Clinical Trials in Ovarian Cancer Maintenance: PRIMA and NOVA
An expert in gynecologic oncology reviews the PRIMA and NOVA clinical trials and discusses their implications for the management of ovarian cancer.
Chirag Shah, MD, MPH: The landmark PRIMA trial was published in late 2019. This trial evaluated over 700 patients in a randomized, double-blinded, placebo-controlled fashion with a 2:1 randomization of niraparib vs placebo. The primary end point in this trial was progression free survival [PFS] in the group of women with homologous or a combination deficiency. There was a coprimary end point of looking at the progression-free survival in the overall patient population. The response rates were derived in terms of resist and response rates. It was an international trial with a robust scientific design as well as large volume of patients.
In addition, in terms of the study trial design, after the completion of chemotherapy, the patients received 3 years of niraparib vs placebo in that 2:1 randomization. In terms of results, 50% of the patients did have HRD [homologous recombination deficiency]. In that patient population, there was a highly statistically significant benefit to the use of niraparib as compared with placebo, with nearly a doubling of the progression-free survival of 22 months vs 10 months. In the overall study population, which was a predefined coprimary end point, there was also a statistically significant benefit with a PFS advantage of over 5 months: 13.8 months vs 8.2 months.
The most common adverse events of grade 3 or higher in the trial were anemia, thrombocytopenia, and neutropenia, ranging in rates from 12% to 30%. These were consistent with what were seen in previous trials and were well managed with dose reductions and modifications. The overall discontinuation rate due to toxicities in the trial was relatively low at 12%. Additional adverse effects that were seen included, nausea, abdominal pain, and fatigue, and these were also seen at fairly common rates in the patients who were in the placebo group.
In terms of my clinical experience, I have both enrolled patients on the PRIMA trial, because we [at Swedish Cancer Institute] were a study site for this trial. In addition, off-trial, we have used niraparib in frontline maintenance, and I have found that the benefit is consistent with what has been seen in this clinical trial. The toxicities often become something that we have to manage. There are the toxicities we see, then there are the toxicities patients feel. Those in the labs in terms of the hematologic toxicities are often things that we have to follow pretty closely. In terms of monitoring, 1 of the additional pieces that has to be monitored to address toxicities is the CBC [complete blood count], but also consistent with the new labeling is watching blood pressure. CBCs and blood pressure should be monitored weekly in the initial period.
Oftentimes, the dose may need to be adjusted within the first month of therapy. Based on this trial, there is new dosing dictated by the patient’s weight and by what their most recent platelet level is. If their platelet level is below 150,000 per mm3 or if their weight is below 70 kg, then the starting dose that is recommended is 200 mg daily, which is 2 capsules daily. For patients who are above that weight or platelet level, the standard dosing is 300 mg. Monitoring these labs and frequent communication with the patients will allow you to be more thoughtful in terms of avoiding significant grade 3 toxicities. Once you get to a stable dose, in my experience, most of the time, patients are able to stay on that dose for an extended period of time. The clinical trial was designed to have maintenance therapy continue for 36 months or 3 years, which is what I recommend to patients. The discontinuation would primarily be because of toxicities or at progression.
When we look at agents in addition to chemotherapy in the treatment of women with ovarian cancer, there has certainly been a push to try to get agents to the earlier lines of therapy, primarily because we know that there is such a high recurrence rate. Additionally, this defined concept of platinum resistance ends up potentially limiting our options. As we look at the PRIMA trial and others like it, such as the SOLO-1 trial, which evaluated the use of olaparib in patients with germline BRCA mutations as maintenance, the primary rationale was to try to get synergy with the PARP inhibitor after platinum-based chemotherapy. This was building on data that we have seen in the preclinical setting that suggest that PARP inhibition after platinum-based chemotherapy is beneficial and prolongs or maintains remission.
In 2019, the international NOVA trial was also published. This trial had 550 patients who were broken into 2 primary cohorts. The first was patients that were germline BRCA mutated, and then the second cohort of patients was those who were nongermline BRCA mutated. These patients were then randomized after platinum-based chemotherapy when they were found to have a response in the platinum-sensitive setting, which means they had a greater than 6-month treatment-free interval to their platinum-based chemotherapy. After re-treatment with platinum chemotherapy, they were started on niraparib vs placebo at a 2:1 randomization. The primary end point in the NOVA trial was progression-free survival. In the trial, progression-free survival was significantly improved in both cohorts: both the germline BRCA-mutated cohort as well as the nongermline BRCA-mutated cohort.
In the NOVA trial, in the germline BRCA-mutated cohort, there was a highly statistically significant benefit in terms of progression-free survival with the patients receiving niraparib having a median progression-free survival of 21 months vs 5.5 months in the placebo group. In the nongermline BRCA-mutated cohort, there was also a statistically significant benefit to niraparib. The niraparib cohort had a 9.3-month progression-free survival vs 3.9 months for the placebo group.
Transcript edited for clarity.
Case: A 67-Year-Old Woman With Ovarian Cancer
Initial Presentation
- A 67-year-old female presented with abdominal discomfort and modest weight loss
- PMH: unremarkable, postmenopausal; no known family history of cancer
- PE: diffuse tenderness to abdominal palpation, abdominal bloating
- ECOG PS 0
Clinical Work-up
- Pelvic exam with transvaginal ultrasound showed a left ovarian mass
- Chest/abdomen/pelvis CT with contrast revealed a left adnexal 5-cm mass, pelvic and inguinal lymph node involvement, no pleural effusion
- Paracentesis (1200cc) cytology confirmed high-grade epithelial ovarian cancer
- Germline molecular testing: HRD+, BRCA1/2-
- CA-125, 360 U/mL
- Diagnosis: Stage 4, high-grade epithelial ovarian cancer
Treatment
- Patient underwent TAH/BSO, lymph node dissection, with optimal debulking; R0
- IP/IV paclitaxel/cisplatin; CR
- Niraparib maintenance was initiated
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