Real-World Evidence of Triplet Therapy in Metastatic Hormone-Sensitive Prostate Cancer: An Austrian Multicenter Study.

INTRODUCTION: Two randomized trials demonstrated a survival benefit of triplet therapy (androgen deprivation therapy [ADT]) plus androgen receptor pathway inhibitor [ARPI] plus docetaxel) over doublet therapy (ADT plus docetaxel), thus changing treatment strategies in metastatic hormonesensitive prostate cancer (mHSPC). PATIENTS AND METHODS: We conducted the first real-world analysis comprising 97 mHSPC patients from 16 Austrian medical centers, among them 79.4% of patients received abiraterone and 17.5% darolutamide treatment. Baseline characteristics and clinical parameters during triplet therapy were documented. Mann-Whitney U test for continuous or X²-test for categorical variables was used. Variables on progression were tested using logistic regression analysis and tabulated as hazard ratios (HR), 95% confidence interval (CI). RESULTS: Of 83.5% patients with synchronous and 16.5% with metachronous disease were included. 83.5% had high-volume disease diagnosed by conventional imaging (48.9%) or PSMA PET-CT (51.1%). While docetaxel and ARPI were administered consistent with pivotal trials, prednisolone, prophylactic gCSF and osteoprotective agents were not applied guideline conform in 32.5%, 37%, and 24.3% of patients, respectively. Importantly, a nonsimultaneous onset of chemotherapy and ARPI, performed in 44.3% of patients, was associated with significantly worse treatment response (P = .015, HR 0.245). Starting ARPI before chemotherapy was associated with significantly higher probability for progression (P = .023, HR 15.781) than vice versa. Strikingly, 15.6% (abiraterone) and 25.5% (darolutamide) low-volume patients as well as 14.4% (abiraterone) and 17.6% (darolutamide) metachronous patients received triplet therapy. Adverse events (AE) occurred in 61.9% with grade 3 to 5 in 15% of patient without age-related differences. All patients achieved a PSA decline of 99% and imaging response was confirmed in 88% of abiraterone and 75% of darolutamide patients. CONCLUSIONS: Triplet therapy arrived in clinical practice primarily for synchronous high-volume mHSPC. Regardless of selected therapy regimen, treatment is highly effective and tolerable. Preferably therapy should be administered simultaneously, however if not possible, chemotherapy should be started first.

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.

Transurethral resection of the prostate in 85+ patients: a retrospective, multicentre study.

PURPOSE: To determine the safety and efficacy of transurethral resection of the prostate (TUR-P) in patients 85 years or older. METHODS: In this retrospective, multicentre study, patients equal or older than 85 years at the time of surgery (2015-2020) were included. Several pre-, peri- and postoperative parameters were collected. The main outcome criterion was spontaneous voiding with a post-void residual (PVR) volume < 100 ml at dismission and at 12 months after surgery. RESULTS: One hundred sixty-eight patients (median age: 87 years, interquartile range [IQR]: 86-89) were recruited. The patients took on average 5.2 permanent medications (3-8), 107 (64%) were anticoagulated preoperatively and neurological co-morbidities were present in 29 (17%). The indication for surgery was recurrent urinary retention in 66.3% (n = 110) with a mean retention volume of 849 ml. The mean PVR volume of the remaining 35% was 146 ml. Surgery was successfully completed in all patients. A perioperative surgical revision had to be performed in 3% and 13 patients (7.7%) required blood transfusion. After catheter removal, 85% of patients were able to void spontaneously with a PVR < 100 ml, and 14.3% were dismissed with a catheter. Twelve months data were available for 93 patients (55%). Of this cohort, 78 (83.9%) were able to void spontaneously with a PVR < 100 ml, 12 (12.9%) were on permanent catheterization. One patient (0.6%) died perioperatively. The only significant factor associated with an unsuccessful outcome was the number of permanent medications (6.8 vs. 5.0, p = 0.005). CONCLUSION: This retrospective multicentre study documents the safety and efficacy of TURP (monopolar and bipolar) in the old-old cohort.

Effects of cycling and rowing on serum concentrations of prostate-specific antigen: A randomized study of 101 male subjects.

