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Olaparib confers ‘unprecedented’ PFS benefit in ovarian cancer
MUNICH — Maintenance olaparib significantly improved PFS among women with advanced ovarian cancer who harbored BRCA1 or BRCA2 mutations, according to results of the randomized phase 3 SOLO1 trial presented at European Society of Medical Oncology Congress.
Median PFS among women who received olaparib (Lynparza; AstraZeneca Merck) was nearly 3 years longer than that achieved by women who received placebo.
Study author Kathleen Moore, MD, associate professor at Stephenson Cancer Center at University of Oklahoma, described the improvement as “substantial and unprecedented.”
“We believe the SOLO1 data really promise a change in the standard of care for women with advanced ovarian cancer who harbor a BRCA mutation, and we hope this will be available to patients relatively soon,” Moore said during a press conference.
Women with newly diagnosed ovarian cancer typically undergo cytoreductive surgery and platinum-based chemotherapy. The majority of them relapse within 3 years and undergo additional chemotherapy; however, they are largely uncurable after relapse.
“The percentage of patients who survive disease free for long periods of time is dismally low, hovering in the 10% to 15% range,” Moore said. “If we are going to make meaningful improvements on that rate, it has to be in frontline treatment.”
The prospective, international, double-blind SOLO1 trial evaluated maintenance therapy with the PARP inhibitor olaparib for women who underwent platinum chemotherapy for newly diagnosed BRCA-positive ovarian cancer.
The double-blind trial included 390 patients with stage III to stage IV high-grade serous or endometrioid ovarian, primary peritoneal or fallopian tube cancer. All women harbored BRCA mutations and were in clinical complete or partial response after platinum-based chemotherapy.
Researchers randomly assigned 260 patients to 300 mg olaparib twice daily. The other 130 patients received placebo. Treatment continued until disease progression or for a maximum 2 years. Women with stable disease at 2 years had an opportunity to remain on treatment after discussions with their medical team.
Baseline characteristics were balanced between groups.
Investigator-assessed PFS served as the primary endpoint.
Median follow-up was 41 months.
Investigator-assessed PFS, performed at 51% maturity, showed olaparib reduced the risk for progression or death by 70% compared with placebo (median, not reached vs. 13.8 months; HR = 0.3; 95% CI, 0.23-0.41).
Blinded independent central review-assessed PFS, performed at 38% maturity, yielded a similar result (median, not reached vs. 14.1 months; HR = 0.28; 95% CI, 0.2-0.39).
“There was no obvious change in Kaplan-Meier curves after 2 years in the olaparib group, indicating an apparent enduring treatment benefit after stopping treatment,” Moore said.
Olaparib-treated patients also achieved longer time to first subsequent therapy or death (median, 51.8 months vs. 15.1 months; HR = 0.3; 95% CI, 0.22-0.4), as well as longer time from randomization to second progression or death (median, not reached vs. 41.9 months; HR = 0.5; 95% CI, 0.35-0.72).
“[This indicates] olaparib did not diminish patients’ ability to benefit from subsequent therapy,” Moore said.
OS data are immature.
Olaparib appeared well tolerated, exhibiting a safety profile consistent with what has been observed in the relapsed setting.
Most adverse events were low grade, according to researchers. The most common grade 3 or higher toxicities observed among olaparib-treated patients were anemia (22%) and neutropenia (8%).
Twenty-eight percent of patients assigned olaparib required dose reductions, 52% required dose interruptions and 12% discontinued therapy.
Researchers reported no change in baseline health-related quality-of-life scores with olaparib. – Mark Leiser
Reference:
Moore KN, et al. Abstract LBA7_PR. Presented at: European Society for Medical Oncology Congress; Oct. 19-23, 2018; Munich.
Disclosures: AstraZeneca provided funding for this study. Moore reports fees for advisory board roles with AstraZeneca, Advaxis, Clovis, Genentech/Roche, Immunogen, Janssen, Tesaro and VBL Therapeutics. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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This is the first study demonstrating the effectiveness of a PARP inhibitor as maintenance therapy after first-line treatment of BRCA-related ovarian cancers for prolonging time to progression of disease. The results of this study may lead to the FDA expanding the indications for olaparib to include patients in this category.
This is a very exciting addition to our tools for treating BRCA-mutation-positive women after initial therapy. The National Comprehensive Cancer Network recommends BRCA testing for all women with nonmucinous types of ovarian, fallopian tube and primary peritoneal cancers. Women should make sure they speak with their doctors about testing to make sure they have all the options available.
Perspective
Back to TopThese are outstanding results in a worsening disease setting. Not only was olaparib efficacious, but it was also shown to be well tolerated. The findings promise to change practice in this subgroup of patients with a BRCA mutation.
Two questions remain. Can we expand this benefit to all high-grade serous carcinomas? Looking at existing results in relapse with PARP inhibitor maintenance in all comers, we can anticipate excellent results for all patients with high-grade serous or endometrioid ovarian carcinoma. Also, what is the best maintenance therapy? Standard first-line therapy in many countries is chemotherapy plus bevacizumab maintenance for the majority of advanced disease, but the question remains whether maintenance with olaparib alone, or in combination with bevacizumab, is preferable. The PAOLA 1 trial will provide some information, and will probably be available next year.
Perspective
Back to TopPARP inhibitors have made a big impression on the management of recurrent ovarian cancer, but when patients do have a recurrence, eventually it becomes a fatal disease. The real aim of our treatment now needs to be very much focused on preventing that first recurrence. If you look back at the trials that have been done and the drugs that have been developed over the past few years, we actually have made very little impression on first-line treatment for women with advanced ovarian cancer. Seventy percent of these women will still have recurrence.
The opportunity to bring a PARP inhibitor into the first-line setting was very interesting, particularly for women with BRCA mutations. Although PARP inhibitors will work for many groups of patients, they are most effective for those who carry BRCA mutations, so this was the best group to select.
We saw very robust PFS data. The analysis was done when all patients had been followed for a minimum 3 years, having stopped the PARP inhibitor at 24 months. If you look at the curves, as Dr. Moore pointed out, the shape of the curves did not change beyond 2 years, so it does not seem as though the curves are coming together after treatment has been stopped. That is a very interesting result. Of course, we are going to have to wait until the OS data mature. I think that will be a long time because patients with BRCA mutations often survive for long periods of time, and we haven’t even seen the median PFS being reached yet.
There is real hope that this treatment will perhaps lead to an increase in the cure rate, which would be reflected by a reduction in the first relapse rate. We will need to wait longer for that, but there is no doubt this is a big step forward for patients with BRCA-mutated ovarian cancer.
There are many challenges, not least of which are access to the drug and the cost of the drug, as well as the testing of patients for BRCA mutations. That has improved over the last few years as PARP inhibitors have become more widely available, but we will need to get that testing done earlier at diagnosis to know whether patients will be able to qualify for olaparib maintenance after their first chemotherapy regimen. Overall, though, this is a very big step forward and very much a landmark trial for the treatment of patients with ovarian cancer.