There are few prospective studies addressed toward the role of 68Gallium-labelled prostate-specific membrane antigen-11 ([68Ga]Ga-PSMA-11) compared to [18F]Fluorocholine ([18F]FCH) PET/CT in clinical decision-making as prostate-specific PET-tracers. This study aims to evaluate the impact of PET/CT using [68Ga]Ga-PSMA-11 and [18F]FCH in clinical management of recurrent prostate cancer (PCa) and correlates imaging findings with clinical characteristics of PCa. Forty-six patients with PCa (mean age 68.3 ± 6.3 years) with biochemical recurrence were enrolled in this prospective crossover trial. All patients underwent both [68Ga]Ga-PSMA-11 and [18F]FCH PET/CT within a maximum interval of 12 days (median 7d). A standard randomization tool randomized the sequence of PET/CT imaging. Clinical decision-making occurred in an interdisciplinary meeting considering PET/CT findings. PET/CT-blinded readings were performed 3 months after imaging followed by a consensus meeting for final interpretation of detected lesions. Both imaging modalities detected 136 total malignant lesions. [68Ga]Ga-PSMA-11 and [18F]FCH PET/CT detected 125 and 60 lesions with a sensitivity of 96

Representativeness of Study Participants

AbstractPurpose: Surveillance of clinical stage I (CSI) testicular germ cell tumors (GCT) is hampered by low sensitivity and specificity of current biomarkers for detecting relapses. This study evaluated if serum levels of microRNA371a-3p (M371 test) can: (i) Accurately detect relapses, (ii) detect relapses earlier than conventional technology, and (iii) if elevated postoperative M371 levels may predict relapse. Experimental Design: In a multicentric setting, 258 patients with testicular CSI GCT were prospectively followed by surveillance for a median time of 18 months with serial measurements of serum M371 levels, in addition to standard diagnostic techniques. Diagnostic characteristics of M371 for detecting relapses were calculated using ROC curve analysis. Results: Thirty-nine patients recurred (15.1%), all with elevated M371 levels; eight without relapse had elevations, too. The test revealed the following characteristics: area under the ROC curve of 0.993, sensitivity 100%, specificity 96.3%, positive predictive value 83%, negative predictive value 100%. Earlier relapse detection with the test was found in 28%, with non-significant median time gain to diagnosis. Postoperative M371 levels did not predict future relapse. Conclusions: The sensitivity and specificity of the M371 test for detecting relapses in CSI GCTs are much superior to those of conventional diagnostics. However, post-orchiectomy M371 levels are not predictive of relapse, and there is no significant earlier relapse detection with the test. In all, there is clear evidence for the utility of the M371 test for relapse detection suggesting it may soon be ready for implementation into routine follow-up schedules for patients with testicular GCT.

The implementation of triplet therapy, consisting of androgen deprivation therapy (ADT), androgen pathway inhibitor (ARPI) and chemotherapy, recently changes the treatment regimens in metastatic hormone-sensitive prostate cancer (mHSPC). Here, we present real-world clinical data on the performance and tolerability in 97 Austrian patients. Among our broad and variable patients collective we show great response rates combined with an acceptable tolerability. Furthermore, we show that treatment was not started simultaneously in 44.8% of patients which was associated with worse response rates. Starting ARPI before chemotherapy was associated with significant higher probability for progression ( P = .023, HR 15.781) than vice versa. 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 dur ing tr iplet therapy were documented. Mann -Whitney U test for continuous or X 2 -test for categor ical var iables 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 pr imar ily 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.

Importance:Studies with nivolumab, an approved therapy for metastatic urothelial carcinoma (mUC) after platinum-based chemotherapy, demonstrate improved outcomes with added high-dose ipilimumab. Objective:To assess efficacy and safety of a tailored approach using nivolumab + ipilimumab as an immunotherapeutic boost for mUC. Design, Setting, and Participants:In this phase 2 nonrandomized trial, patients with mUC composed 2 cohorts. Cohort 1 received first-line or second-/third-line nivolumab with escalating doses of ipilimumab, and cohort 2 received second-/third-line nivolumab with high-dose ipilimumab. Recruitment spanned 26 sites in Germany and Austria from August 8, 2017, to February 18, 2021. All patients had a 70% or higher Karnofsky Performance Score and measurable disease per Response Evaluation Criteria in Solid Tumours, version 1.1. Interventions:All patients initiated 4 doses of 240-mg nivolumab (1× every 2 wk). Week 8 nonresponders received nivolumab + ipilimumab (1× every 3 wk). Cohort 1 received 2 doses of 3-mg/kg nivolumab + 1-mg/kg ipilimumab followed by 2 doses of 1-mg/kg nivolumab + 3-mg/kg ipilimumab if no response. Due to safety concerns, cohort 1 treatment was halted, and first-line cohort 2 treatment was not pursued. Cohort 2 received 2 to 4 doses of 1-mg/kg nivolumab + 3-mg/kg ipilimumab. Responders continued with nivolumab maintenance but could receive nivolumab + ipilimumab for later progression. Main Outcomes and Measures:The primary end point was objective response rate. Results:The study comprised 169 patients (118 [69.8%] men; median [range] age, 68 [37-84] years): 86 in cohort 1 (42 first-line; 44 second-/third-line) and 83 in cohort 2. The median (IQR) follow-up times were 10.4 (4.2-23.5) months (first-line cohort 1), 7.5 (3.1-23.8) months (second-/third-line cohort 1), and 6.2 (3.2-22.7) months (cohort 2). Response rates to nivolumab induction were 12/42 (29%, first-line cohort 1), 10/44 (23%, second-/third-line cohort 1), and 17/83 (20%, cohort 2). Response rates to a tailored approach were 20/42 (48% [90% CI, 34%-61%], first-line cohort 1), 12/44 (27% [90% CI, 17%-40%], second-/third-line cohort 1), and 27/83 (33% [90% CI, 23%-42%], cohort 2). Three-year overall survival rates for first-line cohort 1, second-/third-line cohort 1, and cohort 2 using the Kaplan-Meier method were 32% (95% CI, 17%-49%), 19% (95% CI, 8%-33%), and 34% (95% CI, 23%-44%), respectively. Conclusions and Relevance:In this nonrandomized trial, although first-line cohort 1 treatment improved objective response rates, considerable progression events urge caution with this as a first-line therapy. Second-/third-line cohort 1 treatment did not improve response rates compared with nivolumab monotherapy. However, added high-dose ipilimumab may improve tumor response and survival in patients with mUC. Trial Registration:ClinicalTrials.gov Identifier: NCT03219775.

