Safety

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Special Interest Adverse Events

There are several special interest serious adverse events associated with PARP inhibitors that, although relatively uncommon, warrant vigilance. These have been specifically highlighted in regulatory documents such as the prescribing information (FDA) and summary of product characteristics (EMA), and include myelodysplastic syndromes (MDS)/acute myeloid leukaemia (AML), teratogenic effects, bone marrow suppression, hypertension and pneumonitis [1-6].

MDS/AML has occurred in some patients (niraparib, olaparib, rucaparib, talazoparib), and some fatal cases have been reported. The incidence is low (less than 1-1.5%), and has occurred in both active and placebo study arms, but all patients should be carefully monitored for any haematological toxicity, and discontinued from treatment immediately if MDS/AML is confirmed [7-12].

Teratogenic effects have been reported with niraparib, olaparib, rucaparib and talazoparib [1-6].Warn female patients of reproductive age of the potential risk to foetal development, and recommend use of effective contraception during treatment and for at least 6 months after the last dose [1-6, 12].

Bone marrow suppression has been reported for all PARP inhibitors, but at the licenced doses is most marked with niraparib [4, 5].When using niraparib, full blood counts should be recorded weekly for the first month, monthly for the next 11 months and periodically thereafter for clinically significant changes.

Hypertension and hypertensive crisis have been reported in patients taking niraparib [4, 5]. Patients receiving niraparibshould have their blood pressure and heart rate monitored monthly for the first year and periodically thereafter, especially if they have cardiovascular disorders such as coronary insufficiency, cardiac arrhythmias, and hypertension.Medically manage hypertension with antihypertensive medications, and adjust PARP inhibitor dose as necessary.

Pneumonitis has occurred in some patients taking olaparib [1, 2, 13].Monitor patients, if new or worsening respiratory symptoms are observed, treatment should be interrupted and prompt investigation initiated. If pneumonitis is confirmed, treatment should be discontinued.

References

  1. AstraZeneca. LYNPARZA® (olaparib) tablets for oral use. 2018.
  2. European Medicines Agency. Olaparib Summary of Product Characteristics. 2019.
  3. Clovis Oncology. RUBRACA® (rucaparib) tablets, for oral use. 2018.
  4. European Medicines Agency. Rucaparib Summary of Product Characteristics. 2018
  5. Tesaro. ZEJULA® (niraparib) capsules, for oral use [prescribing information]. 2018.
  6. Pfizer. TALZENNA™ (talazoparib) capsules, for oral use [prescribing information]. New York, NY: Pfizer Inc,2018.
  7. Litton JK, Rugo HS, Ettl J et al. Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. N Engl J Med 2018; 379: 753-763.
  8. Coleman RL, Oza AM, Lorusso D et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017; 390: 1949-1961.
  9. Mirza MR, Monk BJ, Herrstedt J et al. Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. N Engl J Med 2016; 375: 2154-2164.
  10. Pujade-Lauraine E, Ledermann JA, Selle F et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 2017; 18: 1274-1284.
  11. Moore K, Colombo N, Scambia G et al. Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med 2018; 379.
  12. LaFargue CJ, Dal Molin GZ, Sood AK, Coleman RL. Exploring and comparing adverse events between PARP inhibitors. Lancet Oncol 2019; 20: e15-e28.
  13. Friedlander M, Banerjee S, Mileshkin L et al. Practical guidance on the use of olaparib capsules as maintenance therapy for women with BRCA mutations and platinum-sensitive recurrent ovarian cancer. Asia Pac J Clin Oncol 2016; 12: 323-331.
Last update: 25 July 2019