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Radiographic PFS feasible endpoint for metastatic castration-resistant prostate cancer trials
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Radiographic PFS served as a clinically meaningful endpoint for men with metastatic castration-resistant prostate cancer, according to results from the phase 3 randomized PREVAIL study.
Several therapies have improved OS among men with metastatic castration-resistant prostate cancer.
“The availability of these effective therapies, although clinically beneficial to patients, can have a secondary effect of blunting the impact of an investigational agent on OS by virtue of postprotocol exposures,” Michael J. Morris, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, and colleagues wrote. “Consequently, development efforts focusing on OS are likely to shift to more advanced and heavily pretreated clinical settings. Endpoints short of survival that represent clinical benefit and can independently support regulatory approval will be necessary to ensure that effective drugs are available to improve outcomes for patients across all stages of disease.”
Morris and colleagues performed sensitivity analyses of radiographic PFS among 1,717 chemotherapy-naive men with metastatic castration-resistant prostate cancer. Researchers randomly assigned the men 1:1 to receive 160 mg of enzalutamide (Xtandi, Pfizer) or placebo until radiographic disease progression or skeletal-related event and subsequent treatment with either cytotoxic chemotherapy or an investigational agent.
The mean age was 72 years in the enzalutamide group and 71 years in the placebo group.
The main outcomes included six sensitivity analyses based on investigator assessments.
In all sensitivity analyses, enzalutamide significantly reduced risk for radiographic progression or death:
- investigator-assessed radiographic PFS using the final radiographic PFS cutoff (HR = 0.22; 95% CI, 0.18-27);
- investigator-assessed radiographic PFS using the interim OS data cutoff (HR = 0.31; 95% CI, 0.27-0.35);
- radiographic PFS to evaluate the impact of skeletal-related events (HR = 0.21; 95% CI, 0.18-0.26);
- radiographic PFS to evaluate clinical progression (HR = 0.21; 95% CI, 0.17-0.26);
- confirmatory scan for soft-tissue disease progression (HR = 0.23; 95% CI, 0.19-0.3); and
- all deaths regardless of time since discontinuation of the study drug (HR = 0.23; 95% CI, 0.19-0.3).
Among patients treated with enzalutamide, radiographic PFS appeared correlated with OS (Spearman = 0.89; 95% CI, 0.86-0.92; Kendall = 0.72; 95% CI, 0.68-0.77).
“In this series of prespecified sensitivity analyses of data from the PREVAIL trial of men with chemotherapy-naive metastatic castration-resistant prostate cancer, the Prostate Cancer Clinical Trials Working Group 2 definition of radiographic PFS was found to be a robust and clinically meaningful endpoint associated with OS in enzalutamide-treated patients,” the researchers wrote. – by Andy Polhamus
Disclosures: Morris reports consultant roles with Advanced Accelerator Applications; uncompensated consultant roles with Astellas Pharma, Bayer, Endocyte, Progenics and Tokai; and research funding for his institution from Bayer, Endocyte and Progenics. Please see the full study for all other authors’ relevant financial disclosures.
Perspective
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OS has long been considered the gold standard for the demonstration of clinical benefit. The problem with OS as a study endpoint is that it requires a large sample size and may require long follow-up. OS analysis may be confounded because of subsequent therapies administered after a study drug is discontinued. OS should be evaluated in randomized controlled trials.
Consequently, efforts have been made to develop outcome measures to ensure the timely development of drugs that further improve patient outcomes.
Rathkopf and colleagues reported on sensitivity analysis of PFS in the PREVAIL trial, which compared enzalutamide with placebo for 1,717 patients with metastatic castration-resistant prostate cancer.
The PREVAIL trial was designed to include both OS and radiographic PFS as coprimary endpoints.
The trial utilized a series of sensitivity analyses to evaluate how clinically meaningful the radiographic PFS results were. Their report supported the use of radiographic PFS as a clinically meaningful endpoint in clinical trials, as there was good correlation between radiographic PFS and OS among patients treated with enzalutamide.
The need to develop surrogate endpoints likely to predict clinical benefit became acutely important in the 1990s in the effort to develop effective treatments for AIDS. This work is important because the establishment of PFS as a study endpoint will speed along the drug approval process for serious and life-threatening diseases without causing harm to patients. Further, the use of endpoints such as radiographic PFS allows patients to cross over to receive active therapies without confounding the interpretation of the data. This report by Rathkopf and colleagues provides groundwork evidence that PFS is a reasonable study endpoint.
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