Poly(ADP-ribose) polymerase (PARP) proteins are used by cells in several DNA repair processes. PARP inhibition can result in preferential death of cancer cells when another mechanism for repairing DNA is defective. Two PARP inhibitors, olaparib and rucaparib, have been approved by the US Food and Drug Administration (FDA) for the treatment of recurrent, BRCA-associated ovarian cancer. More recently, these two and a third PARP inhibitor, niraparib, were approved by the FDA as maintenance therapy following platinum-based chemotherapy for recurrent ovarian cancer. This has caused a paradigm shift in disease management and a challenge for clinicians, who must decide how best to use these agents in individualized treatment. The oral formulation is attractive to patients, but adverse effects such as nausea and fatigue can impact quality of life. As clinicians become comfortable selecting PARP inhibitors and managing associated toxicities, future steps will be to investigate how to safely administer them in combination with other therapies.
Inhibition of poly(ADP-ribose) polymerase (PARP) proteins, which cells use in a variety of DNA damage repair mechanisms, is a promising therapy for ovarian cancer. Because ovarian cancer cells often have preexisting defects in DNA damage repair pathways, the inhibition of PARP can result in preferential death of cancer cells when another mechanism for repairing DNA is defective. This is called synthetic lethality. The concept of synthetic lethality is that cell death occurs when two separate mechanisms for repair of defective DNA are present in a cell and both are incapacitated. (If only one DNA repair mechanism is defective, then the cell can remain viable.) For example, synthetic lethality occurs when ovarian cancer cells with a BRCA mutation are exposed to a PARP inhibitor. The mutation causes defective repair of breaks in double-stranded DNA and the drug prevents repair of breaks in single-stranded DNA. Thus the cancer cells that have BRCA mutations die while cells with a functioning BRCA gene remain unaffected.[1,2]
Two PARP inhibitors, olaparib and rucaparib, received US Food and Drug Administration (FDA) approval in 2014 and 2016, respectively, for the treatment of BRCA-associated ovarian cancer.[3-6] Since 2017, three PARP inhibitors—niraparib, olaparib, and rucaparib—have received FDA approval in the recurrent setting as maintenance therapy following platinum-based therapy.[7-11] The approval of three PARP inhibitors in rapid succession has resulted in a paradigm shift in the management of recurrent ovarian cancer. However, these choices present a challenge for clinicians, who now struggle with the selection of PARP inhibitors for individual patients, as well as with how to best incorporate these agents into existing treatment strategies.
How PARP Inhibitors Are Used in Recurrent Ovarian Cancer
Treatment of recurrent, BRCA-associated ovarian cancer
PARP inhibitors were initially studied in ovarian cancers with germline BRCA mutations. In December 2014, olaparib was the first PARP inhibitor to receive US and European regulatory approval in ovarian cancer.[3-5] It was approved for women with recurrent ovarian cancer who had a deleterious or suspected deleterious germline BRCA1 or BRCA2 mutation, and who had received at least three prior lines of chemotherapy. Olaparib capsules are being phased out, and it is now available as tablets (300 mg twice daily; 4 tablets per day).
Rucaparib was studied in ovarian cancers with germline BRCA mutations and in patients whose tumors demonstrated homologous recombination deficiency (HRD) resulting from alterations in crucial DNA repair genes in the tumor shown to convey sensitivity to PARP inhibition. Consequently, the December 2016 FDA approval for rucaparib permitted its use for somatic (tumor) and/or germline BRCA1/2 mutations in patients with ovarian cancer who had received at least two prior lines of chemotherapy. Rucaparib is available as tablets (600 mg twice daily; 4 tablets per day).
