Can RECIST response predict success in phase 3 trials in men with metastatic castration-resistant prostate cancer?

Abstract

Background Intermediate endpoints are needed in early phase studies of men with metastatic castration-resistant prostate cancer (mCRPC) that can reliably predict success in phase 3 trials. Among men with measurable disease, objective response may provide information as to whether a treatment is likely to be successful. Methods We conducted a systematic review of systemic agents that have proceeded to phase 3 trials in men with mCRPC and examined the relationship between improvements in measurable disease response in phase 2 trials and successful phase 3 trials leading to regulatory approval. Only trials that included men with radiographically measurable disease were included. Results We examined 31 eligible mCRPC phase 3 trials between 1992 and 2017 and 29 of the preceding phase 2 trials for RECIST responses. Measurable tumor responses in phase 2 trials were higher for successful therapies in phase 3 trials in chemotherapy-naive men with mCRPC, but were less correlated with success in trials investigating docetaxel combination regimens or the post chemotherapy mCRPC setting. Many failed agents did not produce higher than expected response rates over control arms; however, several agents such as anti-angiogenic therapies or orteronel produced higher than expected responses without survival benefit. Conclusions Objective responses in men with mCRPC may be associated with prolonged survival, but this association is mechanism dependent and inconsistent across trials or disease states. These data support considering RECIST response as a supportive but not sole endpoint in phase 2 trials to support launching phase 3 trials.

Exploring Heterogeneity in Histology-Independent Technologies and the Implications for Cost-Effectiveness

“…In reality, it is unlikely that this assumption will ever hold and will frequently be far from being a reasonable approximation, as there will be a degree of variability in the strength of response as a predictor and the nature of this relationship. 48 – 50 When applying a response-based modeling approach for the evaluation of HITs, it is therefore important to consider the strength of evidence supporting the surrogacy assumptions and whether the ability to generate histology-specific ICERs outweighs any associated uncertainties. Where there are substantive concerns regarding the potential for heterogeneity in survival endpoints, alternative analysis methods may be more appropriate.…”

The Prognostic Value of Posttreatment68Ga-PSMA-11 PET/CT and18F-FDG PET/CT in Metastatic Castration-Resistant Prostate Cancer Treated with177Lu-PSMA-617 and NOX66 in a Phase I/II Trial (LuPIN)

“…RECIST criteria progression is standard of care for identifying progressive disease on imaging and has a strong correlation with OS in prostate cancer (20). However, RECIST progression was less prognostic than change in either PSMA-TTV or PSA progression at study exit.…”

Updates in advanced prostate cancer 2018

“…Can RECIST response predict success in phase 3 trials in men with metastatic castration-resistant prostate cancer? [3] A major issue in drug development in advanced prostate cancer remains the lack of surrogate intermediate end points for overall survival, which can be quite prolonged in many men. This original study examined all phase-2 and -3 trials of men with mCRPC to look at whether significant measurable disease response rates by RECIST in phase-2 trials led to positive phase-3 trials, and suggests that this may be the case for certain single agents depending on the mechanism of action of the specific therapy.…”