Efficacy and safety of PARP inhibitor in non-small cell lung cancer: a systematic review with meta-analysis

Introduction

Non-small cell lung cancer (NSCLC) accounts for more than 80% of all lung cancers (1,2). Approximately two-thirds of all NSCLC patients have advanced disease at diagnosis (stage IIIB to IV) and are treated with systemic therapies using chemotherapeutic agents, immunotherapy or drugs directed against molecular targets (3,4). Despite the great advances in terms of response, survival and toxicity that are being achieved in these patients, new target therapies are being investigated in NSCLC given the great advances in the molecular characterisation of lung cancers (5,6).

Poly (ADP-ribose) polymerase (PARP) enzymes are a family of nuclear enzymes involved in the recognition and repair of single DNA breaks (7-9). The main activity of PARP is poly-ADP ribosylation of key chromatin components and other proteins involved in DNA repair (10). PARP1 can open chromatin and facilitate the entry of DNA repair factors (11). Therefore, PARP inhibitors (iPARPs) have emerged as a new avenue of research for the treatment of NSCLC, with very promising results at the preclinical level (12).

The activity of iPARPs was originally established in tumours with BRCA1 and BRCA2 gene mutations showing homologous recombination deficiency (HRD) (13,14). Subsequently, its activity was also characterised in HRD tumours with mutations in other homologous recombination (HR)-associated genes such as RAD51C (15), RAD51D (16), PALB2 (17) or BARD1 (18). Given these findings in tumours such as ovarian or prostate tumours, it has also been suggested that they may have potential benefit in tumours where HRD is not fully studied and known, such as NSCLC (19,20).

The Food and Drug Administration (FDA) and the European Medicine Agency (EMA) have approved several iPARPs for the treatment of different tumours such as ovarian, breast, prostate or pancreatic tumours (Figure 1) (21). To date, few studies have evaluated the efficacy of iPARPs in NSCLC; however, the data are promising in some cases, and thus, a pooled assessment is essential to understand these new treatments, which could have important implications (22,23). The presence of tobacco in carcinogenesis has meant that some molecular pathways have not been fully studied in NSCLC. One of the most promising pathways is HRD. The percentage of lung cancer with HRD is currently unknown, and its influence may derive both from treatment with iPARPs and immune checkpoint inhibitors for example.

Figure 1 Main iPARPs approved by the EMA for the treatment of solid tumours with their therapeutic indications. iPARPs, poly ADP ribose polymerase inhibitors; EMA, European Medicine Agency; HRD, homologous recombination deficiency; gBRCA1/2, germline mutation in BRCA1/2; HER2, receptor tyrosine-protein kinase erbB-2; CT, computed chemotherapy; mCRPC, metastatic castration-resistant prostate cancer.

Studies to date with iPARPs have not provided answers as to how these treatments may benefit patients with NSCLC in clinical practice. For this reason, the aim of this systematic review is to evaluate the efficacy and safety of iPARPs in the treatment of NSCLC using the different clinical trials currently conducted and published in this field. We present this article in accordance with the PRISMA reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-23-58/rc).

Methods

Search protocol and strategy

Following the quality criteria of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), we searched PubMed, COCHRANE, Science Direct, EMBASE and the clinical trial registry (http://www.clinicaltrials.gov/) for clinical trials and systematic reviews aimed at evaluating the efficacy in terms of response and survival of iPARP in NSCLC. Publications in English, French and Spanish from 2014 to 2023 were evaluated and included. The flow chart of the study is shown in Figure 2.

Figure 2 PRISMA flow chart of the systematic review. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Search terms and combinations included (non-small-cell lung cancer OR lung cancer) AND (iPARP OR PARP inhibitor) AND (niraparib OR iniparib OR olaparib OR talazoparib OR veliparib OR rucaparib). In addition, the following filters were applied: “clinical trial”, “meta-analysis”, “review” and “systematic review”. No restrictions were applied in terms of study type, publication type, publication date or language.

Selection of studies (inclusion and exclusion criteria)

Studies eligible for systematic review were phase I, II or III clinical trials that evaluated the efficacy and safety of iPARPs (in monotherapy or combination) in NSCLC. The criteria were as follows:

Inclusion criteria:

• Clinical trials or systematic reviews uniquely evaluating the association between iPARPs and the treatment of NSCLC;
• iPARP treatments are associated with combinations with chemotherapy, radiotherapy, immunotherapy or drugs against molecular targets;
• Included studies should indicate response in terms of RECIST1.1 (Response Evaluation Criteria in Solid Tumours) criteria, survival in terms of overall survival (OS) and progression-free survival (PFS) and toxicity in terms of CTCAEv4.0 (Common Terminology Criteria for Adverse Events).

