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Background For muscle-invasive bladder cancer (MIBC), no tissue biomarkers are available for clinical use to predict response to neoadjuvant chemotherapy. Objective To investigate how molecular subtypes impact pathological response and survival in patients receiving preoperative cisplatin-based chemotherapy. Design, setting, and participants Classification of a retrospective cohort of 149 patients was performed by tumor transcriptomic profiling and immunostaining. A cohort treated with radical cystectomy alone and public data sets were used for comparison and external validation. Outcome measurements and statistical analysis Complete pathological response in the cystectomy specimen (ypT0N0) and survival were compared in predefined molecular subtypes. Differential gene expression and chemotherapy response were explored beyond molecular subtypes. Results and limitations Patients with genomically unstable (GU) and urothelial-like (Uro) tumors had higher proportions of complete pathological response (16/31 [52%] and 17/54 [31%]), versus five out of 24 (21%) with the basal/squamous (Ba/Sq) subtype following neoadjuvant chemotherapy and radical cystectomy. Molecular subtype was independently associated with improved survival for patients with GU tumors (hazard ratio [HR] 0.29, 95% confidence interval [CI]: 0.11–0.79) and UroC tumors (HR 0.37, 95% CI: 0.14–0.94) compared with Ba/Sq tumors, adjusting for clinical stage. In addition, expression of the gene coding for osteopontin (SPP1) showed a subtype-dependent effect on chemotherapy response. Conclusions Urothelial cancer of the luminal-like (GU and Uro) subtypes is more responsive to cisplatin-based neoadjuvant chemotherapy. A second-generation of subtype-specific biomarkers, for example, SPP1, may be a way forward to develop a more precision-based treatment approach for neoadjuvant chemotherapy in MIBC. Patient summary This study shows that tumor classification by gene expression profiling and molecular subtyping can identify patients who are more likely to benefit from chemotherapy before radical cystectomy for muscle-invasive bladder cancer. Together with other markers for response, molecular subtypes could have a role in selective administration of such chemotherapy.

Objective: To overview the updated Swedish National Guidelines on Urothelial Carcinoma 2021, with emphasis on non-muscle-invasive bladder cancer (NMIBC) and upper tract urothelial carcinoma (UTUC). Methods: A narrative review of the updated version of the Swedish National Guidelines on Urothelial Carcinoma 2021 and highlighting new treatment recommendations, with comparison to the European Association of Urology (EAU) guidelines and current literature. Results: For NMIBC the new EAU 2021 risk group stratification has been introduced for non-muscle invasive bladder cancer to predict risk of progression and the web-based application has been translated to Swedish (https://nmibc.net.). For patients with non-BCG -responsive disease treatment recommendations have been pinpointed, to guide patient counselling in this clinical situation. A new recommendation in the current version of the guidelines is the introduction of four courses of adjuvant platinum-based chemotherapy to patients with advanced disease in the nephroureterectomy specimen (pT2 or higher and/or N+). Patients with papillary urothelial neoplasms with low malignant potential (PUNLMP) can be discharged from follow-up already after 3 years based on a very low subsequent risk of further recurrences. Conclusions: The current version of the Swedish national guidelines introduces a new risk-stratification model and follow-up recommendation for NMIBC and adjuvant chemotherapy after radical surgery for UTUC.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Initial results from the phase III JAVELIN Bladder 100 trial (ClinicalTrials.gov identifier: NCT02603432 ) showed that avelumab first-line (1L) maintenance plus best supportive care (BSC) significantly prolonged overall survival (OS) and progression-free survival (PFS) versus BSC alone in patients with advanced urothelial carcinoma (aUC) who were progression-free after 1L platinum-containing chemotherapy. Avelumab 1L maintenance treatment is now a standard of care for aUC. Here, we report updated data with ≥ 2 years of follow-up in all patients, including OS (primary end point), PFS, safety, and additional novel analyses. Patients were randomly assigned 1:1 to receive avelumab plus BSC (n = 350) or BSC alone (n = 350). At data cutoff (June 4, 2021), median follow-up was 38.0 months and 39.6 months, respectively; 67 patients (19.5%) had received ≥2 years of avelumab treatment. OS remained longer with avelumab plus BSC versus BSC alone in all patients (hazard ratio, 0.76 [95% CI, 0.63 to 0.91]; 2-sided P = .0036). Investigator-assessed PFS analyses also favored avelumab. Longer-term safety was consistent with previous analyses; no new safety signals were identified with longer treatment duration. In conclusion, longer-term follow-up continues to show clinically meaningful efficacy benefits with avelumab 1L maintenance plus BSC versus BSC alone in patients with aUC. An interactive visualization of data reported in this article is available.

We constructed Bladder Cancer Data Base Sweden (BladderBaSe) 2.0 to expand studies in BladderBaSe on incidence, treatment outcomes, side effects, survival and health economic aspects of men and women with cancer in the urinary bladder, upper tract urothelial carcinoma (UTUC) (renal pelvis and ureter) and urethral carcinoma.BladderBaSe 2.0 includes 53 298 patients with cancer in the urinary bladder, diagnosed from 1 January 1997 to 31 December 2019, and 961 patients with UTUC in the renal pelvis and 792 in the ureter, and 146 patients with urethral urothelial carcinoma, diagnosed from 1 January 2015 to 31 December 2019, and in total 275 816 participants in reference groups, free of cancer in the urinary tract, matched 1:5 on sex, age and county.To date, 18 published studies based on data from the BladderBaSe have investigated calendar time trends in survival; impact of gender, socioeconomic factors, tumour aggressiveness and hospital volume for radical cystectomy on prognosis; survival after radical cystectomy compared with radical radiotherapy; risk factors for complications and side effects after radical cystectomy such as thromboembolism, strictures of ureteroenterostomies and incisional hernia.The BladderBaSe initiators are currently investigating gender-dependent detection delays due to urinary tract infections; survival after non-muscle invasive bladder cancer with respect to the number of transurethral resections; short-term outcomes comparing open and robot-assisted radical cystectomy; studies on risk for intravesical recurrence after different diagnostic measures in UTUC, and suicide risk after bladder cancer diagnosis. The BladderBaSe project group is open for collaborations with national and international colleagues.

Introduction: We aimed to compare short term outcomes after robot assisted radical cystectomy (RARC) and open radical cystectomy (ORC) for urinary bladder cancer in a large population. Materials and methods: We included all patients without distant metastases who underwent either RARC or ORC with ileal conduit between 2011 and 2019 registered in the Bladder cancer data Base Sweden (BladderBaSe) 2.0. Primary outcome was unplanned readmissions within 90 days, and secondary out-comes within 90 days of surgery were reoperations, Clavien 3-5 complications, total days alive and out of hospital, and mortality. The analysis was carried out using multivariate regression models. Results: Out of 2905 patients, 832 were operated with RARC and 2073 with ORC. Robotic procedures were to a larger extent performed during later years, at high volume centers (47% vs 17%), more often for organ-confined disease (82% vs. 72%) and more frequently in patients with high socioeconomic status (26% vs. 21%). Patients operated with RARC were more commonly readmitted (29% vs. 25%). In multi -variable analysis RARC was associated with decreased risk of Clavien 3-5 complications (OR 0.58, 95% CI 0.47-0.72), reoperations (OR 0.53, 95% CI 0.39-0.71) and had more days alive and out of hospital (mean difference 3.7 days, 95% CI 2.4-5.0). Conclusion: This study illustrates the "real-world" effects of a gradual and nation-wide introduction of RARC. Patients operated with RARC had fewer major complications and reoperations but were more frequently readmitted compared to ORC. The observed differences were largely due to more wound related complications among patients treated with ORC.

