Adavosertib plus gemcitabine for platinum-resistant or platinum-refractory recurrent ovarian cancer: a double-blind, randomised, placebo-controlled, phase 2 trial
RCT (n=124) found addition of adavosertib to gemcitabine increased progression free survival vs gemcitabine plus placebo (4.6 vs 3.0 months, HR 0.55, 95%CI 0.35-0.90). Grade 3 neutropenia and thrombocytopenia occurred in 62% and 31% of patients on adavosertib respectively.
Source:
The Lancet
SPS commentary:
Adavosertib is an inhibitor of the checkpoint kinase Wee1 and prevents it from phosphorylating CDK1, the G2/M checkpoint gatekeeper. A related commentary discusses this new mechanism of action and the results of this study. Theoretically, by bypassing the G2/M checkpoint, adavosertib induces the accumulation of cytotoxic levels of replication stress and DNA damage in both homologous recombination-defective and CCNE1-amplified tumours and could have activity in both rapidly cycling and homologous recombination deficient platinum-resistant populations.
It concludes that the study realises the potential of targeting the cell cycle derangement present in a substantial subpopulation of patients with resistant ovarian cancer. The development of rapid immunohistochemical or circulating biomarkers to identify this subpopulation could herald the more widespread use of cell cycle targeting therapies like adavosertib earlier in the disease course. However, optimisation of the combinatorial dose of adavosertib and formal assessment of health related quality of life will be essential if this drug is to be investigated further in phase 3 trials. Overall, these study findings raise hope that we are within reach of further personalisation of treatment and improved outcomes for this devastating disease.