The effect of dutasteride on the detection of prostate cancer: A set of meta-analyses

Abstract

Background: Dutasteride has been shown to significantly improve symptoms of benign prostatic hyperplasia (BPH) and reduce clinical progression. Recent data from studies evaluating 5-alpha reductase inhibitors (5-ARIs) for the prevention of prostate cancer, however, suggest 5ARIs, including dutasteride, may be associated with increased incidence of Gleason 8-10 prostate tumours. This metaanalysis was undertaken to quantify the effect of dutasteride on detection of prostate cancer and high-grade prostate cancer. Methods: Our meta-analysis includes data from GlaxoSmithKlinesponsored phase III randomized clinical trials (with a study duration of ≥2 years) evaluating the effect of dutasteride, alone or in combination with tamsulosin, to treat BPH or to reduce the risk of prostate cancer. The incidence of prostate cancer, including Gleason 7-10 and Gleason 8-10, for patients taking either dutasteride, dutasteride plus tamsulosin, tamsulosin alone, or placebo, were evaluated using the Mantel-Haenszel Risk Ratio (MHRR) method of conducting meta-analyses. Results:The meta-analysis demonstrated that in a population with symptomatic BPH and/or at increased risk of prostate cancer, a statistically significant lower number of detectable prostate cancers was found in men taking dutasteride compared to control groups (MHRR: 0.66, 95% CI 0.52-0.85). In our analysis, there was no increased risk for Gleason 7-10 (MHRR: 0.83, 95% CI 0.56-1.21) or Gleason 8-10 prostate cancers (MHRR: 0.99, 95% CI 0.39-2.53) in men taking dutasteride over control groups. There were several limitations that need to be considered when interpreting these results. Conclusion: These data provide support for the continued use of dutasteride in the treatment of symptomatic BPH patients.

The role of HOXC6 in prostate cancer development

“…Prostatic androgen levels and androgen deprivation therapy, preferably should not influence biomarker expression. Thus, biomarker levels should be unaffected when a drug like dutasteride (an inhibitor of 5α‐reductase activity) is administered for treatment of BPH, an often occurring comorbidity . Furthermore biomarker expression should not be influenced by drugs like abiraterone (an CYP17A1 inhibitor), and bicalutamide and enzalutamide (two AR antagonists), when the marker is to be used for monitoring disease progression and response to therapy.…”

“…These conflicting data might be due to the differences in methods used to determine HOXC6 levels, and/or cut off points used to predict prognosis. Vinarskaja et al used median levels of HOXC6 mRNA, whereas we used the number of nuclear HOXC6 protein expression levels to predict prognosis. However, the study of Vinarskaja et al also may be underpowered, as they only included 45 cases , whereas we used higher number of samples (n = 481) for the analysis.…”

Effects of Steroidal Antiandrogen or 5-alpha-reductase Inhibitor on Prostate Tissue Hormone Content

“…DUTA treatment in the REDUCE trial yielded an absolute increase of 0.3–0.5% in the incidence of grade 8–10 prostate cancers compared to placebo . Although the increased risk of detectable high‐grade prostate tumors was almost denied by the meta‐analysis , we remain skeptical about the effect of continuing stimulation by non‐physiologically increased low active androgens in the prostates of DUTA‐treated patients. Further clinical studies in a large number of patients are required to verify the effect of long‐term elevation of tissue T and 4‐androstene‐3,17‐dione.…”

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“…En un estudio de cohorte de base poblacional, el uso previo al diagnóstico de 5-IRA se relacionó con un diagnóstico tardío y peores resultados específicos del cáncer de próstata (69) . Es probable que la tasa más alta de cáncer de próstata de alto grado que se encontró con el tratamiento con 5-ARI sea el resultado de la inhibición selectiva de los cánceres de bajo grado y la disminución del volumen de la próstata que resultó en un mejor rendimiento de la biopsia (70) . También el descenso de las cifras de PSA por los 5-ARI puede llevar a retrasos en el diagnóstico, mayor graduación y etapa más avanzada del diagnóstico (69) .…”