Olaparib Extends OS in Relapsed Ovarian Cancer

Jonathan Ledermann, MD

The PARP inhibitor olaparib (Lynparza) significantly increased overall survival (OS) in women with platinum-sensitive relapsed serous ovarian cancer when given as maintenance monotherapy. These interim results, a third updated survival analysis, come from an extension of the Study 19 phase II trial and were presented at the 2016 ASCO Annual Meeting.

The greatest OS advantage was seen in women who had a BRCA mutation (hazard ratio [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. ThePvalues were nominal and did not meet the criterion for statistical significance (P<.0095), however.

Other 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<.0001).

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, nominalP= .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, nominalP= .02480).

&ldquo;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,&rdquo; Ledermann said. &ldquo;The difference in mean survival adds further support to the OS advantage of olaparib.&rdquo; 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&ndash;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.

With a median follow-up interval of 5.9 years, 15 patients (11%) were still receiving olaparib (8 with BRCA mutations). One BRCA-mutated patient was still receiving placebo. Twelve percent of BRCA wild type patients on olaparib achieved median follow-up of between 5 and 6 years.

The adverse events (AEs) and dose modifications remained consistent from 2012 and included 3 cases of myelodysplastic syndrome/acute myeloid leukemia. Two of these patients were in the olaparib group (on treatment for 57 and 10 months) and one was on placebo for 44 months. In women receiving olaparib for at least 2 years, frequencies of common AEs (nausea, fatigue, vomiting, anemia) were consistent with the overall population. AEs were generally reported during the first 2 years of treatment.

In the overall study population, 59 patients (43%) experienced an AE of grade 3 or above, while only 28 (22%) of those on placebo did. Those percentages remained fairly consistent among patients who remained on trial for 2 years or more: 15 (47%) in the olaparib arm and 1 (20%) in the control arm. Likewise, the percentages of dose reductions due to AEs were consistent over time: 34 (25%)/5 (4%) active versus control in the overall study population and 8 (25%) and 0, respectively, among those on treatment for 2 years or longer. There were few treatment discontinuations due to AEs: 8 active and 2 control patients overall and 3 olaparib patients from the long-term treatment group. No patients from the long-term placebo group discontinued treatment due to AEs.

Ledermann JA, Harter P, Gourley C, et al. Overall survival (OS) in patients (pts) with platinum-sensitive relapsed serous ovarian cancer (PSR SOC) receiving olaparib maintenance monotherapy: An interim analysis.J Clin Oncol 34, 2016 (suppl; abstr 5501).