Estimation of historical control rate for a single arm de-escalation study – Application to the POSITIVE trial

• Published in: Breast (Edinburgh) 2020-10, Vol.53, p.1-7
• Main Authors: Sun, Zhuoxin, Niman, Samuel M., Pagani, Olivia, Partridge, Ann H., Azim, Hatem A., Peccatori, Fedro A., Ruggeri, Monica, Di Leo, Angelo, Colleoni, Marco, Gelber, Richard D., Regan, Meredith M.
• Format: Article
• Language: English
• Subjects: Original
• ISSN: 0960-9776; 1532-3080
• DOI: 10.1016/j.breast.2020.05.012

Although randomized controlled clinical trials are optimal to evaluate the effect of an experimental therapy, single-arm trials are required whenever randomization is unethical or not feasible, such as de-escalation studies. We propose using prospectively identified historical controls to place results of single-arm, de-escalation trials into context. POSITIVE is a prospective, single-arm study in young women with hormone-receptor-positive early breast cancer to determine if temporarily interrupting adjuvant endocrine therapy in order to become pregnant increases the risk of a breast cancer event. After 272 women enrolled in POSITIVE, we identified a cohort of 1499 SOFT/TEXT patients potentially eligible to enroll in POSITIVE who did not interrupt endocrine therapy. Method I used the SOFT/TEXT cohort to calculate annualized hazard rates by a piecewise exponential model. Method II used the SOFT/TEXT cohort to group-match SOFT/TEXT patients to POSITIVE patients; sample sets of SOFT/TEXT patients were randomly drawn 5000 times to obtain sets having patient, disease, and treatment characteristics more balanced with POSITIVE participants. Compared with SOFT/TEXT, POSITIVE participants were younger, less likely to be overweight/obese, had fewer positive nodes, and fewer received aromatase inhibitor or chemotherapy. The estimated 3-year breast cancer free interval event rates were 9.5% (95% CI: 7.9%,11.1%) for Method I and 9.4% (95% CI: 7.8%,10.9%) for Method II, compared with 5.8% initially assumed when POSITIVE was designed. External control datasets should be identified before launching single-arm, de-escalation trials and methods applied during their conduct to provide context for interim monitoring and interpretation of the final analysis. •Prospective identification of external historical controls for single-arm studies.•Statistical methods for estimating historical control rates for single-arm studies.•Methods applied for interim monitoring and final analysis of the POSITIVE study.