(UPDATE) Niraparib (Zejula)

Commentary by Theresa L. Werner, MD, Ovarian Cancer Site Editor for JNCCN 360

Medical Director, Clinical Trials Office; Associate Professor of Medicine, Oncology Division, Huntsman Cancer Institute, University of Utah, Salt Lake City

Over the past few years, the use of PARP inhibitors has substantially expanded options for maintenance therapy in ovarian cancer, and these agents have been included in the current version of the NCCN Clinical Practice Guidelines in Oncology.¹ We have a better understanding of ovarian cancer biology—including the importance of germline and somatic BRCA mutations, as well as the role of homologous recombination deficiency (HRD) in tumors—and the potential benefit of new therapies.

Considerations for maintenance therapy in advanced-stage ovarian cancer include the response to upfront chemotherapy, BRCA mutational status (both germline and somatic), and whether bevacizumab was used with first-line chemotherapy. For patients not treated with bevacizumab, consideration of PARP inhibitors as an option for maintenance therapy depends on BRCA1/2 mutation status. Niraparib and olaparib are category 1 recommended options for those with germline or somatic BRCA1/2 mutations who are in complete or partial remission after surgery and platinum-based first-line chemotherapy.¹ For those with BRCA wild-type or unknown status who are in complete or partial remission after surgery and first-line platinum-based chemotherapy, niraparib is a category 2A recommended option, as is observation (for those in complete remission). In this clinical scenario, tumor HRD status may provide information on the magnitude of benefit that may be anticipated with niraparib (category 2B).

The U.S. Food and Drug Administration has recently approved the use of niraparib as a first-line maintenance therapy for women with advanced ovarian cancer, with or without a BRCA mutation, who have had a complete or partial response to first-line platinum-based chemotherapy, based on the results of the PRIMA trial.² Of note, about 50% of patients in the trial had tumors with HRD. A progression-free survival benefit with maintenance niraparib was seen in this population compared with placebo. The progression-free survival for the overall population was also improved with niraparib versus placebo, although there was considerably less benefit seen in all comers compared with the HRD population.

The risks versus benefits of maintenance therapy need to be discussed carefully with patients, with special attention to the duration of therapy (niraparib was given for 36 months after chemotherapy in the PRIMA trial), especially for those with non-HRD tumors, where the magnitude of benefit is smaller. Careful monitoring of blood cell counts and blood pressure is essential in patients treated with niraparib.

We must also consider the use of PARP inhibitors as maintenance therapy for patients in complete or partial response after platinum-based chemotherapy for first recurrence or as treatment for recurrent disease. In this clinical scenario, we also have data to support their use.

DISCLOSURES

Dr. Werner reported no conflicts of interest.

REFERENCES

1. Armstrong DK, Alvarez RD, Bakkum-Gamez JN, et al. NCCN Clinical Practice Guidelines in Oncology: Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer. Version 1.2020—March 11, 2020. Accessed June 18, 2020. To view the most recent version of these guidelines, visit NCCN.org.
2. González-Martín A, Pothuri B, Vergote I, et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 2019;381:2391–2402.

On April 29, 2020, the U.S. Food and Drug Administration (FDA) approved niraparib as a maintenance therapy for women with advanced ovarian cancer who are in complete or partial response to first-line platinum-based chemotherapy. This approval applies to women with or without a BRCA mutation.

Niraparib was recently approved for maintenance therapy in advanced ovarian cancer after first-line platinum-based chemotherapy, based on the PRIMA trial.¹ This trial assessed 733 patients who were randomly assigned to receive niraparib or placebo as maintenance therapy after response to first-line platinum-based chemotherapy. About half of the trial patients had tumors with homologous recombination deficiency. Among the patients in this category, the median progression-free survival was significantly longer with niraparib than with placebo (21.9 vs. 10.4 months). Of note, the overall group included women with a high risk of recurrence—those with advanced cancer and those whose tumors could not be fully removed by surgery—making it more representative of a real-world setting. The most common adverse events of grade 3 or higher with niraparib were anemia (31.0%), thrombocytopenia (28.7%), and neutropenia (12.8%).

“Niraparib therapy in patients with advanced ovarian cancer provided a clinically significant improvement in progression-free survival after response to first-line platinum-based chemotherapy in all patients,” said study author Antonio Gonzalez-Martin, MD, of the Clinica Universidad de Navarra, Pamplona, Spain.

A second trial, the ENGOT-OV16/NOVA study, demonstrated that in patients with platinum-sensitive recurrent ovarian cancer in response to the most recent platinum-containing therapy, those who received maintenance niraparib derived a significant clinical benefit relative to placebo regardless of the best response (complete versus partial) to the last platinum-based therapy.² This analysis revealed that patients with a partial response to their last platinum therapy who received maintenance niraparib experienced a progression-free-survival benefit relative to placebo. Symptoms such as pain, fatigue, and nausea remained stable or improved with time during the study. The proportion of patients who reported any-grade or severe vomiting remained low.

