
==== Front
BMC Pulm Med
BMC Pulm Med
BMC Pulmonary Medicine
1471-2466
BioMed Central London

3276
10.1186/s12890-024-03276-3
Research
Clinical and radiological pattern of olaparib-induced interstitial lung disease
Brudon Alexandre alexandre.brudon01@chu-lyon.fr

1
Fournier Dorine 2
Selle Frédéric 3
Seront Emmanuel 4
Conforti Rosa 5
Veyrac Gwenaëlle 6
Gouraud Aurore 7
Lebrun-Vignes Bénédicte 2
Khalil Antoine 8
Zalcman Gérard 1
Gounant Valérie 1
1 grid.508487.6 0000 0004 7885 7602 Thoracic Oncology Department, Université Paris Cité, CIC INSERM 1425, Institut du Cancer AP-HP.Nord, Hôpital Bichat-Claude Bernard, 46 Rue Henri Huchard, Paris, 75108 France
2 Service de Pharmacologie Médicale, Centre Régional de Pharmacovigilance Pitié-Saint-Antoine, Groupe Hospitalier AP-HP-Sorbonne Université, Paris, 75013 France
3 grid.413975.d 0000 0001 1484 3621 Department of Medical Oncology, Hôpital Diaconesses Croix Saint Simon, Paris, 75020 France
4 https://ror.org/01jn2rz36 grid.413908.7 Department of Medical Oncology, Hôpital Jolimont, Haine-Saint-Paul, La Louvière, 7100 Belgique
5 grid.50550.35 0000 0001 2175 4109 Department of Medical Oncology, Sorbonne UniversitéHôpital Pitié Salpêtrière, APHP, Paris, 75011 France
6 grid.277151.7 0000 0004 0472 0371 Clinical Pharmacology Department, CHU Nantes, Nantes, France
7 https://ror.org/01502ca60 grid.413852.9 0000 0001 2163 3825 Service Hospitalo-Universitaire de Pharmaco-Toxicologie (SHUPT), Hospices Civils de Lyon, 162, Avenue Lacassagne, Lyon, 69424 France
8 grid.508487.6 0000 0004 7885 7602 Department of Radiology, Université Paris Cité, Hôpital Bichat-Claude Bernard, Institut du Cancer Paris Nord, APHP, Université Paris Cité, Paris, 75018 France
13 9 2024
13 9 2024
2024
24 44828 5 2024
6 9 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Background

PARP inhibitors (PARPi) are used in the treatment of ovarian, breast, pancreatic, and prostate cancers. Pneumonitis has been identified as a potential side effect, with a higher meta-analysis-assessed risk for olaparib versus other PARPi. Olaparib-induced interstitial lung disease (O-ILD) was first described within the Japanese population, with few information available for Caucasian patients.

Methods

We performed a retrospective study by pooling data from the French and Belgian pharmacovigilance databases from 2018 to 2022. Patients with O-ILD were included following a central review by: 1) pharmacologists using the French drug causality assessment method; 2) senior pneumologists or radiologists, using the Fleischner Society’s recommendations.

Results

Five patients were identified and analysed. All were females, with ovarian or breast cancer. Median age at O-ILD diagnosis was 71 (38–72) years old, with no smoking history. Median delay between treatment initiation and symptom occurrence was 12 (6–33) weeks. Pneumonitis severity assessed using the Common Terminology Criteria for Adverse Events V5 was Grade 3 (n = 4) or 2 (n = 1). CT-scan review (n = 3) described hypersensitivity pneumonitis reaction as a common pattern. Bronchioalveolar lavage (n = 4) revealed lymphocytic alveolitis. Treatments relied on olaparib discontinuation (n = 5) and glucocorticoid intake (n = 4), with no fatal issue. Safe re-challenge with PARPi occurred in two patients. Forty additional O-ILD cases were identified in the WHO VigiBase database, including one fatal case.

Conclusions

PARPi-ILD is a rare but potentially life-threatening disease, presenting as a hypersensitivity pneumonitis pattern within 3 months of PARPi initiation. Treatment primarily relies on medication discontinuation. Re-challenging with another PARPi could be considered.

Clinical trial number

CEPRO #2023–010.

Keywords

Interstitial Lung Disease
PARPi
Hypersensibility pneumonitis
Adverse effect
issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
==== Body
pmcIntroduction

Poly(ADP-ribose) polymerase inhibitors (PARPi) act by trapping PARP on DNA at sites of single-strand breaks, thus preventing their repair and generating double-strand breaks that cannot be repaired accurately in tumours with homologous-recombination deficiency, supporting a synthetic lethal effect [1]. To date, four PARPi are approved by the Food and Drug Administration (FDA), including olaparib, rucaparib, niraparib, and talazoparib. Olaparib was first approved by the FDA in 2014 as a maintenance treatment for germline BRCA-mutated metastatic ovarian cancer [2]. Approval was broadened in 2018 as adjuvant treatment for human epidermal growth factor receptor 2 (HER2) negative metastatic breast cancer in patients with a germline or somatic BRCA mutation [3]. In 2019, the drug was approved as a maintenance treatment for germline BRCA-mutated metastatic pancreatic cancer [4], and in 2020 for patients with a germline or somatic BRCA mutation and metastatic castration-resistant prostate cancer receiving a new hormonal agent [5]. In the olaparib product characteristics, pneumonitis occurrence was mentioned under warnings and precautions. While less than 1% of patients included into clinical trials were reported to experience pneumonitis, some cases turned out to be fatal. Identifying a consistent clinical pattern for these pneumonitis cases is rather challenging given the numerous possible predisposing factors, including cancer or lung metastases, pre-existing lung conditions, smoking history, or previous treatments by chemotherapy and radiotherapy with possible lung toxicity (FDA Ref. 4610866). A recent meta-analysis concluded that PARPi significantly increased the pneumonitis risk (5,771 patients, OR: 2.68, 95%CI [1.31, 5.47], p = 0.007), with a higher risk for olaparib [6]. Pneumonitis incidence with PARPi was 0.79%, serious adverse events (SAEs) occurring in 50% of cases, with a fatality rate of 16%. A recent Japanese study reported three cases of olaparib-induced interstitial lung disease (O-ILD), though only little information is currently available for Caucasian populations [7], which highlights the critical need to detail the clinical characteristics of PARPi-induced pneumonitis so as to improve this potentially life-threatening adverse events (AE)’s management. Given this context, we herein present five O-ILD cases. Our goal was to outline the clinical and radiological characteristics, and bronchoalveolar lavage (BAL) alveolar cell patterns related to O-ILD, which are not extensively described in pharmaco-vigilance databases.

