Abstract S5-06: Randomized, placebo-controlled trial of duloxetine for aromatase inhibitor (AI)-associated musculoskeletal symptoms (AIMSS) in early stage breast cancer (SWOG S1202)

Abstract Background: Adherence to AI therapy for adjuvant treatment of hormone receptor-positive breast cancer is poor, primarily because of AIMSS. Premature discontinuation of AI therapy can lead to increased likelihood of breast cancer recurrence. Duloxetine (dulox) is a serotonin norepinephrine reuptake inhibitor that is FDA-approved for treatment of multiple chronic pain disorders. Phase II data from an open label trial of dulox for treatment of AIMSS demonstrated a 61% improvement in pain. We hypothesized that treatment of AIMSS with dulox would improve average joint pain compared to placebo (plac). Methods: Postmenopausal women with stage I-III breast cancer who had been taking AI therapy for between 3 wks and 36 mo were enrolled. To be eligible, patients were required to have average pain of ≥4/10 using the Brief Pain Inventory (BPI) that developed or worsened since AI therapy initiation, and not have any contraindications to dulox therapy. Patients were randomized 1:1 to dulox 30 mg daily for 7 d then 60 mg daily for 11 wks then 30 mg daily for 7 d, or to matching plac, stratified by baseline pain (4-6 vs 7-10) and prior taxane use (yes vs no). Pain, depression, and quality of life (QoL) were assessed after 2, 6, and 12 wks of therapy, as well as at the 24 wk time point. The primary analysis used linear mixed models to examine average pain through 12 wks by arm, adjusting for the stratification factors and assessment time. Clinically significant change in average pain was defined as a ≥2-point decrease from baseline. Results: 299 patients were randomized between June 2013 and October 2015, 10 of whom were ineligible. 127 dulox-treated and 128 plac-treated patients were evaluable for the primary analysis. No sizeable imbalances in baseline factors were noted by arm. Seventeen pts reported grade 3 adverse events (AEs) (dulox: 12/138 (8.7%), plac: 5/141 (3.5%)), and 40 pts discontinued treatment because of AEs (dulox: 21 (52.5%), plac: 19 (47.5%)). Mean observed average pain, the proportion of pts experiencing clinically significant change in average pain from baseline, and percent reduction in average pain all indicated greater improvement for dulox compared with plac through 12 wks, but were similar by arm at wk 24 (12 wks after completion of intervention; see Table). In multivariable linear mixed model analysis, the BPI average pain was reduced on average by 0.82 points more on dulox compared to plac over the first 12 wks (95% CI -1.24 to -0.40, p=0.0002). Similar patterns were observed for worst pain, pain interference, joint pain, stiffness, and functioning, and QoL. Table: Observed Average Pain Scores by Assessment TimeTime PointBaseline2 weeks6 weeks12 weeks24 weeksduloxplacduloxplacduloxplacduloxplacduloxplacAverage pain5.445.493.514.412.953.962.913.453.373.42Percent reduction--34%20%46%28%46%36%37%37%Patients with clinically significant change--54%44%69%49%69%60%60%59% Conclusions: Treatment with duloxetine was superior to placebo for the treatment of AIMSS among women with early stage breast cancer, was well tolerated, and was associated with improvements in QoL. Clinicaltrials.gov NCT01598298. Citation Format: Henry NL, Unger JM, Schott AF, Fehrenbacher L, Flynn PJ, Prow D, Sharer CW, Lew DL, Moseley A, Fisch MJ, Moinpour C, Hershman DL, Wade III JL. Randomized, placebo-controlled trial of duloxetine for aromatase inhibitor (AI)-associated musculoskeletal symptoms (AIMSS) in early stage breast cancer (SWOG S1202) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S5-06.

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