A phase 3, open-label, multicenter study of a 6-month pre-mixed depot formulation of leuprolide mesylate in advanced prostate cancer patients.

OBJECTIVES: To determine the safety, efficacy and pharmacokinetic (PK) profile of a pre-mixed depot formulation of leuprolide mesylate subcutaneous injectable suspension (LMIS) 50 mg for up to 1 year of treatment for subjects with advanced prostate cancer. PATIENTS AND METHODS: In this open-label, multicenter study, prostate cancer patients with indication for androgen ablation therapy received two subcutaneous injection of LMIS 50 mg 6 months apart and were followed for an additional 6 months. Two efficacy primary end points were the percentage of subjects with a serum testosterone level ≤ 50 ng/dL by Day 28 as well as the percentage of subjects with similar testosterone suppression from Day 28 to Day 336. RESULTS: Of the 137 enrolled subjects, 15 (10.9%) subjects did not complete the study, including 5 subjects who terminated early due to an adverse event. By Day 28, 98.5% (95% confidence interval 94.8-99.8) of the subjects achieved a castrate testosterone level. At the end of the study, 97% and 95.9% of the subjects had serum testosterone level ≤ 50 ng/dL and ≤ 20 ng/dL, respectively. LMIS 50 mg significantly reduced serum prostate-specific antigen levels after its first injection and this PSA declination effect remained until the end of the study. No statistically significant change was observed in worsening bone pain or urinary symptom assessments during the study. Hot flush (48.9%) and hypertension (14.6%) were the two most common adverse events reported. CONCLUSIONS: LMIS 50 mg, administered at 6-month intervals, effectively suppressed serum testosterone level, and demonstrated a consistent safety profile.

Three-year outcomes after Aquablation therapy compared to TURP: results from a blinded randomized trial.

INTRODUCTION: To compare 3-year efficacy and safety after prostate resection with Aquablation therapy or transurethral resection of the prostate (TURP) for the treatment of lower urinary tract symptoms related to benign prostate hyperplasia (BPH). MATERIALS AND METHODS: One hundred and eighty-one patients assigned to either Aquablation therapy or TURP were followed for 3 years postoperatively. Patients and follow up assessors were blinded to treatment. Assessments included International Prostate Symptom Score (IPSS), Male Sexual Health Questionnaire (MSHQ-EjD), International Index of Erectile Function (IIEF) and uroflow. RESULTS: Over 3 years of treatment, improvements in IPSS scores were statistically similar across groups. Mean 3-year improvements were 14.4 and 13.9 points in the Aquablation and TURP groups, respectively (difference of 0.6 points, 95% CI -3.3-2.2, p = .6848). Similarly, 3-year improvements in Qmax were 11.6 and 8.2 cc/sec (difference of 3.3 [95% CI -0.5-7.1] cc/sec, p = .0848). At 3 years, PSA was reduced significantly in both groups by 0.9 and 1.1 ng/mL, respectively; the reduction was similar across groups (p = .5983). There were no surgical retreatments for BPH beyond 20 months for either Aquablation or TURP. CONCLUSIONS: Three-year BPH symptom reduction and urinary flow rate improvement were similar after TURP and Aquablation therapy. No subjects required surgical retreatment beyond 20 months postoperatively. (ClinicalTrials.gov number, NCT02505919).

Symptom relief and anejaculation after aquablation or transurethral resection of the prostate: subgroup analysis from a blinded randomized trial.