OBJECTIVE: To determine the effects if cycling and rowing on serum prostate-specific antigen (PSA) levels. METHODS: Male volunteers (n = 101), aged 20-80 (mean, 49.9) years were randomized to exercise at the first or second study visit. They performed 1 h of either cycling or rowing on a stationary machine. To determine exercise-induced effects on the PSA level, serum total PSA (tPSA) and free PSA (fPSA) concentrations were evaluated before and after exercise and another sampling was performed at the second study visit. Pre-exercise and postexercise tPSA and fPSA concentrations were compared using the Wilcoxon matched-pairs test. The results were analyzed using the Mann-Whitney U-test. RESULTS: A significant (p < 0.001) average increase in tPSA after exercise (1.14 ± 1.11 ng/ml to 1.24 ± 1.26 ng/ml [mean, +8.8%]) was observed after both cycling and rowing, without significant differences between the sports (p = 0.54). The exercise-induced increase in PSA concentration affected participants aged ≥50 years (difference, 0.16 ± 0.37; p < 0.001), but not those aged <50 years (difference, 0.01 ± 0.06; p = 0.23). The effect size was clinically irrelevant in all except two outliers, in whom a distinct increase of PSA level by averages of 1.80 ng/ml (+55%) for tPSA and 1.25 ng/ml (+227%) for fPSA following cycling was observed. CONCLUSION: Rowing and cycling generally do not have a clinically relevant effect on PSA levels. However, outliers exist. Our findings do not support abstaining from exercise during the days approaching PSA sampling.

A real-world comparison of docetaxel versus abiraterone acetate for metastatic hormone-sensitive prostate cancer.

BACKGROUND: Docetaxel (D) or secondary hormonal therapy (SHT) each combined with androgen deprivation therapy (ADT) represent possible treatment options in males with metastasized hormone-sensitive prostate cancer (mHSPC). Real-world data comparing different protocols are lacking yet. Thus, our objective was to compare the efficacy and safety of abiraterone acetate (AA)+ADT versus D+ADT in mHSPC. METHODS: In a retrospective multicenter analysis including males with mHSPC treated with either of the aforementioned protocols, overall survival (OS), progression-free survival 1 (PFS1), and progression-free survival 2 (PFS2) were assessed for both cohorts. Median time to event was tested by Kaplan-Meier method and log-rank test. The Cox-proportional hazards model was used for univariate and multivariate regression analyses. RESULTS: Overall, 196 patients were included. The AA+ADT cohort had a longer PFS1 in the log-rank testing (23 vs. 13 mos., p < 0.001), a longer PFS2 (48 vs. 33 mos., p = 0.006), and longer OS (80 vs. 61 mos., p = 0.040). In the multivariate analyses AA+ADT outperformed D+ADT in terms of PFS1 (HR = 0.34, 95% CI = 0.183-0.623; p = 0.001) and PFS2 (HR = 0.33 95% CI = 0.128-0.827; p = 0.018), respectively, while OS and toxicity rate were similar between both groups. CONCLUSIONS: AA+ADT is mainly associated with a similar efficacy and overall toxicity rate as D+ADT. Further prospective research is required for validation of the clinical value of the observed benefit of AA+ADT for progression-free end-points.

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.

Acceptance of female urologists among patients with suspected prostate disease.

BACKGROUNDS: The number of practicing female urologists is rising. The aim of this study is to evaluate the acceptance of female urologists by male patients and their partners. METHODS: Men who underwent a prostate MRI or a prostate biopsy between January and December 2018 and their partners, were sent questionnaires prior to the examination. Two types of questionnaires were used. One questionnaire asked "I want to be seen by: (I) a male urologist or (II) a female urologist or (III) no preference" (Groupnp), the other questionnaire only offered two possible answers: "I want to be seen by: (I) a male urologist or (II) a female urologist" (Groupm,f). All other questions were on prostate MRI and prostate biopsies. RESULTS: Overall, 377 questionnaires were sent to patients. One hundred and ninety-six questionnaires (52.0%) were returned. In Groupnp, 34.7% wanted to be seen by a male urologist, 60.8% of patients chose "no preference". The answers of the patients' female partners in Groupnp did not differ statistically significant (57.3% chose "no preference", 0% chose a female urologist). In Groupm,f, 54.5% of patients preferred a male urologist, one patient wanted to be seen by a female urologist, 44.3% did not answer the question. In Groupm,f, there was no statistically significant difference in preference in regard to the doctor's gender between the patients and their female partners (57% of partners wanted a male urologist, 0% wanted a female urologist). CONCLUSIONS: A large number of patients with prostate disease and their partners prefer male urologists rather than female urologists.

