A DREAM Challenge to Build Prediction Models for Short-Term Discontinuation of Docetaxel in Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: Docetaxel has a demonstrated survival benefit for patients with metastatic castration-resistant prostate cancer (mCRPC); however, 10% to 20% of patients discontinue docetaxel prematurely because of toxicity-induced adverse events, and the management of risk factors for toxicity remains a challenge. PATIENTS AND METHODS: The comparator arms of four phase III clinical trials in first-line mCRPC were collected, annotated, and compiled, with a total of 2,070 patients. Early discontinuation was defined as treatment stoppage within 3 months as a result of adverse treatment effects; 10% of patients discontinued treatment. We designed an open-data, crowd-sourced DREAM Challenge for developing models with which to predict early discontinuation of docetaxel treatment. Clinical features for all four trials and outcomes for three of the four trials were made publicly available, with the outcomes of the fourth trial held back for unbiased model evaluation. Challenge participants from around the world trained models and submitted their predictions. Area under the precision-recall curve was the primary metric used for performance assessment. RESULTS: In total, 34 separate teams submitted predictions. Seven models with statistically similar area under precision-recall curves (Bayes factor ≤ 3) outperformed all other models. A postchallenge analysis of risk prediction using these seven models revealed three patient subgroups: high risk, low risk, or discordant risk. Early discontinuation events were two times higher in the high-risk subgroup compared with the low-risk subgroup. Simulation studies demonstrated that use of patient discontinuation prediction models could reduce patient enrollment in clinical trials without the loss of statistical power. CONCLUSION: This work represents a successful collaboration between 34 international teams that leveraged open clinical trial data. Our results demonstrate that routinely collected clinical features can be used to identify patients with mCRPC who are likely to discontinue treatment because of adverse events and establishes a robust benchmark with implications for clinical trial design.

A SPATIOTEMPORAL MODEL TO SIMULATE CHEMOTHERAPY REGIMENS FOR HETEROGENEOUS BLADDER CANCER METASTASES TO THE LUNG.

Tumors are composed of heterogeneous populations of cells. Somatic genetic aberrations are one form of heterogeneity that allows clonal cells to adapt to chemotherapeutic stress, thus providing a path for resistance to arise. In silico modeling of tumors provides a platform for rapid, quantitative experiments to inexpensively study how compositional heterogeneity contributes to drug resistance. Accordingly, we have built a spatiotemporal model of a lung metastasis originating from a primary bladder tumor, incorporating in vivo drug concentrations of first-line chemotherapy, resistance data from bladder cancer cell lines, vascular density of lung metastases, and gains in resistance in cells that survive chemotherapy. In metastatic bladder cancer, a first-line drug regimen includes six cycles of gemcitabine plus cisplatin (GC) delivered simultaneously on day 1, and gemcitabine on day 8 in each 21-day cycle. The interaction between gemcitabine and cisplatin has been shown to be synergistic in vitro, and results in better outcomes in patients. Our model shows that during simulated treatment with this regimen, GC synergy does begin to kill cells that are more resistant to cisplatin, but repopulation by resistant cells occurs. Post-regimen populations are mixtures of the original, seeded resistant clones, and/or new clones that have gained resistance to cisplatin, gemcitabine, or both drugs. The emergence of a tumor with increased resistance is qualitatively consistent with the five-year survival of 6.8% for patients with metastatic transitional cell carcinoma of the urinary bladder treated with a GC regimen. The model can be further used to explore the parameter space for clinically relevant variables, including the timing of drug delivery to optimize cell death, and patient-specific data such as vascular density, rates of resistance gain, disease progression, and molecular profiles, and can be expanded for data on toxicity. The model is specific to bladder cancer, which has not previously been modeled in this context, but can be adapted to represent other cancers.