BACKGROUND AND PURPOSE To analyse the cumulative incidence of any failure (AF), prostate cancer-specific failure (PCSF), any death (AD), prostate cancer-specific death (PCSD), and local control in 2387 men with prostate cancer (PC), consecutively treated with combined high-dose-rate brachytherapy (HDRBT) and external beam radiotherapy (EBRT) from 1998 to 2010. MATERIAL AND METHODS A retrospective, single-institution study of men with localised PC. The mean age was 66 years and 54.7% had high-risk PC according to the Cambridge prognostic group (CPG) classification. The treatment was delivered as EBRT (2 Gy × 25) and HDRBT (10 Gy × 2) with combined androgen blockade (CAB). The median follow-up was 10.2 years. RESULTS The cumulative incidence of PCSD at 10 years was 5% [CI 95% 0.04-0.06]. The 10 years PCSD per risk group were: low (L) 0.4%, intermediate favourable (IF) 1%, intermediate unfavourable (IU) 4.3%, high-risk favourable (HF) 5.8%, and high-risk unfavourable (HU) 13.9%. The PCSF rate at 10 years was 16.5% [CI 95% 0.15-0.18]. The PCSF per risk group at 10 years were: L 2.5%, IF 5.5%, IU 15.9%, HF 15.6%, and HU 38.99%. PCSF occurred in 399 men, of whom 15% were found to have local failure. The estimated frequency of local failure in the entire cohort was 1.2%. CONCLUSIONS HDRBT combined with EBRT is an effective treatment with long-term overall survival and excellent local control for patients with PC. The low rate of local recurrence among men with relapse suggests that these patients were micro metastasised at time of treatment, which calls for improved methods to detect disseminated disease.

Background Intravesical recurrence (IVR) after surgery for upper tract urothelial carcinoma (UTUC) is a clinical problem. We investigated if preoperative invasive diagnostic modalities (IDM) such as antegrade/retrograde uretero-pyelography and/or selective urine cytology/barbotage, and URS with or without concomitant biopsy are associated with IVR after radical surgery for UTUC. Risk of death from urothelial cancer and all causes was investigated as secondary outcomes. Methods We investigated a population-based cohort of 1038 consecutive patients subjected to radical surgery for UTUC 2015–2019 in Sweden, using the Bladder Cancer Data Base Sweden (BladderBaSe 2.0), comprising all patients in the Swedish National Registry of Urinary Bladder Cancer. Risk estimates of IVR, death from urothelial cancer, and all causes was assessed using multivariable Cox regression models. Results The study included 536 cases with and 502 without preoperative IDM. IDM was associated with increased risk of IVR (HR 1.24, 95% CI 1.03–1.52) and risk of urothelial cancer death (HR 1.56, CI 1.12–2.18), compared to no IDM after a median follow-up of 1.3 yrs. Stratified analysis for tumor location showed that IDM was associated with risk of IVR in ureteric cancer (HR 1.66, 95% CI 1.21–2.28) but not in renal pelvic cancer (HR 1.07, 95% CI 0.81–1.41). Limitations included the observational setting and the lack of variables such as tumour grade, multifocality and preoperative hydronephrosis. Conclusions Worse outcomes for patients subjected to preoperative IDM highlight the need for carefully considering diagnostic decisions for UTUC patients, specifically in tumours located in the ureter.

Objective: The incidence of benign ureteroenteric strictures following radical cystectomy (RC) for urinary bladder cancer (UBC) is investigated mainly in single-centre studies from high-volume centres. The aim of this study was to evaluate the cumulative incidence of strictures and risk factors in a population-based cohort. Patients and methods: Data was collected from Bladder Cancer Data Base Sweden (BladderBaSe). The primary endpoint was stricture with intervention. Secondary endpoint included hydronephrosis both with/without intervention. Results: In total, 5,816 patients were registered as having had RC due to UBC between 1997 and 2014. After a median follow-up of 23.5 months (IQR = 9.0–63.1 months; range = 0.0–214.0 months), we found that 515 (8.9%) patients underwent intervention for stricture. Seven hundred and sixty-one (13.1%) patients were diagnosed with hydronephrosis without intervention. The cumulative incidence of strictures with intervention was 19.7% (95% CI = 16.7–23.1%) during the 17 years of follow-up. In the first year, the cumulative incidence of strictures was 5.6% (95% CI = 5.0–6.2%), and in the first 2 years 8.4% (95% CI = 7.6–9.3%). For the secondary endpoint, the cumulative incidence was 30.4% (95% CI = 26.7–33.1%) after 17 years. Only the year of RC was associated with stricture incidence in Cox regression analysis, whereas hospital cystectomy volume, patient age and patient sex were not. Conclusion: Ureteroenteric strictures requiring intervention may be more common than previously reported, affecting nearly one fifth of patients who have undergone RC for UBC. The annual incidence was highest in the first 2 years after surgery but the cumulative incidence increased continuously during 17 years of follow-up.

BACKGROUND: Neoadjuvant cisplatin-based chemotherapy is standard care prior to radical cystectomy in patients with muscle-invasive bladder cancer (MIBC). OBJECTIVE: To assess efficacy and safety of two commonly used neoadjuvant schedules with different total doses and dose-intensities of gemcitabine and cisplatin (GC). METHODS: Data were collected retrospectively from all patients treated between 2010 and 2018 with neoadjuvant chemotherapy according to clinical routine at seven centres in Sweden and Denmark. Patients in Sweden received three cycles of a 4-week schedule (GC-4w: cisplatin 70 mg/m2 day 1, gemcitabine 1000 mg/m2 days 1, 8, 15, q 28 days) and in Denmark four cycles of a 3-week schedule (GC-3w: cisplatin 70 mg/m2 day 1, gemcitabine 1000 mg/m2 days 1, 8, q 21 days). Primary endpoint was pathological response at cystectomy (pT0N0 and

The aim of this cross-sectional study was to investigate long-term health-related quality of life (HRQoL) in men with prostate cancer treated 2002–2008 with external beam radiotherapy (EBRT) combined with high dose-rate brachytherapy (HDRBT), Cohort A, and to compare these data with age-adjusted normative data. In addition, differences in HRQoL following adjustments of the brachytherapy technique in 2001 were investigated by comparing Cohort A with men treated at the same clinic from 1998-2000, Cohort B. Cohort A: 1495 men treated with EBRT 2 Gy to 50 Gy and 2 fractions of 10 Gy HDRBT at a single centre, 2002–2008, still alive at five years. As part of routine follow-up, the patients responded to the EORTC QLQ-C30 and PR-25 questionnaires. Cohort B: HRQoL data was retrieved from an earlier study from the original article. In Cohort A, 1046 (70%) men completed the questionnaires at five years, median age 66 years. In general, HRQoL mean scores were high and similar to Swedish age-matched normative data. Concerning disease-specific HRQoL, low levels of bowel and urinary problems were reported, in contrast to a substantial effect on sexual functioning. ‘No’ or ‘A little’ problems with faecal incontinence and urinary incontinence were reported by 98% and 93% of patients, respectively. The corresponding figure for sexual functioning was 39%. A difference in the frequency of nocturia in favour of Cohort A was the only statistically significant difference between Cohort A and B found in general and disease-specific HRQOL (p = 0.03), despite modifications in the brachytherapy procedure introduced in 2001. Long-term general HRQoL was rated high and comparable to an aged-matched reference population five years after treatment with combined radiotherapy. Disease-specific HRQoL was still affected, foremost in the sexual domain.

