Real-world Outcomes and Predictive Biomarkers for 177Lutetium Prostate-specific Membrane Antigen Ligand Treatment in Metastatic Castration-resistant Prostate Cancer: A European Association of Urology Young Academic Urologists Prostate Cancer Working Group Multi-institutional Observational Study.

BACKGROUND: The European Association of Urology guidelines include the lutetium-177 (177Lu) PSMA-617 prostate-specific membrane antigen (PSMA) ligand as a therapy option for metastatic castration-resistant prostate cancer (mCRPC). A major challenge in clinical practice is to pursue a personalized treatment approach based on robust predictive biomarkers. OBJECTIVE: To assess the performance of 177Lu PSMA in real-world practice and to elaborate clinical biomarkers for evaluating treatment responses. DESIGN, SETTING, AND PARTICIPANTS: We conducted a retrospective observational study including 233 patients with mCRPC treated with 177Lu PSMA in eight high-volume European centers. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Baseline characteristics and clinical parameters during and after 177Lu PSMA treatment were documented. Correlations to treatment response were analyzed using χ2 and log-rank tests, with differences between groups with and without disease progression calculated using a Mann-Whitney U test. Univariate and multivariate-adjusted hazard ratios (HRs) were measured using Cox proportional hazards models. RESULTS AND LIMITATIONS: A prostate-specific antigen (PSA) decrease of ≥30% was observed in 41.7%, 63.5%, and 77.8% of patients after the first, second, and third treatment cycle, respectively. Restaging performed via PSMA positron emission tomography-computed tomography revealed that 33.7% of patients had an imaging-based response, including two patients with a complete response, while 13.4% had stable disease. The median time to progression was 5 mo and the median time until the start of a consecutive antineoplastic therapy was 8.5 mo. Of importance, a PSA decrease ≥30% after the first two cycles of 177Lu PSMA (1 cycle: p = 0.0003; 2 cycles: p = 0.004), absolute PSA after the first three cycles (1 cycle: p = 0.011; 2 cycles: p = 0.0005; 3 cycles: p = 0.002), and a PSA doubling time >6 mo (p = 0.009) were significantly correlated to treatment response. Furthermore, gamma-glutamyl transferase ≤31 U/L at the start of 177Lu PSMA therapy was correlated with 1.5 times higher risk of progression for patients without but not with visceral metastases (p = 0.046). CONCLUSIONS: 177Lu PSMA is an effective treatment option in mCRPC in the real-world setting. A PSA decrease ≥30% after the first two cycles is an early marker of response that can be easily implemented in clinical practice. PATIENT SUMMARY: 177Lu PSMA is a radioactive agent approved for treatment of advanced prostate cancer. We reviewed its use outside of clinical trials for patients treated at eight European centers. We found that 177Lu PSMA is an effective treatment option in real-world practice. A PSA (prostate-specific antigen) decrease of ≥30% after the first two therapy cycles is an early indicator of response to treatment and can be used in personalizing treatments for patients.

Real-world comparison of Docetaxel versus new hormonal agents in combination with androgen-deprivation therapy in metastatic hormone-sensitive prostate cancer descrying PSA Nadir ≤ 0.05 ng/ml as marker for treatment response.

