PARP Inhibitors Gain Utility in Multiple Malignancies
Current and emerging indications for use in ovarian, breast, pancreatic, and prostate cancers are presented.
PTCE would like to acknowledge GlaxoSmithKline for their generous support of pharmacist education
The growing use of PARP inhibitors in multiple malignancies was a topic of great interest at the 2020 Directions in Oncology Pharmacy conference in a session titled PARP Inhibition: Current and Emerging Indications for Use in Ovarian, Breast, Pancreatic, and Prostate Cancers. PARP inhibitors impair cellular DNA base excision repair and trap PARP1 on damaged DNA, leading to obstruction at a replication fork. Cell death is most successful when PARP inhibitors are combined with other drugs or in patients with genetic mutations targeting DNA repair.
Laura Alwan, PharmD, BCOP, began the session by explaining that biomarkers for PARP inhibitor therapy can include both germline and somatic mutations. Clinical trials of PARP inhibitors that target specific biomarkers generally enrolled patients with BRCA1/BRCA2 mutations or homologous recombination deficiencies (HRD). Dr Alwan shared recommendations for completing genetic testing for patients with advanced/metastatic disease in ovarian, breast, pancreatic, and prostate cancers to guide therapy decisions.
Analyzing clinical trial data by disease, Dr Alwan began by reviewing the role of PARP inhibitors in ovarian cancer. She concisely reviewed the data that led to FDA approval of olaparib, rucaparib, and niraparib for first-line maintenance therapy, second-line/recurrence maintenance, and treatment of recurrent ovarian cancer. Dr Alwan noted PARP inhibitors are more effective when used earlier in the disease course and offer a more robust response in patients with BRCA mutations or HRD.
In patients with breast cancer and germline BRCA mutations, both olaparib and talazoparib improved progression-free survival by about 3 months. She highlighted the approval of olaparib as maintenance therapy in patients with a germline BRCA mutation and metastatic pancreatic cancer who have not progressed on at least 16 weeks of first-line, platinum-based chemotherapy. Lastly, she described the benefit for olaparib in HRD-positive, and rucaparib in BRCA-positive, metastatic, castration-resistant prostate cancer.
Dr Alwan then demonstrated variation in the frequency of adverse effects based on underlying disease and specific PARP inhibitor utilized. She noted a higher incidence of hematologic toxicity with talazoparib and niraparib. Diarrhea is observed more frequently with olaparib while dyspepsia, dysgeusia, and abdominal pain are more frequent with rucaparib. All of the PARP inhibitors except for talazoparib are moderately to highly emetogenic and patients should receive prophylactic antiemetic prescriptions. Dr Alwan provided tips for managing nausea and vomiting, fatigue, diarrhea, constipation, dysgeusia, headaches, and insomnia. Across different studies, 25% to 60% of patients require dose reductions for adverse effects and 10% to 15% of patients discontinue therapy. Dr Alwan shared that a pharmacist is well-positioned to help with treatment initiation of PARP inhibitors through medication teaching, medication access, and review of dosing. She wrapped up the session by emphasizing that pharmacists can facilitate treatment continuation by offering supportive care manage- ment for adverse effects, assessing adherence, and monitoring ongoing therapy.