NEW YORK – The PARP inhibitor olaparib (AstraZeneca/Merck's Lynparza) appears to extend overall survival when used as a post-chemotherapy maintenance treatment in women with advanced ovarian cancer who carry a BRCA1 or BRCA2 mutation, according to a final survival analysis from the Phase III SOLO2/ENGOT-ov21 trial.
"The results demonstrate that olaparib maintenance monotherapy not only delays disease progression but also improves overall survival in women with platinum-sensitive relapsed ovarian cancer and a BRCA mutation," Andrés Poveda, a gynecological cancer and sarcoma specialist at the Hospital Quirónsalud's Initia Oncology in Valencia, Spain, reported in an online press preview of the American Society of Clinical Oncology's annual meeting this week.
According to experts, the long-term survival data from the study provides confidence that olaparib should be the standard-of-care maintenance therapy for BRCA-mutated relapsed, platinum-responsive ovarian cancer patients.
For the international SOLO2 trial, investigators from Spain, France, the UK, and elsewhere tracked survival outcomes in nearly 300 BRCA1/2 mutation-positive women with platinum chemotherapy-sensitive, relapsed ovarian cancer who had already received two or more lines of platinum-based chemotherapy. In the trial, patients' germline BRCA1/2 mutation status were confirmed using Myriad Genetics' BRCAnalysis CDx.
The participants were randomized roughly two-to-one to receive maintenance olaparib in tablet form or a placebo and continued on until their disease progressed. The investigators stratified the cases to take their response to the prior platinum-based chemotherapy treatment into account.
Poveda noted that it has historically been difficult to identify treatments that consistently increase overall survival time in women with platinum-sensitive, relapsed ovarian cancer — a stage of disease that typically comes with a grim prognosis, despite decades-long efforts to find treatments that significantly improve survival outcomes.
"Therefore, the course of treatment includes delaying symptomatic disease progression and prolonging survival," he explained during the ASCO meeting presentation. "However, improvements in ovarian cancer survival are difficult to demonstrate in ovarian cancer trials because of crossover and numerous post-progression therapy options."
Maintenance therapy with PARP inhibitors such as olaparib has been approved for relapsed ovarian cancer regardless of a patient's a BRCA1/2 mutation status-free in several countries, Poveda noted, and findings from several Phase III trials presented at the European Society for Medical Oncology Congress in September pointed to the possibility of using PARP inhibitors more broadly in advanced ovarian cancer.
Even so, the mechanism of the drugs has prompted interest in applying them to cases with BRCA1/2 mutations where they are often expected to be particularly beneficial.
"There looks to be very broad-based utility of this class of drugs, certainly in tumors that have BRCA1/2 mutations," Richard Schilsky, chief medical officer and executive vice president of ASCO, said during a telephone press briefing this week that discussed the work.
For the double-blind SOLO2 trial, the researchers randomized 196 women with relapsed BRCA1/2-mutated, platinum chemotherapy-responsive ovarian cancer to the maintenance olaparib arm of the study, while 99 patients went on the placebo maintenance arm of the trial.
Initial findings, which were reported in Lancet Oncology in 2017, showed a significant improvement in investigator-assessed progression-free survival in BRCA-mutated ovarian cancer patients who had received at least two lines of prior chemotherapy. Specifically, progression-free survival increased by 13.6 months, on average, in patients who got the PARP inhibitor maintenance therapy in SOLO2 compared with the time-to-disease progression found in the trial participants who received a placebo after chemo.
Schilsky noted that those findings were part of the US Food and Drug Administration's evaluation of olaparib in the maintenance setting. However, the agency also weighed other data on olaparib, and ultimately approved the drug for relapsed, platinum-responsive ovarian cancer patients regardless of BRCA1/2 mutation status.
The latest five-year follow-up data provides additional insights on olaparib's magnitude of benefit in those with BRCA1/2 mutations. While more than 28 percent of those receiving olaparib maintenance treatment survived to the median follow-up point of 65 months without needing an additional treatment, that was the case for just 12.8 percent of patients in the placebo maintenance group, the SOLO2 team reported. More than 38 percent of patients in the placebo group crossed over to a PARP inhibitor treatment, as did 11 percent of the individuals on the SOLO2 olaparib maintenance treatment.
The team also considered overall survival, which Poveda called a key secondary endpoint of the SOLO2 trial. An analysis done at 61 percent data maturity in February of this year suggested women who received the PARP inhibitor maintenance treatment after chemotherapy had overall survival times that were some 12.9 months longer, on average, than patients getting the placebo during the maintenance period — coming in at a median of 51.7 months in the olaparib maintenance group and a median of 38.8 months in the placebo group.
The investigators also reported that 22 percent of patients in the PARP inhibitor maintenance group remained on the drug for at least five years — a finding Poveda called "unprecedented in the setting of relapsed ovarian cancer." Just 9.1 percent of patients continued in the placebo arm over the same time frame.
More than 42 percent of patients in the olaparib maintenance arm survived to the 65-month follow-up point, Poveda and his colleagues reported, while just over 33 percent of the patients receiving placebo during the maintenance period were alive after five years.
"With the addition of overall survival data, this study helps usher in a new era of personalized medicine for women with this difficult-to-treat cancer," Poveda said in a statement.
ASCO's Schilsky noted that the current findings "will not change access to the drug, because it's already FDA approved," though he added that it is "comforting to get the survival data showing that, in fact, the treatment confers a significant survival benefit."
Commenting on Poveda's online preview of the SOLO2 data, Schilsky said in a statement that the trial "confirms that … olaparib should be the standard maintenance therapy for patients with BRCA-related relapsed ovarian cancer responding to platinum-based chemotherapy — a significant advance for women with a cancer that has a historically poor prognosis."