Highlights
- •PARP inhibitors significantly increased the risk of pneumonitis across 16 RCTs with a high proportion of severe cases.
- •In addition to olaparib having the most significant pneumonitis signal, a pneumonitis signal was also detected for niraparib.
- •Most of the PARP inhibitor-related pneumonitis occurred early during treatment course.
- •PARP inhibitor-related pneumonitis can result in serious outcomes with a fatality rate of 16%.
Abstract
Objective/Background
We aimed to evaluate the risk of PARP inhibitors (PARPis) causing pneumonitis in randomized
controlled trials (RCTs) and in the real-world practice.
Methods
First, a systematic review based on meta-analysis was conducted. RCTs with available
data reporting pneumonitis events for PARPis were eligible for analysis. Second, we
conducted a disproportionality analysis based on data from the FDA Adverse Event Reporting
System (FAERS) database to characterize the main features of PARPi-related pneumonitis.
Results
16 trials with 5771 patients were included in our meta-analysis. Compared with control
arms, PARPis showed a significant increase in the risk of pneumonitis events (Peto
OR 2.68 [95% CI 1.31–5.47], p = 0.007) with no heterogeneity (I2 = 0%, χ2 p = 0.70). The incidence of pneumonitis across treatment arms was 0.79% (28/3551).
In the FAERS database, we identified 84 cases of PARPi-pneumonitis with a fatality
rate of 16% (13/79). The median time to event onset was 81 (interquartile range [IQR]
27–131) days and 87% of the adverse events occurred within 6 months.
Conclusion
PARPis increased the risk of pneumonitis that can result in serious outcomes and tend
to occur early. Early recognition and management of PARPi-pneumonitis is of vital
importance in clinical practice. The mechanisms and risk factors should be studied
further to improve clinical understanding and innovative treatment strategies for
these diseases.
Graphical abstract
Graphical Abstract
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Gynecologic OncologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- A decade of clinical development of PARP inhibitors in perspective.Ann. Oncol. 2019; 30: 1437-1447https://doi.org/10.1093/annonc/mdz192
- Incorporating PARP-inhibitors in primary and recurrent ovarian cancer: a meta analysis of 12 phase II/III randomized controlled trials.Cancer Treat. Rev. 2020; 87: 102040https://doi.org/10.1016/j.ctrv.2020.102040
- (Last accessed 2021.1.20)
- Exploring and comparing adverse events between PARP inhibitors.Lancet Oncol. 2019; 20: e15-e28https://doi.org/10.1016/S1470-2045(18)30786-1
- Risk of fatigue and anemia in patients with advanced cancer treated with olaparib: a meta-analysis of randomized controlled trials.Crit. Rev. Oncol. Hematol. 2019 Sep; 141: 163-173https://doi.org/10.1016/j.critrevonc.2019.06.012
- Risk of selected gastrointestinal toxicities associated with poly (ADP-ribose) polymerase (PARP) inhibitors in the treatment of ovarian cancer: a meta-analysis of published trials.Drug Des Devel Ther. 2018 Sep 17; 12: 3013-3019https://doi.org/10.2147/DDDT.S164553
- Risk of severe hematologic toxicities in cancer patients treated with PARP inhibitors: a meta-analysis of randomized controlled trials.Drug Des Devel Ther. 2017 Oct 13; 11: 3009-3017https://doi.org/10.2147/DDDT.S147726
- Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.BMJ. 2009 Jul 21; 339: b2535https://doi.org/10.1136/bmj.b2535
- The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials.BMJ. 2011 Oct 18; 343: d5928https://doi.org/10.1136/bmj.d5928
- Reporting discrepancies between the clinicaltrials.gov results database and peer-reviewed publications.Ann. Intern. Med. 2014; 161: 760https://doi.org/10.7326/L14-5022
- (Last accessed 2021.1.7)
- The Peto odds ratio viewed as a new effect measure.Stat. Med. 2014 Dec 10; 33: 4861-4874https://doi.org/10.1002/sim.6301