INTRODUCTION AND OBJECTIVES: Bladder cancer is primarily a disease of older age and little is known about the differences between patients diagnosed with bladder cancer at a younger versus older age. Our objectives were to compare bladder cancer specific survival in patients aged

Although the bladder cancer treatment field is expanding with several new treatments introduced in the last decade, many patients with an advanced form of the disease can expect a poor prognosis when diagnosed [...]

INTRODUCTION AND OBJECTIVE:The phase 3 JAVELIN Bladder 100 trial (NCT02603432), which enrolled patients (pts) with advanced urothelial carcinoma (UC) that had not progressed with first-line (1L) pl...

For effective clinical management of patients being treated with 223Ra, there is a need for radiographic response biomarkers to minimize disease progression and to stratify patients for subsequent treatment options. The objective of this study was to evaluate an automated bone scan index (aBSI) as a quantitative assessment of bone scans for radiographic response in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: In a multicenter retrospective study, bone scans from patients with mCRPC treated with monthly injections of 223Ra were collected from 7 hospitals in Sweden. Patients with available bone scans before treatment with 223Ra and at treatment discontinuation were eligible for the study. The aBSI was generated at baseline and at treatment discontinuation. The Spearman rank correlation was used to correlate aBSI with the baseline covariates: alkaline phosphatase (ALP) and prostate-specific antigen (PSA). The Cox proportional-hazards model and Kaplan-Meier curve were used to evaluate the association of covariates at baseline and their change at treatment discontinuation with overall survival (OS). The concordance index (C-index) was used to evaluate the discriminating strength of covariates in predicting OS. Results: Bone scan images at baseline were available from 156 patients, and 67 patients had both a baseline and a treatment discontinuation bone scan (median, 5 doses; interquartile range, 3-6 doses). Baseline aBSI (median, 4.5; interquartile range, 2.4-6.5) was moderately correlated with ALP (r = 0.60, P < 0.0001) and with PSA (r = 0.38, P = 0.003). Among baseline covariates, aBSI (P = 0.01) and ALP (P = 0.001) were significantly associated with OS, whereas PSA values were not (P = 0.059). After treatment discontinuation, 36% (24/67), 80% (54/67), and 13% (9/67) of patients demonstrated a decline in aBSI, ALP, and PSA, respectively. As a continuous variable, the relative change in aBSI after treatment, compared with baseline, was significantly associated with OS (P < 0.0001), with a C-index of 0.67. Median OS in patients with both aBSI and ALP decline (median, 134 wk) was significantly longer than in patients with ALP decline only (median, 77 wk; P = 0.029). Conclusion: Both aBSI at baseline and its change at treatment discontinuation were significant parameters associated with OS. The study warrants prospective validation of aBSI as a quantitative imaging response biomarker to predict OS in patients with mCRPC treated with 223Ra.

Background. Vinflunine (VFL) is approved in Europe as second-line treatment of metastatic urothelial cancer after failure of platinum-containing therapy. We performed a systematic review and meta-analysis of real-world data (RWD) to assess utilization, efficacy and safety of VFL. \ud \ud Methods. We performed a MEDLINE search for the period of 1/1/2000-31/8/2017. Full-length articles providing post-marketing RWD on VFL in patients failing previous chemotherapy were eligible. Interventional clinical trials were excluded. \ud \ud Results: Ten studies with 797 patients were identified. According to pooled REs analysis, overall response rate was 19%, most frequent, all-grade toxicities were fatigue (41%), constipation (39%), nausea/vomiting (25%), and most prevalent Grade 3–4 toxicities were neutropenia (13%), anaemia (9%), fatigue (8%). Median OS was comparable to results reported in recent randomized studies.\ud \ud Conclusion. Our findings confirm the efficacy and safety of VFL in an unselected population and support the use of VFL in the changing treatment paradigm of relapsed mUC.

BACKGROUND: Routine VTE prophylaxis within 30 days of radical cystectomy (RC) for urinary bladder cancer (UBC) is used to protect from venous thromboembolism (VTE). However, randomized studies and nationwide population-based studies are lacking. OBJECTIVE: To study VTE and risk factors for VTE in muscle-invasive UBC in a nationwide population-based series, with a focus on the association with RC with and without chemotherapy. MATERIALS AND METHODS: We studied all patients with clinical stage T2-T4 UBC diagnosed 1997 to 2014 in the Bladder Cancer Data Base Sweden (BladderBaSe). Previous VTE events and risk factors for VTE were registered from 1987. Cox regression analyses and Kaplan-Meier curves were performed to study risk factors for VTE and cumulative incidence of VTE. RESULTS: In 9720 patients (71% males) with a median age of 74 years 546 (5.6%) had VTE after diagnosis. In Cox analyses controlling for patients and tumour characteristics, and risk factors for VTE, VTE after diagnosis and first treatment date were associated with chemotherapy with or without RC. Cumulative incidence of VTE increased during 24 months after diagnosis and first treatment date. VTE were less common in patients with previous cardiovascular disease. CONCLUSION: VTE was commonly observed after 30 days from diagnosis and from first treatment date in patients with T2-T4 UBC, particularly after chemotherapy. The findings suggest that long-term intervention studies of benefit and possible harms of VTE prophylaxis after UBC should be undertaken. Funding Agencies|Swedish Cancer SocietySwedish Cancer Society [CAN 2016/470, CAN 2017/278]

Purpose Radium-223 is a life-prolonging therapy for castration-resistant prostate cancer (CRPC) patients with symptomatic bone metastases. However, validated biomarkers for response monitoring are lacking. The study aim was to investigate whether early alkaline phosphatase (ALP) dynamics after the first radium-223 injection can act as surrogate marker for overall survival (OS). Methods This retrospective multicenter study included consecutive CRPC patients treated with radium-223. Patients were divided into four subgroups based on baseline ALP level (normal/elevated) and early ALP response, defined as ≥10% ALP decrease after the first radium-223 injection. Primary endpoint was OS among the subgroups. Secondary endpoints included time to first skeletal-related event, time to ALP progression, and treatment completion rate. Results A total of 180 patients were included for analysis. Median OS was 13.5 months (95% confidence interval 11.5–15.5). Patients with elevated baseline ALP without ALP response after the first injection had significantly worse OS when compared to all other patients (median OS 7.9 months versus 15.7 months, hazard ratio 2.56, 95% confidence interval 1.73–3.80, P Conclusion Early treatment–induced changes in ALP after one radium-223 injection were associated with OS in metastatic CRPC patients.