PROPOSE: Using Docetaxel chemotherapy or new hormonal agents (NHT) to intensify upfront systemic therapy resulted in improved survival rates compared to androgen deprivation monotherapy (ADT). Hence, combination therapies have become the new standard of care (SOC) in metastatic hormone-sensitive prostate cancer (mHSPC). However, head-to-head trails comparing different therapies as well as treatment-guiding biomarkers are still lacking. Thus, the aim of the present study was to compare clinical outcomes of Docetaxel versus NHT therapy in the real-world setting as well as to elaborate biomarkers predicting clinical outcome. METHODS: We retrospectively assessed overall-survival (OS), progression-free survival 1 and 2 (PFS1/2) and time to progression (TTP) in 42 patients treated by either ADT + NHT or ADT + Docetaxel. In addition, we investigated clinical prognostic biomarkers. RESULTS: Our survival analysis revealed 3-year OS of 89.4% in the NHT group compared to 82.4% in the Docetaxel group. 3-year PFS1 was 59.6% in the NHT group compared to 32.2% in the Docetaxel group and the TTP was 53.8% vs 32.2% (pOS = 0.189; pPFS1 = 0.082; pTTP = 0.055). In addition, castration-resistance occurred more often in the Docetaxel group (78.6% vs 25%, p = 0.004). Interestingly, a PSA-Nadir ≤ 0.05 ng/ml during therapy was associated with increased survival rates (p < 0.001) while PSA levels at primary diagnosis had no influence on therapy outcome. Furthermore, a thyroid-stimulating hormone (TSH) increase during therapy was associated with improved clinical outcome (p = 0.06). CONCLUSION: We observed a trend towards a higher benefit of NHT as first-line treatment compared to Docetaxel in men with mHSPC. Of note, a PSA-Nadir ≤ 0.05 ng/ml or a TSH-increase during therapy were predictors for therapy response.

Long-Term Treatment with Simvastatin Leads to Reduced Migration Capacity of Prostate Cancer Cells.

Statins have been shown to improve survival of metastatic prostate cancer (mPCa). Nevertheless, their therapeutic use is still under debate. In the present study, we investigated the short-term effects of three different statins (simvastatin, atorvastatin and rosuvastatin) in various PCa cell lines mimicking androgen-sensitive and -insensitive PCa. Moreover, we generated three new PCa cell lines (LNCaPsim, ABLsim, PC-3sim) that were cultured with simvastatin over several months. Our data showed that the three statins expressed highly diverse short-term effects, with the strongest growth-inhibitory effect from simvastatin in PC-3 cells and almost no effect from rosuvastatin in any of the cell lines. Long-term treatment with simvastatin resulted in a loss of response to statins in all three cell lines, which was associated with an upregulation of cholesterol and fatty acid pathways as revealed through RNA sequencing. Despite that, long-term treated cells exhibited diminished spheroid growth and significantly reduced migration capacity per se and to differentiated osteoclasts. These findings were strengthened by reduced expression of genes annotated to cell adhesion and migration after long-term simvastatin treatment. Notably, mPCa patients taking statins were found to have lower numbers of circulating tumor cells in their blood with reduced levels of PSA and alkaline phosphatase. Our data suggest that long-term usage of simvastatin hampers the metastatic potential of PCa cells and may therefore be a potential therapeutic drug for mPCa.

Validation of Cell-Free RNA and Circulating Tumor Cells for Molecular Marker Analysis in Metastatic Prostate Cancer.

Since tissue material is often lacking in metastatic prostate cancer (mPCa), there is increasing interest in using liquid biopsies for treatment decision and monitoring therapy responses. The purpose of this study was to validate the usefulness of circulating tumor cells (CTCs) and plasma-derived cell-free (cf) RNA as starting material for gene expression analysis through qPCR. CTCs were identified upon prostate-specific membrane antigen and/or cytokeratin positivity after enrichment with ScreenCell (Westford, Massachusetts, USA) filters or the microfluidic ParsortixTM (Guildford, Surrey, United Kingdom) system. Overall, 50% (28/56) of the patients had ≥5 CTCs/7.5 mL of blood. However, CTC count did not correlate with Gleason score, serum PSA, or gene expression. Notably, we observed high expression of CD45 in CTC samples after enrichment, which could be successfully eliminated through picking of single cells. Gene expression in picked CTCs was, however, rather low. In cfRNA from plasma, on the other hand, gene expression levels were higher compared to those found in CTCs. Moreover, we found that PSA was significantly increased in plasma-derived cfRNA of mPCa patients compared to healthy controls. High PSA expression was also associated with poor overall survival, indicating that using cfRNA from plasma could be used as a valuable tool for molecular expression analysis.

