Ovarian Cancer Clinical Trial Endpoints: Society of Gynecologic Oncology White Paper

abstract

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Highlights

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Ovarian cancer has unique considerations for clinical trial endpoint selection

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Optimal endpoint selection should reflect true patient benefit

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PFS as a surrogate has significant advantages and disadvantages in ovarian cancer

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Clinical trial endpoints have profound effects on late phase clinical trial design, results interpretation, drug development, and regulatory approval of therapeutics. Selection of the optimal clinical trial endpoint is particularly provocative in ovarian cancer where long overall survival (OS) is observed even for those who present with advanced disease stages. The lack of new regulatory approvals and the lack of harmony between regulatory bodies globally for ovarian cancer therapeutics are of concern. The advantages and disadvantages of the numerous endpoints available are herein discussed within the unique context of ovarian cancer where both crossover and post-progression therapies potentially uncouple the surrogacy between progression-free survival (PFS) and OS, the two most widely supported and utilized endpoints. The roles of patient reported outcomes (PRO) and health related quality of life (HRQoL) are discussed, but even these widely supported parameters are affected by the unique characteristics of ovarian cancer where a significant percentage of patients may be asymptomatic. Original data regarding the endpoint preferences of ovarian cancer advocates is presented.

Endpoint selection in ovarian cancer clinical trials should reflect the impact on disease burden and unique characteristics of the treatment cohort while reflecting true patient benefit. Both OS and PFS have led to regulatory approvals and are clinically important. However, current regulatory approval guidance by the FDA indicates that surrogates for overall survival, while acceptable, must be clinically meaningful. OS remains the most objective and accepted endpoint because it is least vulnerable to bias; however, the feasibility of OS in ovarian cancer is compromised by the requirement for large trial size, prolonged time-line for final analysis, and potential for unintended loss of treatment effect from active post-progression therapies. A large magnitude of effect in PFS improvement should establish benefit, and further communication with regulatory authorities to clarify acceptable endpoints should be undertaken.