OBJECTIVE: To test the hypothesis that benign prostatic hyperplasia (BPH) robotic surgery with aquablation would have a more pronounced benefit in certain patient subgroups, such as men with more challenging anatomies (e.g. large prostates, large middle lobes) and men with moderate BPH. METHODS: We conducted prespecified and post hoc exploratory subgroup analyses from a double-blind, multicentre prospective randomized controlled trial that compared transurethral resection of the prostate (TURP) using either standard electrocautery vs surgery using robotic waterjet (aquablation) to determine whether certain baseline factors predicted more marked responses after aquablation as compared with TURP. The primary efficacy endpoint was reduction in International Prostate Symptom Score (IPSS) at 6 months. The primary safety endpoint was the occurrence of Clavien-Dindo persistent grade 1 or grade ≥2 surgical complications. RESULTS: For men with larger prostates (50-80 g), the mean IPSS reduction was four points greater after aquablation than after TURP (P = 0.001), a larger difference than the overall result (1.8 points; P = 0.135). Similarly, the primary safety endpoint difference (20% vs 46% [26% difference]; P = 0.008) was greater for men with large prostate compared with the overall result (26% vs 42% [16% difference]; P = 0.015). Postoperative anejaculation was also less common after aquablation compared with TURP in sexually active men with large prostates (2% vs 41%; P < 0.001) vs the overall results (10% vs 36%; P < 0.001). Exploratory analysis showed larger IPSS changes after aquablation in men with enlarged middle lobes, men with severe middle lobe obstruction, men with a low baseline maximum urinary flow rate, and men with elevated (>100) post-void residual urine volume. CONCLUSIONS: In men with moderate-to-severe lower urinary tract symptoms attributable to BPH and larger, more complex prostates, aquablation was associated with both superior symptom score improvements and a superior safety profile, with a significantly lower rate of postoperative anejaculation. The standardized, robotically executed, surgical approach with aquablation may overcome the increased outcome variability in more complex anatomy, resulting in superior symptom score reduction.

WATER: A Double-Blind, Randomized, Controlled Trial of Aquablation® vs Transurethral Resection of the Prostate in Benign Prostatic Hyperplasia.

PURPOSE: We compared the safety and efficacy of Aquablation and transurethral prostate resection for the treatment of lower urinary tract symptoms related to benign prostatic hyperplasia. MATERIALS AND METHODS: In a double-blind, multicenter, prospective, randomized, controlled trial 181 patients with moderate to severe lower urinary tract symptoms related to benign prostatic hyperplasia underwent transurethral prostate resection or Aquablation. The primary efficacy end point was the reduction in International Prostate Symptom Score at 6 months. The primary safety end point was the development of Clavien-Dindo persistent grade 1, or 2 or higher operative complications. RESULTS: Mean total operative time was similar for Aquablation and transurethral prostate resection (33 vs 36 minutes, p = 0.2752) but resection time was lower for Aquablation (4 vs 27 minutes, p <0.0001). At month 6 patients treated with Aquablation and transurethral prostate resection experienced large I-PSS improvements. The prespecified study noninferiority hypothesis was satisfied (p <0.0001). Of the patients who underwent Aquablation and transurethral prostate resection 26% and 42%, respectively, experienced a primary safety end point, which met the study primary noninferiority safety hypothesis and subsequently demonstrated superiority (p = 0.0149). Among sexually active men the rate of anejaculation was lower in those treated with Aquablation (10% vs 36%, p = 0.0003). CONCLUSIONS: Surgical prostate resection using Aquablation showed noninferior symptom relief compared to transurethral prostate resection but with a lower risk of sexual dysfunction. Larger prostates (50 to 80 ml) demonstrated a more pronounced superior safety and efficacy benefit. Longer term followup would help assess the clinical value of Aquablation.

Epigenetic risk score improves prostate cancer risk assessment.

BACKGROUND: Early detection of aggressive prostate cancer (PCa) remains crucial for effective treatment of patients. However, PCa screening remains controversial due to a high rate of overdiagnosis and overtreatment. To better reconcile both objectives, more effective methods for assessing disease severity at the time of diagnosis are needed. METHODS: The relationship between DNA-methylation and high-grade PCa was examined in a cohort of 102 prospectively enrolled men who received standard 12-core prostate biopsies. EpiScore, an algorithm that quantifies the relative DNA methylation intensities of GSTP1, RASSF1, and APC in prostate biopsy tissue, was evaluated as a method to compensate for biopsy under-sampling and improve risk stratification at the time of diagnosis. RESULTS: DNA-methylation intensities of GSTP1, RASSF1, and APC were higher in biopsy cores from men diagnosed with GS ≥ 7 cancer compared to men with diagnosed GS 6 disease. This was confirmed by EpiScore, which was significantly higher for subjects with high-grade biopsies and higher NCCN risk categories (both P < 0.001). In patients diagnosed with GS ≥ 7, increased levels of DNA-methylation were present, not only in the high-grade biopsy cores, but also in other cores with no or low-grade disease (P < 0.001). By combining EpiScore with traditional clinical risk factors into a logistic regression model, the prediction of high GS reached an AUC of 0.82 (95%CI: 0.73-0.91) with EpiScore, DRE, and atypical histological findings as most important contributors. CONCLUSIONS: In men diagnosed with PCa, DNA-methylation profiling can detect under-sampled high-risk PCa in prostate biopsy specimens through a field effect. Predictive accuracy increased when EpiScore was combined with other clinical risk factors. These results suggest that EpiScore could aid in the detection of occult high-grade disease at the time of diagnosis, thereby improving the selection of candidates for Active Surveillance.

