Jonathan Ledermann, MD
In patients with platinum-sensitive relapsed serous ovarian cancer, olaparib (Lynparza) was found to significantly increase overall survival (OS) when given as maintenance therapy, according to interim results of the third survival analysis of the phase II Study 19 trial.
Results of the study's extension, which were presented at the 2016 ASCO Annual Meeting, showed that the PARP inhibitor demonstrated the greatest OS advantage in women who had a BRCA
mutation (HR, 0.62), according to lead author Jonathan Ledermann, MD, professor of Medical Oncology at the University College London Cancer Institute and director of the Cancer Research UK & UCL Cancer Trials Centre. However, the P
values were nominal and did not meet the criterion for statistical significance (P
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 olaparib; again, the greatest benefit was seen in those with a BRCA
mutation. Additionally, the unprecedented long-term exposure meant that 13% of all trial patients (15% of BRCA
-mutated patients) received maintenance olaparib for at least 5 years. In 3 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 (n = 265). They had received 2 or more prior regimens of platinum-based chemotherapy and experienced complete response (CR) or partial response (PR) to their most recent regimen. In a double-blind, 1:1 randomization, half the patients received olaparib 400 mg capsules twice daily as maintenance therapy (n = 136) and half received placebo capsules twice daily (n = 129).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 (n = 136) and those with wild type BRCA
findings (n = 118), meaning that they either did not have a detected BRCA
mutation or they had a BRCA
mutation of unknown significance.
The primary endpoint was progression free survival (PFS) as measured by RECIST 1.0. Secondary endpoints included OS, safety and tolerability. Exploratory endpoints included TFST and TSST.
In Study 19, the median PFS for patients taking maintenance olaparib was 8.4 months, compared to 4.8 months for the control group (HR, 0.35, P
<.0001). The difference in the BRCA
mutation subgroup was even more pronounced: 11.2 months with olaparib and 4.3 months with placebo (HR, 0.18, P
The third data analysis of Study 19, with data cut-off at September 30, 2015, was performed with data at 77% maturity, OS in the overall study population (n = 265) was a median 29.8 months in the olaparib group and 27.8 months in the placebo group (HR, 0.73, 95% CI: 0.55–0.96, nominal P
= .02483). In the BRCA
mutation group (n = 136), where the data were at 70% maturity, median OS was 34.9 months for the olaparib group and 30.2 months for placebo (HR, 0.62, 95% CI: 0.41–0.94, nominal P
“Statistical tests did not provide sufficient evidence to dismiss the proportional hazards assumption for OS, so a restricted means analysis was performed to compare mean survival,” Ledermann said. “The difference in mean survival adds further support to the OS advantage of olaparib.” In the overall study population, the restricted mean OS was 40.1 for the olaparib group and 34.9 for the control group, for a difference of 5.2 months (95% CI: -0.8–11.2). In the BRCA
subgroup, the restricted mean OS was 44.3 months on olaparib (n = 74) versus 36.9 months with placebo (n = 62), a difference of 7.4 months (95% CI: -1.1–16.0).
There were 118 patients in the BRCA
wild type subgroup. Of these, 47 (82%) experienced TFST events. The median TFST was 12.9 months. Of the 61 women who received placebo, 60 (98%) experienced TFST events; for them, the median TFST was 6.9 months (HR, 0.45, 95% CI: .030–0.66, P = .00006). These data were at 91% maturity.
The updated exploratory analysis also examined TSST events. Of the 57 patients in the BRCA
wild type subgroup treated with maintenance olaparib, 47 (82%) experienced TSST. The median TSST was 17.0 months. In the placebo group, 59 (97%) experienced a TSST; the median TSST was 14.7 months (HR, 0.63, 95% CI: 0.43–.94, P
= .02263). These data were at 90% maturity.
The somatic BRCA
mutation consisted of 20 patients. Their OS data were inconsistent with the overall study population, but conclusions were limited by the small group size.