Objective For patients undergoing radical cystectomy for bladder cancer, a procedure requiring complex urinary tract reconstruction prone to major postoperative complications, the timing and quality of the surgery have been associated with outcomes. Patients and methods This study investigated if radical cystectomy for bladder cancer performed during holiday periods had worse disease-specific (DSS) and overall survival (OS), higher 90-day mortality and risk of readmissions. All patients operated on with radical cystectomy for primary bladder cancer during 1997-2014 with holiday periods as exposure (with one narrow (7 weeks) and one wider (14 weeks) definition) in the Swedish population-based bladder cancer research-database (BladderBaSe) were studied. DSS and OS after radical cystectomy during holiday periods were analysed with Cox regression models adjusted for sex, age, comorbidity, marital status, T-stage and nodal metastases, neoadjuvant chemotherapy, hospital volume and year of cystectomy. Results Surgery during the holiday periods (narrow and wide definitions) were not associated with DSS (Hazard ratio [HR] = 1.05, 95% confidence interval [95% CI] = 0.90-1.21 and HR = 1.04, 95% CI = 0.91-1.17), respectively. HRs for OS were similar, and no associations between radical cystectomy during any of the holiday period definitions and 90-day mortality and readmission were found. Conclusion Survival after radical cystectomy in Sweden is similar during holiday and non-holiday periods. Funding Agencies|Swedish Cancer SocietySwedish Cancer Society [CAN 2019/62, CAN 2017/278]; Lund Medical Faculty (ALF); Skane University Hospital Research Funds; Gyllenstierna Krapperup s Foundation; Skane County Councils Research and Development Foundation [REGSKANE-622351]; Gosta Jonsson Research Foundation; Foundation of Urological Research; Hillevi Fries Research Foundation

Platinum-based chemotherapy is standard-of-care first-line treatment for advanced urothelial carcinoma. However, progression-free survival and overall survival are limited by chemotherapy resistance.In a phase 3 trial, we randomly assigned patients with unresectable locally advanced or metastatic urothelial cancer who did not have disease progression with first-line chemotherapy (four to six cycles of gemcitabine plus cisplatin or carboplatin) to receive best supportive care with or without maintenance avelumab. The primary end point was overall survival, assessed among all patients who underwent randomization (overall population) and among those with tumors positive for programmed cell death ligand 1 (PD-L1). Secondary end points included progression-free survival and safety.Among all 700 patients who underwent randomization, the addition of maintenance avelumab to best supportive care significantly prolonged overall survival as compared with best supportive care alone (control). Overall survival at 1 year was 71.3% in the avelumab group and 58.4% in the control group (median overall survival, 21.4 months vs. 14.3 months; hazard ratio for death, 0.69; 95% confidence interval [CI], 0.56 to 0.86; P = 0.001). Avelumab also significantly prolonged overall survival in the PD-L1-positive population; overall survival at 1 year was 79.1% in the avelumab group and 60.4% in the control group (hazard ratio, 0.56; 95% CI, 0.40 to 0.79; P0.001). The median progression-free survival was 3.7 months in the avelumab group and 2.0 months in the control group in the overall population (hazard ratio for disease progression or death, 0.62; 95% CI, 0.52 to 0.75) and 5.7 months and 2.1 months, respectively, in the PD-L1-positive population (hazard ratio, 0.56; 95% CI, 0.43 to 0.73). The incidence of adverse events from any cause was 98.0% in the avelumab group and 77.7% in the control group; the incidence of adverse events of grade 3 or higher was 47.4% and 25.2%, respectively.Maintenance avelumab plus best supportive care significantly prolonged overall survival, as compared with best supportive care alone, among patients with urothelial cancer who had disease that had not progressed with first-line chemotherapy. (Funded by Pfizer and Merck [Darmstadt, Germany]; JAVELIN Bladder 100 ClinicalTrials.gov number, NCT02603432.).

Background Multiple therapies exist for patients with metastatic castration-resistant prostate cancer (mCRPC). However, their improvement on progression-free survival (PFS) remains modest, potentially explained by tumor molecular heterogeneity. Several prognostic molecular biomarkers have been identified for mCRPC that may have predictive potential to guide treatment selection and prolong PFS. We designed a platform trial to test this hypothesis. Methods The Prostate-Biomarker (ProBio) study is a multi-center, outcome-adaptive, multi-arm, biomarker-driven platform trial for tailoring treatment decisions for men with mCRPC. Treatment decisions in the experimental arms are based on biomarker signatures defined as mutations in certain genes/pathways suggested in the scientific literature to be important for treatment response in mCRPC. The biomarker signatures are determined by targeted sequencing of circulating tumor and germline DNA using a panel specifically designed for mCRPC. Discussion Patients are stratified based on the sequencing results and randomized to either current clinical practice (control), where the treating physician decides treatment, or to molecularly driven treatment selection based on the biomarker profile. Outcome-adaptive randomization is implemented to early identify promising treatments for a biomarker signature. Biomarker signature-treatment combinations graduate from the platform when they demonstrate 85% probability of improving PFS compared to the control arm. Graduated combinations are further evaluated in a seamless confirmatory trial with fixed randomization. The platform design allows for new drugs and biomarkers to be introduced in the study. Conclusions The ProBio design allows promising treatment-biomarker combinations to quickly graduate from the platform and be confirmed for rapid implementation in clinical care. Trial registration ClinicalTrials.gov Identifier NCT03903835. Date of registration: April 4, 2019. Status: Recruiting.

Background: The present study (VINGEM) is the first randomised trial comparing vinflunine/gemcitabine (VG) to standard carboplatin/gemcitabine (CG) in patients with advanced urothelial carcinoma (aUC) ineligible for treatment with cisplatin. Patients and methods: Patients with aUC, creatinine clearance 30–60 ml/min, performance status ≤1 and no prior chemotherapy for metastatic disease were randomised to the experimental arm (vinflunine 280 or 250 mg/m2 day 1, gemcitabine 1000 mg/m2 days 1 and 8, q21 days) or the control arm (carboplatin AUC 4.5 day 1, gemcitabine 1000 mg/m2 days 1 and 8, q21 days). Primary end-point was progression-free survival (PFS). Results: Sixty-two patients were randomised; a total of 59 patients were treated (29 VG, 30 CG). There was no significant difference in PFS between the treatment arms: median 6.2 months for VG versus 6.3 months for CG (hazard ratio [HR]: 0.75, 95% confidence interval [CI]: 0.44–1.28; P = 0.293). Median overall survival was 12.5 months for VG versus 10.6 months for CG. The overall response rate (ORR) was higher in the VG arm than in the CG arm (63% versus 40%) but was not statistically significant in the intention-to-treat analysis. Furthermore, VG showed a high complete response (CR) rate, 22% versus 3% in CG. In the per-protocol group, both ORR and CR were significantly higher for VG than for CG. The most common adverse events (AEs) were fatigue, haematological toxicities, gastrointestinal disorders and nausea/vomiting. Common grade III/IV AEs were neutropenia (VG 62%, CG 43%), thrombocytopenia (VG 7%, CG 37%) and febrile neutropenia (VG 31%, CG 7%). Conclusions: The combination of VG did not improve PFS compared with standard treatment with CG in patients unfit for cisplatin due to renal impairment. The response rate of VG indicates, however, an active regimen and warrants further studies. Clinicaltrials.gov number: NCT02665039.

