Using PARP Inhibitors in Advanced Ovarian Cancer

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.[1] Because ovarian cancer cells often have preexisting defects in DNA damage repair pathways,[2] 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.[6] 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.[7] 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]

Gastrointestinal symptoms

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.[14] 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.[3] 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.[6] If a dose of a PARP inhibitor is missed or vomited, an additional dose should not be taken.

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.[14]

Fatigue

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.[14] 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.

Myelosuppression

Anemia and leukopenia are common adverse events with all three PARP inhibitors.[3-11] Before initiating PARP inhibitor maintenance therapy, it is medically appropriate to permit a patient to recover from hematologic toxicity caused by previous chemotherapy. It is important to note, however, that it is recommended that niraparib be started within 8 weeks of completion of the prior platinum-based chemotherapy.[7] RBC transfusions may be required to treat symptomatic anemia, and iron, folic acid, and vitamin B₁₂ supplements may be clinically indicated. Erythropoiesis-stimulating agents are not recommended. With rucaparib and olaparib, complete blood cell counts (CBCs) should be checked monthly, with consideration given to checking every 2 weeks during the first 4 to 6 weeks of therapy. With niraparib, there is also a risk of profound thrombocytopenia, notably in the first 4 to 6 weeks of therapy, necessitating weekly CBCs. Preemptively reducing the starting dose of niraparib from 300 mg to 200 mg daily during the first 4 to 6 weeks can be considered in patients with baseline myelosuppression and/or who weigh less than 77 kg (170 lbs). In the event of a precipitous drop in platelet count, even more frequent CBC monitoring is warranted, and weekly checks should be continued for at least 4 weeks after any dosage change. Niraparib may thus not be the ideal choice for patients who are at increased risk of bleeding, such as those taking long-acting anticoagulants; patients who fall frequently; or those who have a comorbidity that increases the risk of complications in the setting of thrombocytopenia. Bleeding precautions should be carefully reviewed with patients receiving niraparib, including education about signs of thrombocytopenia, such as epistaxis, bleeding of gums, petechiae, melena, and hematuria. If they notice any of these, they should be instructed to hold niraparib and seek immediate medical evaluation and a same-day CBC check.[7] In patients with significant myelosuppression, dose reduction is required once the toxicity has resolved to grade 1.

Elevation of creatinine

Olaparib and rucaparib can be associated with increases in serum creatinine due to their effect on the multidrug and toxin extrusion transporters.[3-6,9-11] This often occurs early, and levels may not increase further. Ruling out other causes, such as hydronephrosis or nephrotoxins, is essential. Dose reductions in olaparib are recommended for patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min).[3-5,8-10] For rucaparib, dose reductions are recommended for patients with creatinine clearance < 30 mL/min. A 24-hour creatinine clearance may help determine whether renal function is compromised.

Elevations of transaminase levels

Rucaparib is often associated with a rise in transaminase levels; this usually occurs within the first 4 months of therapy and is not indicative of liver dysfunction.[6,11] The transaminase increases are not associated with hyperbilirubinemia and generally resolve over time. In 11% of patients, grade 3/4 elevations in liver enzymes are seen. In a patient who already has a large burden of liver disease, it may be challenging to determine if a rise in transaminase levels is due to the PARP inhibitor or progression of disease in the liver. Hy’s law can be used to assess for drug-induced liver injury. In any patient who meets Hy’s criteria for drug-induced liver injury (ie, alanine aminotransferase or aspartate aminotransferase > 3× the upper limit of normal [ULN] with concomitant bilirubin > 2× ULN, without alkaline phosphatase elevations or another clear reason for the elevations), immediate discontinuation of the drug is warranted. Patients receiving rucaparib should be counseled to avoid hepatotoxins, including alcohol, and to discuss all supplements with the treating physician.

Nasopharyngitis

All PARP inhibitors, and especially olaparib, have been reported to cause nasopharyngitis.[3-11] Use of a humidifier at night and a decongestant or throat lozenges as required can be recommended to patients; they should also be counseled to avoid trauma to their nasal passageways.

Rash

Both olaparib and rucaparib are associated with a rash in up to one-fifth of patients.[3-11] Because rucaparib may induce a photosensitive rash, patients should be counseled to reduce sun exposure and wear sunblock.[6,11]

Hypertension and palpitations

Hypertension and palpitations are commonly seen with niraparib due to an off-target effect of the drug on norepinephrine, dopamine, and serotonin transporters.[7] Patients should monitor their blood pressure at home, especially during the first month of treatment, and a plan should be made to initiate/adjust antihypertensives if needed. Heart rate and blood pressure should be monitored monthly in the clinic. Patients with preexisting cardiovascular disorders should be closely monitored.