Exclusion criteria:

• Clinical trials published as preliminary abstracts or conference papers without definitive results;
• Clinical trials or reviews reporting duplicate results, study protocols or editorials;
• Clinical trials evaluating the efficacy of iPARPs in NSCLC as a subgroup within different solid tumours, without analysis in stand-alone NSCLC;
• Studies with non-assessable measures of response to iPARP treatment.

Quality assessment and publication bias

Two authors independently reviewed the articles and abstracts (A.O.H. and J.R.R.). Those publications that passed the inclusion criteria were analysed in depth and selected for the present review with confirmation by a third independent reviewer (E.B.M.). Publication bias was assessed using Egger’s test and a funnel plot (P value of 0.05 showed asymmetry of the plot).

Data extraction and statistical analysis

Data extracted by the two investigators independently were: title, first author, year of publication, number of patients included, type of population selected, tumour stage, histological subtype, phase of clinical trial, clinical trial arms (concomitant treatments to iPARP), primary objective, secondary objectives, OS, PFS, response and toxicity.

Survival, response and toxicity data have been pooled in a database that was subsequently transformed into a summary data table. The variables in the database were analysed with variables expressed in qualitative and quantitative terms, trying to express the data as homogeneously as possible. The statistical software SPSS, version 28 (IBM^®) was used to analyse the data.

In the meta-analysis, study heterogeneity was calculated using the I² test. A value <25% indicated low heterogeneity, a value of 25–50% medium heterogeneity and a value >50% high heterogeneity. Statistical significance was set at P<0.05, with all values reported bilaterally. The influence of each of the studies was compared with a sensitivity analysis.

Results

General characteristics of the sample

The literature search identified a total of 14 articles that were included for analysis. Overall, a total of 2,651 patients were included. Of these patients, 1,503 patients were randomised to receive iPARP alone or in combination with other systemic treatment and 1,148 patients were included in the control arms who were given standard treatment. The most commonly used chemotherapy schedule, adding both experimental and control arms, was carboplatin/paclitaxel (total 1,860 patients).

Seven studies (50%) evaluated iPARP in first line, all used veliparib in combination with carboplatin/paclitaxel, two of them included unresectable stage III patients and evaluated the use of radiotherapy plus veliparib plus chemotherapy schedules. There were also studies including patients in more advanced lines of treatment and one study to evaluate a subsequent maintenance strategy with iPARP vs. placebo.

Eight (57.1%) studies were phase II clinical trials, four (28.6%) were phase I clinical trials and only two (14.3%) studies were phase III clinical trials. The main characteristics of the studies are listed in Table 1. One phase III study stratified and assessed LP52 (clinical and genomic predictor of iPARP response). In the combination group of veliparib plus chemotherapy (carboplatin/paclitaxel) or chemotherapy alone was 13% LP52⁺. In LP52⁻, 25% were in the veliparib plus chemotherapy (carboplatin/paclitaxel) group and 18% in chemotherapy alone. No clinically significant differences were observed between treatment groups based on epidemiology or tumour pathology.

Efficacy analysis of iPARP in localised or locally advanced stages

Three clinical trials have evaluated the role of iPARPs in localised or locally advanced stages. All three studies have analysed this role in combination with radiotherapy plus platinum. In total, 128 patients are part of these three clinical trials, of which 105 patients are in the experimental arm with iPARP and 23 patients in the control arm. All three studies showed that in terms of safety, the combination of radiotherapy with platinum and radiotherapy is well tolerated with an acceptable adverse event rate for its combination in clinical practice.

At the efficacy level, all three studies showed favourable results, although only two of them present the assessment of survival or response as a primary objective. Notably, the study by Kozono et al. (24), shows an objective response rate (ORR) of 73% with a median PFS of 19.6 months with no control group. The other study by Argiris et al. (25), has a similar response and survival rate between the veliparib vs. placebo group, although at the OS level it shows a 1-year survival rate of 89% for the iPARP arm vs. 54% in the placebo arm (not statistically significant). At the response rate level, there was no statistical difference between the veliparib vs. placebo group (56% vs. 69%).

