Maintenance Therapy Landscape for Frontline Ovarian Cancer
A comprehensive overview of the maintenance therapy landscape in ovarian cancer, with a focus on clinical trials investigating bevacizumab, olaparib, and niraparib.
Case: A 49-Year-Old Woman with BRCA-WT Ovarian Cancer
- A 49-year-old presented to her primary care physician complaining of abdominal bloating and nausea
- PMH: mild HTN
- FH: mother died of breast cancer at age 59; cousin on mother’s side died of ovarian cancer at age 65
- Imaging: CT reveals small-volume ascites, bilateral 8-cm adnexal masses
- Labs: CA 125, 285 U/mL
- Surgical intervention: she underwent exploratory laparotomy followed by omentectomy, bilateral salpingo-oophorectomy, and resection of peritoneal nodules; optimal cytoreduction with < 1 cm of residual disease after surgery
- Diagnosis: stage IIIC HGSC
- Treatment: She was treated with IV carboplatin and paclitaxel w/ NK1, 5HT3, and dexamethasone CINV prophylaxis
- TRAEs: She experienced persistent daily nausea with vomiting on day 1 after chemotherapy
- Follow-up: After completion of chemotherapy, CA 125, 14.2; clinically NED; patient reports continuing daily nausea
Transcript:
Chad A. Hamilton, MD: The landscape for maintenance therapy for frontline ovarian cancer has really been driven by 4 relatively large, randomized placebo-controlled trials. This started with bevacizumab in the maintenance setting but has transitioned to the use of PARP inhibitors as well.
The addition of bevacizumab to frontline maintenance therapy was really driven by the [Gynecologic Oncology Group’s phase 3] GOG-0218 trial [NCT00262847], which was a randomized placebo-controlled study involving nearly 2000 women with stage 3 or 4 epithelial ovarian cancer. And this was a pretty high-risk or poor-prognosis group. Women were randomly assigned to standard IV [intravenous] carboplatin and paclitaxel. The second arm was carboplatin-paclitaxel plus bevacizumab. And then the third arm was carboplatin plus paclitaxel with concurrent bevacizumab, followed by maintenance bevacizumab that was continued as monotherapy for 15 months total. Standard chemotherapy, of course, consisted of 6 cycles of carboplatin-paclitaxel, and then the bevacizumab was continued through cycle 22 in GOG-0218.
In this trial, there was no difference in the progression-free survival [PFS] with the addition of concurrent bevacizumab. It was about 11- vs 10-month PFS. But they did see a difference in PFS when bevacizumab was continued as maintenance therapy with a 14-month progression-free survival in that group, and that translated into a statistically significant 28% reduction in risk of disease progression or death. In the final analysis a number of years later, overall survival across all arms was [approximately] 40 or 41 months. But subsequent subgroup analysis did demonstrate that concurrent maintenance treatment with bevacizumab improved progression-free survival and overall survival specifically in a subgroup of patients who had ascites or those with stage 4 disease, but not in women with stage 3 disease. Those results are a subgroup analysis and should be interpreted with some caution. And there’s been a lot of vigorous debate on both sides on the import of that subgroup analysis.
The next trial I’ll mention is the SOLO-1 trial [NCT01844986]. And this really brought olaparib onto the scene for first-line maintenance. This was another phase 3 randomized placebo-controlled trial in which almost 400 patients with advanced high-grade BRCA-associated—that’s mainly germline BRCA-mutated patients with serous or endometrioid ovarian cancer who were in response to platinum-based therapy—were randomly assigned to either maintenance olaparib or placebo. This was a relatively low-risk, advanced-stage population. And by that I mean they were mostly stage 3 patients who had primary cytoreductive surgery, which is always a better prognostic sign than folks who undergo neoadjuvant chemotherapy first. And many of them were debulked to minimal or no residual disease and had a good performance status at baseline. And really, the blockbuster headline from this trial was that olaparib resulted in a 70% lower risk of progression or death in these patients and a 34-month progression-free survival advantage. The 3-year rate of disease progression in this trial was 60%, vs 27% in those patients who received olaparib vs placebo. And again, keep in mind, this was a BRCA-mutated group, and it was a relatively good prognosis advanced ovarian cancer group.
The next trial that has really shaped management is the PRIMA trial [NCT02655016]. And that was a trial involving the PARP inhibitor niraparib. PRIMA was a phase 3 randomized placebo-controlled trial in 733 patients with newly diagnosed advanced ovarian cancer who were in response to platinum-based chemotherapy. This was an all-comers population, as opposed to the SOLO-1 trial that I discussed. This was also a high-risk population. More patients received neoadjuvant chemotherapy. There was more stage IV disease. These patients had poor performance status at baseline. In this trial, the 2 primary end points looked at the HRD, or the homologous recombination deficient, population, and then the other was the overall population. In the HRD population, niraparib had resulted in a 57% reduction in risk of progression or death. That was a 12-month progression-free survival advantage for those patients, 22 months vs 10 months. In the overall population, there was still a 38% reduction in risk of progression or death and nearly a 6-month progression-free survival advantage in that overall population for progression-free survival. And that was 14 months vs 8 months in that group.
The fourth trial that I’ll mention out of these practice-changing trials for frontline therapy was the PAOLA-1 trial [NCT02477644]. And this was a combination of bevacizumab with olaparib. So this was, again, a randomized phase 3 placebo-controlled trial, just over 800 patients with newly diagnosed advanced ovarian cancer in response to platinum-based therapy. And these patients had bevacizumab as part of their initial therapy. The two groups they looked at were continuation of bevacizumab maintenance therapy with the addition of olaparib, or maintenance bevacizumab plus placebo. And so I mentioned that the SOLO-1 population had relatively good prognosis, [and] the PRIMA population had relatively poor prognosis; this is a sort of an intermediate risk population between those two. In the HRD population, the addition of olaparib resulted in a 67% reduction in risk of progression or death, and a nearly 20-month progression-free survival advantage, 37 months vs just shy of 18 months in the olaparib vs placebo group. And then in the overall population, there was a 41% reduction in risk of progression or death, and a nearly 6-month progression-free survival advantage.
Transcript is AI-generated and edited for clarity and readability.
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