Organ-Sparing Surgery in Testicular Tumor: Is This the Right Approach for Lesions ≤ 20 mm?

Background: This study was conducted in order to analyze factors predicting malignancy in patients undergoing organ-sparing surgery (OSS) for small testicular lesions. Methods: Patients with small (£20 mm) marker-negative clinical stage I testicular tumors were managed by OSS with tumor enucleation and frozen section examination (FSE) for the past 15 years at our institution. Benign and malignant cases were compared, focusing on preoperative and postoperative lesion sizes. Results: Eighty-nine patients were enrolled in this retrospective study. Ten (11.2%) of them were treated for synchronous bilateral tumors. Sixty-seven (67.7%) of ninety-nine lesions were benign, confirming a high concordance rate (98%) between FSE and final histology. Patients with benign tumors were significantly older than patients with malignant tumors (p = 0.026), and benign tumors were detected more frequently during urologic work-up of hormone disorders (p = 0.001). Preoperative tumor size was a strong predictor of malignancy (area under the curve (AUC) = 0.726; p < 0.001). According to the Youden index, the best cutoff to predict tumor dignity was 13.5 mm, resulting in a sensitivity and specificity of 53% and 85%, respectively. No cases of local recurrence or distant metastasis were confirmed after a median follow-up of 42 months. Conclusion: Our findings are consistent with previous reports, supporting an OSS approach in small testicular tumors whenever possible. Most tumors ≤ 20 mm were benign, and in the case of malignancy, OSS with FSE and consecutive orchiectomy is oncologically safe due to the high concordance rate of FSE and final histology, thus preventing a two-stage procedure.

Patient-reported urinary incontinence and erectile dysfunction following radical prostatectomy: results from the European Prostate Centre Innsbruck.

INTRODUCTION: Urinary and erectile functions were assessed by using self-administered validated questionnaires in patients undergoing radical prostatectomy. MATERIALS AND METHODS: In a prospective observational study, a total of 253 consecutive patients diagnosed with clinically localised prostate cancer between 2008 and 2009 at the European Prostate Centre Innsbruck were included. Patient-reported outcomes were assessed before radical prostatectomy and 12 months postoperatively using the validated International Consultation on Incontinence Questionnaire (ICIQ) and the International Index of Erectile Function (IIEF). The Wilcoxon signed-rank test and Chi square statistics were used for analysis. RESULTS: The study showed that before radical prostatectomy, urinary incontinence of various severity grades was reported in 18.8, postoperatively in 63.0% (p < 0.001) and erectile dysfunction of various degrees was reported in 39.6 at baseline compared to 80.1% 12 months postoperatively (p < 0.001). CONCLUSIONS: This study suggests that radical prostatectomy is associated with a significantly increased risk of urinary incontinence and erectile dysfunction 12 months postoperatively.

Multiparametric magnetic resonance imaging/transrectal ultrasound fusion targeted biopsy of the prostate: preliminary results of a prospective single-centre study.

PURPOSE: To evaluate multiparametric magnetic resonance imaging/transrectal ultrasound (mpMRI/TRUS) fusion targeted biopsy (TB) of the prostate for prostate cancer (PCa) diagnosis. PATIENTS AND METHODS: From April 2013 to January 2014, 53 men were included in this prospective single-centre study. The degree of PCa suspicion from mpMRI findings was classified according to the PI-RADS scoring system. Of these, 50 patients underwent both an mpMRI/TRUS fusion TB and a 10-core systematic biopsy (SB) of the prostate and were eligible for analysis. RESULTS: 225 targeted and 500 systematic cores were included in this study. PCa was histologically confirmed in 52.0% of patients (26/50), whereas TB revealed PCa in 46.0% (23/50) and SB in 36.0% (18/50). TB identified PCa in 16.0% of all patients (8/50) that were missed by SB. All told, the targeted core was 2.8 times more likely to be PCa-positive than the systematic core (29.3 vs. 10.4%). CONCLUSIONS: mpMRI/TRUS fusion TB of the prostate is safe, practicable and may improve PCa diagnosis using fewer biopsy cores compared to SB.

