Toremifene plus androgen deprivation therapy (TOPADT) significantly improved biochemical recurrence in bone metastatic prostate cancer: A randomized controlled phase IIA trial

INTRODUCTION & OBJECTIVES: Durability of androgen-deprivation therapy (ADT) for prostate cancer (PC) is limited. Selective estrogen receptor modulators (SERMs) have not been fully investigated for treatment-naïve PC. We hypothesized that additional SERMs may prolong the durability of ADT, because androgen and estrogen signalings drive PC progression. In the present study, we conducted a prospective randomized clinical trial phase IIA trial to estimate the effects of SERMs (toremifene and raloxifene) added to ADT in treatmentnaïve bone metastatic PC. MATERIAL & METHODS: Men with treatment-naïve bone metastatic PC were randomly assigned in 1:1:1 fashion to receive ADT, toremifene 60 mg plus ADT (TOPADT), or raloxifene 60 mg plus ADT (RAPADT). The primary endpoint was the biochemical recurrence (BCR) rate, and secondary endpoints were changes of scores of the visual analogue scale (VAS) and the functional assessment of cancer therapy (FACT). Immunohistochemical analysis for androgen receptor (AR), estrogen receptor (ER) α and ERβ was performed with the streptavidin-biotin amplification method, and evaluated by labeling index (LI). LI was determined by counting the percentage of cells with positive immunoreactivity in 1,000 cells. RESULTS: A total of 15 men, 5 each, were allocated to one of the three treatment arms. There was no statistically significant difference in age, serum PSA level, stage, GS, extent of diseases, or LI against anti-AR, -ERα, and-ERβ antibody among three groups (ADT v.s. TOPADT and ADT v.s. RAPADT). The basal serum prostate-specific antigen (PSA) level was 198 ng/mL (median, range; 30-8,428). Bone metastases were graded as 1 (n = 11), 2 (n = 3), and 3 (n = 1) by the extent of disease. During the median follow-up period of 1,370 days (range; 431-1,983), BCR occurred in 3, 0, and 2 men in ADT, TOPADT, and RAPADT group, respectively. The 5-year BCR-free rate was 30%, 100%, and 53%, in ADT, TOPADT, and RAPADT group, respectively (p = 0.04, ADT v.s. TOPADT, p = 0.48, ADT v.s. RAPADT, and p = 0.12, TOPADT v.s. RAPADT).Univariate Cox proportional hazards regression models for BCR associated with treatment and the clinicopathological characteristics showed that TOPADT was only found to be significant in the univariate analysis (p = 0.023, hazard ratio; 1.1 e-9) (Table). Scores of VAS improved in all groups and remained stable throughout the study. CONCLUSIONS: Toremifene with conventional ADT significantly improved the BCR rate in treatment-naïve bone metastatic PC. Further clinical trials are warranted to confirm the promising clinical efficacy of this combination therapy. (Table Presented).