Background Nivolumab is used after platinum-based chemotherapy in patients with metastatic urothelial carcinoma. Studies suggest improved outcomes for dual checkpoint inhibition with high ipilimumab doses. We aimed to examine the safety and activity of nivolumab induction and high-dose ipilimumab as an immunotherapeutic boost as a second-line treatment for patients with metastatic urothelial carcinoma.Methods TITAN-TCC is a multicentre, single-arm, phase 2 trial done at 19 hospitals and cancer centres in Germany and Austria. Adults aged 18 years or older with histologically confirmed metastatic or surgically unresectable urothelial cancer of the bladder, urethra, ureter, or renal pelvis were eligible. Patients had to have progression during or after first-line platinum-based chemotherapy and up to one more second-line or third-line treatment, a Karnofsky Performance Score of 70 or higher, and measurable disease as per Response Evaluation Criteria in Solid Tumors version 1.1. After four doses of intravenous nivolumab 240 mg induction monotherapy every 2 weeks, patients with a partial or complete response at week 8 continued maintenance nivolumab, whereas those with stable or progressive disease (non-responders) at week 8 received a boost of two or four doses of intravenous nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks. Patients who subsequently had progressive disease during nivolumab maintenance also received a boost, using this schedule. The primary endpoint was the confirmed investigator-assessed objective response rate in the intention-to-treat population and had to exceed 20% for the null hypothesis to be rejected (based on the objective response rate with nivolumab monotherapy in the CheckMate-275 phase 2 trial). This study is registered with ClinicalTrials.gov, NCT03219775, and is ongoing.Findings Between April 8, 2019, and Feb 15, 2021, 83 patients with metastatic urothelial carcinoma were enrolled and all received nivolumab induction treatment (intention-to-treat population). The median age of enrolled patients was 68 years (IQR 61-76), and 57 (69%) were male and 26 (31%) were female. 50 (60%) patients received at least one boost dose. A confirmed investigator-assessed objective response was recorded in 27 (33%) of 83 patients in the intention-to-treat population, including six (7%) patients who had a complete response. This objective response rate was significantly higher than the prespecified threshold of 20% or less (33% [90% CI 24-42]; p=0 center dot 0049). The most common grade 3-4 treatment-related adverse events were immune-mediated enterocolitis (nine [11%] patients) and diarrhoea (five [6%] patients). Two (2%) treatment-related deaths were reported, both due to immune-mediated enterocolitis.Interpretation Treatment with nivolumab and nivolumab plus ipilimumab boosts in early non-responders and patients who progress late significantly improved objective response rate after previous platinum-based chemotherapy compared with the rate reported with nivolumab in the CheckMate-275 trial. Our study provides evidence for the added value of high-dose ipilimumab 3 mg/kg and suggests a potential role for the combination as a rescue strategy in platinum-pretreated patients with metastatic urothelial carcinoma.Funding Bristol Myers Squibb. Copyright (c) 2023 Published by Elsevier Ltd. All rights reserved.