Evaluation of the PI-RADS scoring system for mpMRI of the prostate: a whole-mount step-section analysis.

PURPOSE: Evaluation of the Prostate Imaging Reporting and Data System (PI-RADS) scoring system for classifying multi-parametric magnetic resonance imaging findings of the prostate using whole-mount step-section slides as reference standard. MATERIALS AND METHODS: Prospective inclusion of 50 consecutive patients with biopsy-proven prostate cancer (PCa). All patients received a multi-parametric MRI of the prostate, consisting of T2-weighted, diffusion-weighted, and dynamic contrast-enhanced MRI. After prostatectomy, all prostates were prepared as whole-mount step-section slides. For each patient, six lesions were predefined on whole-mount step-sections according to a distinct scheme and the corresponding regions were identified on MRI. Each lesion then was scored on MRI according to PI-RADS by an experienced blinded uro-radiologist and compared with histopathological findings. RESULTS: PCa received significant (p < 0.01) higher overall PI-RADS scores (4.10 ± 0.75) compared with benign changes (2.00 ± 0.74). In the peripheral zone, each single modality score showed good diagnostic accuracy for PCa detection (area under the curve [AUC] > 0.90). When combining all single modality scores, an even higher discriminative ability of PCa detection (AUC = 0.97, 95 % CI 0.95-0.99) could be achieved. In contrast, in the transitional zone, dynamic contrast-enhanced MRI (DCE) showed very low diagnostic accuracy (AUC = 0.60). Regarding tumor malignancy, no high-grade PCa (Gleason >7a) was present at PI-RADS scores <4 and no Gleason 6 PCa at a PI-RADS score of 5. CONCLUSION: The PI-RADS scoring system showed good diagnostic accuracy: Only PI-RADS 4 and 5 showed high-grade PCa. However, it seems necessary to revise the PI-RADS scoring system concerning DCE in the transitional zone.

Adverse pathological findings in needle biopsy gleason score 6 prostate cancers with low and intermediate preoperative PSA levels following radical prostatectomy.

AIM: We retrospectively analyzed the risk associated with undergrading Gleason score 6 (GS6) prostate cancer (PCa) at biopsy, in patients with preoperative PSA levels of 2-3,99 and 4-10 ng/ml. PATIENTS AND METHODS: A total of 674 patients with needle biopsy-diagnosed GS6 PCa, who underwent radical prostatectomy (RP) between 1995 and 2011, were evaluated. Patients were stratified by preoperative PSA levels into low PSA (2-3,99 ng/ml) and an intermediate PSA of 4-10 ng/ml. Subsequently, the percentage of patients with extracapsular disease (pathological stage ≥pT3a) and/or positive surgical margins was determined among those whose RP GS was still 6 and compared to undergraded cases. RESULTS: Out of 674 patients with needle biopsy-diagnosed GS6 PCa, 36.2% had no difference between biopsy and RP GS while 11.4% had been overgraded and 52.4% of patients were undergraded at biopsy. Stratified according to preoperative PSA levels, there was a significantly higher incidence of undergrading in the intermediate PSA group. Among those with ≥pT3a tumors, 74.1 % were undergraded in needle biopsy, out of which 67.7% had intermediate PSA levels and 32.3% low PSA levels. Among patients with R1 resections 75.1 % were underdiagnosed, out of which 75.9% had intermediate PSA levels. Stratifying these data according to preoperative PSA levels, ≥pT3a tumors and R1 resection were found significantly more often in the intermediate-PSA group. CONCLUSION: The incidence of adverse pathological findings, including extraprostatic extension and positive surgical margins, is significantly higher in patients with undergraded biopsy GS6. Low preoperative PSA levels improved the correlation between primary and final GS and led to the reduction of unfavorable pathological findings.