The addition of the Wee1 inhibitor adavosertib to gemcitabine decreased the risk of disease progression and death in women with recurrent, platinum-resistant, or refractory ovarian cancer. This was the result of a randomized phase II study.
For the primary endpoint of progression-free survival (PFS) in 99 patients with high-grade serous tumors, patients treated with gemcitabine plus adavosertib had a mean PFS of 4.6 months compared to 3.0 months with gemcitabine plus placebo (HR 0.55, 95)% CI 0.35-0.90, P = 0.015), reported Dr. Amit Oza of the Princess Margaret Cancer Center in Toronto and colleagues.
The median overall survival was 11.4 months versus 7.2 months (HR 0.56, 95% CI 0.35-0.91, P = 0.017).
“For advanced or heavily pretreated high-grade serous ovarian cancer, few options remain after conventional therapy,” the authors wrote in The Lancet. “This is the first study to show significant benefits (progression-free survival, overall survival and response rate according to RECIST) from adding adavosertib to gemcitabine in heavily pretreated platinum-resistant or platinum-resistant high-grade serous ovarian cancer, an adjustment to clinical need that is not yet achieved with standard therapies was fulfilled. “
Neither patient in either arm achieved a complete response, but 23% in the adavosertib arm had a partial response compared to 6% in the placebo arm. In an exploratory cohort of women with non-high-grade serous tumors, four patients (16%) achieved a partial response.
“Adavosertib plus gemcitabine also showed signs of activity in rare histological subtypes of ovarian cancer (serous and endometrioid, low grade endometrioid, carcinosarcoma and clear cells),” noted Oza and co-authors. “Interestingly, in the low-grade serous ovarian cancer cohort with available genome profile, both patients were KRAS mutation positive, suggesting that replication stress is implicated in managing treatment response.”
In an accompanying editorial, Sarah Blagden, MD, of the University of Oxford, and Shibani Nicum, MD, of the NHS Foundation Trust, University of Oxford, England, identified the correlation of treatment response and tumor histology and molecular characteristics as “a key strength” of the Study.
While the sample sizes were small, the addition of adavosertib appeared to benefit patients with homologous recombination deficiency, BRCA mutations, and patients with CCNE1 amplified tumors.
“This study recognizes the potential for targeted cell cycle disruption in a significant subpopulation of patients with resistant ovarian cancer,” the editors wrote. “The development of rapid immunohistochemical or circulating biomarkers to identify this subpopulation could usher in the wider use of cell cycle targeting therapies such as adavosertib earlier in the disease process.”
From 2014 to 2018, 99 women with high-grade serous ovarian cancer were randomized 2: 1 to intravenous gemcitabine (1,000 mg / m2 on days 1, 8 and 15 of 28-day cycles) plus either orally adavosertib in the double-blind Phase II study (175 mg on days 1, 2, 8, 9, 15, and 16) or placebo at 11 centers in the US and Canada. The exploratory cohort included an additional 25 patients with non-high-grade serous disease, all of whom received the combination treatment.
Patients had a mean age of 62 years and an average of three previous lines of treatment. Most in the study had platinum-resistant disease, while 10% in the study arm and 15% in the control arm had primary platinum-refractory disease. To enroll, women were required to have an Eastern Cooperative Oncology Group (ECOG) performance status ≤2, normal organ function, normal marrow function, and a life expectancy of 3 months or longer.
The toxicity was “generally manageable with intermittent changes in dose and did not lead to serious complications,” according to the authors of the study.
Common Grade ≥3 adverse events in the adavosertib and placebo arms were neutropenia (62% vs 30%), leukopenia (54% vs 18%), lymphopenia (34% vs 18%), anemia (31% vs 21%) )) and thrombocytopenia (31% versus 6%).
Blagden and Nicum said the 175 mg dose of adavosertib “may be unnecessarily high for the severely treated patients with high-grade serous ovarian cancer; the lack of pharmacodynamic evidence of target attachment leaves this question unanswered.”
There were no treatment-related deaths. One patient in the study arm died of sepsis and one patient in the control arm died of disease progression.
The study was funded by AstraZeneca, the cancer therapy evaluation program of the National Cancer Institute (NCI), the Ontario Institute for Cancer Research, the US Department of Defense, and the Princess Margaret Cancer Foundation.
Oza announced grants from the NCI Cancer Therapy Evaluation Program, the Department of Defense, and the Princess Margaret Cancer Foundation during the study. institutional grants from AstraZeneca unrelated to current work; and various relationships with AstraZeneca, Clovis, and GlaxoSmithKline studies. Co-authors reported various competing interests.
Blagden announced grants and institutional support from NuCana plc, Sierra Oncology, Redx Pharma, UCB Pharma, Astex Pharma, Tesaro and BerGenBio. Nicum reported on relationships with AstraZeneca, Roche, Tesaro and GlaxoSmithKline.