Sharing real-world experiences to optimize the management of olaparib toxicities: a practical guidance from an Italian expert panel

Lorusso, Domenica; Bologna, Alessandra; Cecere, Sabrina Chiara; Matteis, Elisabetta De; Scandurra, Giuseppa; Zamagni, Claudio; Arcangeli, Valentina; Artioli, Fabrizio; Bella, Mariangela; Blanco, Giusi; Cardalesi, Cinzia; Casartelli, C.; Vivo, Rocco De; Napoli, Marilena Di; Gisone, Emanuele Baldo; Lauria, Rossella; Lissoni, Alberto Andrea; Loizzi, Vera; Maccaroni, Elena; Mangili, Giorgia; Marchetti, Cláudia; Martella, Francesca; Naglieri, Emanuele; Parolin, Veronica; Ricciardi, Giusy; Ronzino, Graziana; Salutari, Vanda; Scarfone, Giovanna; Secondino, Simona; Spagnoletti, Ilaria; Tasca, Giulia; Tognon, Germana; Guarneri, Valentina

doi:10.1007/s00520-020-05320-4

Cited by 5 publications

(7 citation statements)

References 26 publications

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“…Transfusion support should be considered for hemoglobin levels of ≤7 g/dL or higher in patients with symptoms and pre-existing comorbidities, such as cardiac or lung diseases. Erythropoiesis-stimulating agents are not routinely recommended in this setting, while iron, folate and vitamin B12 deficiency should be ruled out and corrected when needed [ 26 , 43 ].…”

Section: Safety Profile Of Ddr-targeting Agentsmentioning

confidence: 99%

“…Similar incidence of emesis was observed with elimusertib [ 35 ] and adavosertib [ 41 , 42 , 52 ], while it was less frequent with prexasertib, which rarely determined vomiting and G3/4 events [ 23 , 37 , 38 , 39 ]. General recommendations to prevent PARP inhibitor-induced emesis include taking the drug after a light meal, eating small portions of food and maintaining adequate hydration [ 26 , 43 , 55 ]. Even though guidelines suggest daily prophylaxis with 5-hydroxitryptamine 3 receptor (5-HT3) antagonists (ondansetron, granisetron) for oral compounds of moderate emetogenic potential, this is not a standard practice with PARP inhibitors [ 26 , 43 , 56 ].…”

Section: Safety Profile Of Ddr-targeting Agentsmentioning

confidence: 99%

“…General recommendations to prevent PARP inhibitor-induced emesis include taking the drug after a light meal, eating small portions of food and maintaining adequate hydration [ 26 , 43 , 55 ]. Even though guidelines suggest daily prophylaxis with 5-hydroxitryptamine 3 receptor (5-HT3) antagonists (ondansetron, granisetron) for oral compounds of moderate emetogenic potential, this is not a standard practice with PARP inhibitors [ 26 , 43 , 56 ]. In case of G1 toxicity, treatment should be continued, adding anti-emetic medications (e.g., prokinetics, corticosteroids, benzodiazepines) if needed.…”

Section: Safety Profile Of Ddr-targeting Agentsmentioning

confidence: 99%

“…Dose interruption, and eventually dose reductions, should be considered for G2 toxicities, especially if supportive measures are ineffective. Treatment must be withheld in case of G ≥ 3 emesis, and it should be interrupted if nausea and vomiting do not improve after 28 days of discontinuation [ 25 , 26 , 43 , 55 ].…”

Section: Safety Profile Of Ddr-targeting Agentsmentioning

confidence: 99%

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Everything Comes with a Price: The Toxicity Profile of DNA-Damage Response Targeting Agents

