Dutasteride

Prostate cancer is dependent on androgen receptor (AR) activation. Optimal AR antagonism may effectively cytoreduce local disease and suppress or eliminate micrometastases. We evaluated neoadjuvant therapy prior to prostatectomy with the potent AR antagonist enzalutamide (enza) either alone or in combination with dutasteride and leuprolide (enza/dut/LHRHa). Forty-eight of 52 men with intermediate or high-risk localized prostate cancer proceeded to prostatectomy after neoadjuvant enza or enza/dut/LHRHa for 6 months. We assessed pathologic complete response (pCR), minimal residual disease (MRD; ≤3 mm maximum diameter of residual disease), residual cancer burden (RCB), and expression of prostate-specific antigen (PSA) and serum and tissue androgen concentrations. We compared the proportion of patients with pCR in each treatment arm with a historical control rate of 5%, based on previous reports of flutamide with LHRHa. In the enza arm, none of the 25 patients achieved pCR or MRD. In th...

Despite the efficacy of abiraterone, a CYP17A1 inhibitor, in metastatic castration-resistant prostate cancer (CRPC), nearly all patients develop resistance. The purpose of this phase II study was to evaluate mechanisms of resistance to more complete androgen synthesis inhibition with abiraterone and dutasteride. Eligible metastatic CRPC patients underwent a baseline metastasis biopsy. Patients received abiraterone and prednisone for two 4-week cycles. After this time, high-dose dutasteride (3.5mg daily) was added. Patients continued therapy until study withdrawal or radiographic progression. Repeat metastasis biopsy was obtained at progression. The primary endpoint was to assess mechanisms of resistance. Serum hormone and abiraterone levels were assessed. Tissue was assessed for androgen receptor (AR) and AR splice variant-7 (ARV7) expression. Forty patients were enrolled. 60% (n=24) achieved a {greater than or equal to}50% reduction in PSA. The median time to radiographic progressi...

Prostate cancer is dependent on androgen receptor (AR) activation. Optimal AR antagonism may effectively cytoreduce local disease and suppress or eliminate micrometastases. We evaluated neoadjuvant therapy prior to prostatectomy with the potent AR antagonist enzalutamide (enza) either alone or in combination with dutasteride and leuprolide (enza/dut/LHRHa). Forty-eight of 52 men with intermediate or high-risk localized prostate cancer proceeded to prostatectomy after neoadjuvant enza or enza/dut/LHRHa for 6 months. We assessed pathologic complete response (pCR), minimal residual disease (MRD; ≤3 mm maximum diameter of residual disease), residual cancer burden (RCB), and expression of prostate-specific antigen (PSA) and serum and tissue androgen concentrations. We compared the proportion of patients with pCR in each treatment arm with a historical control rate of 5%, based on previous reports of flutamide with LHRHa. In the enza arm, none of the 25 patients achieved pCR or MRD. In th...

Benign prostatic hyperplasia (BPH) is a chronic condition common in older men that can result in bothersome lower urinary tract symptoms. The molecular mechanisms and networks underlying the development and the progression of the disease are still far from being fully understood. BPH results from smooth muscle cell and epithelial cell proliferation, primarily within the transition zone of the prostate. Apoptosis and inflammation play important roles in the control of cell growth and in the maintenance of tissue homeostasis. Disturbances in molecular mechanisms of apoptosis machinery have been linked to BPH. Increased levels of the glycoprotein Dickkopf-related protein 3 in BPH cause an inhibition of the apoptosis machinery through a reduction in B cell lymphoma (Bcl)-2 associated X protein (Bax) expression. Inhibitors of apoptosis proteins influence cell death by direct inhibition of caspases and modulation of the transcription factor nuclear factor-κB. Current pharmacotherapy targe...

The 5α-reductase inhibitors (5-ARI) finasteride and dutasteride are indicated for the treatment of lower urinary tract symptoms caused by benign prostatic hyperplasia. Case reports have suggested that 5-ARIs increase the risk for male breast cancer, with no conclusive evidence. The objective of this study was to quantify the association between use of 5-ARIs and the risk for male breast cancer. A case-control study was conducted with data from the United Kingdom Clinical Practice Research Datalink database among all men aged 45 years and older in the period 1 January 1992 to 31 December 2011. Cases of men diagnosed with breast cancer were matched to up 10 controls on age and general practice. Crude and adjusted odds ratios were estimated for the risk of breast cancer associated with the use of 5-ARIs. Three hundred and ninety-eight cases were identified and matched to 3,930 controls. Ever use of 5-ARIs was associated with an adjusted odds ratio for breast cancer of 1.08 (95 % CI 0.62-1.87) compared to non-users. Increasing cumulative duration of treatment showed no increasing risks: adjusted odds ratios for use for less than 280, for 280 to 1,036 and for more than 1,036 days were 1.21 (95 % CI 0.47-3.10), 0.94 (95 % CI 0.36-2.41) and 1.29 (95 % CI 0.54-3.08), respectively. In this study, there was no evidence of an association between short- or long-term treatment with 5-ARIs and the risk for breast cancer in older men.

A recent meta-analysis showed that aspirin was associated with reduced prostate cancer risk. As anti-inflammatory medications lower PSA levels, whether these findings reflect reduced prostate cancer detection or lower prostate cancer risk is unknown. We tested the association between aspirin and nonaspirin NSAID use on prostate cancer diagnosis in REDUCE, where all men received biopsies at 2 and 4 years largely independent of PSA. REDUCE tested dutasteride for prostate cancer risk reduction in men with a PSA of 2.5 to 10.0 ng/mL and a negative prestudy biopsy. We examined the association between aspirin, NSAIDs, or both and total, low-grade (Gleason < 7), or high-grade (Gleason ≥ 7) prostate cancer versus no prostate cancer using multinomial logistic regression among 6,390 men who underwent ≥1 on-study biopsy. Multivariable analyses were adjusted for age, race, geographic region, PSA, prostate volume, digital rectal examination, body mass index, treatment arm, smoking, alcohol, s...