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.

Final results of a phase 3 study of trebananib plus weekly paclitaxel in recurrent ovarian cancer (TRINOVA-1): Long-term survival, impact of ascites, and progression-free survival-2

“…However, it has proven exceptionally difficult to show a statistically significant prolongation of OS with the addition of targeted therapy to standard treatments in patients with ovarian cancer [10][11][12][13][14][15][16][17][18][26][27][28]. Potential confounding factors for OS include the long postprogression survival period, the administration of multiple postprogression therapies, and the potential for postprogression crossover [27,29]. In the TRINOVA-1 study, 47% of patients had received at least two lines of postprogression therapy, and 14% received an antiangiogenic therapy after progression.…”

Neoadjuvant, adjuvant and long-term intravenous/intraperitoneal chemotherapy, hyperthermic intraperitoneal chemotherapy, early postoperative intraperitoneal chemotherapy for ovarian cancer

“…Lastly, ovarian cancer patients are treated over the course of many years. 24 Great interest has been observed lately in using observation data to explore primary treatment for EOC. Such studies are limited by both selection bias and the influence of multiple measured and unmeasured confounders that influence both treatment selection and outcomes.…”

New Strategies in Ovarian Cancer: Translating the Molecular Complexity of Ovarian Cancer into Treatment Advances

“…For example, in a phase II maintenance study of the poly (ADP-ribose) polymerase inhibitor (PARPi) olaparib in patients with recurrent platinum-sensitive high-grade serous ovarian cancer (HGSC), 23% of patients in the control arm ultimately received a PARPi off study, and an OS benefit was not observed even in the setting of a marked PFS improvement (19,20). Because of the difficulties in attaining OS benefits and hence the lack of drug approvals in the United States for ovarian cancer, achievement of significant PFS benefit as a reason for drug approval has been endorsed (21,22), and this has been a mechanism for drug approval in cancers other than ovarian cancer (23,24). In addition, trials that demonstrate a PFS benefit but no OS improvement must define a clinically and statistically meaningful PFS improvement, document patient benefit using patient-reported outcomes and quality-of-life measures, and demonstrate acceptable acute and long-term toxicities.…”

“…The worldwide incidence of this cancer is 225,500 diagnoses per year; in the United States in 2014, 21,980 women will be diagnosed with ovarian cancer (1,2). Global mortality of this cancer remains high, with 140,200 deaths per year, and minimal improvement in mortality has been observed over the past decade (5).…”