Dr. Jonathan A. Ledermann
In this third interim analysis of Study 19, Dr. Ledermann reported no significant improvement in OS, consistent with prior reports, but showed the feasibility of long-term olaparib maintenance therapy. After a median follow-up of 5.9 years, 15 patients (11%) were still receiving olaparib and 13% of patients had been receiving olaparib for at least 5 years. The investigators also found no new safety findings.
The trial previously reported that in 265 women with relapsed, platinum-sensitive, high-grade serous ovarian cancer who had received at least two platinum-based regimens, maintenance olaparib administered at 400 mg twice daily was associated with a significant improvement in progression-free survival (PFS) compared with placebo, with a median PFS of 8.4 months and 4.8 months, respectively (hazard ratio [HR] 0.35; p < 0.001).1
A subsequent analysis showed that the superiority of olaparib compared with placebo was enhanced in the 54% of patients with a BRCA mutation, in whom the median PFS with olaparib and placebo were 11.2 months and 4.3 months, respectively (HR 0.18; p < 0.0001).2
The trial was not designed to assess OS; however, analyses conducted after 38% and 58% of patients had died showed no significant OS benefit with olaparib.1,2 Despite the lack of OS benefit, olaparib was considered to have a meaningful clinical benefit, as it was associated with improvement in two exploratory endpoints: time to first subsequent therapy or death, and time to second subsequent therapy or death.
During the Oral Abstract Session, Dr. Ledermann presented an updated OS analysis from Study 19. Three years after the previous analysis and with 77% of patients having died, the study still did not show a significant OS improvement with olaparib compared with placebo in the overall population or in the subset of patients with a BRCA mutation.
The investigators conducted alternative statistical analyses—a restricted means analysis—that suggested an OS benefit with olaparib compared with placebo. But this was also not statistically significant. An OS analysis in the subset of 20 patients with somatic BRCA mutations suggested outcomes consistent with the other subgroups, although the small number of patients precluded making full conclusions.
The updated analysis did confirm the benefit of maintenance olaparib compared with placebo in the median time to first subsequent therapy or death in both the BRCA mutation arm (15.6 vs. 6.2 months; HR 0.32; p < 0.00001) and BRCA wild-type arm (12.9 vs. 6.9 months; HR 0.45; p = 0.00006) and in the median time to second subsequent therapy or death in both the BRCA mutation arm (22.0 vs. 15.3 months; HR 0.41; p = 0.00001) and BRCA wild-type arm (17.0 vs. 14.7 months; HR 0.63; p = 0.02263).
Study discussant Isabelle Laure Ray-Coquard, MD, PhD, of Centre Léon Bérard, France, emphasized the importance of the observation of durable responses to olaparib—in some cases, for years—among patients with ovarian cancer who had previously received multiple prior therapies.
“It’s hard to use the word ‘cure,’” she said, “but there is great progress.”