In 2018, an estimated 295 414 new cases and 184 799 deaths related to ovarian cancer occurred, making it the second leading cause of death from gynaecological malignancy worldwide.1 The most common subtype is high-grade serous ovarian cancer.2 For newly diagnosed disease, debulking surgery and platinum-based chemotherapy are the mainstay of treatment,2 with or without antiangiogenic therapy and polyADP ribose polymerase (PARP) inhibitors. PARP inhibitors seem to be most active in patients whose tumours have BRCA1 or BRCA2 mutations, or both, or homologous recombination deficiency.3, 4 However, disease typically recurs, and treatment becomes increasingly challenging with diminishing response to subsequent therapies because of emerging drug resistance. Potential therapeutic opportunities exploit the molecular landscape of high-grade serous ovarian cancer, which is characterised by high genomic instability and alterations in cell cycle (eg, TP53, CCNE1, RB1, PTEN, and CDK12) and DNA repair (BRCA1, BRCA2, and other homologous recombination deficiency) pathway genes.5, 6 In platinum-sensitive recurrent disease, PARP inhibitors are considered standard-of-care maintenance therapy for patients previously untreated with a PARP inhibitor.2 However, platinum-resistant recurrent ovarian cancer remains a clinical challenge with few effective therapeutic options.
Research in context
Evidence before this study
Therapeutic development in the advanced or late setting of platinum-resistant ovarian cancer, in which disease is particularly resistant to treatments and clinically difficult, remains a priority. No targeted therapy has yet shown improvement in overall survival in this setting. We searched PubMed, with no language restrictions, for articles published between Jan 1, 2011, and Jan 1, 2021, using the terms “randomised trial”, “platinum resistant”, “platinum refractory”, AND “ovarian cancer” to identify articles that covered therapies for recurrent platinum-resistant or platinum-refractory ovarian cancer, and the terms “Wee1 inhibitor” and “ovarian cancer” to identify research relevant to adavosertib. We identified 16 randomised trials for platinum-resistant and platinum-refractory disease, and 32 publications related to preclinical and clinical studies with adavosertib. Apart from antiangiogenics (bevacizumab, sorafenib), we found no randomised trials that showed an improvement in progression-free survival in platinum-resistant disease, and none that showed improvement in progression-free survival and overall survival in platinum-refractory and platinum-resistant disease. We found no randomised trials of adavosertib in platinum-resistant or platinum-refractory ovarian cancer.
Added value of this study
To our knowledge, this is the first randomised phase 2 trial to show an improvement in progression-free survival and overall survival with the addition of adavosertib to gemcitabine in patients with high-grade serous ovarian cancer. The most common toxicities were haematological and fatigue. This is also the first study to investigate any association with SLFN11 levels in this population in post-hoc or exploratory analyses.
Implications of all the available evidence
Building on the biology of high-grade serous ovarian cancer, a TP53-mutated tumour type with high replication stress, these results of a Wee1 inhibitor combined with gemcitabine highlight the importance of DNA damage response targeted agents in this disease. This therapeutic approach might be applicable to additional tumour types with high replication stress. Larger confirmatory studies are required.
The DNA and RNA helicase Schlafen family member 11 (SLFN11) has been studied for its potential role in translation of DNA damage response proteins.7 SLFN11 binds to replication protein A (RPA), and high SLFN11 levels have been postulated to inhibit homologous recombination repair by promoting the destabilisation of the interaction between RPA and single-strand DNA.8 Low levels or an absence of SLFN11 have been proposed as potential mechanisms of resistance to DNA-damaging agents (including platinum and gemcitabine) and PARP inhibitors.9, 10, 11
Interest is increasing in targeting DNA damage response to overcome platinum resistance. DNA damage response comprises a network of molecules involved in cell cycle regulation and DNA repair, including cell cycle checkpoint coordination of DNA damage repair with cell cycle progression.12, 13 Cell cycle genes guard cellular integrity by halting proliferation at various checkpoints (G1/S, G2/M), allowing repair of damaged DNA.14 If the G1/S checkpoint is impaired, as in p53-deficient cancers, cancer cells rely on the G2/M checkpoint for DNA repair.15, 16
Wee1 (WEE1hu) kinase is a crucial regulator of the G2/M checkpoint. The G2/M checkpoint prevents entry of the damaged DNA into mitosis and is altered in several cancers.17, 18, 19 TP53 mutations, which are ubiquitous in high-grade serous ovarian cancer, lead to increased dependency on S-phase and G2-phase checkpoints. Wee1 inhibition with adavosertib (AZD1775; MK1775) induces G2 checkpoint escape.20 Gemcitabine is an antimetabolite therapy and blocks the progression of cells through the G1/S phase. Combining gemcitabine with Wee1 inhibition can lead to mitotic catastrophe by compromising the G2/M checkpoint.15 Combinations of gemcitabine and adavosertib have shown synergistic effects in preclinical studies and promising activity in early phase clinical trials.21, 22 Notably, in one of these preclinical studies, tumour regression of more than 50% was observed with the combination of gemcitabine and adavosertib in 25 (51%) of 49 TP53-mutated tumours compared with none of 23 TP53-wild-type tumours, suggesting that TP53 mutations might serve as a potential predictive factor for benefit from the combination.22 Because high-grade serous ovarian cancer is characterised by TP53 alterations,2 we aimed to assess the adavosertib plus gemcitabine regimen identified in a previous phase 1 study21 as treatment for recurrent platinum-resistant or platinum-refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer (hereafter referred to collectively as ovarian cancer).