Material and methods

Patients and methods

In January 2022, based on the occurrence of O-ILD in our medical department, we sought to investigate national drug safety registers in France and Belgium to identify associated case reports. To this end, we performed a retrospective study pooling data from cases extracted from the French and Belgian pharmacovigilance databases (FBPDB), both databases containing anonymous data. The FBPDB compiles spontaneous adverse drug reaction reports from French health professionals and patients. We extracted all cases in which olaparib was listed as the suspected drug causing "ILD". Then, we reviewed all cases, selecting only those meeting the following inclusion criteria: documented drug exposure history; recognizable ILD pattern; suitable temporal relation between drug use and ILD onset; exclusion of other potential ILD causes; observable improvement after stopping the suspected drug and/or after receiving glucocorticoids. Another pharmacovigilance case from Belgium was extracted using the same method.

The following diagnostic criteria of O-ILD were applied: 1) drug exposure history; 2) ILD pattern; 3) temporal eligibility, 4) other ILD aetiologies should be ruled out; 5) improvement should follow discontinuation of suspected drug or glucocorticoid administration. ILD was defined as the occurrence of new and diffuse lung parenchymal abnormalities, including ground-glass opacities (GGOs), consolidations, and reticulations on sequential CT-scan examinations, according to the recommendations of the Fleischner Society [8].

Data collection

Demographic, clinical, radiological, and biological data including BAL were collected with extensive assessments aimed at identifying the ILD cause retrospectively conducted, whether cardiogenic, infectious, inflammatory, or related to tumour progression. All other drugs given concomitantly to olaparib were reviewed after consulting the Pneumotox database (http://www.pneumotox.com). Data were displayed as median values and ranges (minimum; maximum).

All chest CT-scans were reviewed by a senior chest radiologist and pulmonologist. When possible, a suggestive radiology pattern was provided [9].

Cases extraction from other international databases

To further analyse the possible causality between ILD and olaparib, we used VigiBase (https://who-umc.org/vigibase/), the World Health Organization (WHO) global database for individual case safety reports was developed and maintained by Uppsala Monitoring Centre (UMC). Our search was made using the preferred term “ILD” in the Medical Dictionary for Regulatory Activities (MedDRA) and olaparib (request made on 23 August 2023). It must be stressed that this information does not represent the opinion of the UMC or WHO.

Ethical considerations

Patient and sample data were retrospectively collected and systematically de-identified, in accordance with the French law and was ethically approved by the Institutional Review Board of the French learned society for respiratory medicine (CEPRO #2023–010).

Results

By searching the FBPDB from 2018 to 2022, we identified 10 cases. Of these, three were excluded due to incomplete data. Of the seven remaining cases, five were diagnosed with O-ILD (Table 1). Two cases were reclassified as infectious pneumonitis. Radiological data were fully available for three cases. Table 1 Patients’ clinical and nonclinical characteristics

	Index case (72, Female)	Case 2 (56, Female)	Case 3 (71, Female)	Case 4 (72, Female)	Case 5 (38, Female)	
Tobacco history	None	None	None	None	None	
Past medical history	Asthma	HT	None	Cured breast cancer	None	
Cancer histology	Ovarian high-grade papillary serous carcinoma	Ovarian high-grade papillary serous carcinoma	Ovarian high-grade papillary serous carcinoma	Ovarian high-grade papillary serous carcinoma	Breast high-risk invasive lobular carcinoma	
Stage at diagnosis	IV	IV	III	IV	IIB	
Mutation	Somatic BRCA1	Germinal BRCA1	HRD DNA signature	Somatic BRCA1	Germinal BRCA1	
Treatment lines	Debulking surgery	Debulking surgery	Carboplatin-Paclitaxel	Debulking surgery	Epirubicin-Cyclophosphamide	
Carboplatin-Paclitaxel	Carboplatin-Paclitaxel + Bevacizumab	Debulking surgery	Carboplatin-Paclitaxel	Paclitaxel	
Bevacizumab + placebo

(PAOLA trial)

	Bevacizumab	Carboplatin-Gemcitabine-Bevacizumab	Carboplatin-Paclitaxel + Bevacizumab	Mastectomy and axillary clearance + radiotherapy	
Adjuvant surgery	Carboplatin-Pegylated liposomal doxorubicin	Liposomal doxorubicin-Trabectidin	Olaparib 300 mg twice a day	Capecitabine	
Olaparib 300 mg twice a day	Olaparib 400 mg twice a day	Carboplatin-Gemcitabine		Olaparib 300 mg twice a day	
			Olaparib 300 mg twice a day			
Olaparib-induced interstitial lung disease	
 Delay of occurrence	12 weeks	12 weeks	6 weeks	12 weeks	33 weeks	
 Radiological pattern	Gound glass opacities