Efficacy analysis of iPARP in metastatic stages

Among the studies that evaluated iPARPs in metastatic stages, six of them do so in combination with chemotherapy +/− immunotherapy, two the action of iPARPs without combinations, one study the combination of iPARPs with immunotherapy, another the action of NSCLC with target mutations (EGFR) and finally another study the action of iPARPs in the treatment of central nervous system metastases (Table 2). Among the combination studies with chemotherapy, the studies by Ramalingam et al. (26) and Govindan et al. (27), overall, did not show greater efficacy of combination treatments with veliparib vs. placebo, however, in patients with LP52⁺, greater efficacy was observed. The first study showed an OS in the LP52⁺ NSCLC subgroup of 14 months for veliparib vs. 9.6 months for placebo [hazard ratio (HR) =0.66; 95% confidence interval (CI): 0.49–0.89] The second study, with similar results, shows a lack of efficacy in the overall analysis, but with a trend towards a better OS in LP52⁺ tumours of 11.2 months for veliparib vs. 9.2 months for placebo (HR =0.64; 95% CI: 0.40–1.05).

Given the current standard of care for advanced or metastatic NSCLC with chemo-immunotherapy in programmed death-ligand 1 (PD-L1) <50% without target mutations, the study by Clarke et al. (28) is of particular interest. This clinical trial shows a partial response rate as best response of 64.0%, with an ORR of 40.0% for the overall population. In the remaining three studies evaluating the combination of chemotherapy plus iPARP, a trend towards increased response and survival was observed for the combination vs. the platinum doublet, although not statistically significantly.

Of the remaining studies, particularly significant is the clinical trial by Ramalingam et al. (29), which shows that the combination of nivolumab plus niraparib is effective in the treatment of advanced or metastatic NSCLC with higher response and survival rates than single immunotherapy treatment for tumours with PD-L1 values of 1–49% (median PFS 8.4 months and OS not reached). The other important study, being the only one to date that has evaluated the effectiveness of iPARPs in NSCLC with driver mutations, is that of Garcia-Campelo et al. (30). This study compares the combination of a first-generation EGFR inhibitor such as gefitinib with olaparib vs. treatment alone (standard at the time of the study). This study failed its primary endpoint of PFS, with a rate of 12.8 months for the combination vs. 10.9 months for gefitinib alone (HR =1.38, 95% CI: 1.00–1.92). Subsequently, a study published by Karachaliou et al. (38) subanalysed these patients according to BRCA1 messenger ribonucleic acid (mRNA) expression. In these patients with high expression, PFS was 12.9 months for the olaparib arm vs. 9.2 months for placebo (P=0.0449).

Overall analysis of iPARP efficacy in NSCLC

A global analysis of the sample was performed by meta-analysis. The analysis included those studies that provided data in OS and PFS. The only one of the studies analysed that was in localised or locally advanced stages was Argiris et al. (25). In the OS analysis, the use of iPARPs is statistically significantly beneficial (HR =0.85, 95% CI: 0.74–0.97). The heterogeneity of the studies (I²) was 0% (P=0.84), with a weight of 43.3% from the study by Ramalingam et al. (26). The forest plot is shown in Figure 3A.

Figure 3 Forest plot summary of the main clinical trials with iPARP in NSCLC that showed data in OS (top forest plot) (A) and PFS (bottom forest plot) (B). iPARP, poly (ADP ribose) polymerase inhibitor; SE, standard error; IV, inverse variance; CI, confidence interval; NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival.

For PFS, there is no statistically significant benefit for the use of iPARPs (HR =0.93, 95% CI: 0.74–1.17). The I² in this case was 51% (P=0.07). The weight of the studies showed a main effect of the study by Ramalingam et al. (26) with 32.1% of the total. Forest plot in Figure 3B.

Safety of iPARP in NSCLC

Among the top five studies by number of patients [Garcia-Campelo et al. (30), Ramalingam et al. (26), Chabot et al. (37), Ramalingam et al. (36) and Govindan et al. (27)], toxicity was slightly higher in the iPARP arm vs. the control, primarily at the expense of grade ≥3 toxicity. Ramalingam’s studies (26,36) combining platinum doublet therapy with veliparib show an overall toxicity of any grade of both studies of 95.9% (566/590 patients) for the veliparib arm vs. 95.1% (508/534 patients) in the placebo arm. For grade ≥3 toxicity in the veliparib arm the event rate was 61.7% (364/590 patients) vs. 58.2% (311/534 patients) in the placebo arm. In the study by Govindan et al. (27), also combining veliparib with platinum doublet, the toxicity of serious adverse events ≥3 was 11% higher in the veliparib arm vs. placebo. The rate of adverse events of any grade was similar between the two arms. In all three clinical trials, the main toxicity was haematological followed by digestive toxicity.

