A Phase II Trial of Abiraterone With Dutasteride for Second-Generation Antiandrogen- and Chemotherapy-Naïve Patients With Castration-Resistant Prostate Cancer.

The development of a novel therapy to overcome primary and acquired resistance to abiraterone is an unmet need. This study aimed to evaluate the efficacy and safety of adding 5α-reductase inhibitor dutasteride to abiraterone, explore proof of concept, and identify candidates suitable for combination therapy. This phase II, single-arm, and open-label study enrolled second-generation antiandrogen- and chemotherapy-naïve patients with castration-resistant prostate cancer. Patients received abiraterone and prednisolone for 4 weeks, followed by adding dutasteride. The primary end point was a 50% prostate-specific antigen response rate. Serum concentrations of abiraterone and its metabolites as well as HSD3B1 and SRD5A2 genotypes were measured. The association between drug metabolism and genotypes and their impact on the efficacy of combination therapy were assessed. Among 21 patients, 18 (85.7%) achieved ≥50% PSA reduction. Median time to treatment failure was not reached during the median follow-up of 15.4 months. No patients experienced grade ≥3 adverse events. Although dutasteride reduced serum 3-keto-5α-abiraterone concentrations, higher serum 3-keto-5α-abiraterone concentrations on combination therapy were associated with a shorter time to treatment failure. HSD3B1 and SRD5A2 genotypes were associated with serum Δ4-abiraterone and 3-keto-5α-abiraterone concentrations before adding dutasteride, respectively. Time to treatment failure was longer in patients with homozygous wild-type HSD3B1, but comparable between those with the SRD5A2 genotype. The promising outcomes of this study warrant further investigation of combination therapy in a randomized trial. Stratification by HSD3B1 and SRD5A2 genetic profiles might identify patients suitable for combination therapy.

Impact of trough abiraterone level on adverse events in patients with prostate cancer treated with abiraterone acetate.

PURPOSE: We assessed the impact of plasma trough concentrations of abiraterone (ABI) and its metabolite Δ4-abiraterone (D4A) and related polymorphisms on adverse events (AEs) in patients with metastatic prostate cancer who received abiraterone acetate (AA). METHODS: This prospective study enrolled patients with advanced prostate cancer treated with AA between 2016 and 2021. Plasma trough concentrations of ABI and D4A were measured using high-performance liquid chromatography. The impact of HSD3B1 rs1047303, SRD5A2 rs523349, and cytochrome P450 family 3A member 4 rs2242480 polymorphisms on plasma concentrations of ABI and D4A and the incidence of AEs were also assessed. RESULTS: In 68 patients treated with AA, the median ABI and D4A concentrations were 18.1 and 0.94 ng/mL, respectively. The high plasma trough concentration of ABI (≥ 20.6 ng/mL) was significantly associated with the presence of any AE and its independent risk factor based on multivariable analysis (odds ratio, 7.20; 95% confidence interval (CI): 2.20-23.49). Additionally, a high plasma trough concentration of ABI was an independent risk factor of time to withdraw AA (hazard ratio, 4.89; 95% CI: 1.66-14.38). The risk alleles of three polymorphisms were not statistically associated with the ABI and D4A concentrations and the incidence of AEs. CONCLUSIONS: The plasma trough concentration of ABI is associated with the presence of AEs and treatment failure after AA administration. ABI concentration monitoring may be useful in patients with prostate cancer who received AA.

An advanced network pharmacology study to explore the novel molecular mechanism of Compound Kushen Injection for treating hepatocellular carcinoma by bioinformatics and experimental verification.