HP reaction (centrally reviewed)

	Ground glass opacities

HP reaction (centrally reviewed)

	Ground glass opacities

HP reaction (centrally

reviewed)

	Ground glass opacities

HP reaction

(locally

reviewed)

	Ground glass opacities

HP reaction

(locally

reviewed)

	
 Bronchoalveolar lavage	1,000,000 cells/mL (Ly 30%; PNN 23%; PNE 3,9%; Ma 40%) CD4/CD8 = 3.9	650,000 cells/mL (Ly 41%; PNN 1%; PNE 2%; Ma 56%) CD4/CD8 = 2	260,000 cells/mL (Ly 45%; PNN 48%; PNE 0%; Ma 7%) CD4/CD8 = 1	NA	500,000 cells/mL (Ly 60%; PNN 15%; PNE 2%; Ma 18%)	
 Autoimmunity	Negative	Negative	Negative	Negative	Negative	
 Bacteriology	Urine Ag L/P negative

LBA, bronchial aspirate, sputum, blood, and urine cultures sterile

	Urine Ag L/P negative

LBA, bronchial aspirate, sputum, blood, and urine cultures sterile

	Urine Ag L/P negative

LBA, bronchial aspirate, sputum, blood, and urine cultures sterile

	Urine Ag L/P negative

No culture performed

	Urine Ag L/P negative

LBA, bronchial aspirate, sputum, blood, and urine cultures sterile

	
 Virology	Negative PCR	Negative PCR	Negative PCR	NA	Negative PCR	
 Pneumocystis	Negative DFME and PCR	Negative DFME and PCR	NA	NA	Negative DFME and PCR	
 Cardiac examinations	Normal BNP	Normal BNP and TTE	Normal BNP	Normal BNP	Normal BNP	
 Antibiotics	Amoxicillin-clavulanic acid (7 days) followed by Piperacillin-Tazobactam (7 days)	Amoxicillin (7 days)

Amoxicillin-clavulanic acid (7 days)

	Piperacillin-Tazobactam + Clarithromycin (5 days)	No antibiotics	Amoxicillin-clavulanic acid (7 days)	
 Steroids	Steroids 120 mg, 12 weeks tapering	Steroids 80 mg, 6 weeks tapering	Steroids boluses during 72 h (625 mg) followed by steroids 64 mg, 8 weeks tapering	No steroids	Steroids 100 mg, 5 weeks tapering	
 Olaparib treatment	Stopped	Stopped	Stopped	Stopped	Stopped	
 Clinical outcomes	Complete ILD resolution	Complete ILD resolution	Partial ILD resolution	Complete ILD resolution	Complete ILD resolution	
 Rechallenge PARPi	Relayed with Rucaparib	No	No	Rechallenged with olaparib	NA	
Ag L/P Antigens legionella/pneumococcus, BNP Brain natriuretic peptide, CD4/CD8 Ratio of T helper cells/cytotoxic T cells, DFME Direct fluorescent microscopy examination, HP Hypersensitive pneumonitis, HT Hypertension, HRD Homologous recombination deficiency, ILD Interstitial lung disease, BAL Bronchoalveolar lavage, Ly Lymphocyte, Ma Macrophage, NA Not applicable, PNN Polynuclear neutrophil, PARPi Poly(ADP-ribose) polymerase inhibitors, PNE Polynuclear eosinophil, PCR Polymerase chain reaction, TTE Transthoracic echocardiogram

Description of the index case

A 72-year woman carrying a somatic BRCA1 mutation diagnosed in 2015 with a metastatic ovarian carcinoma. She never smoked. Debulking surgery was performed, and the patient received first-line platinum-based chemotherapies (Table 1). She was included in the PAOLA trial and randomised to the bevacizumab + placebo arm. Complete radiological response was obtained, and she underwent adjuvant surgery followed by a maintenance treatment with olaparib (300 mg twice a day).

Fever, cough, and dyspnoea began twelve weeks after olaparib initiation. CT-scan was initially considered as normal, and olaparib was continued. Retrospective analysis showed a diffuse slight high density of the pulmonary parenchyma with a relative respect of lower lobes. The patient was hospitalised three weeks later. Clinical examination discovered bilateral fine inspiratory crackles. She received nasal oxygen therapy at 4L/min maximum. Thoracic CT excluded pulmonary embolism but showed a worsening of lung parenchyma abnormalities with GGOs associated to areas of lobular hypoattenuation and small nodular lesions (Fig. 1). Radiological presentation was typical of HP. C-reactive protein (CRP) was moderately increased (86 mg/dl for normal range < 5 mg/dL) and procalcitonin was negative. No other biological anomalies were reported. Urine antigens for legionella and pneumococcus were negatives. BAL showed alveolitis (107 cells/ml) with increased lymphoid population (30%) with an over-representation of T helpers (CD4/CD8 = 3.9) and few eosinophils (3.9%) (Table 1). BAL cytopathology did not reveal tumour cells. Bacteriological cultures remained sterile. No pneumocystis cyst was observed, and polymerase chain reaction (PCR) for pneumocystis was negative, as well as Β-D-glucan. PCR for viruses (respiratory virus including Covid-19) and respiratory germs (including mycoplasma) were negative. Autoimmune serologies were negative. Brain natriuretic peptide was normal. No respiratory function exploration was carried out.Fig. 1 Index case: Chest CT-scan (CCT). Lung window images on axial transverse CCT were obtained at the right pulmonary artery level, and the coronal-reformatted reconstruction at the carina level. a CCT showing lung quality before olaparib treatment. b Twelve weeks after the beginning of olaparib treatment, CTT showed a diffuse slight high density of the parenchyma. Olaparib was continued. c and d Three weeks later, axial and coronal-reformatted CCT showing a worsening of the parenchyma abnormalities with ground glass opacities associated to areas of lobular hypo-attenuation (arrowheads) and small nodular lesions, with an aspect of hypersensitive pneumonitis. e and f Treatment was stopped and steroid treatment was introduced during three months. The coronal reformatted CCT showed a clear improvement of parenchymal abnormalities with persistence of a small ground glass opacity area to a normal parenchymal appearance

