Phase 3 NOVA Trial: An Overview
Erin Crane, MD, provides an overview of the Phase 3 NOVA trial.
Erin Crane, MD: The phase 3 NOVA trial was a randomized, double-blinded placebo-controlled trial. It was in the setting of recurrent epithelial ovarian cancer, in patients who had either a partial or complete response to a platinum-containing regimen. Patients were randomized in a 2:1 fashion to niraparib 300 mg daily after completion of chemotherapy versus the placebo. There were 2 cohorts, and they were subdivided into patients with BRCA mutations and patients without BRCA mutations. The patients without BRCA mutations were further subdivided into 2 groups: patients who were homologous recombination proficient and patients who were homologous recombination deficient [HRD]. The primary end point for the study was progression-free survival.
In regard to the HRD-negative cohort, we know those patients can be harder to treat, and HRD negativity can essentially serve as a surrogate for platinum resistance. Those patients did not experience as much of a benefit, but still they had a 7-month progression-free survival improvement versus 4 months in the placebo group.
I think it is something to take into consideration for patients in the recurrent setting; a 3-month progression-free survival benefit may be more clinically meaningful for that subset of patients. That is 3 more months that they are off cytotoxic treatment. This led to the FDA approval of niraparib in the particular setting of treating patients with recurrent epithelial ovarian cancer who had had a complete or partial response to prior platinum-containing compounds. This was agnostic of BRCA or HRD status.
The long-term safety outcomes are pretty similar across the board for PARP inhibitors. When you look at the NOVA phase 3 trial, about 25% of patients experienced grade 3 or 4 thrombocytopenia. About 20% of the patients had neutropenia; about 25% had anemia. Most of these issues can be mitigated by dose reductions. Actual discontinuation related to thrombocytopenia, for example, only occurred 3% of the time. In clinical practice, it is pretty easy to mitigate these [adverse] effects. If someone comes in and has grade 3 or 4 toxicity, generally, we hold the niraparib until that toxicity is resolved; for example, for patients with thrombocytopenia, we will wait until the platelet count has resolved to over 100,000 per μL. Once it has resolved, you drop the dose by 100 mg.
In the trial, that was pretty consistent. About one-third of patients did require a dose reduction. We know, from the trial—we say things like weights and plates. For patients who are less than 75 kg, or who have a platelet count that is less than 150,000 per μL starting out of the gate, we know those patients are more likely to require a dose reduction. Other nonhematologic [adverse] effects like nausea are quite common. That was experienced by up to 75% of patients. However, again, this is a heavily pretreated population, and up to 35% of patients in the placebo group also experienced nausea. We know from clinical practice that if patients can stick with a regimen and get through the first 2 weeks with antiemetics, then in general the nausea does get better over time. Of course, fatigue can be an issue for patients. I think it is really important to allow patients to fully recover before starting them on a PARP inhibitor.
Sometimes, during the first month after they finish chemotherapy, patients’ energy levels are not quite back to normal. It is important to give patients a bit of a break if they need it because there are [adverse] effects associated with PARP inhibitors and niraparib. More serious [adverse] effects like myelodysplastic syndrome, which can be fatal, are fairly uncommon. It occurs in 1% or less of the population, but it does require us to continue to monitor our patients’ laboratory test results, at least on a monthly basis, for the first year of treatment.
There was a specific separate publication that came out that looked at patient-reported outcomes, or PROs, which have become a really important part of clinical trials. Of course, we put patients on these experimental drugs that have [adverse] effects, but they also have to be tolerable. Fortunately, the patient-reported outcomes were similar, the quality-of-life scores were similar between the placebo and the niraparib group. It was a regimen that, overall, was well tolerated.\
This transcript was edited for clarity.
Case: A 63-Year-Old Woman With Recurrent Ovarian Cancer
Initial Presentation
- A 63-year-old female presented with early satiety and abdominal discomfort
- PMH: unremarkable, postmenopausal; no known family history of cancer
- PE: left lower quadrant tenderness on palpation
- ECOG PS 1
Clinical work-up
- Pelvic exam with transvaginal ultrasound showed a left ovarian mass
- Transvaginal U/S showed a left ovarian mass
- Chest/abdomen/pelvis CT with contrast confirmed a left adnexal 4.4-cm mass with paraaortic lymph node involvement and ascites
- Paracentesis (1000 cc) cytology confirmed high-grade epithelial ovarian cancer
- Germline molecular testing: HRD+, BRCA1/2-
- CA-125, 370 U/mL
- Diagnosis: Stage III, high-grade epithelial ovarian cancer
Treatment
- Patient underwent TAH/BSO, lymph node dissection, with optimal debulking; R0
- Paclitaxel/carboplatin q3 weeks for 6 cycles; CA-125 decreased; PR
- At 7-month post treatment follow-up imaging showed progression of disease
- Paclitaxel/carboplatin + bevacizumab was initiated q3 weeks for 6 cycles
- At 14-months CA-125 had increased
- Cisplatin/gemcitabine was initiated, PR
- Initiated niraparib maintenance
