Efficacy and safety of poly ADP-ribose polymerase inhibitors (PARPis) in extensive-stage small-cell lung cancer (ES-SCLC) treatment: a systematic review and meta-analysis

Introduction

Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor that accounts for approximately 15% of all lung cancers (1-4). SCLC is classified into extensive-stage (ES) and limited-stage disease (5,6), and nearly 70% of SCLC patients are diagnosed with ES disease (5). The incidence of SCLC has decreased steadily in recent years; however, the treatment options have not changed significantly in the past three decades (3,5,7), and the 5-year survival rate of SCLC patients remains low.

Previously, etoposide or irinotecan combined with carboplatin or cisplatin were the first-line treatment options for extensive-stage small cell lung cancer (ES-SCLC) patients (1,8,9); however, challenges related to quick progression and relapse following an initial effective response remain. In 2019, based on a series of clinical trials (10,11), the Food and Drug Administration approved atezolizumab and durvalumab combined with chemotherapy for the first-line treatment of ES-SCLC. However, due to the limited benefits of only two months increased overall survival (OS), more effective therapies for ES-SCLC need to be developed (1,9,12). From the DeLLphi-304 research, we found that tarlatamab represents an advance for ES-SCLC, leveraging DLL3 as a highly specific target to achieve a survival benefit in chemo-refractory disease. Nevertheless, the exploration of first-line and maintenance treatments for advanced SCLC still needs to persist.

Poly ADP-ribose polymerase (PARP) is a crucial enzyme involved in the repair of DNA single-strand breaks. When the function of PARP is inhibited, single-strand DNA breaks accumulate and subsequently form double-strand breaks, which continually accumulate and eventually result in synthetic lethality with tumor-specific homologous recombination deficiency (13,14). It is well known that PARP inhibitors (PARPis) are effective in the treatment of diverse cancers, such as metastatic castration-resistant prostate cancer, recurrent ovarian cancer, and advanced breast cancer (15-18). In addition, PARP is expressed at much higher levels in SCLC than in other cancers (8,19). Byers tested higher expression of PARP1 in the tissue of SCLC tumors with the method of immunohistochemical analysis than other carcinoma [P=2.3×19⁻⁴, analysis of variance (ANOVA)], which was consistent with the detection of cellular level (19). Up to now, although there have been no clear reports on the drug resistance mechanisms in advanced SCLC, some studies have shown that the high expression of PARP1/2 is considered an adaptive response of SCLC to its inherent genomic instability and DNA damage induced by chemotherapy (19-28). Several pre-clinical and clinical studies have suggested that PARPis play an influential role in the treatment of ES-SCLC both alone and in combination with other drugs (19-28).

SLFN-11 serves as a key marker for selecting patients most likely to respond to PARP inhibitor combinations. Clinical trials demonstrate that SLFN-11 positive patients treated with a veliparib and temozolomide combination achieved longer progression-free survival (PFS) and overall survival (OS) compared to those without the marker. This ability to identify patients who will truly benefit from PARP inhibitor-based therapies helps avoid ineffective treatment and unnecessary side effects for others (28-30). Although several summaries detail the current data for PARPi treatment in SCLC (1,2,6,9,31-33), evidence-based medical data on the effectiveness and toxicities of ES-SCLC treatment are still inadequate. Thus, we conducted an up-to-date systematic review and meta-analysis to clarify the efficacy and safety of PARPis in the treatment of ES-SCLC. We registered our review plan with PROSPERO (CRD42022309876) in advance. We present this article in accordance with the PRISMA reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1306/rc).

Methods

Search strategy

We searched databases, including PubMed, the Cochrane Library, and ClinicalTrials.gov, to retrieve all relevant studies on randomized controlled trials (RCTs) published to March 2025 using the keywords: ES-SCLC, PARP inhibitor, and PARPi. We also manually searched for relevant reviews to identify additional RCTs. Two investigators independently screened every study according to the set criteria.

Inclusion and exclusion criteria

To be eligible for inclusion in the meta-analysis, the articles had to meet the following inclusion criteria: (I) concern an RCT; (II) include patients who had been pathologically diagnosed with ES-SCLC, and those with relapsed or refractory disease; (III) use PARPi interventions, either as a monotherapy or in combination with different agents, and include a control group that received chemotherapy or placebo; and (IV) present the hazard ratios (HRs) and 80–95% confidence intervals (CIs) for PFS or OS, as well as relevant data for the objective response rate (ORR), and include safety-related indicators for myelosuppression, gastrointestinal adverse reactions (e.g., nausea, vomiting, and diarrhea), and other treatment-related adverse events (AEs).