Aim Patients treated with cabazitaxel for metastatic castration-resistant prostate cancer (mCRPC) may experience dose delays and reductions or terminate treatment because of toxicity. A lower and more frequent dose of cabazitaxel could improve dose intensity. Patients and methods This prospective, multi-center, phase II study randomly assigned 101 patients to Arm A, cabazitaxel Q3W, 25 mg/m2 or Arm B, Q1W, 10 mg/m2 5 of 6 weeks. The primary end-point was dose intensity, and we hypothesised that the experimental arm (Arm B) would result in a 20% absolute increase in the relative cumulative dose by week 18. Secondary end-points were overall survival (OS), progression-free survival (PFS), pain progression, radiological and prostate-specific antigen (PSA) response rates, quality of life (Functional Assessment of Cancer Therapy Prostate) and tolerability. Results Median doses of cabazitaxel were 276 mg (45–320) and 257 mg (20–330) in Arms A and B, respectively, at week 18 (p = 0.13). More patients in Arm B stopped treatment because of toxicity. Median PFS in Arms A and B were 6.0 and 6.4 months (hazard ratio [HR] 0.73, 95% confidence interval [CI]: 0.47–1.13, p = 0.156) and for OS, 14.6 and 15.6 months (HR 0.95, CI: 0.58–1.58, p = 0.85), respectively. PSA responses ≥50% were seen in 52% and 46% of patients in Arms A and B, respectively. A higher incidence of febrile neutropenia was observed in the standard arm (10 events versus 1, p Conclusion Weekly cabazitaxel reduces the incidence of febrile neutropenia but does not increase the dose intensity compared with the standard therapy. Cabazitaxel has clinical meaningful efficacy in heavily pre-treated patients with mCRPC.

Purpose Preoperative chemotherapy is underused in conjunction with radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC) due to concerns for complications and delay of surgery. Prospective data on short-term complications from population-based settings with frequent use of preoperative chemotherapy and standardised reporting of complications is lacking. Methods We identified 1,340 patients who underwent RC between 2011 and 2015 in Sweden due to MIBC according to the Swedish Cystectomy Register. These individuals were followed through linkages to several national registers. Propensity score adjusted logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for complications and death within 90 days of surgery, comparing patients receiving preoperative chemotherapy or not. Results Minimum two cycles of preoperative chemotherapy were given to 519 (39%) of the patients, who on average tended to be younger, have higher education, better physical status, and more advanced bladder cancer than patients not receiving chemotherapy. After adjusting for these and other parameters, there was no association between treatment with preoperative chemotherapy and short-term complications (OR 1.06 95% CI 0.82–1.39) or mortality (OR 0.75 95% CI 0.36–1.55). We observed a risk reduction for gastrointestinal complications among patients who received preoperative chemotherapy compared with those who did not (OR 0.49 95% CI 0.30–0.81). Conclusion This nation-wide population-based observational study does not suggest that preoperative chemotherapy, in a setting with high utilisation of such treatment, is associated with an increased risk of short-term complications in MIBC patients treated with radical cystectomy. Electronic supplementary material The online version of this article (10.1007/s00345-019-02770-2) contains supplementary material, which is available to authorized users.

For effective clinical management of patients being treated with (223)Ra, there is a need for radiographic response biomarkers to minimize disease progression and to stratify patients for subsequent treatment options. The objective of this study was to evaluate an automated bone scan index (aBSI) as a quantitative assessment of bone scans for radiographic response in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: In a multicenter retrospective study, bone scans from patients with mCRPC treated with monthly injections of (223)Ra were collected from 7 hospitals in Sweden. Patients with available bone scans before treatment with (223)Ra and at treatment discontinuation were eligible for the study. The aBSI was generated at baseline and at treatment discontinuation. The Spearman rank correlation was used to correlate aBSI with the baseline covariates: alkaline phosphatase (ALP) and prostate-specific antigen (PSA). The Cox proportional-hazards model and Kaplan–Meier curve were used to evaluate the association of covariates at baseline and their change at treatment discontinuation with overall survival (OS). The concordance index (C-index) was used to evaluate the discriminating strength of covariates in predicting OS. Results: Bone scan images at baseline were available from 156 patients, and 67 patients had both a baseline and a treatment discontinuation bone scan (median, 5 doses; interquartile range, 3–6 doses). Baseline aBSI (median, 4.5; interquartile range, 2.4–6.5) was moderately correlated with ALP (r = 0.60, P < 0.0001) and with PSA (r = 0.38, P = 0.003). Among baseline covariates, aBSI (P = 0.01) and ALP (P = 0.001) were significantly associated with OS, whereas PSA values were not (P = 0.059). After treatment discontinuation, 36% (24/67), 80% (54/67), and 13% (9/67) of patients demonstrated a decline in aBSI, ALP, and PSA, respectively. As a continuous variable, the relative change in aBSI after treatment, compared with baseline, was significantly associated with OS (P < 0.0001), with a C-index of 0.67. Median OS in patients with both aBSI and ALP decline (median, 134 wk) was significantly longer than in patients with ALP decline only (median, 77 wk; P = 0.029). Conclusion: Both aBSI at baseline and its change at treatment discontinuation were significant parameters associated with OS. The study warrants prospective validation of aBSI as a quantitative imaging response biomarker to predict OS in patients with mCRPC treated with (223)Ra.

4527 Background: The phase 3 JAVELIN Bladder 100 trial, which enrolled patients (pts) with advanced UC that had not progressed with 1L platinum-containing chemotherapy, showed that maintenance therapy with avelumab + best supportive care (BSC) significantly prolonged overall survival (OS) compared with BSC alone (hazard ratio [HR], 0.69 [95% CI: 0.56, 0.86; 1-sided P= 0.0005]). However, the optimal timing for starting avelumab after completing 1L chemotherapy is unknown. In this post hoc analysis, we report efficacy by duration of the TFI from completion of 1L chemotherapy. Methods: In the JAVELIN Bladder 100 trial (NCT02603432), eligible pts had unresectable locally advanced or metastatic UC without disease progression following 4 to 6 cycles of 1L platinum-containing chemotherapy. Pts were randomized to receive avelumab + BSC (n = 350) or BSC alone (n = 350) after a TFI of 4 to 10 weeks from the last dose of chemotherapy. In this exploratory analysis, subgroups with a TFI of 4 to < 6 weeks ( < 42 days), 6 to < 8 weeks (42 to < 56 days), or 8 to 10 weeks (≥56 days) were evaluated. Results: In the avelumab + BSC and BSC alone arms, the TFI was 4 to < 6 weeks in 143 and 158 pts, 6 to < 8 weeks in 109 and 80 pts, and 8 to 10 weeks in 98 and 110 pts, respectively. Baseline characteristics in these subgroups were generally well balanced between arms. For both arms combined, however, the TFI 4 to < 6 weeks subgroup vs the other 2 subgroups included more pts with visceral metastases (57.8% vs 54.0% and 50.0%), an objective response with 1L chemotherapy (76.4% vs 69.3% and 68.3%), and an ECOG performance status of 1 (44.5% vs 33.3% and 35.6%). OS was prolonged with avelumab + BSC vs BSC alone in all subgroups; the HR was 0.76 (95% CI: 0.546, 1.059) in the TFI 4 to < 6 weeks subgroup (median OS, 19.9 months [95% CI: 16.3, 25.3] vs 13.5 months [95% CI: 11.7, 17.4]), 0.64 (95% CI: 0.404, 1.021) in the TFI 6 to < 8 weeks subgroup (median OS, 26.1 months [95% CI: 19.9, not estimable] vs 21.0 months [95% CI: 10.7, not estimable]), and 0.70 (95% CI: 0.468, 1.035) in the TFI 8 to 10 weeks subgroup (median OS, 20.1 months [95% CI: 13.8, not estimable] vs 14.1 months [95% CI: 11.7, 19.6]). Conclusions: In patients with advanced UC that had not progressed with 1L platinum-containing chemotherapy, avelumab 1L maintenance prolonged OS irrespective of the TFI assessed in this study (4-10 weeks), supporting this new treatment strategy as a standard of care. Differences in duration of TFI were likely related to individual patient- and disease-specific characteristics or logistics and did not impact the OS benefit observed with avelumab 1L maintenance. Clinical trial information: NCT02603432.