BACKGROUND: Compound Kushen Injection (CKI) is a Chinese patent drug that exerts curative effects in the clinical treatment of hepatocellular carcinoma (HCC). This study aimed to explore the targets and potential pharmacological mechanisms of CKI in the treatment of HCC. METHODS: In this study, network pharmacology was used in combination with molecular biology experiments to predict and verify the molecular mechanism of CKI in the treatment of HCC. The constituents of CKI were identified by UHPLC-MS/MS and literature search. The targets corresponding to these compounds and the targets related to HCC were collected based on public databases. To screen out the potential hub targets of CKI in the treatment of HCC, a compound-HCC target network was constructed. The underlying pharmacological mechanism was explored through the subsequent enrichment analysis. Interactive Gene Expression Profiling Analysis and Kaplan-Meier plotter were used to examine the expression and prognostic value of hub genes. Furthermore, the effects of CKI on HCC were verified through molecular docking simulations and cell experiments in vitro. RESULTS: Network analysis revealed that BCHE, SRD5A2, EPHX2, ADH1C, ADH1A and CDK1 were the key targets of CKI in the treatment of HCC. Among them, only CDK1 was highly expressed in HCC tissues, while the other 5 targets were lowly expressed. Furthermore, the six hub genes were all closely related to the prognosis of HCC patients in survival analysis. Molecular docking revealed that there was an efficient binding potential between the constituents of CKI and BCHE. Experiments in vitro proved that CKI inhibited the proliferation of HepG2 cells and up-regulated SRD5A2 and ADH1A, while down-regulated CDK1 and EPHX2. CONCLUSIONS: This study revealed and verified the targets of CKI on HCC based on network pharmacology and experiments and provided a scientific reference for further mechanism research.

[Chemoprevention of prostate cancer - a plea]. / Chemoprävention des Prostatakarzinoms - Ein Plädoyer.

The high disease prevalence, the presentation in older age, a frequently slowly progressing course of disease, and high costs make the diagnosis of and therapy for prostate cancer a special challenge for urologists. Effective prevention of the disease may help to improve some of the problems mentioned above. Two randomised, controlled studies have proved that effective chemoprevention of prostate cancer is viable using 5α-reductase inhibitors (finasteride, dutasteride). Furthermore, there is increasing evidence that other compounds, e. g., selective oestrogen receptor modulators (SERMs), NSAIDs and statins might also be effective. This review investigates potential risks and benefits of chemoprevention including a consideration of health economical aspects. The authors conclude that the options of chemoprevention should be investigated in an open and unbiased way.

Examination of the relationship between symptoms of prostatitis and histological inflammation: baseline data from the REDUCE chemoprevention trial.

PURPOSE: Symptoms of abacterial chronic prostatitis/chronic pelvic pain syndrome are considered to be associated with prostate inflammation. The ongoing Reduction by Dutasteride of Prostate Cancer Events trial is a 4-year, phase III, placebo controlled study to determine whether 0.5 mg dutasteride daily decreases the risk of biopsy detectable prostate cancer. All men underwent biopsy before study entry, allowing review of the relationship between histological prostate inflammation and prostatitis symptoms. MATERIALS AND METHODS: Eligible men were 50 to 75 years old with serum prostate specific antigen 2.5 ng/ml or greater and 10 ng/ml or less (ages 50 to 60 years), or 3.0 ng/ml or greater and 10 ng/ml or less (older than 60 years), and an International Prostate Symptom Score of less than 25 (or less than 20 if already on alpha-blocker therapy). Acute prostatitis was an exclusion criterion. The National Institutes of Health Chronic Prostatitis Symptom Index was used to assess prostatitis-like symptoms. Spearman rank correlations were used to assess the relationship between acute and chronic inflammation, and Chronic Prostatitis Symptom Index scores for the pain, urinary symptoms and quality of life domains as well as average pain, total score and prostatitis-like symptoms. RESULTS: Data were available on 5,597 patients. The distribution of inflammation status was similar for those with and without chronic prostatitis-like symptoms. Significant correlations were found between average chronic inflammation, and total Chronic Prostatitis Symptom Index score and subscores for urinary symptoms and quality of life but the magnitude of these correlations was small. CONCLUSIONS: A lack of clinically meaningful association was found between prostatitis-like pain symptoms and histological inflammation in the Reduction by Dutasteride of Prostate Cancer Events population, suggesting that the view that symptoms of chronic prostatitis/chronic pelvic pain syndrome and prostate inflammation are associated needs further scrutiny.

A review of combination therapy in patients with benign prostatic hyperplasia.