- The reporting odds ratio and its advantages over the proportional reporting ratio.Pharmacoepidemiol. Drug Saf. 2004 Aug; 13: 519-523https://doi.org/10.1002/pds.1001
- A Bayesian neural network method for adverse drug reaction signal generation.Eur. J. Clin. Pharmacol. 1998 Jun; 54: 315-321https://doi.org/10.1007/s002280050466
- (Last accessed 2020.12.10)
- (Last accessed 2020.12.10)
- (Last accessed 2020.12.10)
- (Last accessed 2020.12.10)
- (Last accessed 2020.12.10)
- (Last accessed 2020.12.10)
- (Last accessed 2020.12.10)
- (Last accessed 2020.12.10)
- Olaparib for metastatic castration-resistant prostate Cancer.N. Engl. J. Med. 2020 May 28; 382: 2091-2102https://doi.org/10.1056/NEJMoa1911440
- Olaparib plus bevacizumab as first-line maintenance in ovarian Cancer.N. Engl. J. Med. 2019 Dec 19; 381: 2416-2428https://doi.org/10.1056/NEJMoa1911361
- Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer.N. Engl. J. Med. 2019 Jul 25; 381: 317-327https://doi.org/10.1056/NEJMoa1903387
- OlympiAD final overall survival and tolerability results: Olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer.Ann. Oncol. 2019 Apr 1; 30: 558-566https://doi.org/10.1093/annonc/mdz012
- Maintenance Olaparib in patients with newly diagnosed advanced ovarian Cancer.N. Engl. J. Med. 2018 Dec 27; 379: 2495-2505https://doi.org/10.1056/NEJMoa1810858
- (Last accessed 2020.12.16)
- Rucaparib for patients with platinum-sensitive, recurrent ovarian carcinoma (ARIEL3): post-progression outcomes and updated safety results from a randomised, placebo-controlled, phase 3 trial.Lancet Oncol. 2020 May; 21: 710-722https://doi.org/10.1016/S1470-2045(20)30061-9
- Combination of gefitinib and olaparib versus gefitinib alone in EGFR mutant non-small-cell lung cancer (NSCLC): A multicenter, randomized phase II study (GOAL).Lung Cancer. 2020; 150: 62-69https://doi.org/10.1016/j.lungcan.2020.09.018
- Efficacy and safety of PARP inhibitors in the treatment of advanced ovarian cancer: An updated systematic review and meta-analysis of randomized controlled trials.Crit. Rev. Oncol. Hematol. 2021 Jan; 157: 103145https://doi.org/10.1016/j.critrevonc.2020.103145
- Parp inhibitors as maintenance treatment in platinum sensitive recurrent ovarian cancer: An updated meta-analysis of randomized clinical trials according to BRCA mutational status.Cancer Treat. Rev. 2019 Nov; 80: 101909https://doi.org/10.1016/j.ctrv.2019.101909
- Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation..J. Clin. Oncol. 2015 Jan 20; 33: 244-250https://doi.org/10.1200/JCO.2014.56.2728
- Olaparib in combination with paclitaxel in patients with advanced gastric cancer who have progressed following first-line therapy (GOLD): a double-blind, randomised, placebo-controlled, phase 3 trial.Lancet Oncol. 2017 Dec; 18: 1637-1651https://doi.org/10.1016/S1470-2045(17)30682-4
- PARP inhibitors as a new therapeutic option in metastatic prostate cancer: a systematic review.Prostate Cancer Prostatic Dis. 2020 Dec; 23: 549-560https://doi.org/10.1038/s41391-020-0233-3
- PARP inhibitors in the treatment of early breast Cancer: the step beyond?.Cancers (Basel). 2020 May 27; 12: 1378https://doi.org/10.3390/cancers12061378
- Randomized phase II trial of cisplatin and etoposide in combination with Veliparib or placebo for extensive-stage small-cell lung Cancer: ECOG-ACRIN 2511 study.J. Clin. Oncol. 2019 Jan 20; 37: 222-229https://doi.org/10.1200/JCO.18.00264
- Randomized, placebo-controlled, phase II study of Veliparib in combination with carboplatin and paclitaxel for advanced/metastatic non-small cell lung Cancer.Clin. Cancer Res. 2017 Apr 15; 23: 1937-1944https://doi.org/10.1158/1078-0432.CCR-15-3069
- Magnitude of benefit of the addition of poly ADP-ribose polymerase (PARP) inhibitors to therapy for malignant tumor: a meta-analysis.Crit. Rev. Oncol. Hematol. 2020 Mar; 147: 102888https://doi.org/10.1016/j.critrevonc.2020.102888
- Phase I study of olaparib in combination with liposomal doxorubicin in patients with advanced solid tumours.Br. J. Cancer. 2014 Aug 12; 111: 651-659https://doi.org/10.1038/bjc.2014.345