Background: The role of immune checkpoint inhibitor (ICI) maintenance therapy in metastatic renal cell carcinoma (mRCC) is undefined.Objective: To determine whether switch maintenance therapy with nivolumab improves clinical outcomes in patients with mRCC with tyrosine kinase inhibitor (TKI) sensitivity. Design, setting, and participants: This open-label phase 2 trial randomized patients with a partial response or stable disease after 10-12-wk TKI induction therapy to either TKI or nivolumab maintenance. Key inclusion criteria were measurable disease, clear cell histology, Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2, and adequate organ function.Intervention: Intravenous nivolumab 8 x 240 mg every 2 wk, followed by 480 mg every 4 wk or sunitinib 50 mg (4-2 regimen) or pazopanib 800 mg once daily orally.Outcome measurements and statistical analyses: The primary endpoint was overall sur-vival (OS). Secondary endpoints were the objective response rate (ORR; Response Evaluation Criteria in Solid Tumors v1.1), progression-free survival (PFS), safety (Common Terminology Criteria for Adverse Events v4.03), and patient-reported out-comes (Functional Assessment of Cancer Therapy Kidney Symptom Index). The Kaplan-Meier method, two-sided log-rank tests, and Cox regression models were used for statistical analysis.Results and limitations: Maintenance therapy was nivolumab for 25 patients (51.0%) and TKI for 24 (48.9%). The median age was 65 yr (range 35-79). Nine patients (18.4%) were female, 31 (63.3%) had ECOG PS of 0, and 15 (30.6%) had favorable risk. OS data are immature (17 deaths, 34.7%). The ORR was 20.0% (n = 5) for nivolumab and 52.2% (n = 12) for TKI. PFS was worse with nivolumab (hazard ratio 2.57, 95% confidence inter-val 1.36-4.89; p = 0.003). Grade >= 3 adverse events occurred in 14 patients (56.0%) with nivolumab and 17 (70.8%) with TKI. A major limitation is early termination of our study.Conclusions: TKI treatment achieved superior ORR and PFS in comparison to nivolumab maintenance therapy. Our data do not indicate a role for nivolumab switch maintenance in mRCC.Patient summary: Patients with metastatic kidney cancer who experienced a tumor response or disease stabilization after a short period of targeted treatment with a tyro-sine kinase inhibitor did not benefit from a switch to the immunotherapy drug nivolu-mab. Patients who continued their original treatment achieved better responses and a longer time without disease progression. This trial is registered on EudraCT as 2016-002170-13 and on ClinicalTrials.gov as NCT02959554.(c) 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Introduction:In oncology, anti-drug antibody (ADA) development that significantly curtails response durability has not historically risen to a level of concern. The relevance and attention ascribed to ADAs in oncology clinical studies have therefore been limited, and the extant literature on this subject scarce. In recent years, T cell engagers have gained preeminence within the prolific field of cancer immunotherapy. These drugs whose mode of action is expected to potently stimulate anti-tumor immunity, may potentially induce ADAs as an unintended corollary due to an overall augmentation of the immune response. ADA formation is therefore emerging as an important determinant in the successful clinical development of such biologics.Methods:Here we describe the immunogenicity and its impact observed to pasotuxizumab (AMG 212), a prostate-specific membrane antigen (PSMA)-targeting bispecific T cell engager (BiTE®) molecule in NCT01723475, a first-in-human (FIH), multicenter, dose-escalation study in patients with metastatic castration-resistant prostate cancer (mCRPC). To explain the disparity in ADA incidence observed between the SC and CIV arms of the study, we interrogated other patient and product-specific factors that may have explained the difference beyond the route of administration.Results:Treatment-emergent ADAs (TE-ADA) developed in all subjects treated with at least 1 cycle of AMG 212 in the subcutaneous (SC) arm. These ADAs were neutralizing and resulted in profound exposure loss that was associated with contemporaneous reversal of initial Prostate Surface Antigen (PSA) responses, curtailing durability of PSA response in patients. Pivoting from SC to a continuous intravenous (CIV) administration route remarkably yielded no subjects developing ADA to AMG 212. Through a series of stepwise functional assays, our investigation revealed that alongside a more historically immunogenic route of administration, non-tolerant T cell epitopes within the AMG 212 amino acid sequence were likely driving the high-titer, sustained ADA response observed in the SC arm.Discussion:These mechanistic insights into the AMG 212 ADA response underscore the importance of performing preclinical immunogenicity risk evaluation as well as advocate for continuous iteration to better our biologics.

