Maintenance therapy with olaparib monotherapy provides clinically significant, long-term treatment benefits and is safe in patients with platinum-sensitive relapsed serous ovarian cancer.
Charlie Gourley, PhD, MBChB
Maintenance therapy with olaparib (Lynparza) monotherapy provides clinically significant, long-term treatment benefits and is safe in patients with platinum-sensitive relapsed serous ovarian cancer, according to results reported at the 2017 international meeting of the European Society of Gynaecological Oncology (ESGO 20).
Results from a final analysis of Study 19 confirmed an overall survival (OS) advantage for olaparib maintenance therapy, with median OS of 29.8 months versus 27.7 months for placebo (hazard ratio [HR], 0.73; 95% CI, 0.55-0.95; P = .021). The median follow-up was 78 months at an OS data maturity of 79%.
Previously reported findings demonstrated that olaparib maintenance significantly improved progression-free survival (PFS) compared with placebo (HR, 0.35; 95% CI, 0.25-0.49). Findings from an interim analysis also suggested an OS advantage with olaparib (HR, 0.73; 95% CI, 0.55-0.96).
“The final OS analysis reported here was protocol-specified but not designed to show a statistically significant difference between treatment arms,” said Charlie Gourley PhD, MBChB, chair and honorary consultant in Medical Oncology at Edinburgh Cancer Research Centre in Edinburgh, Scotland. “This OS analysis should be considered descriptive, with P values deemed nominal—the criterion for statistical significance, P < .0095, was not met.
“Nevertheless, this planned final analysis suggests an OS advantage for patients receiving olaparib as maintenance therapy for serous ovarian cancer.”
Study 19 was a randomized, double-blind placebo controlled phase II study comapring outcomes with olaparib as maintenance therapy in 136 patients with platinum-sensitive, recurrent high-grade serous ovarian cancer with outcomes in 129 patients on placebo. All patients had received at least 2 prior regimens of platinum-based chemotherapy and demonstrated either a complete response (CR) or partial response (PR) to their most recent regimen.
Olaparib was administered in 400 mg capsules twice daily. Patients in the control arm received placebo capsules twice daily until disease progression. OS was analyzed using a Cox proportional hazards model.
The primary endpoint of Study 19 was PFS according to RECIST 1.0 criteria and secondary endpoints included OS, safety, and tolerability.
Olaparib is a potent PARP inhibitor that has been approved as maintenance treatment for patients with advanced ovarian cancer for patients with a BRCA1/2 mutation in the European Union. In the US, the FDA extended approval for treatment of patients with relapsed platinum-sensitive ovarian cancer irrespective of BRCA status earlier this year.
“Unprecedented long-term PARP inhibited exposure was seen in Study 19,” Gourley said. “More than 10% of patients received a durable benefit from olaparib maintenance monotherapy for at least 6 years.”
As of the May 2016 data cut-off, 15 (11.0%) patients had received olaparib for 6 or more years, including 8 patients with BRCA mutations. At this time, one (0.8%) BRCA-mutated patient had received placebo for more than 6 years.
BRCA test results obtained from case report forms of previous local germline or BRCA testing resulted in a known BRCA status for 254 (96%) patients.
Homologous recombination deficiency (HRD) scores were calculated regarding whole genome tumor loss of heterozygosity (LOH), telomeric allelic imbalance, and large-scale state transition. A Myriad HRD score ≥42 was considered positive in this analysis of the 15 patients receiving olaparib for ≥6 years. The analysis revealed that 5 patients were BRCA wild-type; of these patients, 1 patient was HRD positive and also showed an HRR mutation (RAD51B). Of the 2 patients who were HRR wild type, 1 patient displayed HRD positivity. Of 2 patients with uncertain HRR status, 1 patient was determined HRD positive.
Investigators identified no new safety signals or changes in olaparib tolerability in the safety analysis. Any-grade adverse events (AEs) occurred in 97.1% of patients receiving olaparib compared with 93.0% of patients on placebo. The most frequently reported ≥grade 3 associated with olaparib were fatigue/asthenia (8.8%), anemia (5.9%), and neutropenia (3.7%).
“Findings from Study 19 showed that maintenance monotherapy with olaparib provides a clinically significant long-term treatment benefit to patients with platinum sensitive relapsed serous ovarian cancer that is irrespective of BRCA mutation status,” Gourley said.
Friedlander M, Gourley C, Matulonis U, et al. Clinically significant long-term maintenance treatment with olaparib in patients with platinum-sensitive relapsed serous ovarian cancer (PSR SOC). Abstract presented at: 2017 ESGO Congress; November 4-7, 2017; Vienna, Austria.