High-dose glucocorticoids (2 mg/kg prednisone) were started, associated with antibiotics pending the results of microbiological investigations. Oxygen weaning was quickly obtained. Glucocorticoids were initially introduced for a period of 6 weeks with progressive tapering. After 4 weeks of tapering (until the posology of 20 mg/day), dyspnoea and fever reappeared. Thus, glucocorticoids posology was increased to 120 mg, and treatment was continued with progressive tapering for 8 extra weeks. The CT-scan performed after completing corticosteroid treatment showed a complete resolution (Fig. 1).

Olaparib was not reintroduced. Based on a recent study suggesting an inferior over-risk of PARPi-induced pneumonitis with rucaparib [6], and given the complete response observed with PARPi maintenance, the physician rechallenged with this new PARPi without pneumonitis recurrence. Nevertheless, the cancer relapsed after 9 months of rucaparib; the patient underwent a new platinum-based chemotherapy.

Description and comparison with other cases

The median age of our five patients was 71 years old (range: 38–72) at the AE time (Table 1). None of them were smokers. Four had ovarian carcinoma and one breast lobular carcinoma. Two patients exhibited a germinal BRCA1 mutation, two a somatic BRCA1 mutation, and one a homologous recombination deficiency (HRD). They received three to four chemotherapy lines before olaparib treatment being started. Initial posology ranged from 300 to 400 mg twice a day. The median delay between olaparib introduction and symptom occurrence was 12 (range: 6–33) weeks. Main symptoms were dyspnoea (n = 5), fever (n = 4), and cough (n = 3). Pneumonia severity (CTCAE V5) was Grade 3 in four patients and Grade 2 in one patient.

GGOs found on lung CT-scan turned out to be the most predominant lesions (Figs. 1, 2 and 3), with a relative respect of lower lobes in two patients (Index case (Fig. 1) and case #3 (Fig. 3)). In Index case, small nodular lesions were present (Fig. 1). We observed symmetrical topography of lesions in all cases. HP reaction was the common pattern.Fig. 2 Case 2: Chest CT-scan (CCT). Lung window images on axial transverse CCT were obtained at the level of the carina, and the coronal reformatted reconstruction at the level of the superior vena cava. a and b CCT showing lung quality before olaparib treatment. c and d Three months after the beginning of olaparib treatment, CTT showed a lung parenchyma with slight high density related to early ground glass opacities and irregularity of pleural fissure related to thickening of inter-lobules septa (red arrows). e and f One month after the drug was stopped and corticosteroid treatment was started, CCT returned to normal

Fig. 3 Case 3: Chest CT-scan (CCT). Lung window images on axial transverse CCT and coronal-reformatted reconstruction were obtained at level of the carina. a and b Six weeks after the beginning of olaparib treatment, images on axial transversal and coronal-reformatted CCT showed diffuse bilateral ground glass opacities with a relative respect of lower areas of the lungs and lobular areas of decreased attenuation and vascularisation (arrowheads). c and d After drug was stopped and a week of corticosteroid treatment, axial and coronal reformatted images showed the slow resolution of parenchymal abnormalities with appearance of a subpleural atelectasis band and reverse halo sign (arrows). e and f Two month later, complete disappearance of ground glass opacities and persistence of a sub-pleural atelectasis band on lower lobes were observed

BAL was performed, revealing lymphocytic alveolitis in all patients. Median CD4/CD8 ratio was 2 (range: 1–3.9). Median CRP concentration was 63 mg/dl (range: 43–86). For each case, bacteriology and autoimmunity were negative, and the O-ILD diagnosis was established.

Olaparib was stopped for each patient. Oxygen supply was administered in four cases, with a median oxygen flow rate of 4L/min (range: 2–6). Four patients initially underwent antibiotic treatment for 5 to 7 days associated with glucocorticoids. Glucocorticoid posology ranged from 1 mg/kg to 2 mg/kg with a median tapering period of 8 (range: 5–12) weeks. Boluses were administrated in one patient during 72 h. No fatal ILD occurred, while ILD resolved completely for four patients and partially for one, with rapid oxygen weaning and home discharge.

One patient was reintroduced to another PARPi (rucaparib), while another was re-administered olaparib a month after discontinuing glucocorticoids 300 mg twice daily (initial prescribed dosage). Three weeks after rechallenge, the patient reported progressive Grade 2 dyspnoea and asthenia assumed by the physician to be a relapse. However, no CT-scan was performed. Olaparib was reduced to 250 mg twice a day during 15 days, without effect, and then reduced to 200 mg twice a day, with an improvement of symptoms. The cancer relapsed four months after rechallenge.

International WHO and FDA databases cases extraction

Of the 40 ILD cases registered after olaparib treatment, 39 occurred in women, all cases were serious. In 90% of cases, olaparib was the only suspected drug. The median age was 69 (range: 34–87) years. The median time between the beginning of olaparib and the AE was 99 (range: 6–815, n = 21) days. Treatment was stopped in most cases (91%). Twenty-nine cases were considered as “recovering” or “recovered” or “recovered with sequelae”; one case was fatal; three cases were “not recovered”, and seven outcomes were “unknown”. There were no available data on cytopathological lung features or radiological patterns.

