Maintenance olaparib in advanced BRCA-mutated ovarian cancer: Insights for clinical practice
Most patients with advanced ovarian cancer (OC) relapse after standard cytoreductive surgery and platinum-based chemotherapy. At a webcast organized by the Hong Kong Society of Clinical Oncology, Dr Kathleen Moore of the University of Oklahoma in Norman, Oklahoma, US, discussed the results of the SOLO-1 trial, which demonstrated significant progression-free survival (PFS) benefits associated with maintenance therapy using the poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitor, olaparib, in patients with newly diagnosed, advanced BRCA-mutated OC who had complete or partial response (CR/PR) to first-line platinum-based chemotherapy.
Prolonging PFS in ovarian cancer
While most patients with advanced OC show no evidence of disease after standard cytoreductive surgery and platinum-based chemotherapy, up to 70 percent may relapse within the next 3 years. [Ann Oncol 2013;24(suppl 6):vi24-vi32]
“Once the cancer recurs, PFS durations after each succeeding line of treatment tend to become shorter and shorter,” noted Moore. [Ann Oncol 2013;24(suppl 6):vi24-vi32]
“Prolongation of PFS is crucial because relapses, even when patients are not yet symptomatic, have negative physical and emotional effects on daily activities,” she explained. [Int J Gynecol Cancer 2017;27:1134-1140]
“Furthermore, PFS duration is associated with the likelihood of response to succeeding lines of therapy,” she continued. “Previous studies have demonstrated that the shorter the platinum-free interval, the lower the response rate to succeeding lines of therapy. In contrast, the longer the time to rechallenge after first- or even second-line platinum therapy, the better the response to subsequent treatment.” [J Clin Oncol 1991;9:389-393; Gynecol Oncol 1990;36:207-211]
Maintenance therapy in advanced ovarian cancer
Results from the phase III GOG-218 and ICON7 trials demonstrated statistically significant and clinically relevant PFS improvements associated with the addition of bevacizumab to carboplatin and paclitaxel, followed by bevacizumab maintenance, in the first-line setting. [N Engl J Med 2011;365:2473-2483; N Engl J Med 2011;365:2484-2496]
“However, no overall survival [OS] benefit was demonstrated with this strategy,” noted Moore. [N Engl J Med 2011;365:2473-2483; N Engl J Med 2011;365:2484-2496] “A subgroup analysis of the ICON7 trial did demonstrate PFS and OS benefits, but only in patients at high risk of disease progression [ie, residual disease >1 cm/stage IV/suboptimal cytoreduction].” [Lancet Oncol 2015;16:928-936]
SOLO-1: Olaparib maintenance provides PFS benefit
Meanwhile, the PARP inhibitor olaparib has emerged as an important maintenance therapy for patients with newly diagnosed advanced BRCA-mutated OC, based on significant PFS benefits demonstrated in the randomized, double-blind, phase III SOLO-1 trial. [N Engl J Med 2018;379:2495-2505]
Olaparib is currently approved as maintenance monotherapy for adult patients with advanced (ie, International Federation of Gynecology and Obstetrics [FIGO] stage III/IV), BRCA1/2-mutated (germline and/or somatic), high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer with CR/PR to first-line platinum-based chemotherapy. [Lynparza Hong Kong prescribing information]
“To our knowledge, SOLO-1 is the first study to use a PARP inhibitor as maintenance therapy for patients with newly diagnosed advanced BRCA-mutated OC,” said Moore.
