Ovarian cancer - Emerging treatments

Pembrolizumab

Pembrolizumab is a programmed death receptor-1 (PD-1)-blocking monoclonal antibody. It works by blocking the pathways leading to tumour tolerance.[210] Pembrolizumab is approved by the US Food and Drug Administration (FDA) to treat patients with unresectable or metastatic solid tumours that have been identified as having a biomarker referred to as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).[211] Additionally, pembrolizumab is FDA-approved for the treatment of patients with unresectable or metastatic tumour mutational burden-high (TMB-H; ≥10 mutations/megabase) solid tumours.[212] Early clinical trials of pembrolizumab in ovarian cancer have shown promise.[213][214]

Dostarlimab

Dostarlimab is a PD-1-blocking monoclonal antibody. In an open-label single-arm study, dostarlimab demonstrated durable anti-tumour activity in patients with dMMR recurrent or advanced solid tumours (including ovarian cancer).[215] The FDA has granted accelerated approval to dostarlimab for treating patients with dMMR recurrent or advanced solid tumours that have progressed on or following prior treatment and who have no satisfactory alternative treatment options. The FDA has approved a companion diagnostic device to select patients with dMMR solid tumours for treatment with dostarlimab. A phase 3, multicentre trial is planned.[216]

Mirvetuximab soravtansine

Mirvetuximab soravtansine is an antibody-drug conjugate comprising a folate receptor alpha-binding antibody linked to the cytotoxic maytansinoid DM4. It is currently under investigation for the treatment of women with platinum-resistant ovarian cancer who have received 1 to 3 prior lines of systemic treatment.[217] The FDA has granted fast-track designation for this indication.

Trabectedin

A compound derived from the sea squirt that binds DNA and prevents cell proliferation. In a phase 3 randomised open-label multicentre trial of women with platinum-sensitive recurrent ovarian cancer, the combination of trabectedin plus pegylated liposomal doxorubicin did not improve overall survival compared with pegylated liposomal doxorubicin alone.[218] The UK National Institute for Health and Care Excellence does not currently recommend trabectedin in combination with liposomal doxorubicin at this time.[219]

Cediranib

Cediranib is an oral anti-angiogenic vascular endothelial growth factor receptor 1-3 inhibitor with anti-tumour activity. In a three-armed randomised placebo-controlled phase 3 trial of patients with platinum-sensitive recurrent ovarian cancer, cediranib plus chemotherapy, with cediranib continued as maintenance therapy, improved progression-free survival compared with cediranib plus chemotherapy without maintenance cediranib, and chemotherapy alone.[220] Analysis of overall survival was underpowered.[221] Combination therapy with olaparib plus cediranib did not improve progression-free survival compared with chemotherapy in patients with high-grade platinum-sensitive ovarian cancer.[222]

Trebananib

Trebananib inhibits angiogenesis by preventing angiopoietins 1 and 2 from binding to the Tie2 receptor. In a randomised placebo-controlled phase 3 trial of patients with recurrent ovarian cancer treated with three or fewer prior regimens and a platinum-free interval of <12 months, weekly paclitaxel plus trebananib improved progression-free survival compared with paclitaxel alone (7.2 months vs. 5.4 months).[223] Trebananib combined with first-line carboplatin and paclitaxel did not improve progression-free survival in patients with advanced ovarian cancer, compared with carboplatin and paclitaxel alone.[224]

Pazopanib

Pazopanib is an oral tyrosine kinase inhibitor that has anti-angiogenic properties. In one randomised open-label phase 2 trial of women with platinum-resistant or platinum-refractory advanced ovarian cancer, the addition of pazopanib to weekly paclitaxel improved progression-free survival compared with paclitaxel alone.[225] In a subsequent phase 2 randomised placebo-controlled trial, the combination of pazopanib plus paclitaxel did not improve progression-free or overall survival compared with paclitaxel alone in women with recurrent ovarian cancer.[226] Pazopanib prolonged progression-free survival in patients with newly diagnosed advanced ovarian cancer when used as maintenance therapy after first-line chemotherapy.[227] Pazopanib was not associated with improved overall survival in this population.[227][228]

Dabrafenib plus trametinib

In an open-label single-arm study, dabrafenib (a selective BRAF inhibitor) plus trametinib (a MEK1/2 inhibitor) demonstrated durable anti-tumour activity in patients with BRAF V600-mutated tumours (including ovarian cancer) who progressed on standard therapy.[229] The FDA has granted accelerated approval for dabrafenib plus trametinib for treating patients with unresectable or metastatic solid tumours with BRAF V600E mutation (detected by an FDA-approved test) who have progressed following prior treatment and have no satisfactory alternative treatment options.