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PARP Inhibitors Associated With Increased Risk of Pneumonitis

Poly (ADP-ribose) polymerase inhibitors (PARPis) are a class of targeted therapy that selectively targets cancer cells with deficiencies in homologous recombination signaling, such as those with BRCA dysfunctional genes. In recent years, these agents have transformed the outcomes of selected patients with ovarian, breast, prostate, and pancreatic cancer and have become an important tool in the treatment armamentarium for these cancers. In addition, their role is evolving to include other tumor types, as single-agent and combination therapy. Currently, olaparib, niraparib, rucaparib, and talazoparib are approved for different cancer indications based on their efficacy and tolerability. Common toxicities of PARPis – which are well described in clinical trials – include hematological and gastrointestinal toxicities, and fatigue. However, with the increased use of PARPis, the spectrum of rare adverse events, including PARPi-induced pneumonitis, is increasing, and it is very important to be aware of these toxicities.

A recently published study sought to evaluate PARPi-associated pneumonitis in a meta-analysis of randomized controlled studies and in ‘’real-world practice’’ using the FDA Adverse Event Reporting System (FAERS) database. The authors conducted a meta-analysis of 16 phase II/III randomized controlled trials, which compared PARPis (alone or in combinations) with a control (placebo, chemotherapy alone, or targeted therapy alone). In total, data from 5771 patients with different cancer types (ovarian, prostate, non-small cell cancer, gastric, breast, and pancreatic cancer) were included. Ten of the trials evaluated olaparib, and 6 evaluated other PARPis (veliparib, niraparib, or rucaprib). The results indicated that patients treated with PARPis had a significantly increased risk of pneumonitis compared with patients in the control arm (P = 0.007). There was no significant heterogeneity across studies. The incidence of all-grade pneumonitis was 0.79% in patients treated with PARPis versus 0.24% in the control group. Of note, half of PARPi-associated pneumonitis events were serious adverse events, including death and extended hospitalizations. Subgroup analysis suggests that dose of olaparib may influence the incidence of pneumonitis – the incidence was lower with doses <600 mg/day compared with the FDA-recommended dose of 600 mg/day.

Additionally, investigators retrospectively evaluated the FAERS database over 16 years (2004 – 2020) and identified 84 cases of PARPi-related pneumonitis. They found that, over the last few years, the number of PARPi-associated pneumonitis reports have increased across different tumor types and with different PARPis. The median time to the onset of pneumonitis events was 81 days, and 87% of the AEs occurred within 6 months. Importantly, the fatality rate was 16%. There was no dose-related information available from the FAERS database to support the finding from the meta-analysis.

The authors concluded that, despite some limitations, the study data indicate that PARPis are associated with an increased risk of pneumonitis that usually occurs early and can be life-threatening. Thus, early recognition and management following the accepted guidelines for drug-induced pneumonitis is essential.

References
Ma ZB, et al. Gynecol Oncol. 2021; 162:496-505.