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Niraparib (Zejula)—Ovarian Cancer

Posted: Friday, February 1, 2019

Niraparib: Third Approved PARP Inhibitor in Ovarian Cancer

Niraparib is the third oral poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor to be approved by the U.S. Food and Drug Administration (FDA) for select women with advanced ovarian cancer and the first approved for maintenance therapy.1 The approved indication for niraparib is as maintenance therapy in patients who have had a recurrence of high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer but who are in a complete or partial tumor response to platinum-based chemotherapy.2 Although PARP inhibitors, which may be characterized as DNA repair–inhibiting agents, when used for treatment of recurrence are known to be most effective against tumors with BRCA1 or BRCA2 mutations, eligibility for maintenance treatment with niraparib does not require the presence of a BRCA mutation.

BRCA Mutation and Homologous Recombination Deficiency Testing

The NOVA study, which was the pivotal trial of niraparib for maintenance treatment in ovarian cancer,3 enrolled all comers but then stratified subjects according to BRCA status and homologous recombination deficiency (HRD) positivity. For patients with a germline BRCA mutation, progression-free survival, which was the primary endpoint of the trial, was 21 months with niraparib versus 5.5 months with placebo. In the overall nongermline BRCA group, progression-free survival was 9.3 months with niraparib versus 3.9 months with placebo; for those with HRD, progression-free survival was 12.9 months versus 3.8 months with placebo.

“The NOVA results indicate that there is a benefit with niraparib [maintenance therapy] in every group, but the magnitude of benefit is highest among those with BRCA mutations, intermediate in those who are positive for HRD, and lowest for patients with neither BRCA mutations nor HRD,” explained Bobbie J. Rimel, MD, Assistant Professor, Obstetrics and Gynecology, Cedars-Sinai, Samuel Oschin Comprehensive Cancer Institute, Los Angeles. “Patients in all groups benefited from treatment. Only the magnitude of benefit is different in each group,” she told JNCCN 360.  

Dr. Rimel pointed out that BRCA germline testing is usually part of upfront evaluation in patients who are diagnosed with ovarian cancer and has been the standard of care for some time.4,5 Therefore, patients with a germline BRCA mutation are identified early. In contrast, she noted that somatic BRCA testing is much more recent. “It’s not easy to do,” she said. “Likewise, there is no standard test for HRD status.6,7 Some institutions test patients with ovarian cancer for HRD,” she observed, but “we don’t do it in our practice. We know that most patients will benefit from a PARP inhibitor; the question is how much?” [Editor’s Note: NCCN Guidelines for Ovarian Cancer4 recommend that all patients with persistent or recurrent disease undergo validated molecular testing.]

In contrast, Laura Doherty, FNPBC, AOCNP, of The Program in Women’s Oncology at Women & Infants Hospital of Rhode Island, Providence, reported that “we have molecular profiles done for all of our patients with recurrent fallopian tube, ovarian, or peritoneal cancer. When treatment is being considered, we have information about not only germline BRCA mutations, but also about somatic mutations. In view of the recent approval of olaparib for front-line maintenance,”8 she added, “we are now evaluating newly diagnosed women for somatic BRCA mutations as well.”

Therapy in Different Settings With Different Patient Populations

Studies in different treatment settings raise questions about whether patient populations differ significantly. “It would make sense to anticipate differences in performance status between patients being treated in a maintenance setting versus those receiving late-line treatment after four, five, six, or more previous regimens,” Ms. Doherty said. Additionally, Dr. Rimel pointed out, there are 14 drugs that are not PARP inhibitors approved to treat patients with ovarian cancer, so patients may receive a wide variety of regimens and drugs prior to a fifth or sixth line of treatment. 

However, Ms. Doherty noted, to be eligible to receive niraparib in the maintenance setting, the patient has to be experiencing a partial or complete response to platinum therapy. “That means that she may be starting niraparib soon after 6 cycles of a fairly aggressive platinum regimen,” she said. Eligibility also requires disease recurrence, “which means that she has had more than the one platinum-based regimen. Each cycle of chemotherapy takes a toll. My sense is that at least some of the fatigue that we see with a maintenance PARP inhibitor may be confounded by the fact that patients are just coming off 6 cycles of platinum-based chemotherapy. And, it seems that the further they get from intravenous chemotherapy, the more their energy levels improve.”

Results from the phase II QUADRA study,9 which was designed to explore the use of niraparib in more than 400 heavily pretreated patients with ovarian cancer, were reported at the European Society for Medical Oncology (ESMO) 2018 Congress. Data suggested a clinical benefit with niraparib, even in the fourth and fifth lines of therapy. 

Some of the fatigue that we see with a maintenance PARP inhibitor may be confounded by the fact that patients are just coming off 6 cycles of platinum-based chemotherapy.