Purpose: Overexperssion of Gastrin-releasing-peptide receptor (GRPr) in prostate carcinoma (PCa) suggests new means in the detection of prostate cancer foci. The bombesin derivative RM2 (DOTA-4-amino-1-carboxy­methyl­piperidine-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2) is a GRPr antagonist with strong binding affinity. Based on promising results from a first-in-man study on PCa detection in patients with local disease, a Phase I/II study was initiated and the ability of [68Ga]Ga-RM2 PET/CT to detect PCa lesions was compared with [18F]fluoromethylcholine ([18F]FCH) PET/CT and multiparameteric prostate Magnetic Resonance Imaging (mpMRI).Methods: This Phase I/II study was conductedwith a pre-specified interim analysis following the enrollment of 30 biopsy-positive PCa subjects, stratified into low, intermediate and high pretreatment risk of extra-glandular metastases with reference to NCCN criteria. Each subject had PCa detected by transrectal ultrasound guided prostate biopsy and subjects were scheduled to undergo prostatectomy with pelvic lymph node (LN) dissection in intermediate and high risk patients. Following administration of an intravenous dose of 140 MBq of [68Ga]Ga-RM2,imaging was conducted at 60 min. p.i.. Twenty-five (25/30) subjects had concomitant [18F]FCH PET/CT imaging. All patients underwent mpMRI. Intra-prostatic and pelvic nodal PET/CT findings were correlated with histopathologic results.Results: High uptake of [68Ga]Ga-RM2 was seen in pancreas and the urinary system with very low background uptake in the rest of the abdomen or thorax. Despite of high bladder activity, focal intraprostatic uptake was readily well detectable. Of overall 312 analyzed regions, 120 regions (4 to 8 lesions per-patient) showed abnormal finding in the prostate gland. In a region-based analysis overall sensitivity and specificity of [68Ga]Ga-RM2 PET/CT in the detection of primary tumor were 74% and 90%, respectively; while it was 60% and 80% for [18F]FCH PET/CT and 72% and 89% for mpMRI. Although, the overall sensitivity of [68Ga]Ga-RM2 PET/CT was higher comparing to [18F]FCH PET/CT and mpMRI; however, the statistical analysis showed only significant difference between [68Ga]Ga-RM2 PET/CT and [18F]FCH PET/CT in intermediate-risk group (P=0.01) and [68Ga]Ga-RM2 PET/CT and mpMRT in high-risk group (p=0.03). [68Ga]Ga-RM2 PET/CT correctly detected 2 histopathologically verified LN metastases in 2 high risk patients; while 18F-FCH PET/CT only identified the LN lesion in 1 patient.Conclusion: [68Ga]Ga-RM2 is a promising new PET-tracer with a high detection rate for intraprostatic PCa. While index lesion detection rates were similar in both PET/CT studies, the improved specificity of [68Ga]Ga-RM2 for canver versus BPH renders it notably better than [18F]FCH in the detection of intraprostatic lesions. In addition, GRP-R-based imaging seems to play a complementary role to Choline-based imaging for full characterization of PCa extent, biopsy guidance in low and intermediate metastatic risk PCa patients and has the potential to discriminate them from whom of those at higher risks.Trial Registeration number: EudraCT-Nr.: 2014-003027-21, Date: 10 June, 2014

AbstractPurpose: There is ongoing controversy about the recommended dose of cabazitaxel in patients with metastatic castration-resistant prostate cancer (mCRPC). Experimental Design: This multicenter phase II open-label, randomized, parallel-group study compared 3-weekly cabazitaxel at 25 mg/m2 (conventional arm A) with cabazitaxel therapeutic drug monitoring (experimental arm B) in mCRPC. The primary objective was to improve the clinical feasibility rate (CFR), defined as the absence of grade 4 neutropenia or thrombocytopenia, any thrombocytopenia with bleeding, febrile neutropenia, severe nonhematologic toxicity, withdrawal for cabazitaxel-related toxicity, or death. A total of 60 patients had to be randomized to detect a difference in CFR of 35% (power 80%, two-sided alpha 10%). Results: A total of 40 patients were randomized to arm A and 33 patients to arm B. CFR was 69.4% in arm A and 64.3% in arm B (P = 0.79). Week-12 PSA response was 38.5% in both arms. A radiological response by RECIST v.1.1 was seen in 3 (9.7%) patients in arm A versus 6 (23.1%) patients in arm B (P = 0.28), disease progression was higher in arm A compared with arm B (61.3% vs. 30.8%, P = 0.05). Median progression-free survival was longer in arm B compared with arm A (9.5 vs. 4.4 months; HR = 0.46; P = 0.005). Median overall survival was higher in arm B compared with arm A (16.2 vs. 7.3 months; HR = 0.33; P < 0.0001). Conclusions: Pharmacokinetic-guided dosing of cabazitaxel in patients with mCRPC is feasible and improves clinical outcome due to individual dose escalations in 55% of patients.

Die molekulargenetische Diagnostik gewinnt in der Urologie durch die zunehmende Verfügbarkeit immer mehr an Bedeutung. Auch für das Prostatakarzinom sind bereits validierte prädiktive und prognostische Biomarker bekannt. Dies ist vor allem in Bezug auf Screening, Diagnose und individuelle Therapieoptionen von klinischer Relevanz. Das bekannteste Beispiel sind BRCA1(„breast cancer 1“)/BRCA2-Mutationen aus der Gruppe der DNA-Reparaturmechanismus-Gene, bei deren Vorliegen der PARP(Poly-ADP-Ribose-Polymerase)-Inhibitor Olaparib seit 2020 zugelassen ist. Durch die ständige Weiterentwicklung wird eine tumorspezifische Therapie auch für das Prostatakarzinom vermehrt möglich. Um eine entsprechende Präzisionsmedizin anbieten zu können, bedarf es jedoch der Kenntnis der wichtigsten Grundprinzipien, einer engen interdisziplinären Zusammenarbeit sowie aufgrund der zunehmenden Komplexität eines molekularen Tumorboards.

Due to the increasing accessibility, molecular diagnostics are becoming more important in urology. There are validated predictive and prognostic biomarkers available for prostate cancer. This has clinical implications for screening diagnosis and personalized treatment options. The best known examples are mutations in the DNA damage repair genes breast cancer 1 (BRCA1) and BRCA2 for which the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib has been approved in 2020. This continuous progress enables a more tumor-specific and personalized treatment for prostate cancer. In order to provide this precision medicine, it is necessary to know the most important basic principles, have a close-knit interdisciplinary cooperation and access to a molecular tumor board due to the increased complexity.