Discussion

We identified five O-ILD cases in France and Belgium whereas the FDA Adverse Event Reporting System (FAERS) database reported 942 cases of respiratory AEs in patients treated in the US with olaparib from 2015 to 2023 (851 serious cases, including 135 deaths) [6]. Among these 942 cases, 96 pneumonitis (91 serious cases and 21 deaths) were reported, while 227 'ILDs' (227 serious cases and 12 deaths), 24 respiratory failure (24 serious cases and 20 deaths), were mentioned, including eight cases of pulmonary fibrosis (eight serious cases and two deaths), five cases of acute respiratory distress syndrome (five serious cases and five deaths). From this study, Ma et al. [6] found a 0.79% incidence in patients treated with PARPi based on the only preferred term “pneumonitis”. This possibly suggests a higher real incidence of “respiratory AEs” in olaparib-treated patients. The Japanese pharmacovigilance database reported 110 potential cases of drug-induced lung disorder due to olaparib from 2018 to 2021 versus 10 potential cases in the FBPDB from 2018 to 2022 [7], thus raising concerns about genetic susceptibility in Asian population.

In our series, PARPi-ILDs were mainly of severe intensity, although non-fatal, and occurred about 12 weeks after olaparib introduction; they were reversible after olaparib discontinuation and glucocorticoid intake. The median age was 72 years old. Ma et al. [6] reported a younger median age of 62 years and similar median time to event of 81 days. Ishimoto et al. [7] also reported a median age of 66 years and median time to event of 12 weeks. Recognised risk-factors for drug-induced AEs included age, previous radiotherapy, higher posology, and impaired kidney function [10].

In all our five cases, CT-scan revealed a progressive bilateral widespread of GGOs predominant in upper lobes resulting in a radiological diagnosis of putative HP. BAL was performed in four cases and showed alveolar lymphocytosis (30–60% lymphocytes), over the 20% cut-off for HP diagnosis [11, 12]. Strikingly CD4/CD8 ratio was measured in three patients and was > 1, in accordance with previous studies involving HP patients [12, 13], while most commune causes of HP are associated with predominant CD8 + alveolitis [14]. Thus, PARPi-ILD shows radiological and biological characteristics of HP reaction, often consisting of drug-induced ILD presentation [10].

Our study displays several limitations, the most prominent being its retrospective with only a few cases with detailed information. Moreover, cultures and stains were all negative but this does not exclude an underlying infection in immunocompromised patients.

PARPi-ILD treatment is not standardised. In this series, four patients did stop olaparib and received glucocorticoids at a high-dose posology between 1 and 2 mg/kg. It should be emphasized, that HP with GGO patterns are reported to be steroid-sensitive requiring lower doses (3/4 mg/ kg) of steroids [15]. In the index case, early tapering of glucocorticoids was associated with a rebound effect and reappearance of initial symptoms, highlighting the role of glucocorticoids and their optimal duration, as already described in other drug-induced or environmental HP [16]. Nevertheless, case 4 only got olaparib discontinuation, thus questioning the potential spontaneous evolution of the pneumonitis of HP-type without glucocorticoids, with such short half-life drug and low-grade symptoms. Ishimoto et al. [7] also reported three cases resolving only by stopping olaparib without glucocorticoids. Using glucocorticoids in drug-induced ILD is actually empiric and relies on limited data. In 2004, Müller et al. [17] recommended glucocorticoids in drug-induced ILD, with doses adjusted according to the severity degree, based on only 10 cases of bleomycin drug-induced ILD. More recently, these recommendations were reiterated [18]. However, a systematic review concluded that the evidence supporting the efficacy and dosage of glucocorticoids was of low quality [15]. Further studies are required to distinguish spontaneous evolution from glucocorticoid effects in drug-induced ILD, and PARPi-ILD in particular.

In our cases series, two patients underwent PARPi re-challenge. Re-challenge with rucaparib (index case) was based on the work of Ma et al. [6]. We did not report any pneumonitis recurrence with rucaparib after a 9-month follow-up. Two cases of olabarib re-challenge were also reported by Natsumi et al. [19], but description of cases was unfortunately not available in English. Those elements might suggest a specific lung toxicity with olaparib rather than a PARPi class-effect which could support an immuno-allergic specific mechanism  linked to the olaparib structure [17]. Indeed, whether most of the pathogenic mechanisms of drug-induced ILD are unknown, they can be divided into cytotoxic drugs with direct or indirect effect on epithelial cells, and immunogenic drugs activating immune cells, by acting as a hapten or mimicking a human cell antigen [20]. Re-challenge with another PARPi in case of PARPi-ILD should be then discussed on a case-by-case basis, according to the initial severity and the radiological pattern. It should be reminded that PARPis are involved in the regulation of DNA cell repair while being also reported to activate myofibroblast differentiation of resident lung fibroblast, as well as tissue remodelling, after in vivo lung injury caused by hyperoxia or bleomycin [21, 22]. However, PARP-1-deficient mice exhibited reduced pulmonary fibrosis in response to bleomycin-induced lung injury, compared with wild-type controls, reminding the versatility of such lung ILD animal models when it comes to recapitulate human disease [18]. In line with the bleomycin-induced mouse model PARPi effects on IL-1, IL-6, and TNF-α were studied as therapy for COVID-19-induced acute respiratory distress syndrome but with un-conclusive results [23]. Thus, to summarize, evidence favouring a direct cytotoxic effect or an immunogenic effect of PARPi on the lungs still remains elusive.