The intercellular crosstalk between hematological malignancies and the tumor microenvironment is mediated by cell-to-cell interactions and soluble factors. One component of the secretome that is gaining increasing attention is the extracellular vesicles and, in particular, the exosomes. Apart from the role as vectors of molecular information, exosomes have been shown to possess intrinsic biological activity. In this study, we found that caspase-3 is activated in L88 bone marrow stroma cell-derived exosomes and identified 1 of the substrates to be the antiapoptotic protein Bcl-xL. The cleaved Bcl-xL is found in a panel of normal and cancer cell-derived exosomes and is localized on the outer leaflet of the exosomal membrane. Incubation of the exosomes with a caspase-3 inhibitor or the pan-caspase inhibitor prevents the cleavage of Bcl-xL. Importantly, MCF-7 cell-derived exosomes that are caspase-3-deficient are enriched in full-length Bcl-xL, whereas ectopic expression of caspase-3 restores the cleavage of Bcl-xL. Chemical inhibition of Bcl-xL with ABT737 or molecular inhibition by using the D61A and D76A Bcl-xL mutant leads to a significant decrease in the uptake of exosomes by hematopoietic malignant cells. These data indicate that the cleaved Bcl-xL is required for the uptake of exosomes by myeloma and lymphoma cells, leading to their increased proliferation. In summary, we demonstrate for the first time that Bcl-xL is an exosomal caspase-3 substrate and that this processing is required for the uptake of exosomes by recipient cells.

The risk stratification currently applied prior to curative treatment for localized prostate cancer (PC) does not take into account comorbidity or age. Therefore, we investigated the impact of comorbidity on overall survival (OS) in PC patients treated with external beam radiotherapy (EBRT) and high-dose rate (HDR) brachytherapy boost.At a single center, 611 consecutive patients diagnosed with localized PC from 1998 to 2004 underwent definitive EBRT (50 Gy) and HDR brachytherapy boosts (2 × 10 Gy) combined with neoadjuvant total androgen blockade. Comorbidity was assessed with the Charlson comorbidity score. The impact of risk factors on OS and disease-free survival (DFS) was calculated using Cox proportional hazard ratios. Risk groups were defined as follows: low-risk PC: PSA 10, WHO grade 1 and T stage 1; high-risk PC: PSA 20 and/or WHO grade 3 and/or T stage 3a; intermediate-risk PC representing patients who did not fit either the low- or high-risk PC group.Mean age in the study cohort was 66.4 years, and 51% of the patients reported some degree of comorbidity. Divided into risk groups 8.2% were categorized as low-risk, 64% as intermediate-risk and 27.8% as high-risk PC. Overall 10-year survival was 72.2%, and 89% of the patients were relapse-free. In the univariate and multivariate analyses using Cox proportional hazard ratios, age, comorbidity and T stage were statistically significant predictors of OS: hazard ratios 1.56, 1.44 and 1.2 (p-values .002, .04 and .05), respectively. WHO grade, PSA at diagnosis, T stage and comorbidity were also significant predictors of DFS (p-values .0001, .0001, .009 and .003, respectively).Comorbidity assessed with the Charlson score predicts OS in patients with localized PC treated with curative intent using combined EBRT and HDR brachytherapy boost, and should be considered when making decisions before radical treatment.

To prospectively study differences in health-related quality of life (HRQoL) in patients with localised/locally advanced prostate cancer (PC) treated with curative intended radiation therapy and randomised to androgen receptor inhibitor monotherapy treatment versus castration plus an androgen receptor inhibitor used continuously. Time to Prostate Specific Antigen (PSA) relapse, time to symptomatic metastasis and overall survival (OS) were also described for the two groups.From 2005 to 2011, a total of 110 patients were randomised at a ratio of 1:1. HRQoL was assessed at six time points: before randomisation, before radiotherapy (RT) start and 9, 12, 15 and 18 months after randomisation, using the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) and EORTC QLQ-PR25.At the 3-month follow-up, statistically significant differences between the two groups were found for overall quality of life (p = 0.006), fatigue (p = 0.023), sexual interest (p 0.001) and urinary problems (p = 0.036). Small clinical differences were noted for overall quality of life, role functioning, fatigue, pain, sleeping problems and urinary problems. At that assessment point, clinical differences between the groups were substantial regarding sexual interest and moderate regarding sexual functioning (the latter indicated only by patients reporting having sexual interest at baseline). All statistical and clinical differences favoured the androgen receptor inhibitor monotherapy arm. At 18 months after randomisation, statistically significant differences were found for cognitive functioning (p = 0.040) and sexual interest (p = 0.011), both favouring the androgen receptor inhibitor monotherapy arm.The results suggest that neo-adjuvant androgen receptor inhibitor monotherapy might be preferred compared to castration plus an androgen receptor inhibitor before curative intended RT in men with localised/locally advanced PC, with higher levels of HRQoL, especially concerning sexual interest. HRQoL differences over time were small. The observation time and study sample were too small for evaluating time to PSA progression and OS. Further studies are needed to confirm the results. The study was registered in, identification number NCT02382094.

In 2009, vinflunine was introduced as a second-line treatment to be used after the failure of platinum therapy in patients with metastatic urothelial carcinoma (mUC). The present study investigated the administered vinflunine to patients with mUC in standard clinical practice with the aim of evaluating treatment patterns, response, survival parameters and side-effects. Data were collected retrospectively from the first 100 mUC patients treated with vinflunine at three Nordic cancer centers associated with the Nordic Urothelial Cancer Oncology Group. The overall response rate was 23% and complete response was observed in one patient. The median progression-free survival (mPFS) and median overall survival (mOS) were 2.8 (range, 0.5-34.3) and 6.3 (range, 0.3-39.7) months, respectively. An Eastern Cooperative Oncology Group performance status (ECOG PS) of 2 was present in 20% of the patients, and those patients exhibited significantly shorter mOS (4.1 vs. 7.0 months, P=0.001) and a significantly higher degree of grade 3/4 toxicity (P=0.026) compared with ECOG PS 0-1 patients. Furthermore, patients without visceral metastases had significantly longer mOS than patients with visceral metastases (10.6 vs. 6.0 months, P=0.008). The median number of cycles of vinflunine was 3 (range, 1-28). The current data confirms that vinflunine is an active agent for second-line treatment in an unselected clinical cohort of patients with mUC. ECOG PS and presence of visceral metastases were significant prognostic parameters. In particular, patients with ECOG PS 2 receiving vinflunine had a shorter mOS and a higher frequency of severe toxicity, and, thus, should be treated with caution. Furthermore, the present study observed large inter-individual differences in radiological response and OS, indicating the need for further development of improved patient selection tools to optimize vinflunine treatment in platinum-refractory mUC patients.