Niraparib Starting Dose and Thrombocytopenia: ‘Weights and Plates’

The question of niraparib dose, and particularly the appropriate starting dose, has been explored. “Although the FDA approved 300 mg as the starting dose,” Dr. Rimel explained, “in clinical trials of all comers, a 300-mg starting dose of niraparib was associated with roughly a 33% rate of thrombocytopenia, which required dose reduction: that translates to 1 in 3 women on that starting dose [requiring] a dose reduction due to low platelets.” As a result of that finding, a retrospective analysis was performed on prior niraparib studies. The analysis showed that patients who weighed less than 70 kg or had a baseline platelet count of less than 150,000/mL accounted for a greater proportion of the cases of thrombocytopenia seen at the 300-mg dose.

The “weights and plates” guidance was then proposed, which recommends that patients weighing less than 70 kg or with baseline platelets below 150,000/mL should be started at a 200-mg dose of niraparib.10 “Using those criteria, namely starting all patients on 300 mg of niraparib, except for those weighing less than 70 kg or with low baseline platelets (> 150,000/mL),” Dr. Rimel said, “can reduce the incidence of severe thrombocytopenia from 33% to about 11%.”11,12 Using this approach brings the incidence of thrombocytopenia with niraparib into alignment with that observed with other PARP inhibitors (specifically olaparib13 and rucaparib14), she added.

Using the weights and plates guidance is very important, according to Ms. Doherty. “About half of our patients would qualify for the lower starting dose of 200 mg of niraparib. Many of our patients are not overweight and, in fact, weigh less than the stipulated 70 kg. Likewise, having recently completed 6 cycles of chemotherapy, their bone marrow may be fairly beaten up, which may show up as thrombocytopenia or at least as platelets below the 150,000/mL level.”

In addition, Dr. Rimel noted that it is appropriate for clinicians who know their patients to make individual judgments about how well a particular woman is likely to tolerate treatment. “If a patient has had trouble with bone marrow before, perhaps during chemotherapy, it might be prudent to start niraparib at 200 mg,” she said. 

Despite the large proportion of patients who may need to start with a reduced dose, “there was a group of patients in the niraparib studies who received 300 mg and benefited from that dose without thrombocytopenia.15 That may simply indicate that the bioavailability of niraparib is more variable than that of the other PARP inhibitors, Dr. Rimel speculated.

Class Effects of PARP Inhibitors

Although all three PARP inhibitors are associated with nausea and fatigue, the once-daily dosing of niraparib (versus olaparib and rucaparib, which are taken twice daily) may represent a slight advantage, Dr. Rimel told JNCCN 360. “I suggest that patients take niraparib at bed time, so they may simply sleep through any nausea and fatigue, rather than trying to cope with these side effects during waking hours.”

Nausea

Another potentially helpful suggestion offered by Dr. Rimel is to have a small but high-fat snack before a bedtime dose of niraparib. “This seems to reduce or prevent morning nausea, which may be triggered by low blood sugar levels,” she said.

Nevertheless, according to Dr. Rimel, almost all patients treated with niraparib may require an antiemetic with these drugs, at least in the beginning. Some patients develop a meal plan or a dosing schedule that allows them to cut back or eliminate the antiemetic after a few months.

“We do extensive counseling about nausea, proactively,” Ms. Doherty said. “It’s very important to proper adherence because this is an oral therapy. If something you are taking is making you very nauseous, it’s going to make you not want to take it.”

Knowing what has already worked well for patients to prevent or treat nausea and vomiting while on chemotherapy is helpful, Ms. Doherty told JNCCN 360. The patient usually starts with whichever two antiemetics (eg, ondansetron, prochlorperazine) were effective during previous regimens. “Then, we talk about a preventive plan,” she said. “We prescribe a specific regimen for using the antiemetic medication (‘take it 3 or 4 times a day’), with the goal of preventing nausea rather than trying to manage it.” According to Ms. Doherty, taking the antiemetic prophylactically throughout the day seems to be much more effective than taking it when the patient is already experiencing upper gastrointestinal distress. “Very often, if a patient reports still feeling nauseous, despite the medication, we will discover that she has taken the medication only several times a week, fairly randomly, rather than as prescribed several times a day,” Ms. Doherty observed.

Using a team approach to reinforce the educational guidelines, Ms. Doherty continued, the pharmacist reviews important instructions and follows up with the patient about 1 week after niraparib is initiated. “We follow up in clinic, as well, fairly frequently, especially at the start of therapy,” she said.