Self-Identified African Americans and prostate cancer risk: West African genetic ancestry is associated with prostate cancer diagnosis and with higher Gleason sum on biopsy.

Concerns about overtreatment of clinically indolent prostate cancer (PrCa) have led to recommendations that men who are diagnosed with low-risk PrCa be managed by active surveillance (AS) rather than immediate definitive treatment. However the risk of underestimating the aggressiveness of a patient's PrCa can be a significant source of anxiety and a barrier to patient acceptance of AS. The uncertainty is particularly keen for African American (AA) men who are about 1.7 times more likely to be diagnosed with PrCa than European American (EA) men and about 2.4 times more likely to die of this disease. The AA population, as many other populations in the Americas, is genetically heterogeneous with varying degrees of admixture from West Africans (WAs), Europeans, and Native Americans (NAs). Recommendations for PrCa screening and management rarely consider potential differences in risk within the AA population. We compared WA genetic ancestry in AA men undergoing standard prostate biopsy who were diagnosed with no cancer, low-grade PrCa (Gleason Sum 6), or higher grade PrCa (Gleason Sum 7-10). We found that WA genetic ancestry was significantly higher in men who were diagnosed with PrCa on biopsy, compared to men who were cancer-negative, and highest in men who were diagnosed with higher grade PrCa (Gleason Sum 7-10). Incorporating WA ancestry into the guidelines for making decisions about when to obtain a biopsy and whether to choose AS may allow AA men to personalize their approach to PrCa screening and management.

Two-Year Outcomes After Aquablation Compared to TURP: Efficacy and Ejaculatory Improvements Sustained.

INTRODUCTION: To compare 2-year safety and efficacy outcomes after Aquablation or transurethral resection of the prostate (TURP) for the treatment of lower urinary tract symptoms related to benign prostate hyperplasia (BPH). METHODS: One hundred eighty-one patients with BPH were assigned at random (2:1 ratio) to either Aquablation or TURP. Patients and follow-up assessors were blinded to treatment. Assessments included the International Prostate Symptom Score (IPSS), Male Sexual Health Questionnaire (MSHQ), International Index of Erectile Function and uroflow. The focus of analysis was 2-year outcomes. RESULTS: At 2 years, IPSS scores improved by 14.7 points in the Aquablation group and 14.9 points in TURP (p = .8304, 95% CI for difference - 2.1 to 2.6 points). Two-year improvements in maximum flow rate (Qmax) were large in both groups at 11.2 and 8.6 cc/s for Aquablation and TURP, respectively (p = 0.1880, 95% CI for difference - 1.3 to 6.4). Sexual function as assessed by MSHQ was stable in the Aquablation group and decreased slightly in the TURP group. At 2 years, PSA was reduced significantly in both groups by 0.7 and 1.2 points, respectively; the reduction was similar across groups (p = 0.1816). Surgical retreatment rates after 12 months for Aquablation were 1.7% and 0% for TURP. Over 2 years, surgical BPH retreatment rates were 4.3% and 1.5% (p = 0.4219), respectively. CONCLUSION: Two-year efficacy outcomes after TURP and Aquablation were similar, and the rate of surgical retreatment was low and similar to TURP. TRIAL REGISTRATION: ClinicalTrials.gov no. NCT02505919. FUNDING: PROCEPT BioRobotics.