Treatment of Metastasized Prostate Cancer Beyond Progression After Upfront Docetaxel-A Real-world Data Assessment.

BACKGROUND: Besides second-generation hormone therapy (sHT), upfront docetaxel along with androgen deprivation therapy is the current standard of care for metastasized hormone-sensitive prostate cancer (mHSPC). Evidence on second-line therapy upon progression on chemohormonal treatment outside clinical trials is scarce. OBJECTIVE: To comparatively assess the efficacy of subsequent therapy after upfront docetaxel in mHSPC in a real-world setting. DESIGN, SETTING, AND PARTICIPANTS: This is a retrospective multicenter analysis. Males with mHSPC on androgen-deprivation therapy progressed to castration-resistant prostate cancer (CRPC) after upfront docetaxel. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall survival (OS), progression-free survival 2 (PFS2), and time to progression 2 (TTP2) were assessed. Chi-square test and Mann-Whitney U test were used for univariate comparison between the sHT and non-sHT (other therapies) cohorts. Median time to event was tested by Kaplan-Meier method and log-rank test. Univariate and multivariate analysis regression was performed with the Cox proportional-hazard model. RESULTS AND LIMITATIONS: Sixty-five patients were included in the final analysis. Median TTP2 was 20 mo, median PFS2 was 29 mo, and median OS was not reached; sHT was an independent predictor of favorable PFS2 as compared with non-sHT. Time to CRPC was also confirmed to be the strongest predictor for novel endpoints PFS2 and TTP2. Time to CRPC >18 mo conferred advantage to sHT over non-sHT in relation to PFS2 and OS. Second-line therapies were well tolerated. The analysis is prone to inherent flaws and biases due to its retrospective nature. CONCLUSIONS: In real-world patients progressing after upfront docetaxel, sHT is independently associated with favorable PFS2 favoring drug class switch. Longer time to CRPC predicts strongly for superior PFS2 and TTP2. Further prospective research is warranted in order to guide treatment sequencing and improve outcomes and quality of life of males with metastasized prostate cancer. PATIENT SUMMARY: We analyzed the efficacy of second-line therapy after docetaxel in hormone-dependent metastatic prostate cancer. Novel hormone therapy appears to be a preferable option for deferring progression optimally. Larger patient databases are eagerly awaited.

Dual Inhibitory Action of a Novel AKR1C3 Inhibitor on Both Full-Length AR and the Variant AR-V7 in Enzalutamide Resistant Metastatic Castration Resistant Prostate Cancer.

The expanded use of second-generation antiandrogens revolutionized the treatment landscape of progressed prostate cancer. However, resistances to these novel drugs are already the next obstacle to be solved. Various previous studies depicted an involvement of the enzyme AKR1C3 in the process of castration resistance as well as in the resistance to 2nd generation antiandrogens like enzalutamide. In our study, we examined the potential of natural AKR1C3 inhibitors in various prostate cancer cell lines and a three-dimensional co-culture spheroid model consisting of cancer cells and cancer-associated fibroblasts (CAFs) mimicking enzalutamide resistant prostate cancer. One of our compounds, named MF-15, expressed strong antineoplastic effects especially in cell culture models with significant enzalutamide resistance. Furthermore, MF-15 exhibited a strong effect on androgen receptor (AR) signaling, including significant inhibition of AR activity, downregulation of androgen-regulated genes, lower prostate specific antigen (PSA) production, and decreased AR and AKR1C3 expression, indicating a bi-functional effect. Even more important, we demonstrated a persisting inhibition of AR activity in the presence of AR-V7 and further showed that MF-15 non-competitively binds within the DNA binding domain of the AR. The data suggest MF-15 as useful drug to overcome enzalutamide resistance.