Rare but serious toxicities

Myelodysplastic syndrome (MDS). Estimates indicate that 0.5% to 2.0% of patients treated with PARP inhibitors will go on to develop MDS or acute myeloid leukemia (AML). When trying to determine patients’ risk of future MDS or AML, it is important to consider prior exposure to alkylating agents such as cyclophosphamide, which they may have received for a prior breast cancer.[3-11] Prior exposure to platinums, as well as topoisomerase II inhibitors (such as etoposide) and anthracyclines (liposomal doxorubicin, or for breast cancer, doxorubicin) may also incrementally increase the risk of future hematologic malignancies. Patients with prolonged myelosuppression, or in whom there is a concern for MDS or AML, should be referred promptly to a hematologist for further evaluation, including bone marrow analysis and cytogenetic studies. MDS/AML may develop years later, so patients should have long-term follow-up.

Pneumonitis. Although dyspnea may be a sign of anemia, it is important to consider the rare possibility of pneumonitis (< 1% incidence) in patients who present with worsening dyspnea, cough, or fever, or associated suspicious radiographic changes.[3-11]

Other Factors to Consider When Selecting a PARP Inhibitor

Oral administration

All three PARP inhibitors are administered orally.[3-11] This is in contrast to IV delivery of most other cytotoxic agents used in the treatment of recurrent ovarian cancer. An oral agent may not be advisable for a patient with a recent history of small bowel obstruction and/or extensive peritoneal disease or preexisting refractory nausea, because of the likelihood of impaired drug absorption. A large burden of disease, and in particular use of PARP inhibitors late in the disease course, may be associated with reduced response rates. Olaparib, which previously required 16 capsules per day, was switched to a more manageable dosing regimen of 4 tablets per day.[3-5,10] Now being phased out, the capsules are not interchangeable with tablets. Rucaparib is administered as 2 capsules twice daily.[6,11] Niraparib’s once-daily dose is convenient and may be best taken at night to decrease nausea during the day.[7]

Cost

PARP inhibitors are frequently only available through specialty pharmacies. Clinicians may need to complete additional paperwork for insurance authorization, which may result in a delay in starting the drug. Even patients with good insurance coverage may discover that their coverage for outpatient oral medications is limited. The cost of PARP inhibitors is as high as $16,000 per month; thus, even a 10% to 20% copay may be a significant out-of-pocket expense. Many larger specialty pharmacies may be able to advise patients about financial assistance programs that can help them mitigate these costs.[15]

Drug and food interactions

It is important to consider potential interactions of PARP inhibitors with concomitant medications. Olaparib is metabolized by CYP3A, so patients should avoid strong or moderate inhibitors or inducers of this enzyme. If coadministration with a strong CYP3A inhibitor cannot be avoided, then the dose should be reduced from 300 mg to 100 mg twice daily. Similarly, patients should be advised to avoid grapefruit, Seville oranges, and the juices of these fruits, which contain furocoumarins, since they may inhibit intestinal CYP3A4 and therefore interfere with metabolism of olaparib. Absorption of olaparib may be slower when taken with a high-fat meal, but this does not appear to decrease efficacy.[3-5] Rucaparib is predominantly metabolized via CYP2D6 and minor pathways, including CYP1A2 and CYP3A4, and may increase systemic levels of substrates of these enzymes that could result in toxicity.[6] Niraparib is not significantly metabolized by the cytochrome enzymes.[7]

Future Directions

As clinicians become comfortable with selecting PARP inhibitors and managing associated toxicities, the next challenge will be to safely and effectively administer these agents in combination with other therapeutic strategies. Current clinical trials are assessing combination approaches, such as PARP inhibition with immune-based strategies and/or other targeted agents, in an effort to overcome mechanisms of resistance to PARP inhibitors. In the recurrent, platinum-sensitive setting, a combination of olaparib and the antivascular agent cediranib is being investigated as an alternative to platinum-based chemotherapy (NRG GY004; ClinicalTrials.gov identifier: NCT02446600). Ongoing trials may soon help establish that PARP inhibitors can be used as part of primary therapy (veliparib: Gynecologic Oncology Group [GOG] 3015 [ClinicalTrials.gov identifier: NCT02470585]) or in the front-line maintenance setting (niraparib: PRIMA/GOG 3012 [ClinicalTrials.gov identifier: NCT02655016]; olaparib: SOLO-1 trial for patients with germline BRCA mutations [ClinicalTrials.gov identifier: NCT01844986]). While these combinations will add to the formidable array of choices with which patients and their clinicians already must contend, they will also allow clinicians to provide more effective treatments, more closely tailored to the individual needs of each patient.

Financial Disclosure:Dr. O’Cearbhaill’s work has been funded in part through National Institutes of Health/National Cancer Institute Support Grant P30 CA008748.

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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.