Editor’s pick of Sylvie Rottey, MD, PhD, medical oncologist, UZ Gent
The phase III SOLO2 trial evaluated maintenance therapy with olaparib in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation. In the primary analysis, progression-free survival was significantly longer with olaparib than with placebo. Now, the final analysis of the study reports a 12.9 months improvement in overall survival. Although not statistically significant, this improvement is arguably clinically meaningful.
Patients with relapsed ovarian cancer have typically received multiple lines of chemotherapy, with the time to relapse shortening with each successive treatment line. The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib, is already approved in many countries as maintenance therapy in platinum-sensitive relapsed, ovarian cancer, regardless of BRCA1 or BRCA2 mutation status and as maintenance therapy in newly diagnosed ovarian cancer. The primary analysis of the phase III SOLO2 trial previously demonstrated a significantly improved progression-free survival (PFS) with olaparib in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation. Now, the final analysis results of the SOLO2 trial reports mature overall survival (OS) data.
This phase III, double-blind, placebo-controlled, multicentre trial enrolled 295 patients with relapsed, high-grade serous or high-grade endometrioid ovarian cancer, including primary peritoneal or fallopian tube cancer. Eligible patients were required to be over 18 years of age and have an ECOG performance status at baseline of 0-1. Additionally, patients were required to have had at least 2 prior lines of platinum-based chemotherapy, be in objective response to their most recent platinum regimen, and have platinum-sensitive disease following the penultimate line of chemotherapy before enrolment. Patients were randomised (2:1) to receive olaparib tablets (300 mg in two 150 mg tablets twice daily) or placebo until disease progression. The primary endpoint of this study was PFS, which has been reported previously. Key secondary endpoints of OS and safety are reported in this final analysis.
Baseline patient characteristics were well balanced among treatment arms. The median age of study participants was 56 years. Most patients (83% and 87% of patients in the olaparib and placebo groups, respectively) had primary ovarian tumours. The total mean duration of treatment was 29.1 months with olaparib, and 13.1 months with placebo. Following disease progression, 10% of olaparib patients, and 38% of placebo patients received subsequent PARP inhibitor therapy.
In this final analysis, the median follow-up for OS was 65.7 months for olaparib, and 64.5 months for placebo. Overall survival was numerically extended from 38.8 months with placebo to 51.7 months with olaparib. Despite not meeting the threshold for statistical significance (HR[95%CI]: 0.74[0.54-1.00], p= 0.054), the clinical benefit of olaparib was evident. In the prespecified sensitivity analysis of patients with a confirmed BRCA1/2 mutation, as evidenced by the Myriad Genetics BRCA test, the median overall survival was 52.4 months vs. 37.4 months compared to placebo (HR[95%CI]: 0.71[0.52-0.97], P= 0.031). Time to first subsequent therapy or death was 27.4 months with olaparib, and 7.2 months with placebo (HR[95%CI]: 0.37[0.28-0.48]). Encouragingly, by Kaplan-Meier estimates, 28% and 13% of patients treated with olaparib and placebo, respectively, were alive and had still not received a first subsequent therapy at 5 years.
Dose interruptions due to treatment-emergent adverse events (TEAEs) occurred in 50% of patients receiving olaparib and 19% of those who received placebo. Consequently, dose reductions occurred in 28% of olaparib patients, and 3% of placebo patients. Treatment discontinuation due to treatment-related adverse events (TRAEs) occurred in 13% and 1%, respectively. The most common reasons for TRAE-associated discontinuation in the olaparib group included anaemia (4%), acute myeloid leukaemia (2%), myelodysplastic syndrome (1%), neutropenia (1%) and thrombocytopenia (1%). The most common grade ≥3 TEAEs was anaemia (21% vs. 2%). Serious TEAEs were more frequent with olaparib, occurring in 26% of patients, compared to 8% of placebo patients. The most common serious TEAEs were due to anaemia (4% of patients receiving olaparib), intestinal obstruction (2% vs. 1%, respectively), myelodysplastic syndrome (2% receiving olaparib), constipation (2% receiving placebo) and small intestinal obstruction (2% receiving placebo). Six patients receiving olaparib (3%) died due to TRAEs, three due to myelodysplastic syndrome, and three due to acute myeloid leukaemia.
Although the 12.9-month improvement in median OS did not meet statistical significance in patients with platinum-sensitive, relapsed ovarian cancer with BRCA1/2 mutations, these results are clinically meaningful and support the use of maintenance olaparib in these patients.
Poveda A, Floquet A, Ledermann JA, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a final analysis of a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2021;22:620-631.