441 Background: Nivolumab (nivo) is an approved 2 nd line treatment after platinum-based chemotherapy in metastatic urothelial carcinoma (mUC). Recent studies suggest improved outcomes for dual checkpoint inhibition in mUC in particular with higher ipilimumab (ipi) doses (nivo 1mg/kg + ipi 3mg/kg). TITAN-TCC uses a response-based approach starting with 4 doses of nivo (8 weeks) followed by nivo+ipi boosts in non-responders. Here we report cohort 2 of TITAN-TCC applying nivo1/ipi3 boost doses in patients after prior platinum-based chemotherapy (2 nd /3 rd line). Methods: Between April 2019 and February 2021 83 patients with histologically confirmed mUC (TITAN-TCC cohort 2) started with nivo 240mg Q2W induction. After 4 doses and tumor assessment at week 8 (i) non-responders (stable (SD)/ progressive disease (PD)) received 2-4 doses nivo1+ipi3 while (ii) responders (complete (CR)/ partial response (PR)) continued with nivo maintenance but could receive nivo1+ipi3 for later PD. Primary endpoint was confirmed investigator-assessed ORR per RECIST1.1. Using a Fleming single-stage phase II design 77 evaluable patients would provide a 90% power to reject the null-hypothesis that ORR was ≤20% at a one-sided 5% type I error if the true ORR was ≥35%. Secondary endpoints included activity of nivo monotherapy at week 8, remission rate with nivo+ipi boosts, progression-free survival (PFS), overall survival (OS), and safety. Results: Median follow-up time was 5.6 months. Of the patients, 78 (94%) were 2 nd line. Median age was 68 years (range 37-84) and 57 patients (69%) were male. ORR with nivo monotherapy at first assessment (week 8) was 20.5%. Of the patients, 44 and 6 received nivo+ipi boosts after week 8 and for later PD, respectively. Confirmed objective response with nivo induction ± nivo+ipi boosts was achieved in 27/83 (32.5%) of the patients (significant > 20%, p < 0.01). Patients with PD-L1 expression in ≥1% of tumor cells had a numerically higher ORR (46% vs. 24% for PD-L1 negatives). Of the patients with initial SD after nivo induction, 4/13 (31%) achieved response upon boost. Of the patients boosted for PD, 9/37 (24%) improved. Median PFS was 1.9 months (95% CI 1.8-3.2), median OS was 7.6 months (95% CI 5.1-14.9). No new safety signals emerged. Conclusions: In patients after prior platinum-based chemotherapy treatment with nivo and nivo+ipi boosts in non-responders significantly improved ORR compared to the one reported for nivo as 2 nd line monotherapy. Patients with PD-L1 positive tumors appear to benefit most. Our study provides further evidence for the added value of high dose (3mg/kg) ipilimumab in mUC. Clinical trial information: NCT0321977.[Table: see text]

We conducted a retrospective National Cancer Registry study in Austria to assess a possible seasonal variation in the clinical diagnosis of testicular germ cell tumors (TGCT). In total, 3615 testicular cancer diagnoses were identified during an 11-year period from 2008 to 2018. Rate ratios for the monthly number of TGCT diagnoses, as well as of seasons and half-years, were assessed using a quasi-Poisson model. We identified, for the first time, a statistically significant seasonal trend (p < 0.001) in the frequency of monthly newly diagnosed cases of TGCT. In detail, clear seasonal variations with a reduction in the tumor incidence during the summer months (Apr–Sep) and an increase during the winter months (Oct–Mar) were observed (p < 0.001). Focusing on seasonality, the incidence during the months of Oct–Dec (p = 0.008) and Jan–Mar (p < 0.001) was significantly higher compared to the months of Jul–Sep, respectively. Regarding histopathological features, there is a predominating incidence in the winter months compared to summer months, mainly concerning pure seminomas (p < 0.001), but not the non-seminoma or mixed TGCT groups. In conclusion, the incidence of TGCT diagnoses in Austria has a strong seasonal pattern, with the highest rate during the winter months. These findings may be explained by a delay of self-referral during the summer months. However, the hypothetical influence of vitamin D3 in testicular carcinogenesis underlying seasonal changes in TGCT diagnosis should be the focus of further research.