Maintenance following platinum-based chemotherapy for recurrent epithelial ovarian cancer
In March 2017, FDA approval of niraparib extended the role of PARP inhibition beyond BRCA-associated ovarian cancers. Niraparib was approved as a post-platinum maintenance therapy in patients with recurrent epithelial ovarian cancer who had responded to their most recent platinum-based therapy. It is available as capsules (300 mg once daily; 3 capsules per day). It was recommended that patients start niraparib maintenance within 8 weeks of the last dose of platinum. Olaparib and rucaparib were approved by the FDA in August 2017 and April 2018, respectively, in a similar maintenance setting for women with recurrent epithelial ovarian cancer who are exhibiting a complete or partial response to platinum-based therapy, but without the 8-week-window stipulation.[8-11]
Impressive progression-free survival (PFS) results (up to a 15.5-month PFS benefit) were seen for all three agents in patients with germline BRCA mutations, and to a lesser degree in those with somatic BRCA mutations.[7-11] In patients with neither germline nor somatic BRCA mutations, the incremental approximate PFS advantage (median, 3–4 months) was comparable to that seen with maintenance bevacizumab.[7-9,11-13] When selecting maintenance therapy for patients with non–BRCA-associated ovarian cancers, it is important not only to consider the toxicity profile of the agent but also to be cognizant that PARP inhibitors are restricted to patients with platinum-sensitive disease in that setting.[7-11] Also, future investigations may lead clinicians to consider using a PARP inhibitor as maintenance therapy for patients with mutations in other DNA damage response genes, such as ATM, RAD51, BRIP1, and PALB2.[1,2]
PARP Inhibitor Selection and Management of Toxicity
Patients like the oral formulation of PARP inhibitors, reporting that it promotes a greater sense of autonomy than intravenous (IV) administration.[3-11,14] However, the daily dosing schedule means that even low-grade symptoms, such as nausea and fatigue, can be particularly troublesome and affect quality of life. It is essential to counsel patients about how to proactively manage such side effects, and to alert them that dose modifications or dose interruptions may be required. Dose interruption and instigation of prophylactic supportive medications may permit resumption at the same dose level once the toxicity has resolved to baseline. However, more severe toxicities may necessitate a dose reduction on resumption of the PARP inhibitor, in addition to supportive measures. Rarely, discontinuation of the PARP inhibitor may be indicated.[3-11,14]
Simple measures such as taking a PARP inhibitor with food or immediately prior to going to bed may help with gastrointestinal side effects. Patients should be counseled about managing nausea and vomiting, and antiemetics should be prescribed at the outset of treatment. It can be helpful to take prophylactic antiemetics 30 to 60 minutes prior to the PARP inhibitor, especially in the initial weeks of therapy. Frequent reevaluation of antiemetic control is important so that the treatment regimen can be revised accordingly. In patients prone to constipation, low-dose olanzapine (2.5–5.0 mg) can be used as an alternative to ondansetron but may cause sedation. Fosaprepitant should be avoided in patients taking olaparib, since inhibition of CYP3A may increase olaparib plasma concentrations. Lorazepam may be helpful for anticipatory nausea. In the case of rucaparib, the gastrointestinal side effects are often most pronounced in the first weeks of therapy and can be mitigated by starting the PARP inhibitor at a lower dose—300 mg instead of 600 mg—twice daily for the first 3 to 4 weeks, and then increasing it up to the full 600-mg dose if tolerated. If a dose of a PARP inhibitor is missed or vomited, an additional dose should not be taken.
- Olaparib is indicated for: 1) treatment of recurrent ovarian cancer in patients with germline BRCA mutations after ≥ 3 prior lines of chemotherapy; 2) as post-platinum maintenance therapy for platinum-sensitive recurrences that responded to platinum-based chemotherapy, regardless of BRCA or homologous recombination deficiency (HRD) status.
- Rucaparib is indicated for: treatment of recurrent BRCA-mutated ovarian cancer (either germline or somatic mutation) after ≥ 2 prior lines of chemotherapy.
- Niraparib is indicated for: post-platinum maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer who responded to platinum-based chemotherapy, regardless of BRCA or HRD status. Niraparib must be started within 8 weeks of the last platinum dose.
- All three poly(ADP-ribose) polymerase (PARP) inhibitors cause fatigue, myelosuppression, and gastrointestinal side effects. Toxicity can be mitigated by preemptive patient education, prescription of prophylactic supportive medications, and careful patient selection.
