Ovarian cancer clinical trial endpoints: Society of Gynecologic Oncology white paper.
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.
Columbia University, New York, NY, USA.
Thomas J
TJ
Herzog
John Hopkins Kimmel Cancer Center, Baltimore, MD, USA.
Deborah K
DK
Armstrong
University at Buffalo, Buffalo, NY, USA.
Mark F
MF
Brady
The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
Robert L
RL
Coleman
Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, USA.
Mark H
MH
Einstein
Creighton University School of Medicine, Phoenix, AZ, USA; University of Arizona Cancer Center, Phoenix, AZ, USA.
Bradley J
BJ
Monk
University of Oklahoma, Oklahoma City, OK, USA.
Robert S
RS
Mannel
University of Mississippi Medical Center, Jackson, MS, USA.
J Tate
JT
Thigpen
UPR Medical Sciences, San Juan, Puerto Rico.
Sharee A
SA
Umpierre
Winthrop University Hospital, Mineola, NY, USA.
Jeannine A
JA
Villella
University of Alabama at Birmingham, Birmingham, AL, USA.
Ronald D
RD
Alvarez
D014408:Biomarkers, Tumor / Q000032:analysis; D002986:Clinical Trials as Topic / Q000379:methods*; D018572:Disease-Free Survival; D017277:Drug Approval; D023381:Endpoint Determination; D005260:Female; D006801:Humans; D008495:Medical Oncology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000401:mortality; D011788:Quality of Life; D012107:Research Design; D012955:Societies, Medical
D014408:Biomarkers, Tumor
Clinical trial endpoints; Ovarian cancer; Overall survival; Progression free survival