Tailored immunotherapy approach with nivolumab with or without ipilimumab in patients with advanced transitional cell carcinoma after platinum-based chemotherapy (TITAN-TCC): a multicentre, single-arm, phase 2 trial.

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=0·0049). 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.

On-treatment risk model for predicting treatment response in advanced renal cell carcinoma.

PURPOSE: The field of immunotherapy combinations for advanced renal cell carcinoma (aRCC) has been expanded in recent years. However, the treatment response varies widely among individual patients. It is still a challenge to predict oncological outcome in clinical practice. We assessed the impact of an activated immune system reflected by changes in C-reactive protein (CRP) levels and the early onset of treatment-related adverse events (TRAEs) on the treatment response. METHODS: In this retrospective analysis of 57 aRCC patients, CRP kinetics based on previous descriptions of CRP flare-response, CRP response or CRP non-response, and the TRAEs, which occurred within a month after therapy initiation, were obtained for this study. According to logistic regression analysis of both factors, we stratified the patients into risk groups: the presence of CRP flare-response/response and early onset of TRAE (low-risk group); the presence of a single factor (intermediate-risk group); and without both factors (high-risk group). RESULTS: Ten patients (17%) experienced primary disease progression. No progressive disease was observed in the low-risk group, while 60% (n = 6/10) of the high-risk group showed a primary disease progression. Significantly, an increased risk of disease progression was observed by patients without CRP response and TRAEs (p < 0.001). CONCLUSION: The present analysis displays the predictive value of the on-treatment risk model based on CRP kinetics and the early onset of TRAEs, which can be easy to implement in clinical practice to optimize the treatment monitoring.

Molecular margin status after radical prostatectomy using glutathione S-transferase P1 (GSTP1) promoter hypermethylation.

OBJECTIVE: To assess the potential for molecular staging in biopsies of the prostatic fossa after radical prostatectomy (RP) by searching for occult tumour cells through analysis of glutathione S-transferase P1 (GSTP1) methylation status. PATIENTS AND METHODS: We analysed 2446 biopsies: 2286 biopsies from a group of 254 patients with clinically organ-confined prostate cancer who underwent RP and 160 biopsies from a control group of 32 patients. After prostate gland excision, biopsies were obtained from defined areas of the prostatic fossa and bisected for histopathological and molecular genetics analyses. Results were related to clinicopathological data including tumour stage, lymph node status, resection status, tumour grading, initial PSA level, and biochemical recurrence. RESULTS: In total, 34 patients (13.4%) had at least one core positive for the GSTP1 promoter hypermethylation, six of whom (17.6%) were characterised as having a clinically localised tumour stage (pT2, pN0) and 28 (82.4%) as an advanced tumour stage (≥pT3 and/or pN1). GSTP1 promoter hypermethylation significantly correlated with tumour stage (P < 0.001), International Society of Urological Pathology grading (P = 0.001), lymph node status (P < 0.001), surgical margin status (P < 0.001), and biochemical recurrence (P = 0.001). Furthermore, in 46 patients (18.1%) further analysis led to a down- or upgrading of conventional surgical margin status. Classical R-status (margins of the specimen) is significantly superior to histological sampling from the fossa (P = 0.006) but not to GSTP1 analysis from the fossa (P = 0.227). CONCLUSION: For the detection of residual tumour in the fossa after RP in order to better predict recurrence, molecular GSTP1 promoter hypermethylation has some value; however, the classical R-status (margins of the specimen) is simpler and more widely applicable with similar results.

German S3 Evidence-Based Guidelines on Focal Therapy in Localized Prostate Cancer: The First Evidence-Based Guidelines on Focal Therapy.

BACKGROUND: Focal therapy (FT) is an option to treat localized prostate cancer (PCa) and preserve healthy prostate tissue in order to reduce known side effects from primary whole-gland treatment. The available FT modalities are manifold. Until now, national and international PCa guidelines have been cautious to propose recommendations regarding FT treatment since data from prospective controlled trials are lacking for most FT modalities. Moreover, none of the international guidelines provides a separate section on FT. In this purpose, we provide a synopsis of the consensus-based German S3 guidelines for a possible international use. SUMMARY: The recently published update of the German S3 guidelines, an evidence- and consensus-based guideline, provides a section on FT with recommendations for diagnostic work-up, indications, modalities, and follow-up. This section consists of 12 statements and recommendations for FT in the treatment of localized PCa. KEY MESSAGE: The German S3 guidelines on PCa are the first to incorporate recommendations for FT based on evidence and expert consensus including indication criteria for FT, pretreatment, and follow-up diagnostic pathways as well as an extended overview of FT techniques and the current supportive evidence.

Time pressure predicts decisional regret in men with localized prostate cancer: data from a longitudinal multicenter study.

