Despite improvements in the treatment of advanced ovarian cancer, less than half of newly diagnosed patients survive longer than 5 years, and relapse rates remain high. At the Society of Gynecologic Oncology (SGO) 2021 Virtual Annual Meeting on Women’s Cancer, experts presented updated results from 2 phase 3 clinical trials showing the benefit of the poly (ADP-ribose) polymerase (PARP) inhibitors olaparib (Lynparza) and niraparib (Zejula) as maintenance therapy in women with advanced or recurrent disease.
5-Year Follow-Up Results: The SOLO-1 Study
SOLO-1 was a randomized, double-blind, placebo-controlled, phase 3 trial that enrolled 391 patients with newly diagnosed, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer and BRCA mutations. All patients had undergone cytoreductive surgery and were in clinical complete or partial response following platinum-based chemotherapy. Patients were randomized in a 2:1 ratio to olaparib 300 mg twice daily as maintenance (N = 260) or to placebo (N = 131). The primary end point was progression-free survival (PFS), as assessed by the investigators.
Results from the primary analysis, based on a data cutoff date of May 17, 2018, showed signficantly longer PFS with olaparib. The median PFS in the placebo arm was 13.8 months, whereas the median PFS had yet to be reached in the olaparib arm (hazard ratio [HR], 0.30; 95% confidence interval [CI], 0.23-0.41; P <.001).
At the 2021 SGO meeting, William H. Bradley, MD, Associate Professor, Gynecology/Oncology, Froedtert & the Medical College of Wisconsin, Milwaukee, presented follow-up data from the trial, which showed that maintenance therapy with olaparib significantly extended 5-year PFS in women with advanced BRCA-positive ovarian cancer.
The results showed that the survival benefit with olaparib was sustained beyond the end of treatment. The median PFS was 56 months in the olaparib arm versus 13.8 months in the placebo arm—a difference of 42.2 months. More than 48% of patients in the olaparib arm had remained progression-free compared with 20.5% of those in the placebo arm.
“This is the longest follow-up for any PARP inhibitor in the setting of maintenance therapy after primary therapy,” Dr Bradley said. “After 5 years, almost half of patients were progression-free versus 20% with placebo. These results further support the use of maintenance olaparib as a standard of care for women with newly diagnosed advanced ovarian cancer and a BRCA mutation and suggest the possibility of long-term remission or even cure for some patients.”
A prespecified exploratory subgroup analysis was also performed to evaluate patients by clinical risk. The PFS benefit was consistent across low- and high-risk disease. In the low-risk cohort, the median PFS was 21.9 months for patients who received placebo and was not reached in those who received olaparib (HR, 0.38; 95% CI, 0.25-0.59). In the high-risk cohort, the median PFS was 11.1 months versus 40.6 months for placebo and olaparib, respectively, (HR, 0.35; 95% CI, 0.25-0.49).
The 5-year follow-up safety profile data remained consistent with previously reported SOLO-1 findings. No new safety signals were observed with long-term follow-up, and no new cases of myelodysplastic syndromes or acute myeloid leukemia were reported.
Updated Analysis: The ENGOT-OV16/NOVA Study
ENGOT-OV16/NOVA was a randomized, double-blind, placebo-controlled phase 3 trial that enrolled 553 patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer after a complete or partial response to platinum-based therapy. Patients were randomized in a 2:1 ratio to niraparib 300 mg once daily as maintenance or to placebo. The study included patients with BRCA mutations (N = 203) and without BRCA mutations (N = 350). The primary end point was PFS, assessed by blinded independent central review.
In the primary analysis of the trial, the median PFS was 21 months for patients with BRCA mutations who received niraparib and 5.5 months for those with BRCA mutations who received placebo (HR, 0.27; 95% CI, 0.17-0.41; P <.001). Among patients with no BRCA mutations, the median PFS was 9.3 months with niraparib and 3.9 months with placebo (HR, 0.45; 95% CI, 0.34-0.61; P <.001).
At the 2021 SGO meeting, Ursula Matulonis, MD, Chief and Director, Division of Gynecologic Oncology, Dana-Farber Cancer Institute, Boston, MA, presented updated results from the trial. She noted that the benefit derived from niraparib maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer extended beyond first progression. The HRs for time to second progression or death with niraparib versus placebo were 0.67 (95% CI, 0.48-0.95) for patients with BRCA mutations and 0.81 (95% CI, 0.62-1.05) for patients without mutations.
Dr Matulonis went on to say that the final analysis of the study was complicated by missing data for many of the patients who were originally randomized.
“During the time from the initial NOVA results in 2016 to this final analysis, PARP inhibitors have become commercially available globally. This availability of PARP inhibitors led to premature unblinding and withdrawals of treatment in patients in the NOVA study and led to missing data,” she noted.
Although crossover to the niraparib arm was not allowed on study, patients could receive a PARP inhibitor following disease progression or study withdrawal. Because of discontinuations, data on post-progression therapy were missing for 25% of patients.
“Both the sample size, which was not powered for OS [overall survival], and the missing data confound the OS analysis and limit interpretations,” Dr Matulonis said.
At the time of the final data cutoff date (October 1, 2020), the mean follow-up was 5.6 years. For the final analysis, the investigators were able to retrieve survival data on 51% of the patients originally enrolled in the trial. In all, 64 patients originally assigned to niraparib treatment were still on study (28 in the BRCA mutation cohort and 36 in the non-BRCA cohort), as were 28 patients originally assigned to placebo (9 and 19, respectively).
Based on adjusted analysis for subsequent PARP inhibitor therapy, the investigators observed no significant difference in median OS between the niraparib and placebo arms, regardless of mutation status. However, there was a trend toward improved OS with niraparib among patients with BRCA mutations. The median OS was 43.8 months with niraparib and 34.1 months with placebo (HR, 0.66; 95% CI, 0.44-0.99).