In conclusion, PARPi-ILD is a rare but potentially life-threatening disease presenting with a predominant HP pattern. Re-challenging with another PARPi might be of interest since data are available suggesting the low probability of cross-reactivity and class effect. Although corticosteroids were efficient in our series of patients, questions remain on their interest on short-term prognosis, comparing to olaparib stopping alone, and on long-term functional consequences. The difference of cases screened in Japan and France could raise concerns about possible genetic susceptibility and potential under-reporting, and clinicians should pay attention to lung symptoms upon olabarib treatment, leading to early CT-scan lung evaluation, especially with the PARPi recent registrations in other cancer types than breast and ovary, including pancreas cancer or the more frequent prostate cancer.

Acknowledgements

We express our sincere gratitude to Isabelle Ray-Coquard, MD (Centre Léon Bérard, Lyon) for fruitful discussion and advices.

Authors’ contributions

A.B, V.G. and G.Z. wrote the main manuscript text. A.B. and D.F. collected the data. V.G. and A.K. reviewed scanners. All authors reviewed the manuscript.

Funding

This study received no funding.

Availability of data and materials

All data generated or analysed during this study are included in this published article.

Declarations

Ethics approval and consent to participate

Patient and sample data were retrospectively collected and systematically de-identified, in accordance with the French law and was ethically approved by the Institutional Review Board of the French learned society for respiratory medicine (CEPRO #2023–010).

Consent for publication

NA.

Competing interests

The authors declare no competing interests.

Take home message: PARPi-induced interstitial lung disease is a rare but life-threatening disease with a HP pattern within 3 months after PARPi introduction. The main treatment relies on medication discontinuation. Rechallenging with another PARPi must be considered.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
==== Refs
References