Correction to: The 68Ga/177Lu-theragnostic concept in PSMA-targeting of metastatic castration-resistant prostate cancer: impact of post-therapeutic whole-body scintigraphy in the follow-up.

The author name Bernhard Nilica was inadvertently interchanged in the original version of this article.

The 68Ga/177Lu-theragnostic concept in PSMA-targeting of metastatic castration-resistant prostate cancer: impact of post-therapeutic whole-body scintigraphy in the follow-up.

INTRODUCTION: A new therapeutic option for metastatic castration-resistant prostate cancer (mCRPC) of heavily pre-treated patients lies in 177Lu-PSMA-617 radioligand therapy. METHODS: On the basis of PSMA-targeted 68Ga-PSMA-11 PET/CT, 32 consecutive mCRPC patients were selected for 177Lu-PSMA-617 therapy (6 GBq/cycle, 2 to 6 cycles, 6-10 weeks apart) and followed until death. Post-therapy whole-body (WB) dosimetry and 68Ga-PSMA-11 PET/CT data were compared and related to progression free and overall survival. RESULTS: 177Lu-PSMA-617 dosimetry after the first cycle indicated high tumor doses for skeletal (4.01 ± 2.64; range 1.10-13.00 Gy/GBq), lymph node (3.12 ± 2.07; range 0.70-8.70 Gy/GBq), and liver (2.97 ± 1.38; range 0.76-5.00 Gy/GBq) metastases whereas the dose for tissues/organs was acceptable in all patients for an intention-to-treat activity of 24 GBq. Any PSA decrease after the first cycle was found in 23/32 (72%), after the second cycle in 22/32 (69%), after the third cycle in 16/28 (57%), and after the fourth cycle in 8/18 (44%) patients. Post-therapy 24 h WB scintigraphy showed decreased tumor-to-background ratios in 24/32 (75%) after the first therapy cycle, after the second cycle in 17/29 (59%), and after the third cycle in 13/21 (62%) patients. The median PFS was 7 months and the median OS 12 months. In the group of PSA responders (n = 22) the median OS was 17 months versus 11 months in the group of non-responders (n = 10), p < 0.05. Decreasing SUVmax values were found for parotid (15.93 ± 6.23 versus 12.33 ± 4.07) and submandibular glands (17.65 ± 7.34 versus 13.12 ± 4.62) following treatment, along with transient (n = 6) or permanent (n = 2) xerostomia in 8/32 (25%) patients. In 3/32 patients, nephrotoxicity changed from Grade 2 to 3, whereas neither Grade 4 nephrotoxicity nor hematotoxicity was found. In most patients a good agreement was observed for the visual interpretation of the tracer accumulation between 24 h WB and PET/CT scans. However, no significance could be calculated for baseline-absorbed tumor doses and SUVmax values of tumor lesions. 5/32 (16%) patients showed a mixed response pattern, which resulted in disease progression over time. CONCLUSION: Serial PSA measurements and post-therapy 24 h WB scintigraphy seems to allow a sufficiently accurate follow-up of 177Lu-PSMA-617-treated mCRPC patients whereas 68Ga-PSMA-11 PET/CT should be performed for patient selection and final response assessment.

Comparison of multiparametric and biparametric MRI of the prostate: are gadolinium-based contrast agents needed for routine examinations?