Aim: We report results of a first-in-human study of pasotuxizumab, a PSMA bispecific T-cell engager (BiTE (R)) immune therapy mediating T-cell killing of tumor cells in patients with advanced castration-resistant prostate cancer. Patients & methods: We assessed once-daily subcutaneous (SC) pasotuxizumab. All SC patients developed antidrug antibodies; therefore, continuous intravenous (cIV) infusion was assessed. Results: A total of 47 patients received pasotuxizumab (SC: n = 31, 0.5-172 mu g/d; cIV: n = 16, 5-80 mu g/d). The SC maximum tolerated dose was 172.0 mu g/d. A sponsor change stopped the cIV cohort early; maximum tolerated dose was not determined. PSA responders occurred (>50% PSA decline: SC, n = 9; cIV, n = 3), including two long-term responders. Conclusion: Data support pasotuxizumab safety in advanced castration-resistant prostate cancer and represent evidence of BiTE monotherapy efficacy in solid tumors. Clinical trial registration:NCT01723475 (ClinicalTrials.gov)

INTRODUCTIONHigh-resolution micro-ultrasound has the capability of imaging prostate cancer based on detecting alterations in ductal anatomy, analogous to multiparametric magnetic resonance imaging (mpMRI). This technology has the potential advantages of relatively low cost, simplicity, and accessibility compared to mpMRI. This multicenter, prospective registry aims to compare the sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of mpMRI with high-resolution micro-ultrasound imaging for the detection of clinically significant prostate cancer.METHODSWe included 1040 subjects at 11 sites in seven countries who had prior mpMRI and underwent ExactVu micro-ultrasound-guided biopsy. Biopsies were taken from both mpMRI targets (PI-RADS >3 and micro-ultrasound targets (PRIMUS >3). Systematic biopsies (up to 14 cores) were also performed. Various strategies were used for mpMRI target sampling, including cognitive fusion with micro-ultrasound, separate software-fusion systems, and software-fusion using the micro-ultrasound FusionVu system. Clinically significant cancer was those with Gleason grade group ≥2.RESULTSOverall, 39.5% were positive for clinically significant prostate cancer. Micro-ultrasound and mpMRI sensitivity was 94% vs. 90%, respectively (p=0.03), and NPV was 85% vs. 77%, respectively. Specificities of micro-ultrasound and MRI were both 22%, with similar PPV (44% vs. 43%). This represents the initial experience with the technology at most of the participating sites and, therefore, incorporates a learning curve. Number of cores, diagnostic strategy, blinding to MRI results, and experience varied between sites.CONCLUSIONSIn this initial multicenter registry, micro-ultrasound had comparable or higher sensitivity for clinically significant prostate cancer compared to mpMRI, with similar specificity. Micro-ultrasound is a low-cost, single-session option for prostate screening and targeted biopsy. Further larger-scale studies are required for validation of these findings.

The main objective of this prospective study was to determine the impact of multiphasic acquisition of 68Ga-PSMA PET/CT in the detection of recurrent prostate cancer in the early stage of biochemical recurrence with a prostate-specific antigen (PSA) level of less than 1 ng/mL. Also, 68Ga-PSMA PET/CT positivity was correlated with clinical parameters for the assessment of predictive markers. Methods: A prospective monocentric study was conducted on 135 prostate cancer patients with biochemical recurrence and a PSA level of less than 1 ng/mL. All patients had undergone initial prostatectomy, with additional radiation therapy in 19.3% of patients and androgen-deprivation therapy in 7.4%. The patients underwent dynamic acquisitions from the prostate bed (1–8 min after injection), standard whole-body acquisitions (60 min after injection), and limited-bed-position delayed acquisitions (120–150 min after injection). The studies were reviewed by 2 board-certified nuclear medicine specialists, independently. A combination of visual and semiquantitative analyses and correlation with morphologic (e.g., MRI) or clinical follow-up findings was used for the final interpretation of lesions as benign or malignant. 68Ga-prostate-specific membrane antigen (PSMA) PET/CT positivity was also correlated with primary clinical findings. Results: Incorporating the information from all phases, we were able to detect 116 lesions in 49.6% of patients (22 local recurrences, 63 lymph nodes, and 31 distant metastases). The detection rates were 31.8%, 44.9%, and 71.4% for PSA < 0.2 ng/mL, 0.2 ≤ PSA < 0.5, and 0.5 ≤ PSA < 1, respectively. Additional dynamic or delayed phases resulted in better determination of equivocal lesions and a higher diagnostic performance in 25.9% of patients. Stand-alone dynamic and delayed images led to better interpretation of equivocal findings in the prostate bed (31.4%) and in other lesions (lymph node or bone) (20%), respectively. Conclusion: 68Ga-PSMA PET/CT showed promise for early detection of recurrent disease in patients with a PSA level of 0.5–1.0 ng/mL. However, it showed limited value in patients with a PSA level of less than 0.5 ng/mL. Multiphasic 68Ga-PSMA PET/CT led to a better determination of equivocal findings. Although dynamic images may provide helpful information for assessment of the prostate bed, delayed acquisitions seem to have a greater impact in clarifying equivocal findings.