In addition to the two FDA indications for maintenance therapy, niraparib has been approved by the FDA for the treatment of patients with advanced ovarian, fallopian tube, or primary peritoneal cancer who had received three or more prior chemotherapy regimens and whose cancer was associated with homologous recombination deficiency–positive status defined by either 1) a deleterious or suspected deleterious BRCA mutation or 2) genomic instability and disease progression more than 6 months after response to the last platinum-based chemotherapy.

Even more positive data on the safety and efficacy of niraparib as maintenance therapy in patients with advanced ovarian cancer were presented at the 2020 Annual Meeting on Women’s Cancer Webinar Series produced by the Society of Gynecologic Oncology. Bradley J. Monk, MD, Professor of Obstetrics and Gynecology at the University of Arizona College of Medicine, Phoenix, reported updated data from the pivotal PRIMA trial (ClinicalTrials.gov identifier: NCT02655016).³

Niraparib in Current Clinical Trials

Several ongoing clinical trials are assessing the utility of niraparib for maintenance therapy in women with advanced ovarian cancer. One is a trial evaluating the safety and efficacy of niraparib in combination with bevacizumab as maintenance therapy in patients with advanced ovarian cancer who have received prior front-line therapy with platinum-based chemotherapy in combination with bevacizumab and who have had at least one prior attempt at debulking surgery (NCT03326193). Safety and tolerability will be assessed by clinical review of adverse events, physical examinations, electrocardiograms, Response Evaluation Criteria in Solid Tumors assessments, and safety laboratory values. Investigators anticipate that primary data will be reported in late 2020.

A clinical trial being conducted in Japan is evaluating the safety and efficacy of niraparib maintenance in participants with relapsed platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer who achieved a complete or partial response with the last platinum-based chemotherapy regimen (NCT03759587). The researchers are expected to provide final data in the latter part of 2020. Niraparib will be administered orally once daily for a 21-day cycle.

Another phase II trial is assessing the combination of niraparib and dostarlimab in patients with advanced, relapsed, high-grade ovarian, fallopian tube, endometrioid, clear cell ovarian, or primary peritoneal cancer without a known BRCA mutation who have platinum-resistant disease and have also been previously treated with bevacizumab (NCT03955471). Dostarlimab is a humanized monoclonal antibody that binds with high affinity to PD-1, resulting in inhibition of binding to PD-L1/PD-L2. The estimated primary completion date is June 2021.

Finally, a poster session recently presented by Mansoor Raza Mirza, MD, and colleagues during the ASCO20 Virtual Scientific Program provided updated data from a phase II trial comparing two chemotherapy-free regimens: niraparib alone versus niraparib plus bevacizumab in women with platinum-sensitive epithelial ovarian cancer.⁴ Of the 97 enrolled patients, 48 were randomly assigned to niraparib monotherapy and 49 to the bevacizumab-containing combination. Of note, the combined treatment significantly improved progression-free survival compared with niraparib alone (updated median progression-free survival 12.5 vs. 5.5 months). The investigators commented: “Updated progression-free survival data consistently demonstrated that the niraparib/bevacizumab combination had clinically and statistically meaningful activity in these patients.”

Preparing Patients for Niraparib Therapy

It is important for clinicians to counsel patients on some of the potential side effects associated with niraparib therapy. Some of the toxicity is mild and easily addressed, whereas other side effects may require additional interventions. One such effect is hypertension. Clinicians should review with patients the signs and symptoms of high blood pressure: dizziness, shortness of breath, headache, nosebleeds, and blurred vision.⁵ Additional side effects for which patients should be counseled include an irregular heartbeat, nausea, constipation, diarrhea, vomiting, abdominal pain, mouth sores, and dry mouth.

In addition, clinicians should talk with patients about all medications they may be taking, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Patients should be advised about medications and other substances that may interfere with the effectiveness and safety of niraparib.

REFERENCES

1. González-Martín A, Pothuri B, Vergote I, et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 2019;381:2391–2402.
2. del Campo JM, Matulonis UA, Malander S, et al. Niraparib maintenance therapy in patients with recurrent ovarian cancer after a partial response to the last platinum-based chemotherapy in the ENGOT-OV16/NOVA trial. J Clin Oncol 2019;37:2968–2973.
3. Monk BJ, Han S, Pothuri B, et al. Efficacy of niraparib therapy in patients with newly diagnosed advanced ovarian cancer by BRCA and homologous recombination status: PRIMA/ENGOT-OV26/GOG-3012 study. 2020 Society of Gynecologic Oncology Annual Meeting. Abstract 31. Presented March 29, 2020.
4. Mirza MR, Nyvang GB, Lund B, et al. Final survival analysis of NSGO-AVANOVA2/ENGOT-OV24: combination of niraparib and bevacizumab versus niraparib alone as treatment of recurrent platinum-sensitive ovarian cancer—a randomized controlled chemotherapy-free study. ASCO20 Virtual Scientific Program. Abstract 6012.
5. GlaxoSmithKline. Zejula (niraparib) Full prescribing information. April 2020. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208447s015s017lbledt.pdf. Accessed June 9, 2020.