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LBA1 Background: Platinum-based chemotherapy is an active 1L regimen for advanced UC; however, progression-free survival (PFS) and overall survival (OS) are generally short because of chemotherapy resistance. This randomized, phase 3 trial (JAVELIN Bladder 100; NCT02603432) evaluated avelumab (anti–PD-L1) as maintenance therapy following response or stable disease with 1L platinum-based chemotherapy in patients with advanced UC. Methods: Eligible patients with unresectable locally advanced or metastatic UC without disease progression after 4-6 cycles of gemcitabine with either cisplatin or carboplatin were randomized 1:1 to receive maintenance avelumab (10 mg/kg IV every 2 weeks) + best supportive care (BSC) or BSC alone, stratified by best response to 1L chemotherapy (complete/partial response vs stable disease) and by visceral vs nonvisceral disease when initiating 1L chemotherapy. The primary endpoint was OS, assessed from randomization in 2 primary populations: all randomized patients and patients with PD-L1+ tumors (Ventana SP263 assay). Secondary endpoints included PFS, objective response, and safety. Results: 700 patients were randomly assigned to maintenance avelumab + BSC (n=350) or BSC alone (n=350) and were followed for a median of 19.6 and 19.2 months, respectively. Overall, 358 (51%) had PD-L1+ tumors. Avelumab + BSC significantly prolonged OS vs BSC alone in all randomized patients (hazard ratio [HR] 0.69; 95% CI 0.56, 0.86; 1-sided p=0.0005); median OS with avelumab + BSC vs BSC alone was 21.4 vs 14.3 months, respectively. Avelumab + BSC also significantly prolonged OS vs BSC alone in patients with PD-L1+ tumors (HR 0.56; 95% CI 0.40, 0.79; 1-sided p=0.0003); median OS was not reached vs 17.1 months, respectively. An OS benefit was also observed across all prespecified subgroups. The HR for PFS based on blinded independent central review with avelumab + BSC vs BSC alone was 0.62 (95% CI 0.52, 0.75) in all randomized patients and 0.56 (95% CI 0.43, 0.73) in patients with PD-L1+ tumors. In treated patients in the avelumab + BSC (n=344) vs BSC alone (n=345) arms, respectively, all-causality adverse events (AEs) were reported at any grade in 98.0% vs 77.7% and at grade ≥3 in 47.4% vs 25.2%, and the most frequent grade ≥3 AEs were urinary tract infection (4.4% vs 2.6%), anemia (3.8% vs 2.9%), hematuria (1.7% vs 1.4%), fatigue (1.7% vs 0.6%), and back pain (1.2% vs 2.3%). Conclusions: JAVELIN Bladder 100 met its primary objective, demonstrating significantly prolonged OS with 1L maintenance avelumab + BSC vs BSC alone in advanced UC in all randomized patients and patients with PD-L1+ tumors. Efficacy benefits were seen across all prespecified subgroups, and the safety profile of avelumab was consistent with previous studies of monotherapy. Clinical trial information: NCT02603432 .

Purpose: To infer the prognostic value of simultaneous androgen receptor (AR) and TP53 profiling in liquid biopsies from patients with metastatic castration-resistant prostate cancer (mCRPC) starting a new line of AR signaling inhibitors (ARSi). Experimental Design: Between March 2014 and April 2017, we recruited patients with mCRPC (n = 168) prior to ARSi in a cohort study encompassing 10 European centers. Blood samples were collected for comprehensive profiling of CellSearch-enriched circulating tumor cells (CTC) and circulating tumor DNA (ctDNA). Targeted CTC RNA sequencing (RNA-seq) allowed the detection of eight AR splice variants (ARV). Low-pass whole-genome and targeted gene-body sequencing of AR and TP53 was applied to identify amplifications, loss of heterozygosity, mutations, and structural rearrangements in ctDNA. Clinical or radiologic progression-free survival (PFS) was estimated by Kaplan–Meier analysis, and independent associations were determined using multivariable Cox regression models. Results: Overall, no single AR perturbation remained associated with adverse prognosis after multivariable analysis. Instead, tumor burden estimates (CTC counts, ctDNA fraction, and visceral metastases) were significantly associated with PFS. TP53 inactivation harbored independent prognostic value [HR 1.88; 95% confidence interval (CI), 1.18–3.00; P = 0.008], and outperformed ARV expression and detection of genomic AR alterations. Using Cox coefficient analysis of clinical parameters and TP53 status, we identified three prognostic groups with differing PFS estimates (median, 14.7 vs. 7.51 vs. 2.62 months; P < 0.0001), which was validated in an independent mCRPC cohort (n = 202) starting first-line ARSi (median, 14.3 vs. 6.39 vs. 2.23 months; P < 0.0001). Conclusions: In an all-comer cohort, tumor burden estimates and TP53 outperform any AR perturbation to infer prognosis. See related commentary by Rebello et al., p. 1699

BackgroundThere are multiple existing and emerging therapeutic avenues for metastatic prostate cancer, with a common denominator, which is the need for predictive biomarkers. Circulating tumor DNA (ctDNA) has the potential to cost-efficiently accelerate precision medicine trials to improve clinical efficacy and diminish costs and toxicity. However, comprehensive ctDNA profiling in metastatic prostate cancer to date has been limited.MethodsA combination of targeted- and low-pass whole genome sequencing was performed on plasma cell-free DNA and matched white blood cell germline DNA in 364 blood samples from 217 metastatic prostate cancer patients.ResultsctDNA was detected in 85.9% of baseline samples, correlated to line of therapy and was mirrored by circulating tumor cell enumeration of synchronous blood samples. Comprehensive profiling of the androgen receptor (AR) revealed a continuous increase in the fraction of patients with intra-ARstructural variation, from 15.4% during first line mCRPC therapy to 45.2% in fourth line, indicating a continuous evolution of AR during the course of the disease. Patients displayed frequent alterations in DNA repair deficiency genes (18.0%). Additionally, the microsatellite instability phenotype was identified in 3.81% of eligible samples (≥0.1 ctDNA fraction). Sequencing of non-repetitive intronic- and exonic regions ofPTEN, RB1andTP53detected biallelic inactivation in 47.5%, 20.3% and 44.1% of samples with ≥0.2 ctDNA fraction, respectively. Only one patient carried a clonal high-impact variant without a detectable second hit. Intronic high-impact structural variation was twice as common as exonic mutations inPTENand RB1. Finally, 14.6% of patients presented false positive variants due to clonal hematopoiesis, commonly ignored in commercially available assays.ConclusionsctDNA profiles appear to mirror the genomic landscape of metastatic prostate cancer tissue and may cost-efficiently provide somatic information in clinical trials designed to identify predictive biomarkers. However, intronic sequencing of the interrogated tumor suppressors challenge the ubiquitous focus on coding regions and is vital, together with profiling of synchronous white blood cells, to minimize erroneous assignments which in turn may confound results and impede true associations in clinical trials.