Articles were excluded from the meta-analysis if they met any of the following exclusion criteria: (I) concerned an animal study, pre-clinical trial, or phase I trial; (II) had incomplete study data; and/or (III) comprised comments, news, case studies, or case reports.

Data extraction

We extracted the relevant data and recorded them in an Excel document. In cases of disagreement, a third-party discussion was held. The following information was extracted: study title, author/s, publication date, intervention measures of the experimental and control groups, study type, relevant information for the risk of bias assessment, and outcomes. As for the outcomes, we extracted the relative risk (RR)/odds ratio (OR) as the research objects. The results were then presented in the form of line tables or forest plots.

Risk of bias assessment

The quality of the RCTs was assessed according to Cochrane’s Handbook 5.1. The quality assessment considered the following aspects: sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, incomplete outcome data, and no selective outcome reporting, and other sources of bias. The risk of bias assessment was performed using RevMan 5.4.

Statistical analysis

RevMan 5.4 was used for the meta-analysis. The OR or HR and their CI were used as the effect statistics, and a P value <0.05 was considered statistically significant. The I² statistic test was used to assess the included statistical heterogeneity of the studies. A fixed-effects model was adopted when I²<50%; otherwise, a random-effects model was used.

Results

Study selection

The search strategy initially identified 31 relevant articles. Six articles were excluded as duplicates. After screening the titles and abstracts, 25 studies were retained. The eligibility of these studies was assessed according to the inclusion/exclusion criteria by reading the full text. Ultimately, six RCTs meeting the inclusion criteria were chosen for further analysis (Figure 1). In the process of screening studies, one study (NCT03830918) that initially appeared to meet the inclusion criteria was later suspended, and thus had to be excluded from our meta-analysis, as did some other studies that were not phase II or above RCTs.

Figure 1 Flow diagram of literature screening.

Study characteristics

The studies included in our analysis reported on the clinical benefits of PARPis alone or in combination with chemotherapeutics in ES-SCLC patients. In total, 924 patients diagnosed with ES-SCLC and a performance status of 0–1 were included in our analysis. The median age of the patients ranged from 62.5 to 66 years. In the intervention group, the PARPi monotherapies included niraparib in NCT03516084 and veliparib in NCT02289690. The combination therapies included veliparib in combination with cisplatin and etoposide, veliparib in combination with temozolomide, and talazoparib in combination with atezolizumab. The characteristics of the included studies and enrolled patients are presented in Table 1.

Risk of bias in the included studies

The general risk of bias in the included studies was low. Random sequence generation and allocation concealment were reported in all of the included RCTs. The blinding of participants and personnel, and outcome assessment were confirmed. Only one trial had incomplete outcomes (12), but this unfortunately affected our reporting of the initial endpoints; the other clinical trials reported all data and no other apparent biases were found. The risk of bias graph is presented in Figure 2.

Figure 2 Risk of bias of the included studies. +, low risk of bias; −, high risk of bias; ?, unclear risk of bias.

PFS

Six RCTs [i.e., Ai 2021 (8), Byers 2021 (34), Owonikoko 2019 (7), Pietanza 2018 (12), Karim 2024 (29) and Woll 2022 (35)] reported on PFS (n=924), and were assessed in our meta-analysis. As 300 mg twice a day is the recommended dose for olaparib, we chose this group in our analysis to compare with the control group. The PFS of patients in our analysis ranged from 1.36 to 6.1 months. Compared with the patients in the control groups, the patients who received PARPis in the intervention groups had longer PFS (HR =0.72; 95% CI: 0.63–0.81) regardless of whether monotherapy or combination therapy was used (Figure 3A). However, Byers et al. found that there was no significant difference in PFS between the veliparib combination-only and control groups (HR =0.979; 80% CI: 0.744–1.288) (34), so veliparib combined with chemotherapy followed by veliparib may be a promising treatment method. The heterogeneity between the included RCTs was low (I²=0, P=0.90). Therefore, a fixed-effects model was chosen for the current analysis. We also performed a subgroup analysis that showed that ES-SCLC patients with SLFN-11 positive (+) expression may receive more benefits from PARPis than those with SLFN-11 negative expression (HR =0.65, 95% CI: 0.51–0.82) (Figure 3B).

Figure 3 Forest plot of the meta-analysis estimating the HRs for (A) PFS, (B) PFS (SLFN-11), (C) OS and (D) OR for ORR. CI, confidence interval; HR, hazard ratio; IV, inverse variance; M-H, Mantel-Haenszel; OR, odds ratio; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; SE, standard error.