PURPOSE: To investigate, if and how omitting gadolinium-based contrast agents (GBCA) and dynamic contrast-enhanced imaging (DCE) influences diagnostic accuracy and tumor detection rates of prostate MRI. METHODS: In this retrospective study, 236 patients were included. The results of biparametric (bpMRI) and multiparametric magnetic resonance imaging (mpMRI) were compared using the PI-RADS version 2 scoring system. The distribution of lesions to PIRADS score levels, tumor detection rates, diagnostic accuracy and RoC analysis were calculated and compared to the results of histopathological analysis or 5-year follow-up for benign findings. RESULTS: Omitting DCE changed PI-RADS scores in 9.75% of patients, increasing the number of PI-RADS 3 scores by 8.89% when compared to mpMRI. No change of more than one score level was observed. BpMRI did not show significant differences in diagnostic accuracy or tumor detection rates. (AuC of 0.914 vs 0.917 in ROC analysis). Of 135 prostate carcinomas (PCa), 94.07% were scored identically, and 5.93% were downgraded only from PI-RADS 4 to PI-RADS 3 by bpMRI. All of them were low-grade PCa with Gleason Score 6 or 7a. No changes were observed for PCa ≥ 7b. CONCLUSION: Omitting DCE did not lead to significant differences in diagnostic accuracy or tumor detection rates when using the PI-RADS 2 scoring system. According to these data, it seems reasonable to use a biparametric approach for initial routine prostate MRI. This could decrease examination time and reduce costs without significantly lowering the diagnostic accuracy.

Visibility of MRI prostate lesions on B-mode transrectal ultrasound.

AIM: Prostate biopsies are usually done with transrectal ultrasound (TRUS) in B-mode (B TRUS) but multiparametric MRI (mpMRI) is the gold imaging standard for the visualization of clinically significant prostate cancer (PCa), since a lowPCa detection rate is reported for B TRUS. The aim of this study was to assess the visibility of MRI lesions on B TRUS and to determine which factors may influence the visibility on B TRUS. MATERIAL AND METHODS: 142 men with 148 lesions reported on mpMRI underwent a B TRUS/mpMRI fusion targeted biopsy of the prostate and were included in this retrospective study. During the biopsy, images were obtained and stored in the institution's PACS. These images were reviewed by two radiologists to determine, whether an mpMRI lesion was or was not visible on B TRUS. RESULTS: Overall 92 from 148 mpMRI lesions (62.2%) were visible on B TRUS. The location of the lesion in the prostate, the PIRADS classification of the lesions and the size of the lesion had no significant influence on the visibility on B TRUS. Only the prostate volume had a significant influence on visibility: in smaller prostates significantly more lesions were visible on B TRUS than in large glands (p+0.041; 45.1 ml vs 54 ml). CONCLUSION: The use of newer high-end ultrasound units as well as experience gained from fusion biopsies enables us to see 62.2 % of all suspicious mpMRI lesions on B TRUS. B TRUS images merit a thorough examination during a conventional biopsy setting.

Retrospective analysis of the development of PIRADS 3 lesions over time: when is a follow-up MRI reasonable?

PURPOSE: Often PIRADS 3 findings are usually followed up with further MRIs of the prostate. Current guidelines do not state an optimal interval between the initial MRI and the follow-up MRI. The aim of this study was to find out if PIRADS 3 lesions evolve over time and to determine how long the optimal interval between initial MRI and follow-ups should be. METHODS: In this retrospective study, 141 consecutive patients were included who underwent at least one follow-up MRI after an initial PIRADS 3 finding. Changes in PIRADS score and the interval between the first and the follow-up MRI were recorded. An optimal duration was calculated. RESULTS: Of all patients, 76.6% had a change from PIRADS 3 to either 2 or 4 in the first follow-up MRI. Reclassifications to PIRADS 4 happened earlier than reclassifications to PIRADS 2 (after 366.5 ± 217.9 days and after 534.2 ± 253.0 days, respectively). An optimal point of time for a follow-up to distinguish between changes to PIRADS 2 versus PIRADS 4 turned out to be 379 days (12.4 months, AUC 0.734, p = 0.0001). Of all patients with a PIRADS 3 lesion 14.8% harboured a prostate carcinoma. CONCLUSION: Performing follow-up mpMRI rather than immediate biopsy may be beneficial for patients with PIRADS 3, as most lesions can be reclassified after a manageable period of time. Upgrades to PIRADS 4 seem to happen earlier and within fewer follow-ups than downgrades to PIRADS 2. The optimal interval for follow-up MRIs seems to be 12.4 months.

The Contemporary Use of Radium-223 in Metastatic Castration-resistant Prostate Cancer.