1. O’Connor MJ Targeting the DNA damage response in cancer Mol Cell 2015 60 4 547 560 10.1016/j.molcel.2015.10.040 26590714
O’Connor MJ. Targeting the DNA damage response in cancer. Mol Cell. 2015;60(4):547–60.26590714 10.1016/j.molcel.2015.10.040
2. Ray-Coquard I Pautier P Pignata S Pérol D González-Martín A Berger R Fujiwara K Vergote I Colombo N Mäenpää J Selle F Sehouli J Lorusso D Guerra Alía EM Reinthaller A Nagao S Lefeuvre-Plesse C Canzler U Scambia G Lortholary A Marmé F Combe P de Gregorio N Rodrigues M Buderath P Dubot C Burges A You B Pujade-Lauraine E Harter P PAOLA-1 Investigators Olaparib plus bevacizumab as first-line maintenance in ovarian cancer N Engl J Med 2019 381 25 2416 2428 10.1056/NEJMoa1911361 31851799
Ray-Coquard I, Pautier P, Pignata S, Pérol D, González-Martín A, Berger R, Fujiwara K, Vergote I, Colombo N, Mäenpää J, Selle F, Sehouli J, Lorusso D, Guerra Alía EM, Reinthaller A, Nagao S, Lefeuvre-Plesse C, Canzler U, Scambia G, Lortholary A, Marmé F, Combe P, de Gregorio N, Rodrigues M, Buderath P, Dubot C, Burges A, You B, Pujade-Lauraine E, Harter P, PAOLA-1 Investigators. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med. 2019;381(25):2416–28.31851799 10.1056/NEJMoa1911361
3. Robson M Im S-A Senkus E Xu B Domchek SM Masuda N Delaloge S Li W Tung N Armstrong A Wu W Goessl C Runswick S Conte P Olaparib for metastatic breast cancer in patients with a germline BRCA mutation N Engl J Med 2017 377 6 523 533 10.1056/NEJMoa1706450 28578601
Robson M, Im S-A, Senkus E, Xu B, Domchek SM, Masuda N, Delaloge S, Li W, Tung N, Armstrong A, Wu W, Goessl C, Runswick S, Conte P. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377(6):523–33.28578601 10.1056/NEJMoa1706450
4. Golan T Hammel P Reni M Van Cutsem E Macarulla T Hall MJ Park J-O Hochhauser D Arnold D Oh D-Y Reinacher-Schick A Tortora G Algül H O’Reilly EM McGuinness D Cui KY Schlienger K Locker GY Kindler HL Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer N Engl J Med 2019 381 4 317 327 10.1056/NEJMoa1903387 31157963
Golan T, Hammel P, Reni M, Van Cutsem E, Macarulla T, Hall MJ, Park J-O, Hochhauser D, Arnold D, Oh D-Y, Reinacher-Schick A, Tortora G, Algül H, O’Reilly EM, McGuinness D, Cui KY, Schlienger K, Locker GY, Kindler HL. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. N Engl J Med. 2019;381(4):317–27.31157963 10.1056/NEJMoa1903387
5. de Bono J Mateo J Fizazi K Saad F Shore N Sandhu S Chi KN Sartor O Agarwal N Olmos D Thiery-Vuillemin A Twardowski P Mehra N Goessl C Kang J Burgents J Wu W Kohlmann A Adelman CA Hussain M Olaparib for metastatic castration-resistant prostate cancer N Engl J Med 2020 382 22 2091 2102 10.1056/NEJMoa1911440 32343890
de Bono J, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, Chi KN, Sartor O, Agarwal N, Olmos D, Thiery-Vuillemin A, Twardowski P, Mehra N, Goessl C, Kang J, Burgents J, Wu W, Kohlmann A, Adelman CA, Hussain M. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. 2020;382(22):2091–102.32343890 10.1056/NEJMoa1911440
6. Ma Z Sun X Zhao Z Lu W Guo Q Wang S You J Zhang Y Liu L Risk of pneumonitis in cancer patients treated with PARP inhibitors: a meta-analysis of randomized controlled trials and a pharmacovigilance study of the FAERS database Gynecol Oncol 2021 162 2 496 505 10.1016/j.ygyno.2021.05.012 34023129
Ma Z, Sun X, Zhao Z, Lu W, Guo Q, Wang S, You J, Zhang Y, Liu L. Risk of pneumonitis in cancer patients treated with PARP inhibitors: a meta-analysis of randomized controlled trials and a pharmacovigilance study of the FAERS database. Gynecol Oncol. 2021;162(2):496–505.34023129 10.1016/j.ygyno.2021.05.012
7. Ishimoto H Sakamoto N Kido T Ozasa M Tsutsui S Mori M Setoguchi D Takemoto S Obase Y Ishimatsu Y Tomonaga C Matsumoto K Morisaki S Miura K Mukae H Drug-induced interstitial lung disease caused by olaparib: three case reports and review of the Japanese adverse drug event report database and literature BMC Pulm Med 2023 23 1 289 10.1186/s12890-023-02569-3 37553592
Ishimoto H, Sakamoto N, Kido T, Ozasa M, Tsutsui S, Mori M, Setoguchi D, Takemoto S, Obase Y, Ishimatsu Y, Tomonaga C, Matsumoto K, Morisaki S, Miura K, Mukae H. Drug-induced interstitial lung disease caused by olaparib: three case reports and review of the Japanese adverse drug event report database and literature. BMC Pulm Med. 2023;23(1):289.37553592 10.1186/s12890-023-02569-3
8. Hatabu H Hunninghake GM Richeldi L Brown KK Wells AU Remy-Jardin M Verschakelen J Nicholson AG Beasley MB Christiani DC San José Estépar R Seo JB Johkoh T Sverzellati N Ryerson CJ Graham Barr R Goo JM Austin JHM Powell CA Lee KS Inoue Y Lynch DA Interstitial lung abnormalities detected incidentally on CT: a position paper from the Fleischner Society Lancet Respir Med 2020 8 (7), 726 737 10.1016/S2213-2600(20)30168-5 32649920
Hatabu H, Hunninghake GM, Richeldi L, Brown KK, Wells AU, Remy-Jardin M, Verschakelen J, Nicholson AG, Beasley MB, Christiani DC, San José Estépar R, Seo JB, Johkoh T, Sverzellati N, Ryerson CJ, Graham Barr R, Goo JM, Austin JHM, Powell CA, Lee KS, Inoue Y, Lynch DA. Interstitial lung abnormalities detected incidentally on CT: a position paper from the Fleischner Society. Lancet Respir Med. 2020;8((7),):726–37.32649920 10.1016/S2213-2600(20)30168-5
9. Johkoh T Lee KS Nishino M Travis WD Ryu JH Lee HY Ryerson CJ Franquet T Bankier AA Brown KK Goo JM Kauczor H-U Lynch DA Nicholson AG Richeldi L Schaefer-Prokop CM Verschakelen J Raoof S Rubin GD Powell C Inoue Y Hatabu H Chest CT diagnosis and clinical management of drug-related pneumonitis in patients receiving molecular targeting agents and immune checkpoint inhibitors: a position paper from the Fleischner Society Radiology 2021 298 3 550 566 10.1148/radiol.2021203427 33434111