The current study endeavored to closely compare the detection rate of 68-Gallium labelled prostate-specific membrane antigen ([68Ga]Ga-PSMA) versus [18F]Fluorocholine in men with prostate cancer (PC), to investigate the benefits and pitfalls of each modality in the setting of various patient characteristics. We retrospectively analyzed 29 biopsy-proven PC patients in two categories, staging and restaging, who underwent both scans within a maximum of 30 days of each other. Variables including patient demographics, prostate specific antigen (PSA) level, Gleason score, clinical course, and following treatments were recorded. The number and location of suspicious lesions as well as uptake values were noted. A total of 148 suspicious lesions were detected, of which 70.9% (105/148) were concordantly visualized in both imaging modalities. [68Ga]Ga-PSMA positron emission tomography/computed tomography (PET/CT) revealed a higher number of metastatic lesions per patients (91% vs 78%). The mean of maximum standardized uptake value (SUV max) in concordant lesions was significantly higher in [68Ga]Ga-PSMA compared to [18F]Fluorocholine PET/CT (14.6 ± 8.44 vs. 6.9 ± 3.4, p = 0.001). Discordant lesions were detected by both modalities, but more frequently by [68Ga]Ga-PSMA PET/CT (20.3% in [68Ga]Ga-PSMA versus 8.8% by [18F]Fluorocholine PET/CT). In patients with PSA levels below 1.0 ng/mL and <2.0 ng/mL, [18F]Fluorocholine PET/CT detection rate was half (57% and 55%, respectively) that of [68Ga]Ga-PSMA PET/CT. Tumor, nodes and metastases (TNM) staging, and subsequently patient management, was only influenced in 4/29 patients (14%), particularly by [68Ga]Ga-PSMA PET/CT with PSA values under 0.5 ng/mL. [68Ga]Ga-PSMA PET/CT revealed superior diagnostic performance to [18F]Fluorocholine PET/CT in staging and restaging of PC patients, especially in cases with low PSA levels. However, in a few hormone resistant high-risk PC patients, [18F]Fluorocholine PET/CT may improve overall diagnostic accuracy.

Introduction: High-resolution micro-ultrasound has the capability of imaging prostate cancer based on detecting alterations in ductal anatomy, analogous to multiparametric magnetic resonance imaging (mpMRI). This technology has the potential advantages of relatively low cost, simplicity, and accessibility compared to mpMRI. This multicenter, prospective registry aims to compare the sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of mpMRI with high-resolution micro-ultrasound imaging for the detection of clinically significant prostate cancer. Methods: We included 1040 subjects at 11 sites in seven countries who had prior mpMRI and underwent ExactVu micro-ultrasound-guided biopsy. Biopsies were taken from both mpMRI CUAJ – Original Research Klotz et al Comparing micro-ultrasound and mpMRI for prostate cancer 2 © 2020 Canadian Urological Association targets (PI-RADS >3 and micro-ultrasound targets (PRIMUS >3). Systematic biopsies (up to 14 cores) were also performed. Various strategies were used for mpMRI target sampling, including cognitive fusion with micro-ultrasound, separate software-fusion systems, and software-fusion using the micro-ultrasound FusionVu system. Clinically significant cancer was those with Gleason grade group ≥2. Results: Overall, 39.5% were positive for clinically significant prostate cancer. Microultrasound and mpMRI sensitivity was 94% vs. 90%, respectively (p=0.03), and NPV was 85% vs. 77%, respectively. Specificities of micro-ultrasound and MRI were both 22%, with similar PPV (44% vs. 43%). This represents the initial experience with the technology at most of the participating sites and, therefore, incorporates a learning curve. Number of cores, diagnostic strategy, blinding to MRI results, and experience varied between sites. Conclusions: In this initial multicenter registry, micro-ultrasound had comparable or higher sensitivity for clinically significant prostate cancer compared to mpMRI, with similar specificity. Micro-ultrasound is a low-cost, single-session option for prostate screening and targeted biopsy. Further larger-scale studies are required for validation of these findings. Introduction About 15% of men will be diagnosed with prostate cancer at some point during their lifetime. While mortality has improved substantially, attributed to early detection and improved treatment, it remains the second leading cause of cancer death in men. Accurate biopsy derived histopathology is a key determinant in treatment selection along with patient-physician shared decision making. Most men with localized, low risk disease are managed via active surveillance, while those with localized, higher risk disease are treated with surgery, radiation, or focal therapy regimens. Accurate biopsy techniques are crucial for determining the optimal treatment path for each patient. Historically, prostate cancer diagnosis has been predicated upon TRUS guided systematic biopsies initiated due to PSA abnormal values and/or an abnormal prostate exam. The limitations of this approach are a high rate of clinically insignificant cancers, especially when performed solely for PSA abnormalities, as well as the potential for missing clinically significant cancer in 25-30% of biopsied patients. Recent randomized studies have demonstrated the superiority of mpMRI guided targeted biopsies in correctly identifying clinically significant cancer and reducing the rate of diagnosis of insignificant cancer. The European Association of Urology (EAU) currently recommends mpMRI imaging prior to all prostate biopsies, with the caveat that systematic biopsy is acceptable if mpMRI is unavailable. The National Comprehensive Cancer Network (NCCN) recommends MRI-assisted biopsy for patients with a prior negative systematic biopsy and CUAJ – Original Research Klotz et al Comparing micro-ultrasound and mpMRI for prostate cancer 3 © 2020 Canadian Urological Association clinical suspicion of cancer. This poses many challenges in terms of access, cost, and expertise. High resolution 29 MHz micro-ultrasound, a novel imaging modality, aims to improve the diagnostic accuracy of prostate biopsy while maintaining the affordability and convenience of ultrasound. Micro-ultrasound operates at 29 MHz, compared to traditional ultrasound systems that operate at frequencies of 6-9MHz. The axial resolution is improved from 200 μm with conventional ultrasound to <70 μm with micro-ultrasound with a similar improvement in lateral resolution due to 90 μm crystal spacing. This resolution is approximately the diameter of a prostatic duct and allows for the visualization of subtle changes in ductal anatomy associated with cancer. Diffusion-weighted imaging (DWI) is based upon measuring the random Brownian motion of water molecules within a voxel of tissue. Highly cellular tissues exhibit lower diffusion coefficients. Both technologies thus identify changes associated with high grade cancer. Real-time targeted biopsy can be performed, avoiding the need for a 2 procedure. A grading system, PRI-MUS, analogous to the PI-RADS system, has been developed to stratify micro ultrasound images according to the risk of significant cancer. This study sought to compare the sensitivity, specificity, NPV and PPV of mpMRI with highresolution micro-ultrasound in patients referred for biopsy who had a prior MRI.

