Ovarian cancer clinical trial endpoints: Society of Gynecologic Oncology white paper

Abstract

Objective: To explore the value of multiple clinical endpoints in the unique setting of ovarian cancer.

Methods: A clinical trial workgroup was established by the Society of Gynecologic Oncology to develop a consensus statement via multiple conference calls, meetings and white paper drafts.

Results: Clinical trial endpoints have profound effects on late phase clinical trial design, result 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. 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 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.

Conclusions: 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. 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.

Keywords: Clinical trial endpoints; Ovarian cancer; Overall survival; Progression free survival.

Fig. 1

Relative overall survival trends: ovarian cancer. Percent changes over time adapted by Coleman RL from van Altena AM, Karim–Kos HE, de Vries E, Kruitwagen RF, Massuger LF, Kiemeney LA. Trends in therapy and survival of advanced stage epithelial ovarian cancer patients in The Netherlands. Gynecol Oncol 2012; 125(3):649-54. (Ref [6]).

Fig. 2

Defining overall survival.

Fig. 3

A. Loss of correlation of PFS with OS as a function of increasing PPS (post-progression survival, referred to below as SPP or survival post progression). B. Power to preserve a PFS effect. SPP (survival post progression). Broglio KR, Berry DA. Detecting an overall survival benefit that is derived from progression-free survival. J Natl Cancer Inst 2009;101(23):1642-164927. Reprinted by permission of Oxford University Press.

Fig. 4

A. Patient endpoint thresholds of minimal benefit. Ovarian cancer (N = 1204). B. How important is stable disease? Ovarian cancer (N = 1088, p < 0.001).