Maintenance olaparib yields survival gains in BRCA-mutated metastatic pancreatic cancer
Use of olaparib in the maintenance setting prolongs progression-free survival (PFS) in patients with a germline BRCA mutation and metastatic pancreatic cancer as compared with placebo, according to the results of the phase III POLO* trial.A total of 154 patients (median age, 57 years; 54.55 percent male) with a germline BRCA1 or BRCA2 mutation and metastatic pancreatic cancer, which had not progressed during first-line platinum-based chemotherapy, underwent randomization to maintenance treatment with olaparib (300 mg twice daily; n=92) or placebo (n=62).
The primary endpoint of PFS, which was assessed by blinded independent central review, was more favourable in the olaparib vs placebo arm (median, 7.4 vs 3.8 months). The study drug almost halved the risk of progression or death (hazard ratio [HR], 0.53, 95 percent CI, 0.35–0.82; p=0.004). [New Engl J Med 2019;doi:10.1056/NEJMoa1903387]
“Separation between the Kaplan–Meier curves for the two trial arms can be seen from approximately 5 months; this result provides support for the observed 47-percent reduction in the risk of disease progression or death. At 2 years, 22.1 percent of the patients in the olaparib arm vs 9.6 percent of patients in the placebo arm did not have disease progression,” the investigators said.
Overall survival, in an interim analysis at 46 percent data maturity, was comparable between the olaparib and placebo arms (median, 18.9 months vs 18.1 months; HR for death, 0.91, 0.56–1.46; p=0.68).
Likewise, health-related quality of life, assessed using the global quality-of-life score based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, did not significantly differ between the two treatment arms (between-group difference, −2.47 points, −7.27 to 2.33).
“The adverse-effect profile of maintenance olaparib was similar to that observed in other tumour types,” the investigators said. [N Engl J Med 2017;377:523-533; N Engl J Med 2018;379:2495-2505; Lancet Oncol 2017; 18:1274-1284]
Higher grade adverse events (AEs; grade ≥3) occurred more frequently in the olaparib vs placebo arm (40 percent vs 23 percent), and AEs led to treatment discontinuation in 5 percent and 2 percent, respectively.
“POLO … was a global trial, and when the trial was designed, 6-month treatment with FOLFIRINOX (fluorouracil, leucovorin, irinotecan and oxaliplatin) was a standard of care. Eligible patients could undergo randomization after at least 16 weeks of chemotherapy; no maximum length of first-line chemotherapy was mandated,” the investigators noted.
“In some clinical practices, patients may receive platinum-based chemotherapy for more than 6 months; however, peripheral neuropathy and other cumulative treatment-related side effects limit an extended duration, making placebo a suitable comparator to maintenance treatment after first-line chemotherapy,” they continued.
Given that patients received platinum-based chemotherapy immediately before maintenance olaparib, the findings suggest that the combined first-line platinum-based chemotherapy and maintenance olaparib strategy produced a PFS of >1 year among patients with a germline BRCA mutation who had disease that had not progressed while they were receiving previous platinum-based chemotherapy, as the investigators pointed out.
“However, our data do not include patients with disease that progressed during the first 4 months of platinum-based treatment or who may have continued to receive chemotherapy for an extended period,” they added.
*Pancreas Cancer Olaparib Ongoing