BACKGROUND: Trials of monotherapy with alpha(1)-adrenergic-receptor antagonists (alpha(1)ARAs) and 5 alpha-reductase inhibitors (5ARIs) have found that the former drug class is effective in managing benign prostatic hyperplasia (BPH)-related lower urinary tract symptoms (LUTS) and improving the maximal urinary flow rate in shortand long-term treatment, regardless of prostate size, whereas the latter drug class is effective in reducing prostate size and preventing disease progression in longer-term treatment. The differing mechanisms of action and areas of efficacy of these 2 drug classes make them promising candidates for combination therapy. OBJECTIVE: This article reviews key trials of monotherapy and combination alpha(1)ARV5ARI therapy in the treatment and prevention of BPH-related voiding dysfunction. METHODS: MEDLINE (1976-2006) and the Cochrane Central Register of Controlled Trials (1976-2006) were searched for relevant clinical trials and reviews using the terms benign prostatic byperplasia, lower urinary tract symptoms, LUTS, alpha-adrenergic-receptor antagonists, alpha-blockers, 5 alpha-reductase inhibitors, combination therapy, MTOPS, SMART, PREDICT, adverse events, alfuzosin, doxazosin, tamsulosin, terazosin, dutasteride, and finasteride. Abstracts from selected professional conferences also were reviewed. RESULTS: Three previous trials of alpha(1)ARA/5ARI therapy found no therapeutic benefit for combination therapy relative to monotherapy, but their conclusions were limited to some extent by their designs, particularly the duration of treatment. Data from the Medical Therapy of Prostatic Symptoms (MTOPS) study, however, indicated a potential role for long-term use of alpha(1)ARA/5ARI therapy, particularly in patients with greater symptom severity (mean score of 17 on the American Urological Association symptom index), larger prostate volume (mean, 32 g), and higher prostate-specific antigen (PSA) levels (>1.5 ng/mL) at baseline. In the MTOPS study, combination therapy with the alpha(1)ARA doxazosin and the SARI finasteride was significantly more effective than either component alone in reducing BPH-related symptoms (P=0.006 vs doxazosin monotherapy; P<0.001 vs finasteride monotherapy) and lowering the rate of overall clinical progression (P<0.001 vs either monotherapy). In addition, there are data from a subgroup analysis of MTOPS suggesting that the presence of prostatic inflammation may indicate a greater likelihood of treatment efficacy with combination alpha(1)ARA/5ARI therapy. CONCLUSIONS: The available data suggest that combination alpha(1)ARA/5ARI therapy is beneficial in the treatment of BPH and the associated symptoms. The greatest efficacy was evident in patients with an enlarged prostate, more severe symptoms, and higher PSA levels. There are limited data suggesting that the presence of prostatic inflammation may indicate a greater likelihood of treatment efficacy with combination therapy.

Dutasteride improves male pattern hair loss in a randomized study in identical twins.

OBJECTIVES: This study compared the efficacy of dutasteride vs. placebo in the treatment of male pattern hair loss (androgenetic alopecia) in 17 pairs of identical twin males with androgenetic alopecia over a 1-year period. METHODS: In this randomized, double-blind, placebo-controlled, single-center study, one twin from each identical twin pair received dutasteride 0.5 mg/day for 12 months while the other received placebo for 12 months. Hair growth was evaluated using standardized clinical photographs, hair counts, and patient self-assessment questionnaires. RESULT: Dutasteride significantly improved hair growth at 1-year compared to placebo based on the analysis of the investigator assessment and the patient self-assessment questionnaires. Sixteen of 17 sets of twins completed the study, of which 15 sets correctly predicted the use of dutasteride. Only one set could not determine the active drug from the placebo. CONCLUSION: Through the use of identical twins, this randomized trial provides evidence that dutasteride significantly reduces hair loss progression in men with male pattern hair loss.

[Factors determining treatment strategies for patients with benign prostatic hyperplasia. The DUO study]. / Facteurs déterminant le choix thérapeutique des urologues pour la prise en charge des patients ayant une hypertrophie bénigne de la prostate. L'étude DUO.

