Elsevier

The Lancet

Volume 397, Issue 10271, 23–29 January 2021, Pages 281-292
The Lancet

Articles
Adavosertib plus gemcitabine for platinum-resistant or platinum-refractory recurrent ovarian cancer: a double-blind, randomised, placebo-controlled, phase 2 trial

https://doi.org/10.1016/S0140-6736(20)32554-XGet rights and content

Summary

Background

The Wee1 (WEE1hu) inhibitor adavosertib and gemcitabine have shown preclinical synergy and promising activity in early phase clinical trials. We aimed to determine the efficacy of this combination in patients with ovarian cancer.

Methods

In this double-blind, randomised, placebo-controlled, phase 2 trial, women with measurable recurrent platinum-resistant or platinum-refractory high-grade serous ovarian cancer were recruited from 11 academic centres in the USA and Canada. Women were eligible if they were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0–2, a life expectancy of more than 3 months, and normal organ and marrow function. Women with ovarian cancer of non-high-grade serous histology were eligible for enrolment in a non-randomised exploratory cohort. Eligible participants with high-grade serous ovarian cancer were randomly assigned (2:1), using block randomisation (block size of three and six) and no stratification, to receive intravenous gemcitabine (1000 mg/m2 on days 1, 8, and 15) with either oral adavosertib (175 mg) or identical placebo once daily on days 1, 2, 8, 9, 15, and 16, in 28-day cycles until disease progression or unacceptable toxicity. Patients and the team caring for each patient were masked to treatment assignment. The primary endpoint was progression-free survival. The safety and efficacy analysis population comprised all patients who received at least one dose of treatment. The trial is registered with ClinicalTrials.gov, NCT02151292, and is closed to accrual.

Findings

Between Sept 22, 2014, and May 30, 2018, 124 women were enrolled, of whom 99 had high-grade serous ovarian cancer and were randomly assigned to adavosertib plus gemcitabine (65 [66%]) or placebo plus gemcitabine (34 [34%]). 25 women with non-high-grade serous ovarian cancer were enrolled in the exploratory cohort. After randomisation, five patients with high-grade serous ovarian cancer were found to be ineligible (four in the experimental group and one in the control group) and did not receive treatment. Median age for all treated patients (n=119) was 62 years (IQR 54–67). Progression-free survival was longer with adavosertib plus gemcitabine (median 4·6 months [95% CI 3·6–6·4] with adavosertib plus gemcitabine vs 3·0 months [1·8–3·8] with placebo plus gemcitabine; hazard ratio 0·55 [95% CI 0·35–0·90]; log-rank p=0·015). The most frequent grade 3 or worse adverse events were haematological (neutropenia in 38 [62%] of 61 participants in the adavosertib plus gemcitabine group vs ten [30%] of 33 in the placebo plus gemcitabine group; thrombocytopenia in 19 [31%] of 61 in the adavosertib plus gemcitabine group vs two [6%] of 33 in the placebo plus gemcitabine group). There were no treatment-related deaths; two patients (one in each group in the high-grade serous ovarian cancer cohort) died while on study medication (from sepsis in the experimental group and from disease progression in the control group).

Interpretation

The observed clinical efficacy of a Wee1 inhibitor combined with gemcitabine supports ongoing assessment of DNA damage response drugs in high-grade serous ovarian cancer, a TP53-mutated tumour type with high replication stress. This therapeutic approach might be applicable to other tumour types with high replication stress; larger confirmatory studies are required.

Funding

US National Cancer Institute Cancer Therapy Evaluation Program, Ontario Institute for Cancer Research, US Department of Defense, Princess Margaret Cancer Foundation, and AstraZeneca.

Introduction

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).

Section snippets

Study design and participants

This double-blind, randomised, placebo-controlled, two-arm, phase 2 trial, with a third non-randomised cohort, was done in 11 recruiting academic cancer centres or departments in the USA (six sites) and Canada (five sites; appendix p 1), all participating as members of the US National Cancer Institute Cancer Therapy Evaluation Program, Princess Margaret, California, Chicago and Mayo Consortia.

Eligible patients were aged 18 years or older, had histologically confirmed platinum-resistant or

Results

Between Sept 22, 2014, and May 30, 2018, 124 women were enrolled, of whom 99 had high-grade serous ovarian cancer and were randomly assigned to the adavosertib plus gemcitabine group (65 from ten sites) or placebo plus gemcitabine group (34 from ten sites). The remaining 25 patients with non-high-grade serous ovarian cancer from seven sites were enrolled in the exploratory cohort and given adavosertib plus gemcitabine (figure 1). Five patients with high-grade serous ovarian cancer were found to

Discussion

In advanced-stage or heavily pretreated high-grade serous ovarian cancer, few options remain after conventional therapy. This is the first trial to show a significant benefit (progression-free survival, overall survival, and response rate according to RECIST) from the addition of adavosertib to gemcitabine in heavily pretreated platinum-resistant or platinum-refractory high-grade serous ovarian cancer, a setting of clinical need that has yet to be met with standard-of-care therapies. In ovarian

Data sharing

Requests for de-identified patient-level data from studies funded through the NCI Cancer Therapy Evaluation Program must comply with US Department of Health & Human Services and Office for Human Research Protections policies and requirements. Requests for sharing of de-identified patient-level data should be sent to the corresponding author, and will be considered on a case-by-case basis with the NCI Cancer Therapy Evaluation Program.

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