Phase III Randomized, Placebo-Controlled Clinical Trial of Donepezil for Treatment of Cognitive Impairment in Breast Cancer Survivors After Adjuvant Chemotherapy (WF-97116)

Author(s): Stephen R. Rapp, PhD^1,2; Emily V. Dressler, PhD³; W. Mark Brown, MA³; James L. Wade III, MD, FACP, FASCO, FACCC⁴; Nguyet Le-Lindqwister, MD⁵; David King, MD⁶; Kendrith M. Rowland, MD⁷; Kathryn E. Weaver, PhD, MPH²; Heidi D. Klepin, MD⁸; Edward G. Shaw, MD, MA⁹; Glenn J. Lesser, MD⁸

Source: https://doi.org/10.1200/JCO.23.01100

Dr. Anjan Patel's Thoughts

It seems donepezil did not show any cognitive benefit when added to standard adjuvant chemotherapy for breast cancer. Unfortunately, adequate treatment for ‘chemo-brain’ remains elusive. There is data that a lipid structure, S1P, may be linked to this process and may be ‘druggable’ with some of the MS agents.

PURPOSE

To test efficacy of donepezil, a cognitive enhancer, to improve memory in breast cancer survivors who report cancer-related cognitive impairment 1-5 years postchemotherapy.

PATIENTS AND METHODS

Adult female BCS exposed to ≥4 cycles of adjuvant chemotherapy 1-5 years before enrollment who reported cancer-related cognitive impairment were eligible. Participants, enrolled at sites affiliated with the Wake Forest NCI Community Oncology Research Program (NCORP) Research Base, were randomly assigned to receive 5 mg of donepezil once daily for 6 weeks titrated to 10 mg once daily for 18 weeks or placebo. Cognition and self-report cognitive functioning was assessed at baseline, 12, 24 (end of intervention), and 36 (washout) weeks postrandomization. Mixed-effects repeated measures analysis of covariance models were used to assess treatment differences in immediate recall (primary outcome) on the Hopkins Verbal Learning Test-Revised (HVLT-R) and other cognitive domains (secondary outcomes) with covariates of treatment, time, time by treatment interaction, baseline outcome level, age stratification, and an unstructured covariance matrix to account for within participant correlation over time.

RESULTS

Two hundred seventy-six BCS from 87 NCORP practices (mean age, 57.1, standard deviation [SD], 10.5) who were at a mean of 29.6 months (SD, 14.2) postchemotherapy were randomly assigned to donepezil (n = 140) or placebo (n = 136). At 24 weeks, treatment groups did not differ on HVLT-R scores (donepezil mean = 25.98, placebo = 26.50, P = .32). There were no statistically significant differences between treatments at 12, 24, or 36 weeks for attention, executive function, verbal fluency, processing speed, or self-reported cognitive functioning. Endocrine therapy and menopausal status did not affect results.

CONCLUSION

BCS 1-5 years after completing chemotherapy with documented memory problems, randomly assigned to 24 weeks of 5-10 mg of donepezil once daily, did not perform differently at the end of treatment on tests of memory, other cognitive functions, or subjective functioning than those randomly assigned to placebo.

Author Affiliations

¹Department of Psychiatry & Behavioral Medicine, Wake Forest University School of Medicine, Winston-Salem, NC; ²Department of Social Sciences & Health Policy, Wake Forest University School of Medicine, Winston-Salem, NC; ³Department of Biostatistics and Data Sciences, Wake Forest University School of Medicine, Winston-Salem, NC; ⁴Heartland Cancer Research NCORP, Cancer Care Specialists of Illinois—Decatur, Decatur, IL; ⁵Heartland Cancer Research NCORP, Illinois CancerCare-Peoria, Peoria, IL; ⁶Metro Minnesota Community Oncology Research Consortium, Unity Hospital, Minneapolis-St Paul, MN; ⁷Carle Cancer Center NCORP, Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana-Champaign, IL; ⁸Department of Internal Medicine, Section on Hematology and Oncology, Wake Forest University School of Medicine, Winston-Salem, NC; ⁹Department of Internal Medicine-Gerontology & Geriatrics Section, Wake Forest University School of Medicine, Winston-Salem, NC

Datopotamab Deruxtecan in Advanced or Metastatic HR+/HER2– and Triple-Negative Breast Cancer: Results From the Phase I TROPION-PanTumor01 Study

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Association Between Neighborhood Opportunity, Allostatic Load, and All-Cause Mortality in Patients With Breast Cancer

Noteworthy NCCI database study showing zip code has a negative influence on tumor burden and outcomes. I wonder if the presence of community oncology practices in similar geographical zones reduces this interaction of environmental opportunity and outcomes.

Final results of RIGHT Choice: Ribociclib plus endocrine therapy vs combination chemotherapy in premenopausal women with clinically aggressive HR+/HER2− advanced breast cancer

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PACE: A Randomized Phase II Study of Fulvestrant, Palbociclib, and Avelumab After Progression on Cyclin-Dependent Kinase 4/6 Inhibitor and Aromatase Inhibitor for Hormone Receptor–Positive/Human Epidermal Growth Factor Receptor–Negative Metastatic Breast Cancer

Findings from the PACE study show that the addition of Palbociclib to Fulvestrant was not better than Fulvestrant alone, and the addition of Avelumab to Fulvestrant improved and nearly doubled the PFS. This is compelling and should be studied further for our patients with HR+ HER2- MBC.

Ribociclib plus Endocrine Therapy in Early Breast Cancer

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