Lynparza (olaparib) demonstrated improved progression-free survival (PFS) compared to the placebo arm for patients with ovarian cancer, according to findings from the phase 3 SOLO-2 trial. The single-agent PARP inhibitor was tested in the maintenance setting for patients with advanced BRCA-positive ovarian cancer.
Although specific data from the trial are not yet available, AstraZeneca, the manufacturer of Lynparza, reported that the median PFS with Lynparza was significantly higher than in the Lynparza arm of the phase 2 Study 19 in a similar population. The safety profile for the PARP inhibitor was consistent with results reported from previous trials.
“We are pleased with the robust improvement in progression-free survival demonstrated by Lynparza in the SOLO-2 trial. We will work with regulatory authorities to make Lynparza tablets available as quickly as possible to patients with ovarian cancer. We remain committed to investigating the full potential of Lynparza, both as monotherapy and in combinations, and to identifying all patients who may benefit from this important medicine,” Sean Bohen, M.D., Ph.D., executive vice president, Global Medicines Development, and Chief Medical Officer at AstraZeneca, said in a statement.
The multicenter phase 3 SOLO-2 trial included 295 patients with platinum-sensitive, relapsed/recurrent, BRCA-positive ovarian cancer who had received two or more prior lines of platinum-based chemotherapy. Patients were randomized to receive either Lynparza at 300 mg twice daily or placebo until disease progression.
The latest data from the phase 2 Study 19, which were presented at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, showed that in patients with platinum-sensitive relapsed serous ovarian cancer, Lynparza increased overall survival (OS) when given as maintenance therapy.
Results of the study’s extension showed that the PARP inhibitor demonstrated the greatest OS advantage in women who had a BRCA mutation, according to lead author Jonathan Ledermann, M.D., professor of Medical Oncology at the University College London Cancer Institute and director of the Cancer Research UK & UCL Cancer Trials Centre, who presented the results at ASCO.
Additional key findings were that both time to first subsequent therapy or death (TFST) and time to second subsequent therapy or death (TSST) were substantially prolonged in patients taking Lynparza; again, the greatest benefit was seen in those with a BRCA mutation. Additionally, the unprecedented long-term exposure meant that 13 percent of all trial patients (15 percent of BRCA-mutated patients) received maintenance Lynparza for at least five years. In three years of follow-up since the 2012 analysis, there were no new safety findings.
Study 19 assessed patients with platinum-sensitive, recurrent high-grade serous ovarian cancer (265 patients). They had received two or more prior regimens of platinum-based chemotherapy and experienced complete response or partial response to their most recent regimen. In a double-blind, one-to-one randomization, half the patients received Lynparza 400 mg capsules twice daily as maintenance therapy (136 patients) and half received placebo capsules twice daily (129 patients).
BRCA testing occurred for all patients in the form of case reports that contained the results of previous local germline BRCA testing or retrospective germline BRCA testing or tumor BRCA testing. The division between patients was nearly even between those BRCA mutations (136 patients) and those with wild-type BRCA findings (118 patients), meaning that they either did not have a detected BRCA mutation or they had a BRCA mutation of unknown significance.
In Study 19, the median PFS for patients taking maintenance Lynparza was 8.4 months, compared to 4.8 months for the control group. The difference in the BRCA mutation subgroup was even more pronounced: 11.2 months with Lynparza and 4.3 months with placebo.
The third data analysis of Study 19, with data cutoff at Sept. 30, 2015, was performed with data at 77 percent maturity, OS in the overall study population (265 patients) was a median 29.8 months in the Lynparza group and 27.8 months in the placebo. In the BRCA mutation group (136 patients), where the data were at 70 percent maturity, median OS was 34.9 months for the Lynparza group and 30.2 months for placebo.
With a median follow-up interval of 5.9 years, 15 patients (11 percent) were still receiving Lynparza (eight with BRCA mutations). One BRCA-mutated patient was still receiving placebo. Twelve percent of BRCA wild-type patients on Lynparza achieved median follow-up of between five and six years.
In the overall study population, 59 patients (43 percent) experienced an adverse event (AE) of grade 3 or above, while only 28 (22 percent) of those on placebo did. Those percentages remained fairly consistent among patients who remained on trial for two years or more: 15 (47 percent) in the Lynparza arm and one (20 percent) in the control arm.
Likewise, the percentages of dose reductions due to AEs were consistent over time, and there were few treatment discontinuations due to AEs: eight active and two control patients overall and three Lynparza patients from the long-term treatment group. No patients from the long-term placebo group discontinued treatment due to AEs.
In June 2014, the FDA’s Oncologic Drugs Advisory Committee voted 11-2 against the accelerated approval of Lynparza as a maintenance therapy for women with platinum-sensitive relapsed ovarian cancer with germline BRCA mutations. By voting no, the committee recommended waiting for results from the SOLO-2 trial before approving Lynparza in this setting.
Following this vote, AstraZeneca submitted an amendment to Lynparza’s new drug application upon the FDA’s request, which led to the drug’s eventual approval in December 2014 for the treatment of women with BRCA-positive advanced ovarian cancer following treatment with three or more prior lines of chemotherapy.
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