- The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial.Lancet Oncol. 2013 Aug; 14: 882-892https://doi.org/10.1016/S1470-2045(13)70240-7
- Comparative safety of drugs targeting the nitric oxide pathway in pulmonary hypertension: a mixed approach combining a Meta-analysis of clinical trials and a disproportionality analysis from the World Health Organization pharmacovigilance database.Chest. 2018 Jul; 154: 136-147https://doi.org/10.1016/j.chest.2017.12.008
- Cardiovascular safety of rapidly accelerated fibrosarcoma B-type and/or mitogen-activated extracellular signal-regulated kinase inhibitors: a mixed approach combining a meta-analysis and a pharmacovigilance disproportionality analysis.Arch. Cardiovasc. Dis. 2020 Jun-Jul; 113: 420-432https://doi.org/10.1016/j.acvd.2020.03.014
- Myelodysplastic syndrome and acute myeloid leukaemia in patients treated with PARP inhibitors: a safety meta-analysis of randomised controlled trials and a retrospective study of the WHO pharmacovigilance database.Lancet Haematol. 2021 Feb; 8: e122-e134https://doi.org/10.1016/S2352-3026(20)30360-4
- A phase I combination study of olaparib with cisplatin and gemcitabine in adults with solid tumors.Clin. Cancer Res. 2012 Apr 15; 18: 2344-2351https://doi.org/10.1158/1078-0432.CCR-11-2425
- PARP inhibitors: synthetic lethality in the clinic.Science. 2017 Mar 17; 355: 1152-1158https://doi.org/10.1126/science.aam7344
- Biology of poly(ADP-ribose) polymerases: the factotums of cell maintenance.Mol. Cell. 2015 Jun 18; 58: 947-958https://doi.org/10.1016/j.molcel.2015.01.034
- Poly(ADP-ribose) polymerase-2: emerging transcriptional roles of a DNA-repair protein.Cell. Mol. Life Sci. 2012 Dec; 69: 4079-4092https://doi.org/10.1007/s00018-012-1003-8
- The therapeutic potential of poly(ADP-ribose) polymerase inhibitors.Pharmacol. Rev. 2002 Sep; 54: 375-429https://doi.org/10.1124/pr.54.3.375
- Poly(ADP-ribose) polymerase inhibition with HYDAMTIQ reduces allergen-induced asthma-like reaction, bronchial hyper-reactivity and airway remodelling.J. Cell. Mol. Med. 2014 Mar; 18: 468-479https://doi.org/10.1111/jcmm.12197
- Repositioning PARP inhibitors for SARS-CoV-2 infection(COVID-19); a new multi-pronged therapy for acute respiratory distress syndrome?.Br. J. Pharmacol. 2020 Aug; 177: 3635-3645https://doi.org/10.1111/bph.15137
- Inhibition of poly (ADP-ribose) polymerase attenuates acute lung injury in an ovine model of sepsis.Shock. 2004 Feb; 21: 126-133https://doi.org/10.1097/01.shk.0000108397.56565.4a
- PARP inhibition by olaparib alleviates chronic asthma-associated remodeling features via modulating inflammasome signaling in mice.IUBMB Life. 2019 Jul; 71: 1003-1013https://doi.org/10.1002/iub.2048
- The role of poly(ADP-ribose) polymerase-1 inhibitor in carrageenan-induced lung inflammation in mice.Mol. Immunol. 2015 Feb; 63: 394-405https://doi.org/10.1016/j.molimm.2014.09.009
- Post-allergen challenge inhibition of poly(ADP-ribose) polymerase harbors therapeutic potential for treatment of allergic airway inflammation.Clin. Exp. Allergy. 2008 May; 38: 839-846https://doi.org/10.1111/j.1365-2222.2008.02943.x
- PARP-1 inhibition ameliorates elastase induced lung inflammation and emphysema in mice.Biochem. Pharmacol. 2018 Apr; 150: 24-34https://doi.org/10.1016/j.bcp.2018.01.027
- Poly(ADP-ribose) polymerase-1 (PARP-1) controls lung cell proliferation and repair after hyperoxia-induced lung damage.Am. J. Phys. Lung Cell. Mol. Phys. 2007 Sep; 293: L619-L629https://doi.org/10.1152/ajplung.00037.2007
- Risk of pneumonitis and pneumonia associated with immune checkpoint inhibitors for solid tumors: a systematic review and Meta-analysis.Front. Immunol. 2019 Feb 4; 10: 108https://doi.org/10.3389/fimmu.2019.00108
Article info
Publication history
Published online: May 19, 2021
Accepted:
May 12,
2021
Received:
March 10,
2021
Identification
Copyright
© 2021 Published by Elsevier Inc.