Purpose Melflufen (melphalan flufenamide, previously designated J1) is an optimized and targeted derivative of melphalan, hydrolyzed by aminopeptidases overexpressed in tumor cells resulting in selective release and trapping of melphalan, and enhanced activity in preclinical models. Methods This was a prospective, single-armed, open-label, first-in-human, dose-finding phase I/IIa study in 45 adult patients with advanced and progressive solid tumors without standard treatment options. Most common tumor types were ovarian carcinoma (n = 20) and non-small-cell lung cancer (NSCLC, n = 11). Results In the dose-escalating phase I part of the study, seven patients were treated with increasing fixed doses of melflufen (25–130 mg) Q3W. In the subsequent phase IIa part, 38 patients received in total 115 cycles of therapy at doses of 30–75 mg. No dose-limiting toxicities (DLTs) were observed at 25 and 50 mg; at higher doses DLTs were reversible neutropenias and thrombocytopenias, particularly evident in heavily pretreated patients, and the recommended phase II dose (RPTD) was set to 50 mg. Response Evaluation Criteria In Solid Tumors (RECIST) evaluation after 3 cycles of therapy (27 patients) showed partial response in one (ovarian cancer), and stable disease in 18 patients. One NSCLC patient received nine cycles of melflufen and progressed after 7 months of therapy. Conclusions In conclusion, melflufen can safely be given to cancer patients, and the toxicity profile was as expected for alkylating agents; RPTD is 50 mg Q3W. Reversible and manageable bone marrow suppression was identified as a DLT. Clinical activity is suggested in ovarian cancer, but modest activity in treatment of refractory NSCLC.

// Pedram Kharaziha 1 , Dimitris Chioureas 1 , Dorothea Rutishauser 2, 3 , George Baltatzis 4 , Lena Lennartsson 1 , Pedro Fonseca 1 , Alireza Azimi 1 , Kjell Hultenby 5 , Roman Zubarev 2, 3 , Anders Ullen 1 , Jeffrey Yachnin 1 , Sten Nilsson 1 , Theocharis Panaretakis 1 1 Department of Oncology-Pathology, Karolinska Institutet and University Hospital, Stockholm, Sweden 2 Department of Medical Biochemistry and Biophysics, Karolinska Institutet and University Hospital, Stockholm, Sweden 3 Science for Life Laboratory, Stockholm, Sweden 4 Department of Medicine, School of Health Sciences, University of Athens, Athens, Greece 5 Department of Laboratory Medicine, Karolinska Institutet and University Hospital, Huddinge, Sweden Correspondence to: Theocharis Panaretakis, e-mail: theoharis.panaretakis@ki.se Keywords: Prostate cancer, exosomes, docetaxel, resistance, biomarkers Received: September 17, 2014 Accepted: January 27, 2015 Published: March 12, 2015 ABSTRACT Docetaxel is a cornerstone treatment for metastatic, castration resistant prostate cancer (CRPC) which remains a leading cause of cancer-related deaths, worldwide. The clinical usage of docetaxel has resulted in modest gains in survival, primarily due to the development of resistance. There are currently no clinical biomarkers available that predict whether a CRPC patient will respond or acquire resistance to this therapy. Comparative proteomics analysis of exosomes secreted from DU145 prostate cancer cells that are sensitive (DU145 Tax-Sen) or have acquired resistance (DU145 Tax-Res) to docetaxel, demonstrated significant differences in the amount of exosomes secreted and in their molecular composition. A panel of proteins was identified by proteomics to be differentially enriched in DU145 Tax-Res compared to DU145 Tax-Sen exosomes and was validated by western blotting. Importantly, we identified MDR-1, MDR-3, Endophilin-A2 and PABP4 that were enriched only in DU145 Tax-Res exosomes. We validated the presence of these proteins in the serum of a small cohort of patients. DU145 cells that have uptaken DU145 Tax-Res exosomes show properties of increased matrix degradation. In summary, exosomes derived from DU145 Tax-Res cells may be a valuable source of biomarkers for response to therapy.

Vinflunine is to date the only registered agent for second-line treatment of metastatic urothelial cell carcinoma (UCC) in Europe. However, the effect is modest. Pemetrexed has demonstrated some single-agent activity in this disease entity. In order to improve treatment possibilities for UCC patients, a phase I trial (VINTREX) was undertaken to assess the safety of vinflunine and pemetrexed in metastatic UCC patients. A dose escalation design was planned to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of a vinflunine/pemetrexed combination. Pemetrexed was added to vinflunine dosed at 280 mg/m2 on day 1 of a 21-day cycle. Three levels of pemetrexed were planned starting at 400 mg/m2. Four patients were enrolled with a mean age of 66 years and with a mean number of prior GC-cycles of 6,8. Two DLT's were observed at the lowest dose-level in cohort 1. One patient experienced grade 4 thrombocytopenia and a second demonstrated hepatobiliary toxicity grade 3 with an increase in alanine aminotransaminase. Most common grade 3 and 4 adverse events were anemia, thrombocytopenia and neutropenia. Three out of four patients received 3 cycles of pemetrexed and vinflunine, all had progressive disease. Based on these observations and due to protocol design, the study was interrupted at dose level 1 for safety reasons. The combined therapy of vinflunine (Javlor®, Pierre Fabre Pharma) and pemetrexed (Alimta®, Eli Lilly) is poorly tolerated in metastatic UCC patients. The combination cannot be recommended for further investigations in metastatic UCC. Vinflunine is to date the only registered agent for second-line treatment of metastatic urothelial cell carcinoma (UCC) in Europe. However, the effect is modest. Pemetrexed has demonstrated some single-agent activity in this disease entity. In order to improve treatment possibilities for UCC patients, a phase I trial (VINTREX) was undertaken to assess the safety of vinflunine and pemetrexed in metastatic UCC patients. A dose escalation design was planned to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of a vinflunine/pemetrexed combination. Pemetrexed was added to vinflunine dosed at 280 mg/m2 on day 1 of a 21-day cycle. Three levels of pemetrexed were planned starting at 400 mg/m2. Four patients were enrolled with a mean age of 66 years and with a mean number of prior GC-cycles of 6,8. Two DLT's were observed at the lowest dose-level in cohort 1. One patient experienced grade 4 thrombocytopenia and a second demonstrated hepatobiliary toxicity grade 3 with an increase in alanine aminotransaminase. Most common grade 3 and 4 adverse events were anemia, thrombocytopenia and neutropenia. Three out of four patients received 3 cycles of pemetrexed and vinflunine, all had progressive disease. Based on these observations and due to protocol design, the study was interrupted at dose level 1 for safety reasons. The combined therapy of vinflunine (Javlor®, Pierre Fabre Pharma) and pemetrexed (Alimta®, Eli Lilly) is poorly tolerated in metastatic UCC patients. The combination cannot be recommended for further investigations in metastatic UCC.

To avoid pubic arch interference, prostate cancer patients are treated with neoadjuvant androgen deprivation therapy (ADT) to achieve prostate volume (PV) reduction prior to radiation treatment. The aim of the present randomised study was to compare the effects on PV of two regimens of ADT, an androgen receptor inhibitor monotherapy vs. castration plus an androgen receptor inhibitor. Consecutive patients with non-metastatic prostate cancer were included in a randomised neoadjuvant study, comparing an androgen receptor inhibitor monotherapy vs. castration plus an androgen receptor inhibitor. PV was assessed prior to the start of endocrine neoadjuvant treatment and prior to the start of radiation therapy (RT). PV assessment was performed by transrectal ultrasound. A total of 110 patients were included. Final sample constituted 88 (80%) patients due to lack of PV information. Castration plus an androgen receptor inhibitor was more effective in PV reduction compared with an androgen receptor inhibitor alone (P