PURPOSE: A substantial proportion of men with localized prostate cancer (lPCa) later regret their treatment decision. We aimed to identify factors contributing to decisional regret. METHODS: We conducted a longitudinal study, in which men with lPCa were surveyed at four measurement points: T0 (baseline) = prior to treatment; T1 = 6; T2 = 12; T3 = 18 months after baseline. χ2-tests and independent t-tests were used to compare men undergoing different treatments [Active Surveillance (AS) vs. local treatment]. Logistic regression models were fitted to investigate the associations between predictors (time pressure, information provided by the urologist, impairment of erectile functioning, satisfaction with sexual life) and the criterion decisional regret. RESULTS: At baseline, the sample included N = 176 men (AS: n = 100; local treatment: n = 76). At T2 and T3, men after local therapies reported higher regret than men under AS. Decisional regret at T3 was predicted by time pressure at baseline (OR 2.28; CI 1.04-4.99; p < 0.05), erectile dysfunction at T2 and T3 (OR 3.40; CI 1.56-7.42; p < 0.01), and satisfaction with sexual life at T1-T3 (OR 0.44; CI 0.20-0.96; p < 0.05). CONCLUSIONS: Time pressure, erectile dysfunction, and satisfaction with sexual life predict decisional regret in men with lPCa. Mitigating time pressure and realistic expectations concerning treatment side effects may help to prevent decisional regret in PCa survivors. TRIAL REGISTRATION NUMBER: DRKS00009510; date of registration: 2015/10/28.

Triggers and oncologic outcome of salvage radical prostatectomy, salvage radiotherapy and active surveillance after focal therapy of prostate cancer.

PURPOSE: Due to the tissue preserving approach of focal therapy (FT), local cancer relapse can occur. Uncertainty exists regarding triggers and outcome of salvage strategies. METHODS: Patients with biopsy-proven prostate cancer (PCa) after FT for localized PCa from 2011 to 2020 at eight tertiary referral hospitals in Germany that underwent salvage radical prostatectomy (S-RP), salvage radiotherapy (S-RT) or active surveillance (AS) were reported. Prostate specific antigen (PSA) changes, suspicious lesions on mpMRI and histopathological findings on biopsy were analyzed. A multivariable regression model was created for adverse pathological findings (APF) at S-RP specimen. Kaplan-Meier curves were generated to determine oncological outcomes. RESULTS: A total of 90 men were included. Cancer relapse after FT was detected at a median of 12 months (IQR 9-16). Of 50 men initially under AS 13 received S-RP or S-RT. In total, 44 men underwent S-RP and 13 S-RT. At cancer relapse 17 men (38.6%) in the S-RP group [S-RT n = 4 (30.8%); AS n = 3 (6%)] had ISUP > 2. APF (pT ≥ 3, ISUP ≥ 3, pN + or R1) were observed in 23 men (52.3%). A higher ISUP on biopsy was associated with APF [p = 0.006 (HR 2.32, 97.5% CI 1.35-4.59)] on univariable analysis. Progression-free survival was 80.4% after S-RP and 100% after S-RT at 3 years. Secondary therapy-free survival was 41.7% at 3 years in men undergoing AS. Metastasis-free survival was 80% at 5 years for the whole cohort. CONCLUSION: With early detection of cancer relapse after FT S-RP and S-RT provide sufficient oncologic control at short to intermediate follow-up. After AS, a high secondary-therapy rate was observed.

MRI targeted single fraction HDR Brachytherapy for localized Prostate Carcinoma: a feasibility study of focal radiation therapy (ProFocAL).

OBJECTIVES: The aim of the study was to establish the setup and workflow for delivering focal MRI-guided high-dose-rate (HDR) brachytherapy for prostate cancer (PCA) and to assess patient comfort and safety aspects of MRI-guided single-fraction HDR. METHODS: Patients with histologically proven focal low- to intermediate-risk PCA with a single PIRADS 4/5 lesion were treated with percutaneous interstitial HDR brachytherapy in a single fraction with a minimum dose for the gross tumor volume of 20 Gy while sparing the organ at risk (OAR). Using a 3T-MRI, brachytherapy catheters were placed transgluteal in freehand technique. No antibiotic therapy or general analgesics were administered. Patient data, procedure time, patient discomfort, and complications were recorded. Quarterly PSA controls, biannual follow-up imaging, and annual re-biopsy were planned. RESULTS: So far, 9 patients were successfully treated and followed for 6 months. Mean intervention time was 34 min. Using the VAS scale, the pain reported for the intervention ranged from 2 to 3. Short-term follow-up showed no acute genitourinary or gastrointestinal toxicity so far. None of the patients displayed signs of infection. PSA levels in all patients decreased significantly. On follow up no residual PCA was detected treated region so far. PSA levels in all patients decreased significantly. On follow-up, no residual PCA was detected so far. CONCLUSIONS: MR-guided single-fraction focal HDR brachytherapy for localized PCA is feasible as well as safe for the individual patient. Catheters can be placed accurately and maximum therapeutic dose distribution can be restricted to the tumor. Countersigning the minimally invasive character of the procedure, no general anesthesia or antibiosis is necessary. KEY POINTS: • MR-guided focal HDR brachytherapy allows an accurate placement of catheters with maximum therapeutic dose distribution restricted to the tumor. • No major anesthesia or antibiosis is necessary emphasizing the minimal invasive character of the procedure. • Patients with low- and intermediate-risk prostate carcinoma in particular may benefit to halt disease progression whereas treatment-related morbidity is reduced compared with radical therapy.

