A Randomized, Phase II Trial of Circulating Tumor DNA-guided Second Line Adjuvant Therapy for High Residual Risk, Estrogen Receptor Positive, HER-2 Negative Breast Cancer (DARE)

Brief Summary

Detailed Description

Surveillance population and ctDNA screening (up to 1000 patients): High risk ER positive, HER2-, breast cancer patients who have completed adjuvant endocrine therapy, or are currently receiving adjuvant endocrine therapy with an aromatase inhibitor or tamoxifen and are within 7 years since completion of definitive breast surgery are eligible for ctDNA screening. In order to start ctDNA surveillance, patients must have completed at least 6 months, but no more than 7 years of adjuvant endocrine therapy of treatment without distant recurrence. Prior adjuvant CDK4/6 therapy is allowed, but at least 12 months must have elapsed since completing CDK4/6 therapy and enrolling into ctDNA surveillance on this study. Participants in the PENELOPE and PALLAS clinical trials who received Palbociclib are also eligible if meet all required eligibility criteria. For screening, patients will undergo Signatera testing during routine follow up clinic visits. The current ASCO/NCCN breast cancer practice guidelines recommend follow up visits every 4 to 6 months at the treating physician's discretion. We anticipate that screening positivity rates will be the highest in patients between years 1-5 after initial diagnosis, based on the annual hazard rates of recurrence in ER positive breast cancer. However, since up to 50% of all recurrences occur after 5 years of follow-up, we allow starting ctDNA screening up to 7 years after starting adjuvant endocrine therapy if a patient meets criteria for high risk. Randomized phase II (N=100): Patients who become ctDNA positive during ctDNA surveillance will have systemic staging with CT of the chest, abdomen and pelvis, and those without radiographic evidence of metastatic disease will be randomized 1:1 to receive palbociclib plus fulvestrant for two years or continue standard of care endocrine therapy. Pre- and peri- menopausal patients randomized to the fulvestrant palbociclib arm will require GnRH analogue therapy. Patients in both treatment arms may continue adjuvant bisphosphonate therapy and patients in the control arm may switch between different brands of aromatase inhibitors for better tolerance or patient preference. No other, non-protocol directed anticancer therapy is allowed. The maximum duration of treatment is 2 years. A patient may complete a maximum of 26 cycles of treatment (for patients without interruptions or delays). The goal is not to administer a specific number of cycles, but to allow for the completion of any cycles initiated prior to 2 years from randomization. Patients who have completed 2 years of fulvestrant and palbociclib without recurrence may resume their originally planned standard of care adjuvant therapy to complete a total of 5 or 10 years of endocrine therapy at the discretion of the treating physician.

Primary Outcomes

Secondary Outcomes

• Secondary Objective 1: Feasibility- correlation between clinically apparent metastatic or local disease and positive ctDNA result.(enrollment)
• Secondary Objective 2: Efficacy- assess the ability of positive ctDNA results to predict clinical relapse.(through study completion, an average of 6 years)
• Secondary Objective 3: Efficacy- assess whether ctDNA clearance is associated with improved relapse free survival and overall survival.(through study completion, an average of 6 years)
• Secondary Objective 4: Efficacy- assess the efficacy of the combination arm, palbociclib plus fulvestrant compared to the control arm.(through study completion, an average of 6 years)
• Secondary Objective 5: Safety and Tolerability- number of participants with treatment-related adverse event as assed by CTCAE V5.0.(through study completion, an average of 6 years)