Maintenance Olaparib Improves PFS in Phase III Ovarian Cancer Trial

Sean Bohen, MD, PhD

Single-agent olaparib (Lynparza) significantly improved progression-free survival (PFS) compared with placebo in the maintenance setting for patients with advanced BRCA-positive ovarian cancer, according to findings from the phase III SOLO-2 trial announced by AstraZeneca, the manufacturer of the PARP inhibitor.

Although specific data from the trial are not yet available, AstraZeneca reported that the median PFS with olaparib was significantly higher than in the olaparib arm of the phase II 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, MD, PhD, executive vice president, Global Medicines Development, and Chief Medical Officer at AstraZeneca, said in a statement.

The multicenter phase III SOLO-2 trial included 295 patients with platinum-sensitive, relapsed/recurrent, BRCA-positive ovarian cancer who had received ≥2 prior lines of platinum-based chemotherapy. Patients were randomized to receive either olaparib at 300 mg twice daily or placebo until disease progression.

The latest data from the phase II Study 19, which were presented at the 2016 ASCO Annual Meeting, showed that in patients with platinum-sensitive relapsed serous ovarian cancer, olaparib 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 (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, who presented the results at the 2016 ASCO Annual Meeting. However, the P values were nominal and did not meet the criterion for statistical significance (P <.0095).

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 or partial response 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 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 cutoff 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 = .02480).

“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 with 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, 0.030-0.66; 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 months. In the placebo group, 59 (97%) experienced a TSST; the median TSST was 14.7 months (HR, 0.63; 95% CI, 0.43-0.94; 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 with earlier data reports from the trial, 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, respectively) and 1 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.

In June 2014, the FDA’s Oncologic Drugs Advisory Committee voted 11-2 against the accelerated approval of olaparib 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 olaparib in this setting.

Following this vote, AstraZeneca submitted an amendment to olaparib’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 3 or more prior lines of chemotherapy.

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).