OBJECTIVES: The DUO study sought to identify the factors determining diagnostic and treatment strategies for benign prostatic hyperplasia (BPH) in daily practice. METHODS: Observational study conducted in France (from June 2004 through March 2005) among a representative sample of French urologists. RESULTS: Two hundred two urologists included 1027 BPH patients (mean age: 68 years +/-9), 856 of whom were seen again six months later. The mean International Prostatic Symptom Score (IPSS) was 14.9 (+/-6.7) at inclusion and 10.5 (+/-6.7) at the follow-up visit. At inclusion, pharmacologic treatment was prescribed to 84% of patients, surgery was recommended to 13% and no treatment to 3%. Factors favoring surgery (versus drugs) were BPH severity (OR=2.5 for IPSS>or=20), patient choice (OR=2.5), expected quality of life improvement (OR=2.2), post-void residual (OR=2.1) and dribbling (OR=1.6). This choice was not associated with patient age, prostatic volume or active sex life. Choice of a 5alpha reductase inhibitor (versus alpha-blocker) was associated with large prostatic volume (OR=7.6), PSA results (OR=5.8), and patient age (OR=5.5 for >or=74 years, OR=2.1 for >or=68 years). Prescription of a combination of alpha-blocker plus 5alpha-reductase inhibitor (versus alpha-blocker alone) was associated with severity of BPH (OR=7.9), prostatic volume (OR=7.8), prevention of complications (OR=3.1), patient age (OR=3.0 if >or=74 years) and post-void residual (OR=2.3). DISCUSSION: Both medical and surgical treatment of BPH resulted in improved IPSS scores at 6 months. Patient age and prostatic volume are reasons urologists prescribe 5alpha reductase inhibitors, but they do not affect the decision about surgical treatment. Surgery is performed in severe BPH or when patients choose surgery in the expectation of improving their quality of life. The factors determining treatment strategies identified in this study are patient age, BPH severity, prostatic volume, patients' wishes, PSA results and post-void residual.

Use of 5alpha-reductase inhibitors to prevent benign prostatic hyperplasia disease.

A histologic change in the prostate, benign prostatic hyperplasia (BPH), is a normal part of aging. However, BPH disease, defined here as a life-altering urinary condition caused by BPH requiring prompt medical intervention, is a serious medical disorder associated with major complications, surgical intervention, and severe lifestyle interference. BPH disease is preventable. The rationale for BPH disease prevention rests on four pillars of evidence: (1) BPH disease generally is a progressive disorder; (2) complications and severe lifestyle interference from BPH disease are common and serious; (3) men at greatest risk of BPH disease can be identified using prostate-specific antigen (PSA) level higher than 1.5 ng/mL as a surrogate marker for an enlarged prostate; and (4) 5alpha-reductase inhibitors (5ARIs) reduce the primary androgen responsible for prostate growth (dihydrotestosterone), shrink the prostate, and arrest the disease process regardless of symptom status. Thus, we now can identify men with an enlarged prostate at risk for BPH disease who may be candidates for preventive therapy with 5ARIs, regardless of urinary symptoms or bother.

Lipedematous alopecia of the scalp.

Lipedematous scalp is a rare disorder, mainly described in adult African-American females. We report 2 adult caucasian males with lipedematous scalp associated with androgenetic alopecia. Patients were studied by dermoscopy and histopathology; they were treated with finasteride 1 mg. In our patients, lipedematous scalp affected the occipital and the vertex areas and pathologically exhibited mild edema and thickening of the adipose subcutaneous layer. At videodermoscopy, lipedematous scalp areas showed linear areas of teleangiectasia within the scalp creases, possibly caused by compression of the superficial blood capillaries by the increased volume of the subcutaneous fat layer within the thickened scalp. Finasteride at a dose of 1 mg per day for 1 year induced mild improvement of androgenetic alopecia in one patient and stabilization of the disease in the other. The lipedematous scalps remain unchanged. Lipedematous scalp is apparently a rare disease even though the condition is probably underdiagnosed. As a matter of fact, we diagnosed lipedematous scalp in our patients during a clinical examination for androgenetic alopecia, which was the patients' complaint. The association of lipedematous scalp and androgenetic alopecia in our two patients appears to be coincidental.

