First-Line Olaparib Maintenance New Standard for BRCAm Ovarian Cancer

Treatment for newly diagnosed advanced ovarian cancer most often includes cytoreductive surgery and platinum-based chemotherapy. While this combination is highly effective, most patients will relapse within three years. For recurrent platinum-sensitive ovarian cancer, maintenance with poly(ADP-ribose) polymerase (PARP) inhibitors such as olaparib, niraparib, and rucaparib is standard of care following platinum-based chemotherapy, based on substantial delay of progression. This benefit in recurrent ovarian cancer was observed regardless of BRCA status, though the benefit is greatest in BRCA-mutated patients. At the 2018 European Society for Medical Oncology (ESMO) Congress, Kathleen Moore, MD (Stephenson Cancer Center, Oklahoma City, Oklahoma, United States), presented results from the randomized phase III SOLO1 trial, which evaluated the PARP inhibitor olaparib as maintenance therapy following surgery and platinum-based chemotherapy in patients newly diagnosed with advanced ovarian cancer who carry a somatic or germline mutation in BRCA1/2 genes. These results were simultaneously published in The New England Journal of Medicine.

 

Patients (N = 391) with FIGO stage III or IV high-grade serous or endometroid ovarian cancer, primary peritoneal or fallopian cancer, or a combination thereof, who were in complete or partial response following cytoreductive surgery and platinum-based chemotherapy, received either placebo or olaparib maintenance (300 mg twice daily) for up to two years or until disease progression. At 3 years, 60.4% of patients receiving olaparib maintenance remained free of disease, compared to only 26.9% of patients receiving placebo. The median progression-free survival (PFS) has not been reached in the olaparib arm and is 13.8 months in the placebo arm (HR 0.30, P<.0001). Importantly, the benefit of two years of olaparib was sustained after stopping treatment. The PFS benefit of olaparib maintenance was consistent across patient subgroups and independent of disease stage and response to chemotherapy. Olaparib maintenance did not impact efficacy of subsequent therapy, and patients receiving olaparib in the first-line setting continued to have significantly improved outcomes following progression (PFS2: Not reached vs 41.9 months; HR 0.50, P = .0002).

 

Olaparib was associated with a manageable toxicity profile (mostly grade 1 or 2) and did not diminish health-related quality of life compared to placebo. Serious treatment-emergent adverse events (AEs) occurred in 20.8% of patients receiving olaparib and 12.3% of patients receiving placebo. The most common treatment-related AEs of any grade associated with olaparib included nausea, fatigue/asthenia, vomiting, anemia, and diarrhea. grade 3/4 AE was anemia that occurred in 21.5% of patients receiving olaparib. AEs were usually managed by dose interruption (52%) or dose reduction (28%), rather than treatment discontinuation (12%).

 

Dr Moore concluded that maintenance therapy with olaparib following surgery and chemotherapy resulted in a clinically meaningful improvement in PFS with a manageable toxicity profile, supporting olaparib maintenance as a new standard in patients with newly diagnosed BRCA-mutated advanced ovarian cancer following platinum-based chemotherapy. The discussant of this study, Jonathan Ledermann, MD (UCL Cancer Institute, London, United Kingdom), agreed that, based on these results, olaparib maintenance will move into first-line setting for BRCA-mutated ovarian cancer, while for BRCA wild-type patients, PARP inhibitors will be used for recurrent disease. He emphasized the importance of BRCA mutation testing at diagnosis and noted that these results will likely affect design of first-line clinical trials.

 

N Engl J Med. 2018 October 21. [Epub ahead of print].

Ann Oncol. 2018;29, Suppl 8: Abstract LBA7_PR.

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