OS

Four RCTs included in our study reported on OS (n=600), and all relevant data were reported for the intervention and control groups. In Owonikoko (2019), there were 51 deaths in the carboplatin and etoposide (CE) + veliparib arm and 54 deaths in the CE + placebo arm, and the estimated median OS times of these groups were 10.3 and 8.9 months, respectively, with no significant difference observed between the two groups (7). Similarly, in Byes (2021) and Ai (2021) (8,34), the differences in OS between the two arms were not statistically significant. In addition, the analysis using pooled data from all studies also failed to identify a significant OS benefit in favor of PARPis (HR =1.05, 95% CI: 0.90–1.22; Figure 3C).

ORR

An ORR analysis was undertaken using data from Byes (2021), Owonikoko (2019), and Pietanza (2018) (7,12,34) (Figure 3D). These three RCTs provided specific data illustrating that PARPi treatment improved the ORR of the ES-SCLC group (OR =2.03, 95% CI: 1.26–3.28) compared with the control group. Further, the heterogeneity analysis revealed no significant heterogeneity (I²=47%, P=0.15). Thus, the fixed-effects model was chosen for the analysis.

AEs

Our meta-analysis also examined the effect of PARPis on the safety of patients. All the included studies mentioned toxicities, including lymphopenia, neutropenia, thrombocytopenia, anemia, leukopenia, nausea, alanine transaminase elevation, hypertension, hyperglycemia, loss of appetite, cough, vomiting, and fatigue (7,8,12,34). During the systematic analysis of the included cases, we obtained some new data (Figure 4A-4D). The patients who received PARPi treatment either as a single agent or in combination with chemotherapy had higher risks of hematological toxicity, including anemia (OR =2.53, 95% CI: 1.82–3.51), leukopenia (OR =3.24, 95% CI: 2.02–5.21), thrombocytopenia (OR =3.47, 95% CI: 2.26–5.33), and neutropenia (OR =2.83, 95% CI: 1.90–4.22).

Figure 4 Forest plots of ORs for haematological adverse events. (A) Anaemia. (B) Leucopenia. (C) Thrombocytopenia. (D) Neutropenia. CI, confidence interval; M-H, Mantel-Haenszel; OR, odds ratio; PARPi, poly ADP-ribose polymerase inhibitor.

Except for the hematological toxicity, the difference in the risks of nausea, vomiting, and fatigue between the two arms were also statistically significant, with ORs of 3.73 (95% CI: 2.36–5.87), 1.57 (95% CI: 1.01–2.45), and 1.54 (95% CI: 1.01–2.34), respectively (Figure 5A-5C). Further, in Ai (2021) (8), the researchers reported that severe AEs resulted in treatment discontinuation in 4.0% (5/125) of the niraparib-treated patients and 5.0% (3/60) of the placebo-treated patients, and several patients died of other reasons than the study treatment. A single case of grade 5 febrile neutropenia was recorded in the placebo arm, while no such event occurred in the PARPi arm (7). In Byers (2021), the most frequent AE resulting in death was tumor progression, which was not treatment-related (34). Among the risk factors, prolonged thrombocytopenia led to treatment termination in two patients, including one patient in each group, indicating that PARPi treatment did not increase the risk of treatment discontinuation compared to the control (12).

Figure 5 Forest plots of ORs for other adverse events between PARPis and placebo. (A) Nausea. (B) Vomiting. (C) Fatigue. CI, confidence interval; M-H, Mantel-Haenszel; OR, odds ratio; PARPi, poly ADP-ribose polymerase inhibitor.

Based on these analyses, although some side effects of PARPis were identified, they were not life-threatening. Some measures can be taken to prevent the relevant toxicities of PARPis to allow these drugs to better exert their effects.

Discussion

In this meta-analysis, we examined the data of six RCTs involving 924 participants to assess the effectiveness and safety of PARPis as both single-agent and combination therapies in patients with pathologically diagnosed ES-SCLC. The results of our meta-analysis indicated that the application of PARPis in patients with ES-SCLC is associated with increases in PFS and the ORR, and has an acceptable level of AEs. Our findings are similar to the benefit trends reported in some pre-clinical studies and phase-I/II trials (19-22,24,25,36,37). However, the difference in OS did not reach statistical significance between the groups. Thus, additional trials with longer follow-up times are needed to investigate the effects of PARPis on the long-term survival of patients with ES-SCLC.

