Although only five studies were included for meta‐analysis and only three of these were phase 3 studies, there were a large number of patients (1474) and we believe that the conclusions drawn are clinically meaningful. We acknowledge the different choice of PARP inhibitors and difference in study design. However, there was homogeneity of results and minimal statistical heterogeneity, with each study individually concluding PARP inhibitors are superior to their comparator treatments and our meta‐analysis adds weight to this.

The results included in this systematic review allow a robust conclusion regarding the primary objective addressed in the overview, that of overall survival benefit in advanced/metastatic HER2‐negative, BRCA germline mutated breast cancer patients. Similar high‐quality evidence was available for the outcome of PFS. See summary of findings Table 1.

Lower quality evidence was available for the outcomes of response rates and grade 3 to 4 overall toxicity. We considered the quality of evidence for response rates to be low and was downgraded due to inconsistency. We considered the quality of evidence for grade 3 to 4 overall toxicity to be moderate and was downgraded due to imprecision. See summary of findings Table 1.

Potential biases in the review process

A thorough search was conducted to find all relevant studies including searching relevant databases and handsearching other resources. Relevant data were obtained from published sources, as well as an unpublished source in the case of BROCADE 3. We attempted to obtain complete data by contacting the authors, including data on overall survival from Kummar 2016. Methods used for the meta‐analysis were standard and unlikely to have introduced bias. We believe our systematic review and meta‐analysis has a low risk of bias.

Agreements and disagreements with other studies or reviews

There are a number of other meta‐analyses looking at PARP inhibitors in all tumour types but very few meta‐analyses looking at the role of PARP inhibitors in breast cancer specifically.

We note that Bao and colleagues (Bao 2016) published a meta‐analysis on the effectiveness and safety of PARP inhibitors in cancer therapy and concluded that PARP inhibitors do well in improving PFS with little toxicity, especially in patients with BRCA deficiency. However, no significant difference in overall survival between the PARP inhibitors and controls, even in the BRCA mutation group, was found. This meta‐analysis did not include the studies we have included for our meta‐analysis. In fact, the only studies that were included looking at PARP inhibitors in breast cancer specifically were two studies using iniparib (O'Shaughnessy 2011; O'Shaughnessy 2014), which has since been disproved to be a PARP inhibitor mechanistically (Liu 2012).

We note that Poggio and colleagues published a meta‐analysis on single‐agent PARP inhibitors for the treatment of patients with BRCA‐mutated HER 2‐negative metastatic breast cancer (Poggio 2018) and included two RCTs (EMBRACA; OLYMPIAD) for meta‐analysis. We agree with their conclusions that PARP inhibitors were associated with significantly improved PFS and response rates. They found no difference in overall survival when analysing only these two studies. Also, use of single‐agent PARP inhibitors was associated with a significantly increased risk of anaemia and any grade of headache, but a reduced risk of neutropenia and any grade of palmar‐plantar erythrodysesthesia syndrome, as compared with chemotherapy. This study has similar methodology to ours, however, we are investigating a larger group and therefore have relevant findings for more breast cancer patients.

There is growing evidence regarding the role of immune checkpoint inhibitors, especially in triple‐negative metastatic breast cancer. Impassion130 (Schmid 2018) showed a modest but statistically significant difference in progression‐free survival in favour of combination atezolizumab with nabpaclitaxel compared with nabpaclitaxel alone. However, the question remains whether PARP inhibitors or checkpoint inhibitors are more effective in metastatic BRCA mutated triple‐negative patients, or whether a combination may be superior.

From the current information available, including the addition of our systematic review results, it remains difficult to know which PARP inhibitor to choose for which patient. There are also two other PARP inhibitors on the market, niraparib and rucaparib, and these are under investigation for breast cancer patients. The phase 3 BRAVO trial, assessing single‐agent niraparib in locally advanced or metastatic, HER2‐negative, BRCA1/2‐mutated breast cancer, ended prematurely (BRAVO). But with more studies underway and the minimal chance of head‐to‐head studies being performed, it will likely come down to physician preference and drug availability.