Efficacy and safety of abiraterone acetate in an elderly patient subgroup (aged 75 and older) with metastatic castration-resistant prostate cancer after docetaxel-based chemotherapy.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) is a disease that primarily affects older men. Abiraterone acetate (AA), a selective androgen biosynthesis inhibitor, in combination with low-dose prednisone (P) improved overall survival (OS) in a randomised trial in mCRPC progressing after docetaxel versus placebo (PL) plus P. OBJECTIVE: To examine the efficacy and safety of AA plus P versus PL plus P in subgroups of elderly (aged ≥ 75 yr) (n=331) and younger patients (<75 yr) (n=863). DESIGN, SETTING, AND PARTICIPANTS: We conducted a post hoc analysis of a randomised double-blind PL-controlled study in mCRPC patients progressing after docetaxel chemotherapy. INTERVENTION: Patients were randomised 2:1 to AA (1000 mg) plus low-dose P (5mg twice daily) (n=797) or PL plus P (n=398). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary end point was OS. Secondary end points were time to prostate-specific antigen (PSA) progression (TTPP), radiographic progression-free survival (rPFS), and PSA response rate. Treatment differences were compared using the stratified log-rank test. The Cox proportional hazards model was used to estimate the hazard ratio (HR) and 95% confidence interval (CI). The key limitation was the post hoc analysis. RESULTS AND LIMITATIONS: Elderly patients treated with AA plus P showed improved OS (HR: 0.64; 95% CI, 0.478-0.853; p=0.0022), TTPP (HR: 0.76; 95% CI, 0.503-1.155; p=0.1995), and rPFS (HR: 0.66; 95% CI, 0.506-0.859; p=0.0019), and higher PSA response rate with relative risk (HR: 4.15; 95% CI, 2.2-8.0]; p ≤ 0.0001) compared with patients treated with PL plus P. Grade 3/4 adverse events occurred in 62% of elderly patients and in 60% of patients aged <75 yr treated with AA plus P. Incidences of hypertension and hypokalaemia, although increased in the AA plus P arm, were similar in both age subgroups and readily managed. CONCLUSIONS: AA improves OS and is well tolerated in both elderly patients and younger patients with mCRPC following docetaxel, hence providing an important treatment option for elderly patients who may not tolerate alternative therapies with greater toxicity. TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT00638690.

Gene expression and biological pathways in tissue of men with prostate cancer in a randomized clinical trial of lycopene and fish oil supplementation.

BACKGROUND: Studies suggest that micronutrients may modify the risk or delay progression of prostate cancer; however, the molecular mechanisms involved are poorly understood. We examined the effects of lycopene and fish oil on prostate gene expression in a double-blind placebo-controlled randomized clinical trial. METHODS: Eighty-four men with low risk prostate cancer were stratified based on self-reported dietary consumption of fish and tomatoes and then randomly assigned to a 3-month intervention of lycopene (n = 29) or fish oil (n = 27) supplementation or placebo (n = 28). Gene expression in morphologically normal prostate tissue was studied at baseline and at 3 months via cDNA microarray analysis. Differential gene expression and pathway analyses were performed to identify genes and pathways modulated by these micronutrients. RESULTS: Global gene expression analysis revealed no significant individual genes that were associated with high intake of fish or tomato at baseline or after 3 months of supplementation with lycopene or fish oil. However, exploratory pathway analyses of rank-ordered genes (based on p-values not corrected for multiple comparisons) revealed the modulation of androgen and estrogen metabolism in men who routinely consumed more fish (p = 0.029) and tomato (p = 0.008) compared to men who ate less. In addition, modulation of arachidonic acid metabolism (p = 0.01) was observed after 3 months of fish oil supplementation compared with the placebo group; and modulation of nuclear factor (erythroid derived-2) factor 2 or Nrf2-mediated oxidative stress response for either supplement versus placebo (fish oil: p = 0.01, lycopene: p = 0.001). CONCLUSIONS: We did not detect significant individual genes associated with dietary intake and supplementation of lycopene and fish oil. However, exploratory analyses revealed candidate in vivo pathways that may be modulated by these micronutrients. TRIAL REGISTRATION: ClinicalTrials.gov NCT00402285.

Nutritional supplements, COX-2 and IGF-1 expression in men on active surveillance for prostate cancer.

BACKGROUND: Nutritional factors are associated with reduced risk of prostate cancer progression, yet mechanisms remain unclear. We examined the effects of lycopene and fish oil supplements versus placebo on the normal prostate microenvironment, among men pursuing active surveillance for low-burden prostate cancer. We hypothesized that lycopene or fish oil supplements would down-regulate insulin-like growth factor-1 (IGF-1) and cyclooxygenase 2 (COX-2) gene expression, respectively, reflecting putative proliferation (IGF-1) and inflammatory (COX-2) pathways relevant to carcinogenesis. METHODS: We conducted a 3-month randomized, double-blinded, clinical trial comparing prostate tissue gene expression profiles (assessed by qRT-PCR) among men with favorable-risk prostate cancer receiving either 30 mg/day lycopene, 3 g/day fish oil (including 1,098 mg eicosapentaenoic and 549 mg docosahexaenoic fatty acids) or placebo. RESULTS: Among 69 men (22 assigned to lycopene, 21 to fish, and 26 to placebo), there was no difference in the change from baseline to the 3 months in IGF-1 expression level between the placebo and lycopene arms (p = 0.93) nor in COX-2 expression between the placebo and fish arms (p = 0.99). CONCLUSION: Compared to placebo, 3-month intervention with lycopene or fish oil did not significantly change IGF-1 and COX-2 gene expression in the normal prostate microenvironment in men with low-burden prostate cancer. Further analysis of global gene expression profiles may shed light on the bioactivity and relevance of these nutrients in prostate cancer.