Clinical and economic outcomes in patients treated for enlarged prostate.

BACKGROUND: Benign prostatic hyperplasia (BPH), also referred to as enlarged prostate, is a highly prevalent condition in men aged 50 years or older. It is a progressive disease with significant morbidity from complications. OBJECTIVE: The purpose of this study was to assess the likelihood of having acute urinary retention (AUR) and prostate surgery after initiating therapy with an alpha blocker or 5-alpha reductase inhibitor in a real-world setting. STUDY DESIGN: This was a retrospective study of patients who were treated for BPH between January 1, 2003, and November 30, 2003, in a large, national managed care claims database. Outcomes measures of interest included rate of AUR, prostate surgery, and surgical complications. RESULTS: There were 2959 patient records with a diagnosis of BPH who were taking prostate medications in the database. Eighty-nine percent of patients were receiving alpha blocker therapy, whereas 11% of patients were receiving 5-alpha reductase inhibitors. Overall, the 1-year AUR rate was 12.1%, and the prostate surgery rate was 5.8%. Patients who initiated 5-alpha reductase inhibitor therapy only were less likely to have AUR or surgery compared with patients taking alpha blockers, although surgical differences did not reach statistical significance (P = .0576). Overall, the surgical complication rate was 49.4%, and the rate of AUR within 180 days of prostate surgery was 30.6%. Rates of prostate surgery, AUR, and surgical complications all increased with age. CONCLUSION: Patients receiving 5-alpha reductase inhibitor therapy alone were less likely to have AUR compared with patients receiving alpha blockers and tended to be less likely to have surgery (P = .054).

Dutasteride: a potent dual inhibitor of 5-alpha-reductase for benign prostatic hyperplasia.

Dutasteride is a 5alpha-reductase inhibitor that inhibits both types 1 and 2 isozymes of 5alpha-reductase, the enzyme responsible for converting testosterone to dihydrotestosterone in the prostate and other tissues. Dihydrotestosterone is the primary cause of prostate growth and has been proven to play a key role in the development and progression of benign prostatic hyperplasia. Dutasteride has been investigated in three multicenter studies involving 4325 men aged 50 years and above with benign prostatic hyperplasia. Data from these two-year, placebo-controlled studies demonstrated that dutasteride 0.5 mg once daily reduced the risk of both acute urinary retention and the need for benign prostatic hyperplasia-related surgical intervention, improved benign prostatic hyperplasia-related symptoms, decreased prostate volume and increased maximum urinary flow rates with a low incidence of generally mild to moderate adverse events.

Who will benefit from combination therapy? The role of 5 alpha reductase inhibitors and alpha blockade: a reflection from MTOPS.

PURPOSE OF REVIEW: The purpose of this review is to revisit the medical treatment of benign prostatic hyperplasia in the light of the most recent data concerning the association of alpha-blockers and 5alpha-reductase inhibitors. Combining these two drugs is not a new concept in treating benign prostatic hyperplasia patients. Alpha blockers are believed to improve symptoms and flow rate by inducing relaxation of the smooth muscle neck and prostate area (dynamic component), while 5alpha-reductase inhibitors are believed to improve symptoms and flow rate by shrinking the transition zone of the prostate through hormonal mechanisms (static component). The proof of this concept, however, could not be clinically demonstrated up until now. The design of previous studies investigating combination therapy with the 5alpha-reductase inhibitor finasteride has been questionable. RECENT FINDINGS: Extrapolated from the Medical Therapy of Prostatic Symptoms (MTOPS) study, not yet fully published, again raises the question of the effectiveness of such a combination. There is now some evidence to suggest that combining alpha-blockers and finasteride may be more effective in relieving and preventing the progression of symptoms than either of the two drugs alone. SUMMARY: Patients most likely to benefit from combination therapy are those in whom baseline risk of progression is significantly higher, generally patients with larger glands and higher prostatic specific antigen values.