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Practice-Changing PARP Inhibitor Study in Ovarian Cancer

— "Unprecedented" increase in PFS with upfront olaparib maintenance

MedpageToday

MUNICH -- Upfront maintenance therapy with a PARP inhibitor led to an "unprecedented" improvement in progression-free survival (PFS) in women with newly diagnosed, advanced BRCA-positive ovarian cancer, a randomized trial showed.

After 3 years, 60.4% of patients remained alive without disease progression after maintenance therapy with olaparib (Lynparza), following chemotherapy and surgery. That compared with 26.9% in the group that received standard treatment without anti-PARP maintenance, reported Kathleen Moore, MD, of the Stephenson Oklahoma Cancer Center in Oklahoma City.

Action Points

  • Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Perhaps even more impressive, maintenance therapy stopped after 2 years, yet the survival curve for women who received the PARP inhibitor remained stable through the third year of follow-up, suggesting a persistence of the treatment effect.

"We feel the has demonstrated an unprecedented improvement in progression-free survival in patients who have a BRCA mutation and advanced ovarian cancer when olaparib is incorporated following platinum-based chemotherapy," Moore said at the European Society for Medical Oncology congress. "It appears that the benefit of olaparib maintenance is extended beyond the 2-year time point during which patients were receiving treatment."

"We believe the SOLO1 data 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," she added.

The results suggest the benefits of PARP inhibitor therapy in recurrent ovarian cancer may extend into the front-line setting, said Jonathan Ledermann, MD, of University College London, in response to the findings.

"When patients have a recurrence, eventually that becomes a fatal disease," said Ledermann. "Although we extend survival or the time the disease is controlled, they will die of their disease. The real aim of our treatment now needs to be very much focused on preventing that first recurrence, which occurs in 70% of patients."

"If you look back at all the trials that have been done and the drugs developed over the last few years, we've made very little impression on the first-line treatment of women with ovarian cancer," he noted. "The opportunity to bring a PARP inhibitor into the first-line setting was a very interesting opportunity, particularly for women with a BRCA mutation. We know that PARP inhibitors are more effective in patients who carry a BRCA mutation."

The final word on the trial's success awaits data on overall survival, which could be a long wait, Ledermann added. As a group, patients with BRCA-mutated ovarian cancer live longer than patients with non-mutated disease, and the "impressive" prolongation of the recurrence-free interval with olaparib maintenance therapy could increase the lifespan.

"There is no doubt this is a big step forward for the patients with BRCA-mutated ovarian cancer," Ledermann said.

The international randomized phase III SOLO-1 trial had as its primary objective the prolongation of the recurrence-free interval in women with newly diagnosed, advanced ovarian cancer associated with a BRCA mutation. As Moore and Ledermann both pointed out, most patients initially respond to treatment, but the vast majority eventually have a relapse, at which point, the disease becomes incurable.

Investigators hypothesized that following primary treatment with 2 years of olaparib maintenance therapy might extend the recurrence-free period, and possibly even increase the number of women who obtain a cure. Olaparib maintenance already is widely used in setting of recurrent ovarian cancer, after studies showed that the treatment substantially increased PFS.

SOLO-1 included patients with newly diagnosed FIGO stage III-IV high-grade serous or endometroid ovarian cancer associated with germline or somatic BRCA mutations. All patients underwent cytoreductive surgery and received platinum-based chemotherapy. Investigators then randomized the patients 2:1 to receive olaparib maintenance therapy or placebo for 2 years.

Moore reported findings after a median follow-up of 41 months. The primary analysis included 391 patients.

The analysis showed a 33% absolute difference in 3-year PFS, which translated into a 70% reduction in the risk of death or disease progression with olaparib (95% CI 0.23-0.41, P<0.0001). The placebo arm had a median PFS of 13.6 months, whereas the median had yet to be reached in the olaparib arm. Nonetheless, statistical projections indicate that median PFS for the olaparib group will turn out to be about 3 years longer than the PFS in the placebo group, said Moore.

Analysis of second PFS interval (PFS2) and time to first subsequent therapy or death also favored the olaparib arm.

"The statistically significant improvement in PFS2 suggests to us that there is no detriment to using olaparib following front-line chemotherapy for patients who do recur and need subsequent therapy," said Moore.

Adverse events were generally low grade and consistent with the clinical experience with olaparib.

  • author['full_name']

    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined ֱ in 2007.

Disclosures

The study was supported by AstraZeneca, Merck, Myriad Genetics, and the Gynecologic Oncology Group.

Moore disclosed relevant relationships with AstraZeneca, Advaxis, Clovis, Tesaro, Genentech/Roche, Immunogen, VBL Therapeutics, Merck, and Janssen.

Primary Source

European Society for Medical Oncology

Moore K, et al "SOLO-1: Phase III trial of maintenance olaparib following platinum-based chemotherapy in newly diagnosed patients with advanced ovarian cancer and a BRCA1/2 mutation" ESMO 2018; Abstract LBA7-PR.