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Final Analysis of Phase II Trial in Recurrent Platinum-Sensitive Ovarian Cancer


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In a poster presentation at the ASCO20 Virtual Scientific Program, Mansoor Raza Mirza, MD, of the the Department of Oncology, Rigshopitalet, Copenhagen University Hospital, Denmark, and colleagues reported the final analysis of the phase II NSGO-AVANOVA2/ENGOT-OV24 trial comparing the chemotherapy-free regimens of niraparib/bevacizumab vs niraparib alone in recurrent platinum-sensitive ovarian cancer.1 The results indicate a maintained significant progression-free survival benefit with niraparib/bevacizumab, as well as observed improvements in secondary efficacy endpoints with the combination. 

Mansoor Raza Mirza, MD

Mansoor Raza Mirza, MD

Study Details

In the open-label trial, 97 women with measurable/evaluable, high-grade serous or endometrioid recurrent platinum-sensitive disease were randomly assigned to receive niraparib at 300 mg once daily and bevacizumab at 15 mg/kg every 3 weeks (n = 49) or niraparib at 300 mg once daily (n = 48) until disease progression. Randomization was stratified by homologous recombination deficiency (HRD) status and chemotherapy-free interval (6–12 months vs > 12 months). First-line maintenance bevacizumab was permitted. The primary endpoint was progression-free survival. The trial was not powered for formal statistical testing of overall survival or other secondary efficacy endpoints. 

Progression-Free Survival

Median follow-up was 24.7 months. Updated median progression-free survival was 12.5 months in the niraparib/bevacizumab group vs 5.5 months in the niraparib group (hazard ratio [HR] adjusted for stratification factors = 0.34, 95% confidence interval [CI] = 0.21–0.55, P < .0001). No difference in benefit was observed between 54 patients with HRD-positive disease (HR = 0.41, 95% CI = 0.23–0.76) and 43 patients with HRD-negative disease (HR = 0.40, 95% CI = 0.20–0.79).

Secondary Outcome Measures

Preplanned exploratory analyses showed benefit of the combination for secondary outcome measures:

  • Median time to first subsequent therapy (TFST) was 14.3 vs 7.2 months (adjusted HR = 0.4, 95% CI = 0.25–0.64).
  • Median progression-free survival-2 (PFS-2) was 20.5 months vs 15.7 months (adjusted HR = 0.55, 95% CI = 0.35–0.88).
  • Median time to second subsequent therapy (TSST) was 21.8 months vs 17.3 months (adjusted HR = 0.56, 95% CI = 0.35–0.90).
  • Median overall survival at event maturity of 52% (49 events) was 29.4 vs 27.8 months (adjusted HR = 0.77, 95% CI = 0.42–1.41).

Adverse Events

No difference in incidence of grade 3 or 4 adverse events was observed between the 2 groups except for a higher incidence of hypertension (22.9% vs 0%) and neutropenia (8.3% vs 2.0%) in the combination group. Adverse events led to discontinuation of both niraparib and bevacizumab in nine patients in the combination group and of niraparib in five patients in the niraparib group.

Patient-reported outcomes assessed by the European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30 (EORTC QLQ-C30) showed no difference over time in global health status/quality of life between patient groups.

The investigators concluded: “Updated [progression-free survival] consistently demonstrates that the niraparib/bevacizumab combination had clinically and statistically meaningful activity in [platinum-sensitive relapsed ovarian cancer]. This phase II study was not powered to detect differences in [overall survival] or any other efficacy endpoints; however, TFST, PFS2 & TSST are significantly improved whereas there is a trend towards [overall survival] improvement with the niraparib/bevacizumab combination.”

Discussion

Barbara Norquist, MD

Barbara Norquist, MD

In discussing the study findings, Barbara Norquist, MD, from the Division of Gynecologic Oncology, University of Washington, noted, “These were patients with high grade serous or endometrioid platinum-sensitive recurrent ovarian cancers… making this a unique trial in this population in that it’s treating platinum-sensitive recurrence without platinum. The updated PFS [progression-free survival] curve shows an exciting hazard ratio for PFS of 0.34. But, somewhat disappointingly, there was no significant difference in overall survival—which is starting to feel like a common refrain for us in ovarian cancer. And it’s interesting to note that with this combination therapy of bevacizumab and niraparib, HRD test positivity or negativity did not seem to be a great predictor of response to the combination. There were no reported differences in quality of life.

And then an existential question for us all: If there is no difference in overall survival and there isn’t better quality of life, then what is the primary advantage of prolonging the PFS in this circumstance—or in this case, prolonging the amount of time that a patient who is on two medications before switching to a different one? These patients are going to an infusion center every 3 weeks and taking a medication daily that can have side effects, as well as significant costs.”

Dr. Norquist concluded, “In this setting, it’s great to have some nonchemotherapy options. However, I would be curious to compare this regimen to our usual standard of rechallenging patients with platinum-based chemotherapy. And I understand that there is a phase III trial planned to investigate that.” 

DISCLOSURE: Dr. Mirza has a leadership role with Karyopharm Therapeutics and Sera Prognostics; has stock and other ownership interests in Karyopharm Therapeutics and Sera Prognostics; has received honoraria from Advaxis, AstraZeneca, Cerulean Pharma, Clovis Oncology, Novocure, Pfizer, Roche, and Tesaro; has had a consulting or advisory role with AstraZeneca, BioCad, Cerulean Pharma, Clovis Oncology, Genmab, Karyopharm Therapeutics, Novocure, Pfizer, Sotio, and Tesaro; has received institutional research funding from AstraZeneca, Boehringer Ingelheim, Clovis Oncology, Pfizer, and Tesaro; and has received reimbursements for travel, accommodations, and other expenses from AstraZeneca, Karyopharm Therapeutics, Pfizer, Roche, SeraCare, and Tesaro.

REFERENCE

1. 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.

 


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