The AEs likely occurred due to the widespread distribution of PARP in the body; PARPis can not selectively target SCLC cells only, which results in the deregulation of physical functions of various tissues (38). Additionally, a randomized, double-blind phase-III study suggested that PARPi-related AEs were more likely related to the disease itself and prior chemotherapy than the PARPis, with high percentages of any treatment emergent adverse events (TEAEs) in both treatment groups (100% for niraparib group and 95% for placebo) (8).

The rates of anemia, leukopenia, and thrombocytopenia were higher in the PARPi arm than the placebo arm; however, these AEs were not life-threatening. Given the effectiveness and acceptable toxicities of PARPis, we are eager to identify the patients that would most likely to benefit from PARPis. Identifying relevant biomarkers could guide the stratification of ES-SCLC patients. Several pre-clinical and clinical trials have found that the expression of SLFN11 is associated with the sensitivity of ES-SCLC to PARPis; thus, SLFN11 could be a promising predictive biomarker for practical evaluation (39). Moreover, some researchers have reported that the most commonly mutated tumor suppressive genes TP53 and Rb1 are critically consistent with PARP1 overexpression, and increased sensitivity to PARPis (40,41). Thus, research also needs to be conducted on the TP53, Rb1, PARP-1, and MGMT promoters, and their hypermethylation status. Mutations in ATM, BRCA1/2, and other homologous repair genes have been reported to influence the effects of PARPis in prostate, ovarian, and breast cancers, but these mutations do not exist in ES-SCLC (12,15,17,18,42,43).

Meanwhile, to improve the curative effect of PARPis, investigations of monotherapies and combination therapies with various drugs are being conducted in the first-line and maintenance settings. First, Owonikoko et al. and Byers et al. showed that PARPis could chemosensitize SCLC, suggesting that ES-SCLC patients might benefit from the combination of PARPis and chemotherapy (7,34). Data from a clinical trial (NCT02289690) prompted us to examine whether the drug delivery sequence could be adjusted to improve the therapeutic effect (34). Additionally, research suggests that PARPis could improve the efficacy of radiotherapy (24,44,45). Laird et al. showed that the combination of talazoparib and radiation was significantly more effective than radiation alone (P<0.05), therefore, the combination of PARPis and radiotherapy could represent another effective treatment strategy. Further, research suggests that combining PARPis with PI3K/mTOR or Wee1 inhibitors exerts a synergistic effect in pre-clinical/phase-Ib models of SCLC (28,46,47). For example, the combination of talazoparib and PI3K inhibitor (BKM-120) in two SCLC animal models showed an additive effect greater than either single agent alone (P≤0.008). Further, the STAMP study (NCT04933175) aimed to provide evidence on the combination of PARPis and anlotinib, while, unfortunately, this study was unable to recruit a sufficient number of patients (48). Therefore, in the future, we intend to explore the combination of PARPis with other anti-tumor therapies. Our analysis had some obvious strengths. First, this was the first meta-analysis to examine the effectiveness and safety of PARPis in patients with ES-SCLC, especially those with SLFN-11+ expression. Additionally, all included studies were RCTs, which provide higher-quality evidence than other clinical trial types. Further, the risk of bias in the included studies was low, and thus, the quality of evidence was high.

This meta-analysis had several limitations. First, because the data extraction was performed according to study-level evidence rather than the level of individual patients, the results might have low credibility. Second, only six RCTs involving 924 patients were included in meta-analysis; thus, further research with a larger sample size urgently needs to be conducted to verify our results. Third, additional data are needed to confirm the subgroup analysis results on the efficacy and safety in patients with SLFN-11+ expression. Finally, there was no review protocol.

Conclusions

Our findings confirmed that PARPis represent an effective treatment option for ES-SCLC patients, especially those with SLFN-11+ expression. The meta-analysis revealed no apparent increase in OS, but this might be due to the lack of sufficient data in the clinical trials; thus, more extensive studies with longer follow-up periods need to be conducted. In addition, further research needs to be conducted to identify characteristic biomarkers to optimize PARPi-containing regimens. We recently identified that NCT04728230 aims to explore the efficacy and safety of olaparib combined with durvalumab, carboplatin, etoposide, and/or radiation therapy for the treatment of ES-SCLC. Additionally, given the significance of SLFN-11, another study (NCT06217757) was conducted to investigate the safety and tolerability of low-dose radiation therapy (LDRT) plus sugemalimab, chemotherapy, and olaparib in the first-line treatment of SLFN-11-positive ES-SCLC. Both trials are currently in the recruiting phase, and we look forward to more positive outcomes for ES-SCLC.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1306/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1306/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1306/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.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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