Johkoh T, Lee KS, Nishino M, Travis WD, Ryu JH, Lee HY, Ryerson CJ, Franquet T, Bankier AA, Brown KK, Goo JM, Kauczor H-U, Lynch DA, Nicholson AG, Richeldi L, Schaefer-Prokop CM, Verschakelen J, Raoof S, Rubin GD, Powell C, Inoue Y, Hatabu H. Chest CT diagnosis and clinical management of drug-related pneumonitis in patients receiving molecular targeting agents and immune checkpoint inhibitors: a position paper from the Fleischner Society. Radiology. 2021;298(3):550–66.33434111 10.1148/radiol.2021203427
10. Schwaiblmair M Behr W Haeckel T Märkl B Foerg W Berghaus T Drug induced interstitial lung disease Open Respir Med J 2012 6 63 74 10.2174/1874306401206010063 22896776
Schwaiblmair M, Behr W, Haeckel T, Märkl B, Foerg W, Berghaus T. Drug induced interstitial lung disease. Open Respir Med J. 2012;6:63–74.22896776 10.2174/1874306401206010063
11. Churg A Hypersensitivity pneumonitis: new concepts and classifications Mod Pathol 2022 35 15 27 10.1038/s41379-021-00866-y 34531525
Churg A. Hypersensitivity pneumonitis: new concepts and classifications. Mod Pathol. 2022;35:15–27. 10.1038/s41379-021-00866-y.34531525 10.1038/s41379-021-00866-y
12. Patolia S Tamae Kakazu M Chami HA Chua A Diaz-Mendoza J Duggal A Jenkins AR Knight SL Raghu G Wilson KC Bronchoalveolar lavage lymphocytes in the diagnosis of hypersensitivity pneumonitis among patients with interstitial lung disease Annals ATS 2020 17 11 1455 1467 10.1513/AnnalsATS.202005-420OC
Patolia S, Tamae Kakazu M, Chami HA, Chua A, Diaz-Mendoza J, Duggal A, Jenkins AR, Knight SL, Raghu G, Wilson KC. Bronchoalveolar lavage lymphocytes in the diagnosis of hypersensitivity pneumonitis among patients with interstitial lung disease. Annals ATS. 2020;17(11):1455–67.10.1513/AnnalsATS.202005-420OC
13. Caillaud DM Vergnon JM Madroszyk A Melloni BM Murris M Dalphin JC French Group of Environmental Immunoallergic Bronchopulmonary Diseases Bronchoalveolar lavage in hypersensitivity pneumonitis: a series of 139 patients Inflamm Allergy Drug Targets 2012 11 1 15 19 10.2174/187152812798889330 22309080
Caillaud DM, Vergnon JM, Madroszyk A, Melloni BM, Murris M, Dalphin JC, French Group of Environmental Immunoallergic Bronchopulmonary Diseases. Bronchoalveolar lavage in hypersensitivity pneumonitis: a series of 139 patients. Inflamm Allergy Drug Targets. 2012;11(1):15–9.22309080 10.2174/187152812798889330
14. Costabel U Uzaslan E Guzman J Bronchoalveolar lavage in drug-induced lung disease Clin Chest Med 2004 25 1 25 35 10.1016/S0272-5231(03)00143-6 15062594
Costabel U, Uzaslan E, Guzman J. Bronchoalveolar lavage in drug-induced lung disease. Clin Chest Med. 2004;25(1):25–35.15062594 10.1016/S0272-5231(03)00143-6
15. Kubo K Azuma A Kanazawa M Kameda H Kusumoto M Genma A Saijo Y Sakai F Sugiyama Y Tatsumi K Dohi M Tokuda H Hashimoto S Hattori N Hanaoka M Fukuda Y Japanese Respiratory Society Committee for formulation of Consensus statement for the diagnosis and treatment of drug-induced lung injuries Consensus statement for the diagnosis and treatment of drug-induced lung injuries Respir Investig 2013 51 4 260 277 10.1016/j.resinv.2013.09.001 24238235
Kubo K, Azuma A, Kanazawa M, Kameda H, Kusumoto M, Genma A, Saijo Y, Sakai F, Sugiyama Y, Tatsumi K, Dohi M, Tokuda H, Hashimoto S, Hattori N, Hanaoka M, Fukuda Y, Japanese Respiratory Society Committee for formulation of Consensus statement for the diagnosis and treatment of drug-induced lung injuries. Consensus statement for the diagnosis and treatment of drug-induced lung injuries. Respir Investig. 2013;51(4):260–77.24238235 10.1016/j.resinv.2013.09.001
16. Spagnolo P Rossi G Cavazza A Bonifazi M Paladini I Bonella F Sverzellati N Costabel U Hypersensitivity pneumonitis: a comprehensive review J Investig Allergol Clin Immunol 2015 25 4 237 250 26310038
Spagnolo P, Rossi G, Cavazza A, Bonifazi M, Paladini I, Bonella F, Sverzellati N, Costabel U. Hypersensitivity pneumonitis: a comprehensive review. J Investig Allergol Clin Immunol. 2015;25(4):237–50.26310038
17. Costabel U Miyazaki Y Pardo A Koschel D Bonella F Spagnolo P Guzman J Ryerson CJ Selman M Hypersensitivity Pneumonitis Nat Rev Dis Primers 2020 6 1 65 10.1038/s41572-020-0191-z 32764620
Costabel U, Miyazaki Y, Pardo A, Koschel D, Bonella F, Spagnolo P, Guzman J, Ryerson CJ, Selman M. Hypersensitivity Pneumonitis. Nat Rev Dis Primers. 2020;6(1):65.32764620 10.1038/s41572-020-0191-z
18. Durante M Sgambellone S Lanzi C Nardini P Pini A Moroni F Masini E Lucarini L Effects of PARP-1 deficiency and histamine H4 receptor inhibition in an inflammatory model of lung fibrosis in mice Front Pharmacol 2019 10 525 10.3389/fphar.2019.00525 31164820
Durante M, Sgambellone S, Lanzi C, Nardini P, Pini A, Moroni F, Masini E, Lucarini L. Effects of PARP-1 deficiency and histamine H4 receptor inhibition in an inflammatory model of lung fibrosis in mice. Front Pharmacol. 2019;10:525.31164820 10.3389/fphar.2019.00525
19. Sakaia N, Kimuraa Y, Hayashia M, Koyaa T, Enomotob T, Kikuchia T. Successful re-administration of drug-induced interstitial lung injury caused by olaparib in two cases, AJRS. 2020;9(3):200–4.
20. Consensus statement for the diagnosis and treatment of drug-induced lung injuries | Elsevier Enhanced Reader. 10.1016/j.resinv.2013.09.001.
21. Pagano A, Métrailler-Ruchonnet I, Aurrand-Lions M, Lucattelli M, Donati Y, Argiroffo C. B. Poly(ADP-Ribose) Polymerase-1 (PARP-1) Controls Lung Cell Proliferation and Repair after Hyperoxia-Induced Lung Damage. Am J Physiol Lung Cell Mol Physiol. 2007;293(3):L619-629. 10.1152/ajplung.00037.2007.
22. Hu B, Wu Z, Hergert P, Henke CA, Bitterman PB, Phan SH. Regulation of Myofibroblast Differentiation by Poly(ADP-Ribose) Polymerase 1. Am J Pathol. 2013;182(1):71–83. 10.1016/j.ajpath.2012.09.004.
23. Curtin N, Bányai K, Thaventhiran J, Le Quesne J, Helyes Z, Bai P. Repositioning PARP Inhibitors for SARS‐CoV‐2 Infection(COVID‐19); a New Multi‐pronged Therapy for Acute Respiratory Distress Syndrome? Br J Pharmacol. 2020;177(16):3635–45.10.1111/bph.15137.