In the study by Chabot et al. (37) evaluating the combination of radiotherapy with veliparib, an adverse event rate of any grade was 98% in the iPARP arm vs. 90% in the placebo arm. In grade ≥3 toxicity, the event rate was 25% for veliparib vs. 43% for placebo. Finally, in the study by Garcia-Campelo et al. (30) the rate of grade ≥3 adverse events were equal between both arms (61.54% vs. 61.54%). All patients in both arms (100%) had some type of toxicity. In this study, the occurrence of grade ≥3 anaemia was statistically significantly higher in the veliparib arm (16.5%) vs. placebo (2.2%). In both studies, as in the previous three, the most important toxicity was haematological toxicity followed by digestive toxicity.

Discussion

The treatment of NSCLC has changed dramatically in the last decade (39). The discovery and characterisation of different molecular targets has led to survival rates that were unimaginable more than a decade ago (40-42). HRD is one of the most promising targets in this field, with important studies having already evaluated the efficacy of iPARPs in NSCLC (43). In this systematic review, we found a total of 14 clinical trials in different phases that have evaluated this efficacy. An overall analysis of the different clinical trials shows that the results of iPARPs as a potential new treatment in NSCLC are limited. Most of the clinical trials failed in their primary endpoints, failing to demonstrate that the addition of an iPARP to standard therapy increases response rate or survival, regardless of the line of therapy initiated. Nevertheless, there are several data supporting new clinical trials in patients selected for biomarkers predictive of response to iPARPs such as HRD and somatic or germline mutations in BRCA1 and BRCA2 genes (44,45).

Clinical trials in iPARP without HRD biomarkers or driver mutations

The two main clinical trials conducted were those of Govindan et al. (27) and Ramalingam et al. (26). Both phase III studies compared the combination of platinum-based chemotherapy with veliparib vs. placebo in non-squamous NSCLC histology in the former and in squamous NSCLC in the latter. Both studies failed in their primary objectives of showing OS benefit in the veliparib arm, however, both showed the importance of patient selection for these treatments in NSCLC. In these cases, the use of a genomic platform known as LP52 was shown to be a possible clinical tool for the use of iPARPs in NSCLC (46,47), although these results will need to be assessed in independent studies. Therefore, this opens a way to assess the need for HRD or BRCA1/2 status in NSCLC, as is done for other molecular alterations such as EGFR, ALK, ROS1 or K-RAS (48).

Furthermore, these studies did not compare current treatment standards with chemo-immunotherapy at PD-L1 <50% (49) or immunotherapy at PD-L1 ≥50% (50). Preclinical investigations suggest the hypothesis of an increased response to immunotherapy in patients with HRD⁺ tumours, particularly NSCLC (51). Therefore, the results of both clinical trials are likely to be affected by the lack of immunotherapy treatment in either arm. Of all the clinical trials conducted with iPARP in NSCLC, there are two that jointly assessed immunotherapy together with iPARP. These two clinical trials [Ramalingam et al. (29) and Clarke et al. (28)] phase I and II, showed similar results in response rates to the pivotal drug approval clinical trials. Most notably, the Clarke et al. phase I trial assessed the response rate of the combination of chemotherapy plus nivolumab and veliparib in 25 patients with advanced-stage NSCLC. The ORR of these patients was 64.0%, which was similar to the response rate of the KEYNOTE-189 (47.6%) (52) and KEYNOTE-407 (57.9%) (53) studies that assessed the chemo-immunotherapy combination. Therefore, this also opens a new avenue to evaluate new phase III clinical trials assessing the combination treatment of chemo-immunotherapy plus iPARP in advanced NSCLC and PD-L1 <50% and of immunotherapy plus iPARP with PD-L1 ≥50%.