Radium-223 dichloride (radium-223) was approved for the treatment of patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases in the United States and Europe in 2013. This followed a reported overall survival benefit for patients treated with radium-223 and best standard of care (BSoC) when compared with placebo and BSoC in the ALpharadin in SYMptomatic Prostate CAncer (ALSYMPCA) trial. At that time, docetaxel was the standard first-line choice for patients with metastatic CRPC (mCRPC). Since then, the treatment landscape has changed dramatically with new hormonal agents (abiraterone and enzalutamide) considered to be the first-line choice for many patients. The optimal patient profile for radium-223 in the modern setting, and its best use either in sequence or in combination with other approved agents are unclear, with few definitive guidelines available. This article reports on the views of a group of urologists and medical oncologists experienced in treating patients with mCRPC with radium-223 in routine clinical practice. The aim is to provide an overview of the current use of radium-223 in the treatment of patients with mCRPC, and to discuss best practices for patient selection and on-treatment monitoring. Where agreement was reached, guidance on the optimal use of radium-223 is provided.

Early PET imaging with [68]Ga-PSMA-11 increases the detection rate of local recurrence in prostate cancer patients with biochemical recurrence.

PURPOSE: PET/CT using 68Ga-labelled prostate-specific membrane antigen PSMA-11 (HBEDD-CC) has emerged as a promising imaging method in the diagnostic evaluation of prostate cancer (PC) patients with biochemical recurrence. However, assessment of local recurrence (LR) may be limited by intense physiologic tracer accumulation in the urinary bladder on whole-body scans, normally conducted 60 min post-tracer injection (p.i.). It could be shown on early dynamic imaging studies that 68Ga-PSMA-11 uptake in PC lesions occurs earlier than tracer accumulation in the urinary bladder. This study aims to investigate whether early static PET acquisition increases detection rate of local recurrence on 68Ga-PSMA-11 PET/CT in comparison to PET imaging 60 min p.i.. METHODS: 203 consecutive PC patients with biochemical failure referred to 68Ga-PSMA-11 PET/CT were analysed retrospectively (median prostate specific antigen (PSA) value: 1.44 ng/ml). In addition to whole-body PET/CT scans 60 min p.i., early static imaging of the pelvis was performed, starting at a median time of 283 s p.i. (range: 243-491 s). Assessment was based on visual analysis and calculation of maximum standardized uptake value (SUVmax) of pathologic lesions present in the pelvic area found on early PET imaging and on 60 min-PET scans. RESULTS: 26 patients (12.8%) were judged positive for LR on PET scans 60 min p.i. (median SUVmax: 10.8; range: 4.7-40.9), whereas 50 patients (24.6%) revealed a lesion suggestive of LR on early PET imaging (median SUVmax: 5.9; range: 2.9-17.6), resulting in a significant rise in detection rate (p < 0.001). Equivocal findings on PET scans 60 min p.i. decreased significantly with the help of early imaging (15.8% vs. 4.5% of patients; p < 0.001). Tracer activity in the urinary bladder with a median SUVmax of 8.2 was present in 63 patients on early PET scans (31.0%). However, acquisition starting time of early PET scans differed significantly in the patient groups with and without urinary bladder activity (median starting time of 321 vs. 275 s p.i.; range: 281-491 vs. 243-311 s p.i.; p < 0.001). Median SUVmax value of lesions suggestive of LR on early images was significantly higher in comparison to gluteal muscle, inguinal vessels and seminal vesicle/anastomosis (median SUVmax: 5.9 vs. 1.9, 4.0 and 2.4, respectively). CONCLUSIONS: Performance of early imaging in 68Ga-PSMA-11 PET/CT in addition to whole-body scans 60 min p.i. increases the detection rate of local recurrence in PC patients with biochemical recurrence. Acquisition of early PET images should be started as early as 5 min p.i. in order to avoid disturbing tracer activity in the urinary bladder occuring at a later time point.

The 68Ga/177Lu theragnostic concept in PSMA targeting of castration-resistant prostate cancer: correlation of SUVmax values and absorbed dose estimates.