A Stent for Every Stone? Prestenting Habits and Outcomes from a German Multicenter Prospective Study on the Benchmarks of Ureteroroscopic Stone Treatment (BUSTER).

INTRODUCTION: Previous studies have shown that prestenting in ureterorenoscopic stone removal (URS) is carried out more frequently in Germany than in other countries. OBJECTIVE: This investigation evaluated the impact of high prestenting rates on outcomes as well as the influence of stone characteristics and treatment habits on prestenting. METHODS: The dataset from the BUSTER observational study was used. Patient and stone characteristics, as well as treatment outcomes, were analyzed for 307 cases from 14 urological clinics in Germany. RESULTS: The overall prestenting rate was 70.0%. Prestenting rates were significantly higher for renal stones than ureteric stones (84.6 vs. 60.6%, p < 0.0001). Compared to the unstented cases, prestenting for renal stones improved stone-free rates (73.2 vs. 11.1%, p < 0.0001) and increased the rate of completely lesion-free URS (45.4 vs. 16.7%, p = 0.034) while reducing the rate of poststenting (from 100 to 80.8%, p = 0.041). None of these effects could be demonstrated when prestenting for ureteric stones. Prestenting rates were less variable for renal stones (57-100%) than for ureteric stones (0-100%, p < 0.01). CONCLUSIONS: This study confirms the benefits of prestenting in URS for renal stones but not for ureteric stones. There were considerable differences in prestenting rates between the participating clinics.

Use of the Prostate Health Index and Density in 3 Outpatient Centers to Avoid Unnecessary Prostate Biopsies.

OBJECTIVES: We investigated the diagnostic efficacy of the prostate health index (PHI) and PHI density (PHID) to avoid unnecessary prostate biopsies in 3 urological practices. METHODS: In 122 patients, total prostate-specific antigen (PSA), free PSA (f-PSA), the quotient from total PSA and f-PSA (f-PSA%), and [-2]pro-PSA were measured in the serum; PHI, PHID, and PSA density (PSAD) were calculated prior to prostate biopsy. Tissue sampling via transrectal biopsy was indicated in case of suspicious PSA (progression and/or elevation of PSA) and/or suspicious digital rectal examination. PSAD, PHI, and PHID were not used for biopsy indication. The diagnostic efficacy was determined with receiver-operating characteristic (ROC)and decision curve analyses. RESULTS: Based on prostate biopsies, 38% (n = 46) of the cases had no prostate carcinoma (PCa), 21% (n = 26) no clinically significant (insignificant) PCa, and 41% (n = 50) had clinically significant PCa. ROC analyses of the PSA parameters showed higher diagnostic efficacy for PHI and PHID (AUC 0.722 and 0.739) than for f-PSA%, PSA, and PSAD (AUC 0.612, 0.595, and 0.698, respectively) regarding carcinoma diagnosis. With a combined use of PHI and PHID (cutoff >40 and >0.9, respectively), only 1 clinically significant PCa would have been missed (sensitivity 98%); in 24 (20%) patients, biopsy could have been avoided. CONCLUSION: The integration of PHI and PHID could improve the diagnostic efficacy of risk calculators to avoid unnecessary prostate biopsies. However, as a prerequisite, validation of cutoff values in prospective studies is urgently required.

A Phase 4 Study of Everolimus to Evaluate Efficacy and Safety in Patients with Metastatic Renal-Cell Carcinoma after Failure of First-Line Sunitinib or Pazopanib (SUNPAZ).

INTRODUCTION: Sunitinib and pazopanib are both standard first-line therapies for clear-cell metastatic renal-cell carcinoma (mRCC). Everolimus is a well-established second-line treatment. OBJECTIVE: To estimate the efficacy and safety of second-line everolimus following pazopanib or sunitinib. METHODS: SUNPAZ was an open-label, phase 4 clinical trial of everolimus in patients with clear-cell mRCC progressing after first-line sunitinib or pazopanib. The primary end point was the number of patients without progression 6 months after starting everolimus. Secondary end points included progression-free survival (PFS), overall survival (OS), and overall response rate. Enrollment was terminated early due to slow recruitment; all analyses are descriptive. RESULTS: Patients who received prior sunitinib (n = 16) or pazopanib (n = 13) were enrolled. One of 12 patients in the sunitinib group and 6/13 patients in the pazopanib group were progression-free by month 6 in the full analysis set. Median PFS in the sunitinib and pazopanib groups was 2.8 and 8.0 months, and median OS was 14.8 months and 20.4 months, respectively. Fifteen patients in the sunitinib group and 13 in the pazopanib group experienced adverse events. CONCLUSIONS: Safety and efficacy results confirm the second-line everolimus profile. However, baseline differences in patient populations should be taken into consideration.