Ms. Doherty’s team recommends one of two approaches to further reduce nausea with niraparib or any of the PARP inhibitors: as previously mentioned, patients can try taking the medication at bedtime, so they sleep through the initial nausea. Or, in contrast, many patients find that taking their antiemetic medication in the morning, eating some breakfast, and then taking the niraparib also works well,” she said.  

Fatigue

“There’s no magic bullet for fatigue,” Dr. Rimel acknowledged. “I encourage all of my patients to move regularly, but patients on a maintenance regimen are especially urged to develop an exercise plan. The more they can exercise and improve their stamina, the less overall fatigue they seem to have. Exercise also tends to help with sleep, which, of course, helps lessen fatigue. But I think exercise also contributes to better overall reserves. If fatigue is significant and the patient is either distressed or needs to go back to work, then we should consider a dose reduction,” Dr. Rimel said.

Ms. Doherty stressed that patients usually feel their worst when they first start niraparib, because, as previously mentioned, they are just finishing chemotherapy cycles and are likely to feel tired. “We prepare them for fatigue but explain that they are likely to feel better as time goes on,” she said. The team discusses proper rest and nutrition and encourages patients to get back to their routines as soon as they can. The team further supports patients to get as much exercise as they can tolerate and may refer them to physical therapy. These efforts may help patients “cope with whatever deconditioning may have occurred during chemotherapy. After a few months, most patients feel better,” Ms. Doherty reported. 

Insomnia

Dr. Rimel observed that patients who take a PARP inhibitor at night may report insomnia. “To address insomnia, we start with good sleep hygiene but have also added melatonin, when necessary. That seems to work,” she said. Nevertheless, these drugs [ie, PARP inhibitors] are not without adverse effects, and “it may take a number of years and especially patient-reported outcomes before we figure out how to manage PARP inhibitors perfectly.”

It may take a number of years and especially patient-reported outcomes before we figure out how to manage PARP inhibitors perfectly.

A Team Approach

The take-away for colleagues, according to Ms. Doherty, is to provide a great deal of education and support at the start of treatment, when niraparib is first considered and prescribed. A good supportive team is helpful. Patients need to understand the side-effect profile and to be ready to implement a prophylactic plan that will help them tolerate the regimen.

Close follow-up by the team is important in the beginning to help support patients through the first few months. Encouraging patients to keep a journal, diary, or calendar in which they can record their medication doses, any symptoms or side effects, and what supportive measures were taken is very helpful. “When we review these records, we can discover what seems to work and make tweaks that improve tolerability,” Ms. Doherty told JNCCN 360.

Selecting a PARP Inhibitor

The FDA-approved indication of each PARP inhibitor varies, which should aid in drug selection, according to Dr. Rimel. For maintenance therapy, niraparib, olaparib and rucaparib are approved for patients who are in a complete or partial response to platinum-based chemotherapy treatment for recurrence. Rucaparib is approved for treatment of recurrence in patients with deleterious BRCA mutations (germline and/or somatic) who have been treated with two or more chemotherapies, and olaparib is approved for patients with deleterious or suspected deleterious germline BRCA mutations who have been treated with three or more prior lines of chemotherapy; niraparib is not approved in this setting. Based on newly released SOLO-1 data,16 olaparib is also FDA approved as maintenance therapy for those with deleterious or suspected deleterious BRCA mutations (germline or somatic) who are in complete or partial response to first-line platinum-based chemotherapy.

“We stay within approved labeling whenever we can. If I have a patient for whom multiple PARP inhibitors may be appropriate, I consider two primary questions: Is the patient likely to be consistently adherent with therapy as prescribed? Has the patient experienced significant nausea with previous regimens? Twice-daily dosing with olaparib or rucaparib is more challenging for patients who tend to forget or who will not be vigilant about taking medication; niraparib, which is taken once daily, may be preferable in such cases,” Dr. Rimel explained. “Likewise, at least in my experience, olaparib is associated with more nausea, so I am less likely to use it in a woman who has had upper gastrointestinal distress with other treatments.”

Often times, drug choice comes down to co-pay, Dr. Rimel said. “If a company offers a free year of a drug, that is very attractive to patients. These are expensive drugs, so there are times (when clinically reasonable) that we pick the drug with the lowest cost to the patient.”

Niraparib is similar to the other PARP inhibitors, Dr. Rimel noted, “except with regard to thrombocytopenia, unless you follow the previously mentioned ‘weights and plates’ guidance,” she said. Starting those subsets of patients (ie, those who weigh less than 70 kg or have baseline platelet counts below 150,000/mL) at 200 mg of niraparib will bring the use of the drug into alignment with the other drugs in the PARP inhibitor class, she reiterated.