INTRODUCTION: A targeted theragnostic approach based on increased expression of prostate-specific membrane antigen (PSMA) on PC cells is an attractive treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: Ten consecutive mCRPC patients were selected for 177Lu-PSMA617 therapy on the basis of PSMA-targeted 68Ga-PSMA-HBED-CC PET/CT diagnosis showing extensive and progressive tumour load. Following dosimetry along with the first therapy cycle restaging (68Ga-PSMA-HBED-CC and 18F-NaF PET/CT) was performed after 2 and 3 therapy cycles (each 6.1 ± 0.3 GBq, range 5.4-6.5 GBq) given intravenously over 30 minutes, 9 ± 1 weeks apart. PET/CT scans were compared to 177Lu-PSMA617 24-hour whole-body scans and contrast-enhanced dual-phase CT. Detailed comparison of SUVmax values and absorbed tumour doses was performed. RESULTS: 177Lu-PSMA617 dosimetry indicated high tumour doses for skeletal (3.4 ± 1.9 Gy/GBq; range 1.1-7.2 Gy/GBq), lymph node (2.6 ± 0.4 Gy/GBq; range 2.3-2.9 Gy/GBq) as well as liver (2.4 ± 0.8 Gy/GBq; range 1.7-3.3 Gy/GBq) metastases whereas the dose for tissues/organs was acceptable in all patients for an intention-to-treat activity of 18 ± 0.3 GBq. Three patients showed partial remission, three mixed response, one stable and three progressive disease. Decreased 177Lu-PSMA617 and 68Ga-PSMA-HBED-CC uptake (mean SUVmax values 20.2 before and 15.0 after 2 cycles and 11.5 after 3 cycles, p < 0.05) was found in 41/54 skeletal lesions, 12/13 lymph node metastases, 3/5 visceral metastases and 4/4 primary PC lesions. CONCLUSION: Due to substantial individual variance, dosimetry is mandatory for a patient-specific approach following 177Lu-PSMA617 therapy. Higher activities and/or shorter treatment intervals should be applied in a larger prospective study.

Early dynamic imaging in 68Ga- PSMA-11 PET/CT allows discrimination of urinary bladder activity and prostate cancer lesions.

PURPOSE: PET/CT with 68Ga-labelled prostate-specific membrane antigen (PSMA)-ligands has been proven to establish a promising imaging modality in the work-up of prostate cancer (PC) patients with biochemical relapse. Despite a high overall detection rate, the visualisation of local recurrence may be hampered by high physiologic tracer accumulation in the urinary bladder on whole body imaging, usually starting 60 min after injection. This study sought to verify whether early dynamic 68Ga-PSMA-11 (HBED-CC)PET/CT can differentiate pathologic PC-related tracer uptake from physiologic tracer accumulation in the urinary bladder. METHODS: Eighty consecutive PC patients referred to 68Ga -PSMA-11 PET/CT were included in this retrospective analysis (biochemical relapse: n = 64; primary staging: n = 8; evaluation of therapy response/restaging: n = 8). In addition to whole-body PET/CT acquisition 60 min post injection early dynamic imaging of the pelvis in the first 8 min after tracer injection was performed. SUVmax of pathologic lesions was calculated and time-activity curves were generated and compared to those of urinary bladder and areas of physiologic tracer uptake. RESULTS: A total of 55 lesions consistent with malignancy on 60 min whole body imaging exhibited also pathologic 68Ga-PSMA-11 uptake during early dynamic imaging (prostatic bed/prostate gland: n = 27; lymph nodes: n = 12; bone: n = 16). All pathologic lesions showed tracer uptake within the first 3 min, whereas urinary bladder activity was absent within the first 3 min of dynamic imaging in all patients. Suvmax was significantly higher in PC lesions in the first 6 min compared to urinary bladder accumulation (p < 0.001). In the subgroup of PC patients with biochemical relapse the detection rate of local recurrence could be increased from 20.3 to 29.7%. CONCLUSIONS: Early dynamic imaging in 68Ga-PSMA-11 PET/CT reliably enables the differentiation of pathologic tracer uptake in PC lesions from physiologic bladder accumulation. Performance of early dynamic imaging in addition to whole body imaging 60 min after tracer injection might improve the detection rate of local recurrence in PC patients with biochemical relapse referred for 68Ga-PSMA-11 PET/CT.