Clinical trials in iPARP with HRD biomarkers or driver mutations

A key study that expands the knowledge on iPARPs in NSCLC is the one conducted by Garcia-Campelo et al. (30). This phase II clinical trial evaluated the efficacy of iPARPs in EGFR-mutated tumours. Data on both survival and response were unfavourable for the olaparib arm with no difference between the anti-EGFR drug alone or in combination. Furthermore, these results were consistent regardless of EGFR mutation type. It is likely that EGFR-mutated NSCLCs are HRD⁻ tumours and have a lower accumulation of mutations, so that the action of iPARPs is more deficient than in tumours without target mutations. As in the previous cases, patient selection is key to understanding the poor results in all the clinical trials that have been done in this field. Of particular importance in understanding this point is the study by Karachaliou et al. (38), which demonstrated the superiority of the combination of EGFR with iPARP in NSCLC with high mRNA expression of the BRCA1 gene.

One aspect on which there is consensus in most studies in the literature, both in EGFR-mutated and naïve tumours, is the importance of the presence of co-mutations to those existing in HRD-associated genes (BRCA1, BRCA2, RAD51C, PALB2, etc.) (54). The presence of TP53 mutations in NSCLC (50–65%) is suspected to confer worse response to anti-EGFR, so their existence may condition unfavourable response to iPARPs even in HRD⁺ tumours (55). However, the involvement of TP53 mutations in the response to immunotherapy is doubtful, with some studies indicating a greater response to immune checkpoint inhibitors. Therefore, in selected patients with HRD⁺ NSCLC and mutated TP53, a combination of iPARP with immunotherapy (in addition to chemotherapy depending on PD-L1 values) could be a highly recommended option. Along with TP53 mutations, other mutations such as PTEN or RB1 are also suspected to influence the efficacy of iPARPs, which shows the importance of proper patient selection for clinical trials with iPARPs (56).

Global efficacy of iPARP in NSCLC

In the overall analysis of the efficacy of iPARPs in NSCLC, a statistically significant benefit is observed for OS with a HR of 0.85. In the fixed-effect statistical analysis, a high homogeneity of the studies was noted. However, in the PFS no statistically significant final value was found in the forest plot with an intermediate heterogeneity for the clinical trials (random-effect). The finding of these results highlights the importance of the primary objective sought in clinical trials. Most studies have PFS or response as this objective, without looking for OS. It is likely that the effect of iPARPs in NSCLC is more long-term and their effect on tumour biology is more durable than classical chemotherapy through changes in the tumour genome or microenvironment.

It is important to consider the relative weight of the studies. In the case of our study, the clinical trial by Ramalingam et al. in 2021 (26) has a weight of 43.3% in OS and 32.1% in PFS. This may significantly influence the results because it is the largest clinical trial of iPARP in NSCLC. However, as previously indicated, this study may mark the beginning of the benefit of iPARPs in clinical practice using genomic platforms or biomarkers that allow for proper patient selection. In addition, when evaluating the results, it is also important to consider in the meta-analysis the presence of the study by Argiris et al. (25) which was performed in localised and locally advanced stages. The weight of this study was 1.7% in OS and 5.3% in PFS and this may have conditioned part of the results, especially for PFS.

Side effects of iPARP in NSCLC

Overall, clinical trials have shown a similar rate of adverse events of any grade between the iPARP vs. placebo combination arms. Serious adverse event rates were slightly higher in the iPARP groups, with rates 0–12% higher than the placebo groups. However, rates of minor adverse events were similar between the two groups. This higher percentage of grade ≥3 toxicity in the iPARP arms was mainly due to the combination of iPARP with anti-EGFR, with no such association observed in the iPARP with chemotherapy combination. The rates of grade 5 adverse events were similar in both groups. Therefore, iPARP combinations in NSCLC appear to be safe in their different modalities.

In summary, it would be important to consider standardised HRD status for patients with advanced NSCLC in the future, as in other tumours such as ovarian cancer. In these patients, just as PD-L1, EGFR, ALK, ROS or K-RAS determination is routinely performed (57), HRD status could also be considered for a better understanding of the patients and their correct selection. Future clinical trials in this field should certainly optimise the section of patients to obtain correct results.

Conclusions

Studies to date on iPARP treatment in NSCLC have failed in terms of response and survival. The correct selection of patients, through predictive biomarkers of response to iPARPs, appears to be the right way forward for future clinical trials. Undoubtedly, iPARPs are opening a very promising path in the treatment of NSCLC, which in the future could be standardised in properly selected patient tumours.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-23-58/rc

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-23-58/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-23-58/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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