PARP Inhibitors and Ovarian Cancer
This article was produced by ONS and sponsored by AstraZeneca.
Before poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors were approved for ovarian cancer (https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf), traditional treatment (https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf) consisted of surgical cytoreduction and platinum-based chemotherapy with a taxane, with or without bevacizumab, depending on stage and type. With the surgery-chemotherapy combination, 70%–75% of patients had recurrence (https://doi.org/10.1007/s11864-022-00938-4) and overall five-year survival rates were 29% (https://doi.org/10.1007/s11864-022-00938-4), indicating a need for additional therapies.
What Are PARP Inhibitors?
PARP inhibitors are a type of targeted therapy that affects DNA repair. When DNA develops errors or breaks, the body uses different mechanisms to repair them. BRCA1 and BRCA2, for example, are tumor suppressor genes that aid in DNA repair. Likewise, PARP enzymes recruit proteins to repair DNA breaks (https://doi.org/10.1007/s11864-022-00938-4). Blocking repair of single-stranded breaks with PARP inhibition allows the breaks to progress to double stranded, and if homologous recombination (HR) cannot repair those, the cell relies on error-prone pathways, accumulates damaged DNA, and ultimately dies.
Patient Selection and Dosing
Upon diagnosis, patients with epithelial ovarian cancer should undergo biomarker testing to help inform their treatment course and predict their response to PARP inhibitor therapy. Germline and somatic testing identify whether a tumor has BRCA1/BRCA2 pathogenic variants or is HR deficient, both of which indicate susceptibility to PARP inhibitors.
To date, the U.S. Food and Drug Administration approved three PARP inhibitors—niraparib (https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208447s015s017lbledt.pdf), olaparib (https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208558s013lbl.pdf), and rucaparib (https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209115s004lbl.pdf)—for the treatment of epithelial ovarian cancer. Their dosing and indications vary; refer to the sidebar for more details. For example, niraparib’s starting dose (https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208447s015s017lbledt.pdf) is either 200 mg or 300 mg, depending on patients’ weight or platelet counts. Patients who weigh less than 170 lbs or have a platelet count less than 150,000 mcl should start with 200 mg daily. Patients who weigh more than 170 lbs or have platelet counts higher than 150,000 mcl should begin with 300 mg daily.
Symptom Management and Patient Education
Across the three PARP inhibitors’ clinical trials, fatigue, nausea, and hematologic toxicities were the most commonly reported side effects (https://doi.org/10.1016/j.ctrv.2020.102040). See the sidebar for links to each medication’s package insert for additional potential side effects.
Patients report fatigue as a distressing side effect of cancer (https://www.cancer.gov/about-cancer/treatment/side-effects/fatigue/fatigue-hp-pdq) or treatment that negatively affects their everyday activities, such as mood, work performance, and social interactions. Fatigue is further exacerbated by concurrent side effects such as anemia, altered nutrition, pain, and insomnia. Because it is a subjective experience and varies in severity, oncology nurses should assess it at regular intervals during treatment.
Preventing fatigue starts with educating patients and their caregivers about self-monitoring fatigue levels, maintaining good nutritional habits, incorporating physical activities into their daily routine (https://www.ons.org/make-a-difference/quality-improvement/get-up-get-moving), and limiting naps during day so not to diminish their quality of sleep at night (https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf). If it becomes debilitating, consider referring them for psychosocial interventions; if it progresses to severe, holding or reducing doses may be warranted. To promote adherence, nurses should continually ask patients about fatigue and tailor interventions accordingly.
Nausea is not always accompanied with vomiting (https://oncologypro.esmo.org/oncology-in-practice/anti-cancer-agents-and-biological-therapy/parp-inhibition-and-dna-damage-response-ddr/parp-inhibitors/safety) and generally improves with time, usually around four weeks (https://oncologypro.esmo.org/oncology-in-practice/anti-cancer-agents-and-biological-therapy/parp-inhibition-and-dna-damage-response-ddr/parp-inhibitors/safety). Because PARP inhibitors may be taken with or without food, taking an antiemetic with food 60 minutes prior to dosing may help prevent nausea (https://doi.org/10.1016/S1470-2045(18)30786-1). Educate patients on the possibility of nausea and to report it to their provider. Holding or reducing doses may be warranted for persistent nausea or if vomiting or weight loss occurs. Patients are at risk for underadherence if their nausea is not well managed.
Monitor for hematologic toxicities such as anemia, thrombocytopenia, and neutropenia with complete blood counts (CBCs) monthly for the first year, then periodically. Because niraparib is associated with more severe thrombocytopenia (https://doi.org/10.1016/S1470-2045(18)30786-1), patients receiving that PARP inhibitor should obtain CBCs weekly for the first month. Supportive care for hematologic toxicities typically involves blood transfusions, but severe grades (https://www.uptodate.com/contents/image/print?imageKey=HEME/64984) may require holding or reducing PARP inhibitor doses. Consider bone marrow or cytogenetic analysis for toxicities that persist after four weeks (https://oncologypro.esmo.org/oncology-in-practice/anti-cancer-agents-and-biological-therapy/parp-inhibition-and-dna-damage-response-ddr/parp-inhibitors/safety) despite dose interruption.
Niraparib is also associated with hypertension and hypertensive crisis. The package insert highlights (https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208447s015s017lbledt.pdf) recommend monitoring blood pressure weekly for the first two months, monthly for a year, and periodically thereafter.
Many factors influence patients’ ability to adhere to PARP inhibitor therapy (https://doi.org/10.1016/j.ygyno.2021.08.025), including difficulty managing side effects; lack of understanding the benefits, particularly for long-term maintenance therapy; and financial toxicity. Patient education on preventing potential side effects and offering other support and resources are critical to optimizing adherence. Assess patients’ and caregivers’ information comprehension at each encounter and reinforce as needed, and consider other strategies recommended in the ONS Guidelines™ to Support Patient Adherence to Oral Anticancer Medications (https://www.ons.org/ons-guidelines-support-patient-adherence-oral-anticancer-medications).