Abstract OT1-01-01: A randomised phase II trial of palbociclib and fulvestrant vs standard endocrine therapy in patients with ER positive HER2 negative breast cancer and ctDNA detected molecular relapse during adjuvant endocrine therapy (TRAK-ER)
Authors: Turner Nicholas , Phillips Edward R. , Bunce Catey , Robert Marie , Bailleux Caroline , Garcia-Murillas Isaac , Khabra Komel , Macpherson Iain , O’Brien Ciara S. , Okines Alicia F. , Palmieri Carlo , Schmid Peter , Swift Claire , Yara Sabrina , Connolly Simon , Lemonnier Jérôme , Lee Dymphna , Andre Fabrice 
Published: March 2023

Abstract
Background: Most patients with early stage oestrogen receptor positive (ER+) and HER2 negative breast cancer will be cured of their cancer. However, up to 20% of patients may experience disease recurrence in the first 10 years. Molecular relapse of ER+ breast cancer can be detected with circulating tumour DNA (ctDNA) before clinical relapse occurs. Palbociclib, a CDK4/6 inhibitor, plus fulvestrant, a selective oestrogen receptor degrader, is a standard first line therapy for patients with ER+ breast cancer who have relapsed on standard endocrine therapy. We designed TRAK-ER to establish a surveillance system for ctDNA detection and then to assess whether treating patients, who have ctDNA detected molecular relapse, with palbociclib and fulvestrant may defer or prevent relapse. Design: TRAK-ER is a phase 2 multi-centre, randomised, open-label parallel superiority trial in patients with ER+ early breast cancer, recruiting at centres in the UK and France. In the surveillance phase patients will be monitored for molecular recurrence with ctDNA testing. To be eligible for the surveillance phase patients must be aged 18 or over, have ER+ (≥10% or Allred score 6/8 or greater) and HER2 negative breast cancer and have completed their primary surgery, chemotherapy and radiotherapy. Standard endocrine therapy (GnRH analogues, aromatase inhibitors and tamoxifen) must have been received for a minimum of 6 months and a maximum of 7 years and be planned to continue for at least another 3 years. Inclusion criteria in patients who did not receive neoadjuvant chemotherapy are at least one of: (a) four or more involved axillary or positive supraclavicular lymph node; (b) tumour size &gt;5cm; (c) one to three involved axillary lymph nodes together with at least one of: tumour size &gt;3cm, grade 3 or a high genomic risk score. Patients who received neoadjuvant chemotherapy require at least one lymph node positive or a tumour size &gt;3cm after chemotherapy. Invitae Personalized Cancer Monitoring (PCM TM) will be used for ctDNA analysis, a pan-cancer, tumour-informed liquid biopsy test that uses next-generation sequencing to detect minimal or molecular residual disease (MRD) in solid tumours. ctDNA analysis will be every 3 months for up to 3 years. Detection of ctDNA will trigger staging imaging. If no overt metastatic disease is identified, patients will be able to enter the treatment phase of the study, and be 1:1 randomised using minimisation to either remain on standard endocrine therapy or switch to palbociclib plus fulvestrant. Those who are allocated to remain on endocrine therapy are allowed to continue on the same therapy or change standard endocrine therapy. Duration of palbociclib and fulvestrant will be 2 years, or until relapse. Up to 1300 patients will enrol for tissue screening to allow 1100 patients to enter into ctDNA surveillance. 132 patients will enter the treatment part of the study. The primary endpoint of the surveillance phase is ctDNA detection rate. The primary endpoint of the treatment phase is relapse free survival (RFS). RFS will be calculated in the intention to treat population using Kaplan Meier methods from the date of randomisation to the date of recurrence or death from any cause. Secondary endpoints include relapse free interval, invasive disease free survival, distant recurrence free survival, overall survival and ctDNA clearance. (NCT04985266)
Citation Format: Nicholas Turner, Edward R. Phillips, Catey Bunce, Marie Robert, Caroline Bailleux, Isaac Garcia-Murillas, Komel Khabra, Iain Macpherson, Ciara S. O’Brien, Alicia F. Okines, Carlo Palmieri, Peter Schmid, Claire Swift, Sabrina Yara, Simon Connolly, Jérôme Lemonnier, Dymphna Lee, Fabrice Andre. A randomised phase II trial of palbociclib and fulvestrant vs standard endocrine therapy in patients with ER positive HER2 negative breast cancer and ctDNA detected molecular relapse during adjuvant endocrine therapy (TRAK-ER) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-01-01.