- Niraparib is associated with significant thrombocytopenia, especially in the first 4 to 6 weeks of treatment. Olaparib and rucaparib may cause a rise in the serum creatinine level, thought to be due to their effect on the multidrug and toxin extrusion transporter in the kidney. Rucaparib may cause clinically insignificant transient elevations in liver transaminase levels.
Consultation with a nutritionist may be beneficial for management of gastrointestinal side effects. Often patients may tolerate smaller, frequent snacks more readily than larger meals; avoidance of trigger foods can also be helpful. Patients who experience diarrhea should be counseled regarding increasing fluid intake and modifying what they eat, using the bananas, rice, apples, and toast (BRAT) diet. Other etiologies of diarrhea, such as infection or progression of disease, should be ruled out. Pharmacologic interventions include antimotility agents, such as loperamide. Dietary modifications in conjunction with education regarding mouth and dental care may help patients who experience stomatitis or dysgeusia. Proton pump inhibitors may be required for dyspepsia. A referral to a gastroenterologist for possible endoscopy should be considered if symptoms persist despite dose interruption and use of supportive medications.
Fatigue is a common side effect and is reported with all three PARP inhibitors.[3-11,14] When a patient receiving a PARP inhibitor complains of fatigue, it is important to rule out other contributing factors, such as disease-related fatigue, depression, insomnia, and anemia, as well as sedation from concomitant medications. Patients should be advised to self-monitor fatigue levels and be encouraged to remain active and to exercise as tolerated. Consultation with a physical therapist or rehabilitation specialist may be helpful. Psychosocial interventions, including counseling, mind-body therapies, and even simple techniques such as massage and education regarding sleep hygiene may also help. Early involvement by palliative care specialists for additional support may be appropriate. Pharmacologic interventions, including treatment of underlying pain, depression, or insomnia, as well as consideration of methylphenidate, a psychostimulant, may improve energy levels. A red blood cell (RBC) transfusion may be required for symptomatic anemia, but it is also important to proactively investigate and treat any underlying vitamin and/or iron deficiencies. Brief interruptions in dosing may be sufficient to address fatigue and may allow resumption of the PARP inhibitor at the same dose level. However, a dose reduction may be warranted if the fatigue is still intolerable despite these interventions.
1. Scott CL, Swisher EM, Kaufmann SH. Poly (ADP-ribose) polymerase inhibitors: recent advances and future development. J Clin Oncol. 2015;33:1397-406.
2. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474:609-15.
3. Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015;33:244-50.
4. Domchek SM, Aghajanian C, Shapira-Frommer R, et al. Efficacy and safety of olaparib monotherapy in germline BRCA1/2 mutation carriers with advanced ovarian cancer and three or more lines of prior therapy. Gynecol Oncol. 2016;140:199-203.
5. Kaye SB, Lubinski J, Matulonis U, et al. Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer. J Clin Oncol. 2012;30:372-9.
6. Drew Y, Ledermann J, Hall G, et al. Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly(ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer. Br J Cancer. 2016;114:723-30.
7. Mirza MR, Monk BJ, Herrstedt J, et al; ENGOT-OV16/NOVA Investigators. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375:2154-64.
8. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366:1382-92.
9. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 2014;15:852-61.
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;18:1274-84.
11. 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;390:1949-61.
12. Aghajanian C, Goff B, Nycum LR, et al. Final overall survival and safety analysis of OCEANS, a phase 3 trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent ovarian cancer. Gynecol Oncol. 2015;139:10-6.
13. Coleman RL, Brady MF, Herzog TJ, et al. Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18:779-91.
14. Moore KN, Monk BJ. Patient counseling and management of symptoms during olaparib therapy for recurrent ovarian cancer. Oncologist. 2016;21:954-63.
15. Smith HJ, Walters Haygood CL, Arend RC, et al. PARP inhibitor maintenance therapy for patients with platinum-sensitive recurrent ovarian cancer: a cost-effectiveness analysis. Gynecol Oncol. 2015;139:59-62.