Long-term follow-up shows meaningful OS improvement with olaparib mono and in combo with bevacizumab in advanced OC patients

Two phase 3 trials, namely PAOLA-1 and SOLO-1, have demonstrated the clinical efficacy of olaparib, with or without bevacizumab, in patients with homologous recombination deficiency (HRD)-positive or breast cancer gene (BRCA)-mutated advanced ovarian cancer (OC), leading to regulatory approval across multiple countries.1 In the latest long-term follow-up of the 2 trials, olaparib monotherapy and in combination with bevacizumab demonstrated clinically meaningful improvement in overall survival (OS) among the patients, consolidating its role as a first-line maintenance therapy in HRD-positive or BRCA-mutated advanced OC.1

OC is one of the most common cancers among women worldwide and has the highest mortality rate among gynecologic cancers, with a 5-year survival rate of merely 30%-50% in newly diagnosed patients.2 The presence of mutations in BRCA1 and BRCA2 were associated with an increased risk of developing OC by 15%-45% and 10%-20%, respectively.3 About 50% of advanced OC patients are HRD-positive, encompassing a wide range of genetic abnormalities, including BRCA mutations.4 The current management approach is the adoption of drug treatments, such as olaparib monotherapy or olaparib in combination with bevacizumab, to delay disease progression so as to achieve long-term remission among patients.1

SOLO-1 was a phase 3 randomized, double-blinded, placebo-controlled, multicenter trial that assessed the efficacy and safety of olaparib as a maintenance monotherapy compared with placebo in newly-diagnosed patients with advanced BRCA-mutated OC following platinum-based chemotherapy.1,5 The study enrolled 391 eligible patients who were randomized 2:1 to receive olaparib or placebo for 24 months or until disease progression.5 The primary study endpoint was progression-free survival (PFS), which was significantly improved with olaparib vs. placebo (HR=0.30; 95% CI: 0.23-0.41; p<0.001).5 The prespecified descriptive OS analysis was planned 7 years after randomization of the last patient.1

In the long-term OS analysis of SOLO-1, the 7-year OS rate with olaparib monotherapy was 67.0% vs. 46.5% with the placebo arm.1 The olaparib monotherapy significantly reduced the risk of death by 45% vs. placebo (HR=0.55; 95% CI: 0.40-0.76; p=0.0004).1 In addition, olaparib also significantly prolonged the time to the first subsequent therapy (TFST), with a median TFST of 64.0 months in the olaparib group vs. 15.1 months in the placebo group (HR=0.37; 95% CI: 0.28-0.48).1

PAOLA-1 was a double-blinded phase 3 trial that evaluated the efficacy and safety of olaparib in combination with bevacizumab vs. bevacizumab alone as a first-line maintenance treatment for newly diagnosed advanced OC patients. The study recruited a total of 806 patients who were randomized 2:1 to receive olaparib + bevacizumab or placebo + bevacizumab.1,6 The primary endpoint was PFS, which was met in the intention-to-treat (ITT) population with a median follow-up of 22.1 months for olaparib/ bevacizumab (HR=0.59; 95% CI: 0.49-0.72; p<0.001).1,6

In the 5-year OS analysis of PAOLA-1, olaparib-bevacizumab achieved a median OS of 56.5 months and a 5-year OS rate of 47.3%, which did not differ significantly with the placebo group (median OS=51.6 months; 5-year OS rate=41.5%).1 In other words, no significant difference in OS was observed with the olaparib-bevacizumab group vs. the placebo-bevacizumab group in the overall population (HR=0.92; 95% CI: 0.76-1.12; p=0.4118).1 However, the olaparib-bevacizumab regimen showed greater OS benefits among the subgroup of patients who were HRD-positive, with a median OS of 75.2 months vs. 57.3 months in the placebo group (HR=0.62; 95% CI: 0.45-0.85).1 The 5-year OS rate was also higher at 65.5% among this group of patients in the olaparib-bevacizumab arm vs. 48.4% in the placebo-bevacizumab arm.1

In both studies, the rates of treatment-emergent adverse events (TEAEs) with olaparib, such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), were comparable between the primary PFS analyses and the long-term OS analyses.1 No new safety signals were identified.1

In summary, the positive long-term OS results of PAOLA-1 and SOLO-1 pointed to the consolidation of the role of olaparib, with or without bevacizumab, as a first-line maintenance treatment for HRD-positive or BRCA-mutated advanced OC.1,5,6

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