SOLO-1 included 391 patients with newly diagnosed, advanced, high-grade serous or endometrioid OC, primary peritoneal cancer, fallopian tube cancer, or a combination thereof, with BRCA1/2 mutation who had CR/PR after platinum-based chemotherapy. Patients were assigned in a 2:1 ratio to receive either olaparib tablets (300 mg BID) or placebo. Study treatment continued until disease progression or when patients had no evidence of disease after 2 years. Patients with a PR at 2 years were allowed to continue treatment. [N Engl J Med 2018;379:2495-2505]
After a median follow-up of 41 months, olaparib significantly reduced the risk of disease progression or death by 70 percent vs placebo (hazard ratio [HR], 0.30; 95 percent confidence interval [CI], 0.23 to 0.41; p<0.001), with a 3-year PFS rate of 60 percent vs 27 percent. (Figure 1) [N Engl J Med 2018;379:2495-2505]
“These PFS data represent results at the data cut-off on 17 May 2018,” explained Moore. “After 41 months of follow-up, the median PFS was not yet reached in patients treated with olaparib, and was 13.8 months in patients treated with placebo. This represents a marked improvement in PFS for a maintenance therapy in the first-line setting.”
“A 50 percent reduction in the risk of second progression or death [PFS2] was also observed with olaparib [median PFS2, not reached vs 41.9 months for placebo; HR, 0.50; CI, 0.35 to 0.72; p<0.002], demonstrating that olaparib maintenance does not does not diminish the benefit conferred by subsequent therapy,” said Moore. [N Engl J Med 2018;379:2495-2505]
“The efficacy of olaparib was consistent across all PFS subgroups investigated in SOLO-1, including low-risk patient groups,” she noted. “This included patients with stage III disease who underwent upfront surgery and had no residual disease, which accounted for up to 44 percent of patients in SOLO-1 [median PFS, not reached for olaparib vs 21.9 months for placebo; PFS HR, 0.32; 95 CI, 0.20 to 0.51].” (Figure 2) [Mathews C, et al, ASCO 2019, poster 5541]
“These additional PFS benefits with olaparib are unprecedented,” said Moore. “Patients with newly diagnosed advanced OC with no evidence of residual disease after upfront surgery are often considered to have the best prognosis and have been excluded from a number of contemporary first-line trials. Yet, if you add olaparib as maintenance therapy, significant PFS benefits are still achieved in these patients.” [Mathews C, et al, ASCO 2019, poster 5541]
“Up to 52 percent of patients in SOLO-1 experienced an adverse event leading to dose interruption,” said Moore. “Nevertheless, most patients [about 70 percent] remained on the 300 mg BID starting study dose throughout long-term maintenance treatment, suggesting that olaparib maintenance therapy is well tolerated.” [N Engl J Med 2018;379:2495-2505; Colombo N, et al, ASCO 2019, poster 5539]
Early and sustained benefits with olaparib maintenance
“The early ‘shoulder’ sign, which represents patients progressing within about 6 months after primary platinum chemotherapy, as seen in the placebo curve of SOLO-1, is eliminated with olaparib maintenance therapy,” explained Moore. (Figure 3A) “This indicates that the PFS benefit associated with olaparib may occur early.” [N Engl J Med 2018;379:2495-2505]
“Meanwhile, PFS curves in trials of anti-angiogenesis agents, such as with bevacizumab in ICON7, show a characteristic ‘banana’ sign, wherein the PFS curves for the maintenance therapy and placebo groups gradually converge after treatment discontinuation,” she continued. (Figure 3B) [N Engl J Med 2011;365:2484-2496] “This is not seen SOLO-1, which indicates that the PFS benefit of olaparib maintenance therapy does not diminish even after treatment discontinuation.” (Figure 3A)
“The early effects of PARP inhibitors appear to set the stage for patients to do well even beyond treatment discontinuation,” Moore reiterated. “For olaparib, we are still seeing a very high percentage of patients not progressing after 2 years. Thus, there is no indication to extend treatment beyond the 2-year mark in those who have no evidence of disease.” [N Engl J Med 2018;379:2495-2505]
“Given the PFS benefit of olaparib demonstrated in the SOLO-1 trial, it is important to test all OC patients for BRCA1/2 mutation at the time of diagnosis,” Moore suggested.
“The OS data for SOLO-1 are not yet available. Elimination of the early shoulder and banana signs in the PFS curve of olaparib indicates that its benefit may occur early and does not diminish after discontinuation in patients with newly diagnosed advanced OC and BRCA1/2 mutation,” she concluded.