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

Abstract

Background 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. Methods 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. Results 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. Conclusion 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.

Who are the women who enrolled in the POSITIVE trial: A global study to support young hormone receptor positive breast cancer survivors desiring pregnancy

“…The primary endpoint of the study was breast cancer-free interval (BCFI), defined as the time from study enrolment to the first invasive BC event (local/regional/distant recurrence or contralateral BC). The statistical design of the POSITIVE study has been reported previously [ 11 ], which included 3 interim analyses permitting early trial stopping if the incidence of BC event was higher than anticipated.…”

External control arms in oncology: current use and future directions

“…Various contexts for the use of external control data for clinical trials in oncology have been discussed [1,5,6,7,8,9,10]. Some articles focus on general considerations for studies that include external control data focusing on the key questions and criteria that aim to ensure the quality of an external control data source and the adequacy of an analytical plan.…”

Challenges in Adjuvant Therapy for Premenopausal Women Diagnosed With Luminal Breast Cancers

“…Although not randomly assigned, outcomes in women in POSITIVE will be assessed, and there are outcomes for women with comparable age/ tumors/treatments in SOFT/TEXT who did not interrupt therapy for pregnancy attempt. 71 Currently reversible OFS is recommended by administration of GnRHa injections. It is recommended that these be administered every 4 weeks if concurrent aromatase inhibitor therapy is given, as there are not currently data for use of 3-monthly GnRHa with adjuvant aromatase inhibitor in premenopausal women.…”