The side-effect profiles for the three PARP inhibitors are slightly different, Ms. Doherty observed, “but all of them are associated with some degree of nausea, vomiting, and fatigue.” Olaparib seems to cause arthralgias and musculoskeletal pain in about one-fifth of patients, she said, whereas the other PARP inhibitors have not been associated with that symptom in clinical trials to date. In contrast, olaparib causes much less thrombocytopenia, whereas niraparib tends to cause pancytopenia. Patients who are concerned about their bone marrow might consider olaparib or rucaparib, she pointed out, or can be started on the lower 200-mg dose of niraparib. “With niraparib,” she said, “we will order a complete blood cell count for the patient on a weekly basis in the beginning, whereas with olaparib or rucaparib, after the first week, blood work will be scheduled monthly.”

Remember the Goals of Treatment

“We need to stress to our patients that the goal of treatment in this setting is maintaining a good quality of life and progression-free survival,” Ms. Doherty told JNCCN 360. “We don’t want patients sitting at home, feeling sick. If they continue to feel unwell, we need to hear about it. We want them out and doing what they love. Helping them live their lives well should be the priority,” she concluded.

Similarly, Dr. Rimel observed that in the maintenance setting, “we need to find a dose that will allow the patient to live her life. The good news is that patients who tolerate niraparib well can continue treatment for years. I am seeing a patient today who has been on niraparib for 3 years.”

 

Disclosures

Bobbie J. Rimel, MD, has served as an advisory board member for AstraZeneca, Genentech, Clovis Oncology, and Tesaro.

Laura Doherty, FNP, BC, AOCNP, reported no conflicts of interest.

 

 

References

  1. National Institutes of Health. National Cancer Institute. FDA approves niraparib as maintenance therapy for recurrent ovarian cancer. Available at: https://www.cancer.gov/news-events/cancer-currents-blog/2017/fda-niraparib-ovarian. Accessed January 14, 2019.
  2. Zejula (niraparib). FDA prescribing information. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208447lbl.pdf. Accessed January 14, 2019.
  3. Mirza MR, Monk B, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive recurrent ovarian cancer. N Engl J Med 2016;375:2154–2164.
  4. Armstrong DK, Plaxe SC, Alvarez RD, et al. NCCN Clinical Practice Guidelines in Oncology: Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer. Version 2.2018. Accessed January 3, 2019. To view the most recent version of these guidelines, visit NCCN.org.
  5. Daly MB, Pilarski R, Berry MP, et al. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 2.2019. Accessed January 3, 2019. To view the most recent version of these guidelines, visit NCCN.org.
  6. da Cunha Colombo Bonadio RR, Fogace RN, Miranda VC, et al. Homologous recombination deficiency in ovarian cancer: a review of its epidemiology and management. Clinics (Sao Paulo) 2018;73(suppl 1):e450s.
  7. Frey MK, Pothuri B. Homologous recombination deficiency (HRD) testing in ovarian cancer clinical practice: a review of the literature. Gynecol Oncol Res Pract 2017;4:4.
  8. U.S. Department of Health and Human Services. U.S. Food and Drug Administration. FDA approves olaparib for first-line maintenance of BRCA-mutated advanced ovarian cancer. Available at: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm628876.htm. Accessed January 14, 2019.
  9. Moore KN, Secord AA, Geller MA, et al. QUADRA: a phase 2, open-label, single-arm study to evaluate niraparib in patients with relapsed ovarian cancer in 4th or later line of therapy: results from the BRCAmut subset [abstract]. European Society for Medical Oncology (ESMO) 2018 Congress; October 19–23; Munich, Germany. Abstract 944P.
  10. Lord R, Mirza MR, Woelber L, et al. Safety and dose modification for patients with low body weight receiving niraparib in the ENGOT-OV16/NOVA phase III trial. Gynecol Oncol 2018;149(suppl 1):11.
  11. Gallagher JR, Heap KJ, Carroll S. Real world occurrence of top three clinical-trial reported adverse events of PARP inhibitor niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer: a national retrospective observational study of a 200 mg/day starting-dose cohort [abstract]. European Society for Medical Oncology (ESMO) 2018 Congress; October 19–23; Munich, Germany. Abstract 986P.
  12. Lynparza (olaparib). Full prescribing information. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208558s000lbl.pdf. Accessed January 14, 2019.
  13. Rubraca (rucaparib). Full prescribing information. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209115s003lbl.pdf. Accessed January 14, 2019.
  14. Sackeyfio A, Nussey F, Friedlander M, et al E. Comparative efficacy and tolerability of the PARP inhibitors olaparib 300 mg tablets BID, niraparib 300 mg capsules QD and rucaparib 600 mg tablets BID as maintenance treatment in BRCA-mutated platinum-sensitive relapsed ovarian cancer. Gynecol Oncol 2018;149(suppl 1): 43–44.
  15. Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 2018;379:2495–2505.



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