Background Tyrosine kinase inhibitors (TKI) and nivolumab (NIVO) are key components of systemic therapies in metastatic renal cell carcinoma (mRCC). We tested if TKI induction followed by an early switch to NIVO improved outcome in mRCC. Methods Key inclusion criteria were measurable advanced or metastatic ccRCC, ECOG PS 0-2, adequate organ function, and PR or SD after sunitinib (50 mg, 4-2 regime) or pazopanib (800 mg OD) for 10-12 weeks. 1:1 randomized to either continue TKI treatment or receive nivolumab 240 or 480 mg IV q2-4wks, until PD or intolerance. Imaging occurred q12wks and health-related quality of life (HR-QoL) was assessed monthly x3 and q12wks thereafter (FKSI-15). Primary and key secondary endpoints were survival rate at 2 years and ORR, respectively. The trial stopped prematurely for low accrual after 49 of 244 patients were randomized. Results 25 and 24 pts. were randomized to receive NIVO or TKI continuation, respectively. Median age was 65 years (range: 35-79), 40 pts. (82%) were male and 2 pts. (4%) had an ECOG PS of 2. MSKCC risk categories: favorable, intermediate, poor were (n; %): 15 (31), 32 (65) and 2 (4). Pazopanib was used in 22 (45). Response to TKI induction was PR in 29 (59) and SD in 20 (41). In the ITT population, best overall response rate measured from start of induction therapy was not significantly different for NIVO vs. TKI (64 vs. 70%, P = 0.76). However, when measured from time of randomization, ORR for NIVO vs. TKI was 16 vs. 48% (P = 0.029). Adverse events (AE) for NIVO vs. TKI occurred in 96% vs. 100% (all grades) and 44% vs. 67% (grades 3-5), respectively. Serious AE (SAE) for NIVO vs. TKI continuation were reported in 10 (40) and 9 (38), respectively. Table . 959P Best overall response to nivolumab or TKI treatment (ITT population) From start of TKI induction From randomization Category NIVO TKI Total NIVO TKI Total n 25 23 48 25 23 48 CR -- 1 (4%) 1 (2%) -- 1 (4%) 1 (2%) PR 16 (64%) 15 (65%) 31 (65%) 4 (16%) 10 (43%) 14 (29) SD 9 (36%) 7 (30%) 16 (33%) 6 (24%) 7 (30%) 13 (27%) PD -- -- -- 11 (44%) 3 (13%) 14 (29%) NE -- -- -- 4 (16%) 2 (9%) 6 (12%) Conclusions TKI induction followed by early switch to NIVO did not improve ORR in patients responsive to TKI. These results do not support the notion that TKI pretreatment sensitizes for nivolumab efficacy. Major limitations of our trial are the premature closure and the limited sample size. Clinical trial identification 2016-002170-13; NCT02959554. Legal entity responsible for the study AIO-Studien-gGmbH, Berlin. Funding Bristol-Myers Squibb. Disclosure V. Grunwald: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Shareholder / Stockholder / Stock options: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Ipsen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Eisai; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Novartis; Research grant / Funding (self): Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Shareholder / Stockholder / Stock options: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Cerulean; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Shareholder / Stockholder / Stock options: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony: Art tempi; Advisory / Consultancy, Speaker Bureau / Expert testimony: Astellas; Advisory / Consultancy, Speaker Bureau / Expert testimony: COCS; Advisory / Consultancy, Speaker Bureau / Expert testimony: ClinSol; Advisory / Consultancy, Speaker Bureau / Expert testimony: EUSAPharm; Advisory / Consultancy, Speaker Bureau / Expert testimony: MedUpdate; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Serono; Advisory / Consultancy, Speaker Bureau / Expert testimony: MedKomAkademie; Advisory / Consultancy, Speaker Bureau / Expert testimony: NewConceptOncology; Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Johnson & Johnson; Advisory / Consultancy, Speaker Bureau / Expert testimony: PharmaMar; Advisory / Consultancy, Speaker Bureau / Expert testimony: PeerVoice; Advisory / Consultancy, Speaker Bureau / Expert testimony: StreamedUp!; Advisory / Consultancy, Speaker Bureau / Expert testimony: ThinkWired!. All other authors have declared no conflicts of interest.