Martorana

Silva

Sessa

et al. 2022

Cancers

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Targeting the inherent vulnerability of cancer cells with an impaired DNA Damage Repair (DDR) machinery, Poly-ADP-Ribose-Polymerase (PARP) inhibitors have yielded significant results in several tumor types, eventually entering clinical practice for the treatment of ovarian, breast, pancreatic and prostate cancer. More recently, inhibitors of other key components of DNA repair, such as ATR, CHK1 and WEE1, have been developed and are currently under investigation in clinical trials. The inhibition of DDR inevitably induces on-target and off-target adverse events. Hematological and gastrointestinal toxicities as well as fatigue are common with all DDR-targeting agents, while other adverse events are drug specific, such as hypertension with niraparib and transaminase elevation with rucaparib. Cases of pneumonitis and secondary hematological malignancies have been reported with PARP inhibitors and, despite being overly rare, they deserve particular attention due to their severity. Safety also represents a crucial issue for the development of combination regimens incorporating DDR-targeting agents with other treatments, such as chemotherapy, anti-angiogenics or immunotherapy. As such, overlapping and cumulative toxicities should be considered, especially when more than two classes of drugs are combined. Here, we review the safety profile of DDR-targeting agents when used as single agents or in combination and we provide principles of toxicity management.

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Section: Safety Profile Of Ddr-targeting Agentsmentioning

confidence: 99%

Section: Safety Profile Of Ddr-targeting Agentsmentioning

confidence: 99%

Section: Safety Profile Of Ddr-targeting Agentsmentioning

confidence: 99%

Section: Safety Profile Of Ddr-targeting Agentsmentioning

confidence: 99%

See 2 more Smart Citations

Everything Comes with a Price: The Toxicity Profile of DNA-Damage Response Targeting Agents

Martorana

Silva

Sessa

et al. 2022

Cancers

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“…In a meta-analysis of olaparib safety from four randomized clinical trials data, Ricci et al reported an overall incidence of grade III-IV adverse events of 41% [ 11 ]. However, despite this high frequency of significant adverse events, factors associated with olaparib toxicity remain largely unknown, supporting the need for reports from “real-life” patients [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Association between Olaparib Exposure and Early Toxicity in BRCA-Mutated Ovarian Cancer Patients: Results from a Retrospective Multicenter Study

et al. 2021

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Factors associated with olaparib toxicity remain unknown in ovarian cancer patients. The large inter-individual variability in olaparib pharmacokinetics could contribute to the onset of early significant adverse events (SAE). We aimed to retrospectively analyze the pharmacokinetic/pharmacodynamic relationship for toxicity in ovarian cancer patients from “real life” data. The clinical endpoint was the onset of SAE (grade III/IV toxicity or dose reduction/discontinuation). Plasma olaparib concentration was assayed using liquid chromatography at any time over the dosing interval. Trough concentrations (CminPred) were estimated using a population pharmacokinetic model. The association between toxicity and clinical characteristics or CminPred was assessed by logistic regression and non-parametric statistical tests. Twenty-seven patients were included, among whom 13 (48%) experienced SAE during the first six months of treatment. Olaparib CminPred was the only covariate significantly associated with increased risk of SAE onset (odds ratio = 1.31, 95%CI = [1.10; 1.57], for each additional 1000 ng/mL). The ROC curve identified a threshold of CminPred = 2500 ng/mL for prediction of SAE onset (sensitivity/specificity 0.62 and 1.00, respectively). This study highlights a significant association between olaparib plasma exposure and SAE onset and identified the threshold of 2500 ng/mL trough concentration as potentially useful to guide dose adjustment in ovarian cancer patients.

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The impact of olaparib dose reduction and treatment interruption on treatment outcome in the SOLO2/ENGOT-ov21 platinum-sensitive recurrent ovarian cancer

et al. 2022

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Sharing real-world experiences to optimize the management of olaparib toxicities: a practical guidance from an Italian expert panel

Cited by 5 publications

References 26 publications

Everything Comes with a Price: The Toxicity Profile of DNA-Damage Response Targeting Agents

Everything Comes with a Price: The Toxicity Profile of DNA-Damage Response Targeting Agents

Association between Olaparib Exposure and Early Toxicity in BRCA-Mutated Ovarian Cancer Patients: Results from a Retrospective Multicenter Study

The impact of olaparib dose reduction and treatment interruption on treatment outcome in the SOLO2/ENGOT-ov21 platinum-sensitive recurrent ovarian cancer

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